Journal articles: 'AVL/APC data'

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Düwel, Michael, and Ernst J. Ungewickell. "Clathrin-dependent Association of CVAK104 with Endosomes and the Trans-Golgi Network." Molecular Biology of the Cell 17, no. 10 (2006): 4513–25. http://dx.doi.org/10.1091/mbc.e06-05-0390.

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CVAK104 is a novel coated vesicle-associated protein with a serine/threonine kinase homology domain that was recently shown to phosphorylate the β2-subunit of the adaptor protein (AP) complex AP2 in vitro. Here, we demonstrate that a C-terminal segment of CVAK104 interacts with the N-terminal domain of clathrin and with the α-appendage of AP2. CVAK104 localizes predominantly to the perinuclear region of HeLa and COS-7 cells, but it is also present on peripheral vesicular structures that are accessible to endocytosed transferrin. The distribution of CVAK104 overlaps extensively with that of AP1, AP3, the mannose 6-phosphate receptor, and clathrin but not at all with its putative phosphorylation target AP2. RNA interference-mediated clathrin knockdown reduced the membrane association of CVAK104. Recruitment of CVAK104 to perinuclear membranes of permeabilized cells is enhanced by guanosine 5′-O-(3-thio)triphosphate, and brefeldin A redistributes CVAK104 in cells. Both observations suggest a direct or indirect requirement for GTP-binding proteins in the membrane association of CVAK104. Live-cell imaging showed colocalization of green fluorescent protein-CVAK104 with endocytosed transferrin and with red fluorescent protein-clathrin on rapidly moving endosomes. Like AP1-depleted COS-7 cells, CVAK104-depleted cells missort the lysosomal hydrolase cathepsin D. Together, our data suggest a function for CVAK104 in clathrin-dependent pathways between the trans-Golgi network and the endosomal system.

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Petrova, Milla, Mariyana Eneva, Jeliazko Iliev Arabadjiev, et al. "High neutrophil to lymphocyte ratio as a predictor for hyperprogressive disease in patients with metastatic non-small cell lung cancer treated with pembrolizumab as a second line." Journal of Clinical Oncology 38, no. 15_suppl (2020): e21546-e21546. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e21546.

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e21546 Background: In this study we evaluated the incidence of early non-responders (which are potential hyper-progressors (HP)) and its relation to Neutrophil-Lymphocyte Ratio (NLR), Platelet-Lymphocyte Ratio (PLR) as well as their dynamics in patients with Non-small Cell Lung Cancer (NSCLC) treated with pembrolizumab (P) as a second line. Methods: Patients with metastatic NSCLC (n=119) whose tumors expressed PD-L1≥1% were retrospectively analyzed between Apr 2017 and Oct 2019. All patients received platinum-containing chemotherapy (CT) as a first line treatment. Hematological parameters of interest were absolute neutrophil (ANC), absolute lymphocyte (ALC) and platelet (APC) counts, enabling calculation of NLR (ANC/ALC) and PLR (APC/ALC). NLR1 and PLR1 were calculated before CT, NLR2 and PLR 2 – before the first P infusion. ΔNLR (NLR2-NLR1) and ΔPLR (PLR2-PLR1) were calculated. The tumor response was assessed according to the RECIST (version 1.1) at every 3 months. Early progressors (EP) were defined as non-responders at the first computed tomography scan evaluation of the CT. As HP on P were considered patients with time to progression ≤ 3 months, clinical deterioration and appearance of ≥2 new lesions in organ already involved or spread to a new organ. Results: Twelve (10.1%) patients in the CT group were EP. Fourteen (11.8%) patients in the immunotherapy group were assessed as HP. Four patients (3.4%) did not respond either to CT or to P and had clinical aggravation. HP had significantly higher NLR2 (9.1±1.9 vs 4.8±3.2, p<0.001), PLR2 (400±173.8 vs 214.7±117.3, p<0.001), ΔNLR (2.3±1.9 vs 0.3±2.0, p=0.001), ΔPLR (107.9±167.3 vs 0.6±94.9, p=0.012) than the rest of the patients. ROC analysis revealed that at the optimal cutoff values of all markers, NLR2 achieved the greatest AUC=0.855 (95% CI, 0.77-0.93) and could distinguish between patients with or without hyperprogressive disease (HPD) with sensitivity of 85.7% and specificity of 72.4%. HP had significantly shorter mean OS - 12.5 months (95%, CI 10.9-14.1) than the rest – 32.2 months (95%, CI 28.4-36.1). Patients who did not respond either to CT or to P had significantly shorter mean OS – 9.2 months (95%, CI 6.6-11.8) than the rest – 29.8 months (95%, CI 26.4-33.4). NLR was found to be an independent predictive factor for HPD, HR=1.22 (95% CI,1.11-1.35; p<0.001). Conclusions: Our data suggest that the incidence of intrinsic aggressive disease phenotype, irrespective of treatment, is low. NLR is a novel predictive marker for HPD.

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Goy, Andre, Tatyana Feldman, Lori Ann Leslie, et al. "Prognostic value of the absolute lymphocyte to monocyte (ALC/AMC) ratio on overall survival among patients with mantle cell lymphoma." Journal of Clinical Oncology 35, no. 15_suppl (2017): e19030-e19030. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e19030.

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e19030 Background: The peripheral blood absolute lymphocyte-to-monocyte ratio (ALC/AMC) is prognostic of overall survival (OS) in Hodgkin Lymphoma, Diffuse Large B-cell Lymphoma, and several solid tumors. Lymphocyte and monocytes have been suggested to be surrogate biomarkers of immune homeostasis and tumor microenvironment, respectively. We sought to determine if the post-induction therapy ALC/AMC is prognostic in mantle cell lymphoma. Methods: A retrospective review was conducted of 96 consecutive mantle cell lymphoma patients (pts) with available data treated at the John Theurer Cancer Center (n=77) and 4 Regional Cancer Care Associate practices (n=19) by 24 physicians between Aug 2005 and Dec 2015 (90% cases after 2009). Cases were identified via the COTA database which extracts and organizes relevant data from the electronic health records. Peripheral blood counts (to calculate the ALC/AMC) were determined approximately 30 days following completion of initial therapy or immediately prior to stem cell mobilization in those pts undergoing first line transplant. All analyses were performed using the R statistical language. Results: 67 pts had ALC/AMC less than 2 and 29 pts had ALC/AMC greater than or equal to 2. The cohorts (<2 vs >2) had similar median ages (64 vs 68; p=0.18), ethnicities (p=0.38), stage distributions (including 87% vs 79% stage IV disease; p=0.51), elevated beta-2-microglobulin (p=1), elevated LDH (p=1) and MIPI scores (including 19% vs 41% high risk; p=0.13). ALC/AMC was <2 in 10 of 13 (77%) transplanted pts and 57 of 83 (69%) non-transplanted pts (p=0.57). With a median follow-up of 43 months, the median OS has not been reached in either cohort; the 5-year survival rates were higher among pts with ALC/AMC greater than or equal to 2 (90% vs 68%; log-rank p<0.05). Similar ALC/AMC 5-year survival trends were noted when sub-setting to the 25 pts with high risk MIPI scores (72% vs 45%; p=0.07). Conclusions: An elevated ALC/AMC >2, following induction therapy, is associated with improved overall survival in MCL. Novel maintenance programs, including targeting the microenvironment or immune response, might be appropriate among pts with low ratios.

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Rufino, João Pedro, Ana Laura Maciel Monteiro, Julia Português Almeida, Karolina Moreira dos Santos, Mariana da Cruz Andrade, and Silvia Cristina Marques Nunes Pricinote. "Cancer mortality trends in Brazilian adults aged 80 and over from 2000 to 2017." Geriatrics, Gerontology and Aging 14, no. 4 (2020): 274–81. http://dx.doi.org/10.5327/z2447-212320202000097.

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INTRODUCTION: Adults aged 80 and over represent the fastest growing segment of the population in emerging countries. Studies of cancer mortality trends in the oldest old population are scarce in Brazil. OBJECTIVE: To describe trends in cancer mortality in the Brazilian oldest old, by gender and cancer type, from 2000 to 2017. METHODS: This was a descriptive study with a time trend design, based on data from the Mortality Information System (of the Informatics Department of the Unified Health System). The variables analyzed were year of death, sex and cancer site. The five most common types of cancer were identified, and mortality rates and trends were calculated for each one. Trends were determined using joinpoint regression. In all cases where one or more joinpoints were statistically significant, the average annual percent change (AAPC) was calculated based on the arithmetic mean of the annual percent change (APC), weighted by the length of each segment. The statistical significance of the APC and AAPC was estimated by calculating 95% confidence intervals (CI) with an alpha level of 0.05. RESULTS: Mortality rates increased over time (AAPC = 1.50; 95%CI, 1.20 – 1.70) in both males (AAPC = 1.90; 95%CI, 1.70 – 2.10) and females (AAPC = 1.30; 95%CI, 1.00 – 1.50). Men had higher mortality rates than women. The most common causes of cancer-related death were prostate cancer (AAPC = 1.70; 95%CI, 1.10 – 2.30) in men, and breast cancer (AAPC = 1.90; 95%CI, 1.50 – 2.20) in women, followed by cancers of the lung and bronchus, stomach and colon. All rates increased over time, except in the case of stomach cancer. CONCLUSION: The study revealed increasing mortality rates for screenable and/or preventable cancers, alerting to the need for preventive measures.

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Thebo, Umera, Tomas Radivoyevitch, Surbhi Sidana, et al. "Time to Complete Remission As a Function of Kinetics of White Blood Cell Elimination and Recovery in Acute Myeloid Leukemia Patients Undergoing Remission Induction Chemotherapy." Blood 124, no. 21 (2014): 5266. http://dx.doi.org/10.1182/blood.v124.21.5266.5266.

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Abstract Background: While achieving complete remission (CR) is a major treatment milestone in acute myeloid leukemia (AML) patients (pts) undergoing induction chemotherapy (IC), it is the time to achieve CR (Tc) that has greater prognostic value in predicting subsequent survival. We are particularly interested in seeing whether trends in white blood cell (WBC) count elimination and recovery during induction phase can aid in prediction of Tc, thus enabling real-time prognostication. Methods: Adult pts diagnosed with AML (excluding acute promyelocytic leukemia) at the Cleveland Clinic from 10/08 - 11/12 who underwent IC with 7+3 (cytarabine and anthracycline) and achieved CR were included. Pretreatment variables including age, gender, race, smoking status, body mass index at dx, peripheral blood counts at diagnosis (dx), peripheral and marrow blasts at dx, disease classification and metaphase cytogenetics (per CALGB/Alliance 8461 criteria) were assessed. For mapping WBC elimination and recovery kinetics, we collected data on total WBC, absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) at several different time points after IC – day 1, day 7, day 14 (range, 13-17), day 21, day 35 (range 30-45) and the day CR was achieved. Time intervals selected for analysis included time taken for clearance of peripheral circulating blasts; time to reach nadirs for WBC, ANC and ALC; and time to ANC recovery (from ANC nadir to > 500/µL). Tc was assessed as a function of WBC, ANC and ALC measurements (at the above predefined time points); time intervals; and magnitude of drop and rise in WBC, ANC and ALC (log reductions and improvements in counts) using multivariable logistic and Cox proportional hazards models and stepwise regression using Akaike’s Information Criterion (AIC) for model selection. Due to multiple testing, parameters are reported as significant if p<0.01. Cell counts and time interval metrics were also analyzed as a function of pretreatment covariates using standard linear regression. Results: Of 80 pts, 58% (n=46) were female, 79% (n=63) were Caucasian, 68% (n=54) were younger than 60 years, the median age at treatment was 53.5 years (range, 19 to 77) & 18% (n=14) received 2 cycles of induction therapy. Twenty one pts (26%) had secondary AML. Disease characteristics (per WHO classification) were – AML with recurrent cytogenetic abnormalities 31% (n=25), secondary AML 27% (n=22), therapy-related AML 6% (n=5), AML not otherwise specified 34% (n=26), myeloid sarcoma 1% (n=1) and unknown 1% (n=1). Cytogenetic risk groups per CALGB 8461 were – favorable 19% (n=15), intermediate 53% (n=42), unfavorable 23% (n=18), & unknown cytogenetics (n=5). In the final model of a multivariable stepwise regression analysis, none of the cell counts at the defined time points of IC predicted for Tc. Of pretreatment covariates, only male sex correlated slightly with longer Tc (p=.04). Longer times to reach ANC (p=.01) and ALC (p=.03) nadirs had borderline correlations with longer Tc. In contrast, longer times to reach ANC > 500/µL was significantly associated with delayed Tc (p<<.001). Greater fold change drop and rise in ANC counts correlated with Tc but was not significant at the p<.01 level. Conclusions: In this study the only WBC cell kinetic parameter post IC that independently predicted Tc was time to ANC recovery, which seems intuitive. Biologically, this could represent resiliency of the underlying hematopoietic stem cell reserve which is a function of age, prior therapies or antecedent hematologic disorder. Interestingly, in our series, WBC kinetics did not correlate with the number of induction cycles required (1 vs. 2), age (using age cut-offs of 60 and 70 years) or body mass index. Although the concept of using WBC kinetics during IC as a clinical surrogate for chemotherapy responsiveness or toxicity (overdosing vs. underdosing) is appealing, it is not supported by our data. Disclosures Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corp: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim Corp: Membership on an entity's Board of Directors or advisory committees. Mukherjee:GlaxoSmithKline: Research Funding.

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Acosta-Maldonado, Brenda Lizeth, Ana Ramirez-Ibarguen, Flavio A. Grimaldo-Gomez, Luis Oñate-Ocaña, and Silvia Rivas-Vera. "The Prognostic Significance of the Absolute Lymphocyte to Monocyte Count Ratio (ALC/AMC-dx) at Diagnosis in Hodgkin´s Lymphoma." Blood 124, no. 21 (2014): 2953. http://dx.doi.org/10.1182/blood.v124.21.2953.2953.

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Abstract Background. In Classic Hodgkin's lymphoma (cHL), malignant cells constitute only about 1% of the bulk of tumor tissue, the rest constitutes the microenvironment and is made up of a compound of inflammatory cells. Lymphocytopenia and increased CD68+ tumor-associated macrophages (TAMs) are adverse prognostic factors in cHL. TAMs are derived from circulating monocytes and are possibly related to absolute monocyte count (AMC). We have sought to investigate the relationship of circulating lymphocytes and monocytes with response and survival in patients. Recently, Porrata et al. reported that a low absolute lymphocyte count/absolute monocyte count at diagnosis [ALC/AMC-Dx] (<1.1) is an independent prognostic factor in cHL. Subsequent studies used different cutoffs for ALC/AMC (1.5 and 2.9). Currently, there are no studies that evaluate the usefulness of the index relative to the overall response. Aim To determine the prognostic value of ALC /AMC at diagnosis in patients with cHL and its impact on treatment response to therapy, progression and overall survival. Methods: We evaluated 262 consecutive individuals with cHL, referred and treated at the National Cancer Institute in Mexico between 2006 to 2013. The great majority of patients were treated with ABVD with or without radiotherapy, and all had available data for ALC/AMC determined at diagnosis. It was made a multivariate analysis and ROC curves for cutoff point of ALC/AMC. Results: Median age was 35 y (14-89), 59.2% of patients were male, 77% had B-symptoms, 36.3% had stage IV disease, 85% had advanced stage (IB,IIB,III,IV), 51.5% had IPS ≥3, 46.2% nodular sclerosing histology and 45.4% mixed cellularity. The overall response (CR + PR) was obtained in 188 patients (72%) and failure (stable disease or progressive disease) in 73 patients (28%). A new cutoff point, 1.77 in ALC/AMC-Dx ratio with area under the curve of 0.62. Multivariate analysis showed that the ALC/AMC-Dx index was an independent predictor for response to treatment, progression as well as overall survival (Table 1). Additionally the IPS≥3 showed to be an independent factor for response 68.8% vs 41.7% in low and high risk, respectively (p<0.0000). Conclusion: In our population ALC/AMC-Dx index was established with a cutoff of 1.77. The group of patient with < 1.77 had a less overall response and overall survival. It proves that ALM/AMC-Dx is an independent predictor of response, progression and overall survival in patients with classical cHL. That differs of other reviews where the cutoff was lower. Table 1. Multivariate analysis according to ALC/AMC-DX ratio ALC/AMC -Dx index p Low< 1.77 High >1.77 Overall Response 58.1% 79.8% OR 0.25-.0.84p 0.011 Overall Survival8 years 81% 94% p 0.004 Disclosures No relevant conflicts of interest to declare.

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Jucá, Carlos, Leandro Colli, Clarissa Martins, et al. "Impact of the Canonical Wnt Pathway Activation on the Pathogenesis and Prognosis of Adamantinomatous Craniopharyngiomas." Hormone and Metabolic Research 50, no. 07 (2018): 575–81. http://dx.doi.org/10.1055/a-0593-5956.

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Abstract CTNNB1 mutations and abnormal β-catenin distribution are associated with the pathogenesis of adamantinomatous craniopharyngioma (aCP). We evaluated the expression of the canonical Wnt pathway components in aCPs and its association with CTNNB1 mutations and tumor progression. Tumor samples from 14 aCP patients and normal anterior pituitary samples from eight individuals without pituitary disease were studied. Gene expression of Wnt pathway activator (WNT4), inhibitors (SFRP1, DKK3, AXIN1, and APC), transcriptional activator (TCF7), target genes (MYC, WISP2, and, CDH1), and Wnt modulator (TP53) was evaluated by qPCR. β-Catenin, MYC, and WISP2 expression was determined by immunohistochemistry (IHC). The transcription levels of all genes studied, except APC, were higher in aCPs as compared to controls and TCF7 mRNA levels correlated with CTNNB1 mutation. CDH1 mRNA was overexpressed in tumor samples of patients with disease progression in comparison to those with stable disease. β-Catenin was positive and aberrantly distributed in 11 out of 14 tumor samples. Stronger β-catenin immunostaining associated positively with tumor progression. MYC positive staining was found in 10 out of 14 cases, whereas all aCPs were negative for WISP2. Wnt pathway genes were overexpressed in aCPs harboring CTNNB1 mutations and in patients with progressive disease. Recurrence was associated with stronger staining for β-catenin. These data suggest that Wnt pathway activation contributes to the pathogenesis and prognosis of aCPs.

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Iwanaga, Masako, and Midori Soda. "Time Trend and Age-Period-Cohort Effects on the Incidence of Patients with Adult T-Cell Leukemia in a Population-Based Study in Japan, 1991-2010." Blood 124, no. 21 (2014): 2616. http://dx.doi.org/10.1182/blood.v124.21.2616.2616.

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Abstract Background: Adult T-cell leukemia-lymphoma (ATL) is an aggressive T-cell malignancy, which is exclusively associated with human T-cell leukemia virus type I (HTLV-1) infection. Japan is a well-known endemic area of ATL, with approximately 400 new cases and 1,000 deaths annually. A recent Japanese study reported that the trend in the age-standardized incidence rate of ATL has remained relatively stable. However, age-standardized rate may mask important epidemiological characteristics related with age and birth-cohort. To date, several epidemiological studies reported the interesting birth-cohort patterns on the incidence of lymphoid malignancies. However, little has been known about the effects of age and birth-cohort on the time trend in the incidence of ATL. Methods: A dataset of patients with ATL (ICD-O-3 code 9827) was obtained from the Nagasaki Prefecture Cancer Registry that contains all cancer data from a population of approximately 1.5 million since 1985. To calculate the average annual percent change (AAPC) for crude incidence rate and age-standardized (world) incidence rate (ASRw) (per 100,000), the Joinpoint Regression Program with Hudson’s method was used. The effects of age, calendar-period, and birth-cohort on the time trends of the ATL incidence were evaluated by performing the age-period-cohort (APC) analysis using the R-package Epi. For the APC analysis, ten 5-year age groups and five 5-year calendar periods were set, resulting to create 14 birth cohorts. Parameter estimates of the APC models were obtained by fitting five models (age, age-drift, age-period, age-cohort, and age-period-cohort). In the full model of the age-period-cohort model, period and birth cohort effects were evaluated as relative risk (RR). This work was supported in part by the Health Labour Sciences Research Grant (H26-sinkoujitsuyouka-ippan-013). Results: A total of 1,971 patients (1,085 men and 886 women) who were diagnosed during 1991-2010 were analyzed. The crude incidence rate showed a slightly increasing tendency from 8.2 (year 1991) to 9.7 (year 2010) for men (AAPC, +0.6, 95%CIs, -1.6 to 1.8) and 5.7 (year 1991) to 8.4 (year 2010) for women (AAPC, +1.3, 95%CIs, -0.2 to 2.8), without statistically significant. Meanwhile, the ASRw showed a significantly decreasing tendency from 5.2 (year 1991) to 3.7 (year 2010) for men (AAPC, -2.1, 95%CIs, -3.2 to -1.1) and from 3.5 (year 1991) to 2.5 (year 2010) for women (AAPC, -1.8, 95%CIs, -3.3 to -0.3). The age-specific incidence rate was highest in patients aged 70 years or older, particularly the rate in patients aged 80 years or older drastically increased after year 2003. In the APC analyses, both the age-cohort model and age-period model were statistically significant for men (P<0.0001 for both) and women (P=0.002 for both), indicating that both a cohort effect and a period effect were the major effects on the incidence of ATL. The RR among various cohorts showed a drastic difference of the cohort effect on the ATL incidence from a higher risk in cohorts before 1931 but a lower risk in cohorts after 1931 in men, and from a higher risk in cohorts before 1940 but a lower risk in cohorts after 1940 in women. The RR among various periods was almost stable in 1, but becomes high after the period 2000 in both sexes. Discussion and Conclusion: The earlier birth-cohort and the recent calendar period were significantly associated with the incidence of ATL beyond the age effect. The birth cohort effect reflects the exposure to environmental factors, thus the effect can be explained by the higher HTLV-1 infection in early generation. Sex difference in the cohort effect may be reflected the way of life, biological, and behavioral factors. Continued ATL incidence and careful analysis of period effects are of importance to elucidate this unique epidemiology of ATL. Disclosures No relevant conflicts of interest to declare.

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Zaidi, Syed Ziauddin A., Ibraheem H. Motabi, Shahid Iqbal, et al. "Evaluation of Absolute Lymphocytes: Absolute Monocytes (ALC:AMC) Ratio As Prognostic Marker in Classical Hodgkin Lymphoma Patients Treated with ABVD Chemotherapy at a Single Center in Saudi Arabia." Blood 126, no. 23 (2015): 5005. http://dx.doi.org/10.1182/blood.v126.23.5005.5005.

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Abstract In our clinical practice, international prognostic score (IPS) comprising of seven parameters has been in use for prognostication of advance stage Hodgkin's lymphoma (HL). Simple scoring system, that can stratify patients and or predict outcome both in early stage and advance stage HL, would be both helpful and practical to apply in daily practice. This is a retrospective study to find out whether recently reported absolute monocyte count (AMC) and absolute lymphocyte : monocyte ratio (LMR) at diagnosis are valid parameters for predicting prognosis of classical Hodgkin lymphoma (cHL) patients treated with ABVD at our center. Among many cut-off values for ALC/AMC ratio reported in literature (1.1, 1.5, 2.1, 2.8, 3.5) we chose the cut off of ≥2.1 as reported in the largest series by Tadmore et al. Data from patients' records were collected after approval by local institutional review board. All studies were performed in accordance with the principles of the Declaration of Helsinki. Patients were included into this study if they had histopathological diagnosis of cHL, no human immunodeficiency virus infection, availability of data on all clinical and laboratory features and treatments given, as well as outcome, and follow-up. Only patients treated with ABVD as initial chemotherapy with or without subsequent radiation therapy were included as this chemotherapy regimen is currently considered the standard of care in North America and at our institution. Response criteria were based on the guidelines from the International Harmonization Project on Lymphoma revised by Cheson et al. We excluded 4 patients with Nodular Lymphocyte Predominant HL(NLPHL), as NLPHL is considered to be a different disease entity. Hence we found 164 patients with cHL treated at King Fahad Medical City, Riyadh from 2006, through July 2015 with ABVD. Out of 164 patients we identified nodular sclerosis 116/164 (70%) and mixed cellularity 31/164 (19%) were the most common. The median age of the patients was 26 years (range, 14-86 years); 70 (41.6%) patients had bulky disease, 84 (52.1%) had extranodal disease; Median IPS was 3; Pre-Treatment ALC median was 1635/ul (range 192-825), AMC median was 841/ul (range 60-9600), and Pre-Treatment ALC/AMC Ratio (LMR) median was 2.168 (range 0.28-19.81). Overall survival was for ALC/AMC Ratio of >=2.1 was 97.5% and 92.8% for ALC/AMC Ratio of <2.1 (p=0.172) indicating some trend for better outcome. This study confirms that L/M ratio has prognostic value in cHL. However we plan to define our own best cut off value by ROC and AUC analysis as ALC/AMC Ratio of ≥2.1 did not discriminate survival advantage clearly in our patients. In addition to geographical and genetic differences, variations in hematology cell counters may be a plausible contributing factor.Table.VariablesNumber(%)Age(yr)<=45140(85.4)> 4524(14.6)GenderMale88(53.7)Female76(46.3)Stage of diseaseEarly15(9.1)Advanced149(90.9)BulkyNo94(57.3)Yes70(42.7)Stage IVNo92(56.1)Yes72(43.9)HistopathologyLymphocyte Rich6(3.7)Classical11(6.7)Mixed Cellularity31(18.9)Nodular Sclerosis116(70.7)ExtranodalNo80(48.8)Yes84(51.2)Albumin<40134(85.4)>=4023(14.6)Hemoglobin<10.559(36.0)>=10.5105(64.0)WBC<15127(77.4)>=1537(22.6)IPS Score05(3.0)134(20.7)242(25.6)342(25.6)432(19.5)57(4.3)62(1.2)ALC<60016(10.3)>=600140(89.7)ALC<0.622(14.1)>=0.6134(85.9)AMC<75070(44.9)>=75086(55.1)ALC/AMC Ratio<2.172(46.2)>=2.184(53.8) Disclosures No relevant conflicts of interest to declare.

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Sokol, D. K., D. R. Wagenknecht, and J. A. McIntyre. "Testing for Antiphospholipid Antibody (aPL) Specificities in Retrospective Normal Cerebral Spinal Fluid (CSF)." Clinical and Developmental Immunology 11, no. 1 (2004): 7–12. http://dx.doi.org/10.1080/10446670410001670436.

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Antiphospholipid antibodies (aPL) have been found in the blood of patients with systemic and neurological disease. The rare reports of aPL in cerebral spinal fluid (CSF) have been limited mostly to IgG and IgM anticardiolipin (aCL). Our published finding of IgA aPE in the CSF of a young stroke victim prompted us to establish “normal” CSF aPL values for a panel of aPL, which included aCL, antiphosphatidylserine (aPS), antiphosphatidylethanolamine (aPE) and antiphosphatidylcholine (aPC). CSF samples were tested by ELISA for IgG, IgM and IgA aPL. In addition, the CSF samples were tested for activity in the presence and absence of phospholipid (PL) binding plasma-proteins. A total of 24 data points were obtained for each CSF sample.We tested 59 CSF samples obtained from 59 patients who were undergoing evaluation for systemic or neurologic diseases. All CSF samples had normal protein, glucose and cell counts. Ten of the 59 CSF samples (17%) had elevated aPL optical density (OD) values an order of magnitude higher than the other 49 CSF samples for one or more aPL specificity and/or isotype. One CSF sample had both PL-binding protein dependent and independent IgG aPE activity. Another CSF sample showed both IgG aPE and aPC reactivity. The remaining eight CSF samples showed single aPL findings; IgG aPE (5), IgG aPC (1), IgG aCL (1) and IgM aPC (1). Seven of 10 patients with elevated CSF values were females. As expected, most “normal” aPL OD values were substantially lower in CSF than those we have reported in blood samples from volunteer blood donors.

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Beaulieu, John C., Edna Pesis, and Mikal E. Saltveit. "AA or Basic pH Causes in vitro and Nonenzymatic Cleavage of ACC to Ethylene." Journal of the American Society for Horticultural Science 123, no. 4 (1998): 675–80. http://dx.doi.org/10.21273/jashs.123.4.675.

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An in vitro assay was used to determine the effect of AA and pH on the enzymatic and nonenzymatic production of ethylene (C2H4) from ACC. We were interested in the effect of AA on C2H4 production from ACC because aldehydes, primarily AA, can accumulate in tissue as the result of ripening, storage under modified atmospheres, packaging, and stress. Using crude extracts of ACC oxidase from tomato (Lycopersicon esculentum Mill. `Castlemart') and apple (Malus ×domestica Borkh. `Golden delicious'), C2H4 production from ACC was shown to increase in response to an increase in pH above 7.2 and inclusion of 0.2 to 2 mm AA. Nonenzymatic C2H4 production from ACC also increased linearly with increasing AA concentrations in all the buffers tested. Removal of ascorbate or O2 suppressed AA-induced nonenzymatic C2H4 production. Nonenzymatic AA-induced production of C2H4 from ACC appeared to be an ascorbate dependent oxidation, which was augmented by O2 and was sensitive to minor pH fluctuation. The nonenzymatic AA-stimulated conversion of AEC to 1-butene lacked stereospecificity. Formaldehyde and propionaldehyde also stimulated C2H4 production from ACC. These data indicate that ACC oxidase assays or C2H4 measurements assessing physiological status can be seriously affected by the presence of aldehydes, such as AA. Chemical names used: AA, acetaldehyde; ACC, 1-aminocyclopropane-1-carboxylic acid; AEC, 1-amino-2-ethylcyclopropanecarboxylic acid; ADH, alcohol dehydrogenase; EtOH, ethanol.

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Arain, Saad, Eshana Shah, Betul Gok Yavuz, et al. "Hematologic Predictors of Outcomes in Patients Undergoing Intensive Induction Chemotherapy for Newly Diagnosed Acute Myeloid Leukemia." Blood 136, Supplement 1 (2020): 39–40. http://dx.doi.org/10.1182/blood-2020-136708.

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Background Presently, acute myeloid leukemia (AML) risk stratification is estimated prior to treatment by incorporating patient and disease characteristics. However, apart from the limited use of minimal residual disease measurement, few methodologies assess AML relapse risk post-treatment. In attempts to correlate pre- and post-treatment blood cell counts with hematologic disease outcomes, the ratio, LNR, between absolute lymphocyte count (ALC) and neutrophils (ANC) has been utilized to approximate the relationship between the lymphoid system and the myeloid microenvironment (in particular myeloid-derived suppressor cells), and increased LNR is prognostic in myeloma and lymphoma. Similarly, increased LMR (lymphocyte to monocyte ratio), utilized as a crude marker of tumor-infiltrating lymphocytes and tumor-associated macrophages, predicts better outcomes in Hodgkin's disease (Romano et al. Ann Hematol2018). However, analyses correlating such ratios with AML outcomes have not been performed. Here we specifically investigate whether LNR, LMR, or neutrophil-monocyte (NMR) ratios, measured at multiple time-points, correlate with outcomes. Methods We identified patients &gt;18 yrs receiving induction chemotherapy at our institution between 1/1/2005 - 12/31/2019. Data collected included demographics, comorbidities (Charlson Comorbidity Index [CCI]), AML subtype, cytogenetics/molecular data, ELN risk stratification, and response to therapy. We recorded patients' total WBC, ANC, ALC and AMC both prior to treatment, at first ANC recovery (ANC &gt; 1.0 x 109/L with ALC and AMC &gt; 0), and just prior to next therapy. We also identified a subset of patients who received consolidation chemotherapies with curative intent and collected their first WBC counts ~100 days post-therapy completion (range 50-150 days). The calculated LNR, LMR, and NMR at these time-points were correlated with Event-Free Survival (EFS), defined as time to relapse, death from any cause, or last follow-up. Data was censored on 6/1/2020. WBC ratios were categorized into tertiles. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models, survivor functions estimated using Kaplan-Meier and the equality of survivor functions tested using stratified log-rank tests. Outcomes were adjusted for CCI, age, sex, race, subtype, presence of inflammation/infection, and ELN risk. Results 145 patients met eligibility criteria, however 23 with primary refractory AML were excluded from EFS analysis. Using WBC ratios at first ANC recovery, both intermediate and high LNR trended towards a lower HR for EFS: HR 0.54 (95% CI 0.24-1.23,p= 0.142) and 0.68 (95% CI 0.32-1.33,p= 0.329), respectively, however differences were not statistically significant (Table 1 and Figure 1). A high NMR also trended towards a worse EFS: HR 1.71 (95% CI 0.74-3.99,p= 0.212), though it was also not statistically significant. LMR did not correlate with improved EFS. Notably, pre-induction ratios and the ratios measured just prior to next treatment were not associated with any differences in EFS. In a subset of patients who received curative intent consolidation chemotherapies (generally ELN favorable risk), a t-test correlating for relapse was performed, though limited by small numbers (16 without, 8 with relapse). Patients in this group who did not relapse trended toward a numerically higher LNR and LMR, 0.57 vs 0.50 (p =0.36) and 4.33 vs 3.97 (p= 0.39), respectively. Discussion In our patient population, high LNR after induction chemotherapy trended towards predicting an improved EFS. Thus, recovery WBC ratios, although crude approximations of the immune system and the tumor microenvironment, may predict patients at higher risk of relapse, however, more patients are clearly needed to show whether a statistically significant association exists. The optimal time to evaluate these counts is also not clear. Nonetheless, as blood counts are obtained routinely post-treatment, these ratios may represent a low-cost strategy to predict relapse risk, potentially allowing for earlier treatment and donor searches for allogeneic transplantation. We propose to repeat these analyses using a multi-center approach - we are especially interested in ratios measured at the 100 days post-therapy mark, as we suspect these may better reflect the immune system at steady state and, potentially, risk of relapse. Disclosures Arain: Astellas:Other: Spouse is employed.Calip:Flatiron Health:Current Employment.Khan:Takeda:Research Funding;Celgene:Consultancy;Incyte:Honoraria;Amgen:Consultancy.Patel:Amgen:Consultancy;Janssen:Consultancy;Celgene:Consultancy.Quigley:Amgen:Other: Advisory board;Agios:Speakers Bureau;Alnylam:Speakers Bureau.

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MUHAMMAD, AMINU YAHAYA. "Intra-Party Conflict and the Future of Nigerian Democracy: Examining the All Progressives Congress (APC)." Asia Proceedings of Social Sciences 2, no. 4 (2018): 20–23. http://dx.doi.org/10.31580/apss.v2i4.248.

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This study is an analysis of the nature and pattern of intra-party conflict in Nigeriaâ€™s Fourth Republic with specific reference to the ruling All Progressives Congress (APC). Intra-party conflict has been the norm in Nigerian politics leading to crises, setback and failure of many parties to forge ahead for proper democratisation in Nigeria including the ruling parties in many instances. The problem is the way in which intra-party conflict is becoming the bane of democratisation and good governance in Nigeria for many decades and despite the previous experiences, the phenomenon continued unabated. The study investigated the new dimension of intra-party conflict in Nigeria taking the All Progressives Congress as the case study. The study used a qualitative method of data collection and analysis. Primary and secondary sources of data were used. The primary data involved an in-depth interview with some selected informants from the relevant institutions and agencies related to the APC and the crises such as the national party executives, senior officials of the Independent National Electoral Commission (INEC) and academicians that are experts in the area of study. The secondary sources include books, journals, newspapers, internets and other documented materials. The data obtained were discussed using content analysis where thematic analytical interpretations were used in the discussions. The research discovered that, the intra-party conflict under the APC has taken a new dimension where the members of the ruling party constituted an opposition and a stumbling block for the partyâ€™s progress and governance. The work recommends that intra-party conflict of APC and other Nigerian political parties can be resolved through constitutional reforms, institutionalisation of party ideology and principles and strict sanctions from the national leaders of the party.

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Somer, Robert A., Rakesh Surapaneni, and Douglas Francis Beach. "Relationship of testicular cancer incidence and cellular phone use." Journal of Clinical Oncology 30, no. 15_suppl (2012): e12008-e12008. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e12008.

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e12008 Background: Because of the ubiquitous usage of cellphones, any health consequences, if found, would be of paramount importance. Many have questioned the relationship of cellphone radiofrequency waves and malignancies such as brain tumors. Because men usually store their phones in close proximately to the testicles, we analyzed the relationship between cell phone usage and testicular cancer. Methods: Testicular cancer data was obtained from SEER-9 United States Population Data Base of the National Cancer Institute. Cell phone subscription data was obtained from the World Health Organization publication. Initial data analysis was done from 1991 to 2008, with subsequent age specific and other analyses performed from 1999 to 2008. Trends over time were calculated as Annual Percentage Change of incidence rates (APC) by using log linear models. Results: Rates of United States mobile subscriptions increased exponentially since the late 1990’s reaching 88.87 percent of the population by 2008. There was no statistically significant change in incidence rates of all testicular tumors (APC 0.7; CI -0.2, 0.7), Seminoma (APC 0.2; CI 0.8, 1.1) and non-Seminoma (APC 1.4; CI -0.6, 3.4) from 1999 to 2008. In the age specific analysis, three groups showed an increase in incidence rates: all testicular cancer age 25-34 (APC 2; CI 0.6, 3.4), All testicular cancer age greater than 45 (APC 1.7; CI 0.1, 3.3) and Seminoma age 25-34 (APC 2.1; CI 0.6, 3.7). All these changes were only minor percentage increase when compared to mobile subscriptions. Conclusions: Based on incidence data, there is no convincing evidence of increased risk of testicular cancer from cell phone use. Given possible lag time incidence, continued monitoring is needed.

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Yen, E., D. Singh, M. Wu, and R. Singh. "OP0248 PREMATURE MORTALITY BURDEN FOR SYSTEMIC SCLEROSIS: NATIONWIDE POPULATION-BASED STUDY." Annals of the Rheumatic Diseases 79, Suppl 1 (2020): 156.1–156. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2270.

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Background:Premature mortality is an important way to quantify disease burden. Patients with systemic sclerosis (SSc) can die prematurely of disease, however, the premature mortality burden of SSc is unknown. The years of potential life lost (YPLL), in addition to age-standardized mortality rate (ASMR) in younger ages, can be used as measures of premature death.Objectives:To evaluate the premature mortality burden of SSc by calculating: 1) the proportions of SSc deaths as compared to deaths from all other causes (non-SSc) by age groups over time, 2) ASMR for SSc relative to non-SSc-ASMR by age groups over time, and 3) the YPLL for SSc relative to other autoimmune diseases.Methods:This is a population-based study using a national mortality database of all United States residents from 1968 through 2015, with SSc recorded as the underlying cause of death in 46,798 deaths. First, we calculated the proportions of deaths for SSc and non-SSc by age groups for each of 48 years and performed joinpoint regression trend analysis1to estimate annual percent change (APC) and average APC (AAPC) in the proportion of deaths by age. Second, we calculated ASMR for SSc and non-SSc causes and ratio of SSc-ASMR to non-SSc-ASMR by age groups for each of 48 years, and performed joinpoint analysis to estimate APC and AAPC for these measures (SSc-ASMR, non-SSc-ASMR, and SSc-ASMR/non-SSc-ASMR ratio) by age. Third, to calculate YPLL, each decedent’s age at death from a specific disease was subtracted from an arbitrary age limit of 75 years for years 2000 to 2015. The years of life lost were then added together to yield the total YPLL for each of 13 preselected autoimmune diseases.Results:23.4% of all SSc deaths as compared to 13.5% of non-SSc deaths occurred at <45 years age in 1968 (p<0.001, Chi-square test). In this age group, the proportion of annual deaths decreased more for SSc than for non-SSc causes: from 23.4% in 1968 to 5.7% in 2015 at an AAPC of -2.2% (95% CI, -2.4% to -2.0%) for SSc, and from 13.5% to 6.9% at an AAPC of -1.5% (95% CI, -1.9% to -1.1%) for non-SSc. Thus, in 2015, the proportion of SSc and non-SSc deaths at <45 year age was no longer significantly different. Consistently, SSc-ASMR decreased from 1.0 (95% CI, 0.8 to 1.2) in 1968 to 0.4 (95% CI, 0.3 to 0.5) per million persons in 2015, a cumulative decrease of 60% at an AAPC of -1.9% (95% CI, -2.5% to -1.2%) in <45 years old. The ratio of SSc-ASMR to non-SSc-ASMR also decreased in this age group (cumulative -20%, AAPC -0.3%). In <45 years old, the YPLL for SSc was 65.2 thousand years as compared to 43.2 thousand years for rheumatoid arthritis, 18.1 thousand years for dermatomyositis,146.8 thousand years for myocarditis, and 241 thousand years for type 1 diabetes.Conclusion:Mortality at younger ages (<45 years) has decreased at a higher pace for SSc than from all other causes in the United States over a 48-year period. However, SSc accounted for more years of potential life lost than rheumatoid arthritis and dermatomyositis combined. These data warrant further studies on SSc disease burden, which can be used to develop and prioritize public health programs, assess performance of changes in treatment, identify high-risk populations, and set research priorities and funding.References:[1]Yen EY….Singh RR. Ann Int Med 2017;167:777-785.Disclosure of Interests:None declared

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Harzstark, A. L., C. Ryan, M. Diamond, et al. "A phase I trial of nordihydroguareacetic acid (NDGA) in patients with non-metastatic prostate cancer and rising PSA." Journal of Clinical Oncology 25, no. 18_suppl (2007): 15500. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.15500.

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15500 Background: NDGA is a butanediol with effects on tumor cells, including inhibition of insulin growth factor receptor (IGF-1R) autophosphorylation. In vitro studies suggest that NDGA attenuates androgen-mediated prostate cancer growth without competitive androgen receptor blockade. Its effects on PSA in pts were studied. Methods: Eligible pts included men with recurrent prostate cancer following definitive local therapy with a rising PSA and no metastasis. Both androgen dependent prostate cancer (PSA rising with a normal tesosterone - ADPC) and androgen independent prostate cancer (PSA rising with castrate level of testosterone - AIPC) was allowed. Treatment consisted of continuous oral daily dosing of NDGA according to a planned dose escalation of 750, 1,250, 1,750, 2,250 and 2,500 mg. Pts were followed for safety and changes in PSA and PSA doubling time (PSADT). Results: 15 pts were enrolled: 11 pts with ADPC and 4 pts with AIPC. Median baseline serum PSA was 3.6 ng/mL in ADPC pts and 5.74 mg/mL in AIPC pts. Median age was 66 (range 48–81). Following a median of 5.5 cycles (range 1–13), transaminase elevations occurred in five pts (33%): 1 gr 1, 1 gr 2 and 3 gr 3- all occurring in month 3 or later. Transaminase elevations resolved after drug discontinuation but recurred with repeated dosing. Doses up to 2,500 mg/day were otherwise well- tolerated. The median baseline PSADT was 6.1 months for ADPC and 6.7 months for AIPC and was and 8.4 months on therapy (p=0.12) for ADPC and 4.2 months for AIPC. Of 11 ADPC pts, one (9%) had a decline in PSA by >50% compared to baseline and one (9%) had a decline of 3 fold increase in PSADT while on therapy, one from 11 to 46 months (750 mg), one from 9.5 to 49.5 months (1,750 mg), and one from 5.9 to 46.2 months (2,500 mg). There were no PSA reductions in the AIPC pts, however one pt had a >3 fold increase in PSADT (from 1.4 to 7.5 months). No significant effects on testosterone, adrenal androgen or estradiol levels were observed while on study. Conclusions: NDGA is well tolerated with the exception of transaminase elevations which occur after approximately 3 cycles in a minority of patients. Combined with preclinical data, the modest effects on PSA kinetics suggest that further study on androgen dependent tumors is justified. No significant financial relationships to disclose.

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Choo, Kyochan, and Suckjoo Hong. "The Features of Acrylonitrile-Butadiene-Styrene Graphite (AGC), One of Big Data of Electronic Heat Sink." Advanced Science Letters 22, no. 11 (2016): 3343–47. http://dx.doi.org/10.1166/asl.2016.7942.

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Ross, Justine Abella, Jana Dickter, Bernard Tegtmeier, and Sanjeet Dadwal. "1760. Outcomes of Acyclovir-Resistant Herpes Simplex Virus Infections in Hematologic Malignancies and Hematopoietic Cell Transplant." Open Forum Infectious Diseases 6, Supplement_2 (2019): S647. http://dx.doi.org/10.1093/ofid/ofz360.1623.

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Abstract Background Acyclovir-resistant (ACVr) herpes simplex virus (HSV) infection management is a challenge in patients with hematologic malignancies (HM) and hematopoietic cell transplant (HCT) recipients. Methods Retrospective review of patients aged ≥ 18 years with underlying HM and/or HCT and culture-positive ACVr HSV between 1/1/2009 and December 1/2017 at a tertiary cancer center. Clinical, laboratory, microbiological, and treatment data collected. Results 33 patients identified; 25 (76%) acute leukemias, 3 (9%) chronic myeloid leukemia/chronic lymphocytic leukemia (CML/CLL), 3 (9%) lymphoma, 2 (6%) other HM, and 32 (97%) had HCT. Median age of patients was 59 years (25–73) and 64% of them are females. HCT type: 22 (67%) matched unrelated donor, 3 (9%) cord blood, and 7 (21%) matched related donor. All patients were on acyclovir prophylaxis prior to diagnosis. The median time to onset of ACVr HSV infection was 147 days after transplant. Infection site: 16 (49%) oral, 10 (30%), ano-genital, 5 (15%) oral and esophagus/lung, 2 (6%) esophagus/lung. Pertinent laboratory data on day of viral culture (median/range): white blood cell (WBC) 4.6 cells/µL (0.1–85.9), absolute neutrophil count (ANC) 2,316 cells/µL (0–17,000), absolute lymphocyte count (ALC) 574.5 cells/µL (0–84,182). Serum creatinine at start and end of treatment are 0.8 mg/dL (0.32–1.98) and 0.92 mg/dL (0.36–2.7), respectively. The median duration of treatment was 30 days (4–116). Treatment: 20 (61%) foscarnet, 2 (6%) cidofovir, 4 (12%) foscarnet and cidofovir, 1 (3%) valacyclovir, 5 (15%) high-dose acyclovir, 1 (3%) unknown. 8 (24%) received adjunctive topical therapy: 5 imiquimod, 3 cidofovir. 31 included in outcome analysis (data missing in 2). Infection resolved in 15/31 (48%) while 5/31 (16%) had persistent infection. Median ANC and ALC in those with resolved vs. persistent infection (respectively): 3,082 cells/µL and 642 cells/µL vs. 1,895 cells/µL and 380 cells/µL with a trend toward lower ANC and ALC in patients with persistent infection. Overall mortality was 35% (9/31) while ACVr HSV attributable mortality was 6.4% (2/31). Conclusion ACVr HSV is predominantly encountered in allogeneic HCT, particularly the unrelated donor recipients, and lower ANC/ALC may predispose to persistent infection. Disclosures All authors: No reported disclosures.

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Hart, Simon, Scott Nicholls, Howard Amos, and Jill Benn. "Making sense of flipping data." Performance Measurement and Metrics 20, no. 3 (2019): 159–67. http://dx.doi.org/10.1108/pmm-08-2019-0030.

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Purpose The purpose of this paper is to detail the approach used in a project that worked with journal publication, subscription and article processing charges (APC) data. The project aim was to test if the resources allocated by the Matariki Network of Universities, a group of seven medium-sized universities, would pay for APC at the current level of publishing activity. Design/methodology/approach Data were collated and analysed from three years (2015–2017) for each of the seven partners. Findings A range of assumptions were made in dealing with the data. It was difficult to identify a subscription package that was common to all the partners. Data were not always consistent and in some instances it was incomplete. An iterative and flexible approach was required in this project. Even though testing had been carried out during planning, changes had to be made as the project was carried out. The timetable had to be flexible as those working on the project dealt with their day-to-day operational priorities and to enable each of the partners to contribute as resources allowed. Practical implications As alternative models of scholarly journal publication are evolving, it is important that the implications of these be tested to inform planning. Details of this testing need to be shared so that others can confirm the results, consider the approach and apply lessons learned. Originality/value This paper focuses on the details of the investigation so that others interested in repeating this project, or carrying out a similar project, can consider this in their planning.

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Chiarenza, Annalisa, Nunziatina Laura Parrinello, Anna Maria Triolo, et al. "The Combined Evaluation of Neutrophil, T-Lymphocyte and Monocyte Counts Provides New Prognostic Information in CLL Patients." Blood 128, no. 22 (2016): 5565. http://dx.doi.org/10.1182/blood.v128.22.5565.5565.

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Abstract The recent advances in cytogenetic and molecular diagnostic techniques has provided a better understanding of biology of CLL and a better prediction of disease progression and refractoriness but they are not easily accessible to all Institutions. CLL cells depend on microenvironmental interactions for proliferation and survival that are at least partially mediated through B cell receptor (BCR) signaling. An increased number of studies describe the emerging role of neutrophils and monocytes as mediators of the inflammation process and antitumor immunity modulation that support tumorigenesis and tumor progression. The neutrophil to lymphocyte ratio (NLR), has been recently published as new marker of systemic inflammation associated with outcome in different cancer types. In our study we retrospectively evaluated the prognostic significance of peripheral blood neutrophils, monocytes and non-neoplastic lymphocytes in a unicentric, unselected, CLL cohort of 400 CLL patients (160 were treated). The study was approved by the institutional board review;informed consent was obtained from patients. Using the blood count and the Flow cytometric analysis reports, peripheral blood absolute neutrophil count (ANC), absolute monocyte count (AMC) and absolute T-lymphocyte count (ALC-CD3+) were evaluated and the neutrophil to T-lymphocyte ratio (NLR), the monocyte to T-lymphocyte ratio (MLR) and the neutrophil to monocyte ratio (NMR) were calculated. Clinical and biological data from all patients were also retrieved. Serial count and ratio were evaluated at diagnosis, during follow up and at relapse to make a better comparison with the major clinical and prognostic markers commonly used. The median ratio for NLR 2.67 and patients with pre-treatment NLR > 3 had a shorter time from diagnosis to treatment initiation. CLL patients showed an increase in the absolute number of monocytes compared to normal controls (788±65 cells/μL vs 469±51 cells/μL, p=0.005) and MLR appeared higher in advanced stage (stage Binet C) and bulky disease (p=0.06). High level of both NLR and MLR (cut off >3) correlated with the presence of a complex karyotype detected by FISH (p=0.03, p=0.016). NLR ratio was associated with the absence of serum prognostic markers, such as the expression of CD38, ZAP-70 and CD49d. This result, apparently conflicting, could strengthen the NLR as an independent prognostic factor. NMR was higher in asymptomatic patients (absence vs. presence of B symptoms, p=0.02) and this data resulted independent from disease stage. NMR median value was significantly higher in untreated patients than in patients who received treatment (p=0.01), strengthening the hypothesis that this ratio is associated with a more indolent form of disease. In this contest, the subset of patients with CD49d positive disease showed the lowest NMR value. This data seems of relevance, being CD49d a recently discovered and validated prognostic marker. ANC/ALC and AMC/ALC ratio significantly increased at relapse compare to baseline (NLR average onset 2.3±0.4 vs 3.4±0.6 at relapse). The median NMR value showed conversely the opposite trend: NMR is reduced in first relapse (NMR average onset 7.2±0.4 vs. 5.4±0.5 at relapse). These combined ratios reflect both the inflammatory status, the immune response and the microenviromental network that contribute to aggressive tumor biology and disease progression. They are simple, cheap, easily measured and reproducible and can be integrated into daily clinical practice as new prognostic markers for CLL. Disclosures Chiarenza: Gilead: Consultancy; Janssen: Consultancy; Roche: Consultancy.

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PARK, Y. J., J. M. KIM, B. R. LEE, T. H. KIM, and E. G. LEE. "Annual prevalence and economic burden of genital warts in Korea: Health Insurance Review and Assessment (HIRA) service data from 2007 to 2015." Epidemiology and Infection 146, no. 2 (2017): 177–86. http://dx.doi.org/10.1017/s0950268817002813.

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SUMMARYThis study evaluated the annual prevalence of anogenital warts (AGW) caused by human papillomavirus (HPV) and analysed the trend in annual per cent changes (APC) by using national claims data from the Health Insurance Review and Assessment of Korea, 2007–2015. We also estimated the socio-economic burden and co-morbidities of AGW. All analyses were performed based on data for primary A63.0, the specific diagnosis code for AGW. The socio-economic cost of AGW was calculated based on the direct medical cost, direct non-medical cost and indirect cost. The overall AGW prevalence and socio-economic burden has increased during the last 9 years. However, the prevalence of AGW differed significantly by sex. The female prevalence increased until 2012, and decreased thereafter (APC + 3·6%). It would fall after the introduction of routine HPV vaccination, principally for females, in Korea. The male prevalence increased continuously over time (APC + 11·6%), especially in those aged 20–49 years. Referring to the increasing AGW prevalence and its disease burden, active HPV infection control surveillance and prevention in males are worth consideration.

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Gladfelter, Amy S., Nicoleta Sustreanu, A. Katrin Hungerbuehler, Sylvia Voegeli, Virginie Galati, and Peter Philippsen. "The Anaphase-Promoting Complex/Cyclosome Is Required for Anaphase Progression in Multinucleated Ashbya gossypii Cells." Eukaryotic Cell 6, no. 2 (2006): 182–97. http://dx.doi.org/10.1128/ec.00364-06.

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ABSTRACT Regulated protein degradation is essential for eukaryotic cell cycle progression. The anaphase-promoting complex/cyclosome (APC/C) is responsible for the protein destruction required for the initiation of anaphase and the exit from mitosis, including the degradation of securin and B-type cyclins. We initiated a study of the APC/C in the multinucleated, filamentous ascomycete Ashbya gossypii to understand the mechanisms underlying the asynchronous mitosis observed in these cells. These experiments were motivated by previous work which demonstrated that the mitotic cyclin AgClb1/2p persists through anaphase, suggesting that the APC/C may not be required for the division cycle in A. gossypii. We have now found that the predicted APC/C components AgCdc23p and AgDoc1p and the targeting factors AgCdc20p and AgCdh1p are essential for growth and nuclear division. Mutants lacking any of these factors arrest as germlings with nuclei blocked in mitosis. A likely substrate of the APC/C is the securin homologue AgPds1p, which is present in all nuclei in hyphae except those in anaphase. The destruction box sequence of AgPds1p is required for this timed disappearance. To investigate how the APC/C may function to degrade AgPds1p in only the subset of anaphase nuclei, we localized components and targeting subunits of the APC/C. Remarkably, AgCdc23p, AgDoc1p, and AgCdc16p were found in all nuclei in all cell cycle stages, as were the APC/C targeting factors AgCdc20p and AgCdh1p. These data suggest that the AgAPC/C may be constitutively active across the cell cycle and that proteolysis in these multinucleated cells may be regulated at the level of substrates rather than by the APC/C itself.

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Edgerton-Morgan, Heather, та Berl R. Oakley. "γ-Tubulin plays a key role in inactivating APC/CCdh1 at the G1–S boundary". Journal of Cell Biology 198, № 5 (2012): 785–91. http://dx.doi.org/10.1083/jcb.201203115.

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A γ-tubulin mutation in Aspergillus nidulans, mipA-D159, causes failure of inactivation of the anaphase-promoting complex/cyclosome (APC/C) in interphase, resulting in failure of cyclin B (CB) accumulation and removal of nuclei from the cell cycle. We have investigated the role of CdhA, the A. nidulans homologue of the APC/C activator protein Cdh1, in γ-tubulin–dependent inactivation of the APC/C. CdhA was not essential, but it targeted CB for destruction in G1, and APC/CCdhA had to be inactivated for the G1–S transition. mipA-D159 altered the localization pattern of CdhA, and deletion of the gene encoding CdhA allowed CB to accumulate in all nuclei in strains carrying mipA-D159. These data indicate that mipA-D159 causes a failure of inactivation of APC/CCdhA at G1–S, perhaps by altering its localization to the spindle pole body, and, thus, that γ-tubulin plays an important role in inactivating APC/CCdhA at this point in the cell cycle.

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Vernieri, Claudio, Elena Chiroli, Valentina Francia, Fridolin Gross, and Andrea Ciliberto. "Adaptation to the spindle checkpoint is regulated by the interplay between Cdc28/Clbs and PP2ACdc55." Journal of Cell Biology 202, no. 5 (2013): 765–78. http://dx.doi.org/10.1083/jcb.201303033.

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The spindle checkpoint arrests cells in metaphase until all chromosomes are properly attached to the chromosome segregation machinery. Thereafter, the anaphase promoting complex (APC/C) is activated and chromosome segregation can take place. Cells remain arrested in mitosis for hours in response to checkpoint activation, but not indefinitely. Eventually, they adapt to the checkpoint and proceed along the cell cycle. In yeast, adaptation requires the phosphorylation of APC/C. Here, we show that the protein phosphatase PP2ACdc55 dephosphorylates APC/C, thereby counteracting the activity of the mitotic kinase Cdc28. We also observe that the key regulator of Cdc28, the mitotic cyclin Clb2, increases before cells adapt and is then abruptly degraded at adaptation. Adaptation is highly asynchronous and takes place over a range of several hours. Our data suggest the presence of a double negative loop between PP2ACdc55 and APC/CCdc20 (i.e., a positive feedback loop) that controls APC/CCdc20 activity. The circuit could guarantee sustained APC/CCdc20 activity after Clb2 starts to be degraded.

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Wariz, Rahmat, Keng-Liang Ou, Muhammad Ruslin, Bahruddin Thalib, Chung-Ming Liu та Hsin-Hua Chou. "Long exposure of argon plasma coagulation induces more thermal damage accompanied by a higher expression of NF-κB and caspase-3". Journal of Dentomaxillofacial Science 3, № 1 (2018): 5. http://dx.doi.org/10.15562/jdmfs.v3i1.734.

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Objective: Long exposure of argon plasma coagulation (APC) causes thermal damage and apoptosis in tissues. However, whether the APC-induced thermal damage in tissues involves the expression of NF-κB and caspase-3 remains undetermined. In this study, we compared the effect of APC on liver damage at two different exposure time and tested the hypothesis that thermal injuries induced by APC are accompanied by induction of NF-κB and caspase-3 expression in rat liver.Material and Methods: Liver injuries were induced in rats by an APC device with pulse mode for 2 or 4 seconds under the same frequency of power (40W). The animals were sacrificed 0, 3, 7 and 21 days after injury and the liver tissues were harvested and used for western blotting, histological and immunohistochemical analyses.Results: Haematoxylin and eosin (H&E) stained sections of the liver tissues showed that two-second application of APC caused minimum thermal damage and apoptotic areas, less carbonization, and more fibrosis formation in liver than the four-second APC application at all time points examined. All of these APC-induced thermal effects and morphological changes in the two-second APC application group but not the four-second APC application group recovered 21 days after the treatment. Western blot results indicated that APC induced the expression of NF-κB on day 3, and peaked on days and 14. In the two-second APC application group, the expression of NF-κB returned to the normal level on day 28. However, the expression of NF-κB induced by 4 seconds of APC application remained high even 28 days after injury. The expression of caspase-3 induced by the 2 seconds or 4 seconds of APC application peaked at 7 or 14 days, respectively. Similarly, the APC-induce expression of caspase-3 returned to the normal level in the 2-second APC application group, but it still remained high in the 4-second APC application group even 28 days after injury. These results were further confirmed by The immunofluorescence data also indicated that APC exposure for 4 seconds induced a much higher expression of NF-κB than APC exposure for 2 seconds. The similar pattern was observed in the caspase-3 expression.Conclusions: Taken together, our results show that 2-second APC exposure causes minimum liver injury accompanied by the expressions of NF-κB and casapase-3 which return to the normal level 28 days after injury. These findings strongly suggest that the shortest pulse mode (2 seconds) application of APC is a safe, convenient, and effective approach for the treatment of particularly thermosensitive tissues.

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Kalafatis, Michael, Rihard E. Chiott, Richard F. Branda, and Kenneth G. Mann. "Activated Protein C-Resistance Induced by a Low Molecular Weight Inhibitor." Blood 106, no. 11 (2005): 2136. http://dx.doi.org/10.1182/blood.v106.11.2136.2136.

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Abstract Activated protein C (APC) inactivates factor Va (fVa) following three cleavages in the heavy chain at R506, R306 and R679. Cleavage at R506 precedes cleavage at R306. Cleavage at Arg306 is strictly lipid-dependent and results in total inactivation of the factor Va molecule with dissociation of fragments from the A2 domain from the rest of the molecule. Factor VLeiden is associated with an R→Q substitution at position 506 and is present at approximately 8% of the Caucasian population. The heterozygous presentation of factor VLeiden results in delayed inactivation of factor Va and “APC-resistance” with attendant increased risk of venous thrombosis. However, not all cases of “APC-resistance” are explained by factor VLeiden. We observed “APC-resistance” in a patient displaying heterozygous factor VLeiden, Waldenstrom’s macroglobulinenemia, systemic lupus erythrematosus (anticoagulant) and a history of coronary artery disease. The patient’s plasma resistance to APC inactivation was not repaired by immunodepletion of his factor VLeiden and replacement by normal plasma factor V. Conversely when the patient’s fVa was returned to factor V immunodepleted normal plasma it did not display APC-resistance. Cleavage of the patient’s plasma fVa at R306 was not detected following prolonged incubation of his clotted plasma at 37°C even when 2 nM APC was added following clotting. These data suggested that the APC-resistance observed in the patient was not due to the presence of factor VLeiden, but due to some property which inhibited the lipid dependent cleavage at Arg306. The patient’s plasma was depleted of IgG/IgM and the purified immunoglobulin fraction assessed for inhibition of APC cleavage and inactivation of fVa in a system using purified reagents. The data were compared with the inhibition of fVa inactivation by APC by an IgG/IgM fraction obtained from normal plasma under similar experimental conditions. No inhibition of APC cleavage and inactivation of fVa by the IgM/IgG fraction obtained from either plasma were observed. In addition, the fVa molecule contained in the IgM/IgG-depleted patient plasma was still resistant to cleavage and inactivation by APC. Following dialysis the patient’s plasma lost its ability to inhibit fVa cleavage and inactivation by APC. Overall these studies indicate that inhibition of fVa cleavage and inactivation by APC in the patient’s plasma is caused by a hitherto undescribed metabolite of low molecular weight. The mechanism of action of this metabolite is not yet known, but the evidence suggests that the metabolite interferes with the lipid-dependent cleavage and inactivation of fVa by APC at R306. These data demonstrate the existence of an as yet unknown APC inhibitor of low molecular weight in the plasma of a patient with lupus anticoagulant and severe thrombotic symptoms.

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Liu, Hong, Constance M. Yuan, Raul C. Braylan, Myron N. Chang, John R. Wingard, and Jan S. Moreb. "Flow Cytometric Disease Monitoring in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation: A Retrospective Study." Blood 108, no. 11 (2006): 5014. http://dx.doi.org/10.1182/blood.v108.11.5014.5014.

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Abstract The persistence of abnormal neoplastic plasma cells (APC) detectable in the bone marrow by flow cytometry at more than 3 months after autografting for multiple myeloma (MM) has been reported to predict early disease progression. In this study, we retrospectively reviewed the flow cytometric data from bone marrow aspirates of MM patients before and after autologous stem cell transplantation (ASCT). Light scatter properties and CD38 expression were used to identify plasma cells, and CD19/CD45/CD56 further distinguished normal plasma cells (NPC) from APC. Conventional response criteria (Blade criteria) and survival data were also collected. Forty-seven (47) patients treated with the same conditioning regimen were screened. Median follow up from ASCT was 19 months. After ASCT, 66% (31/47) patients achieved complete remission (CR)/very good partial remission (VGPR), as compared to only 36% (17/47) prior to ASCT. In 39 patients with data before and after ASCT, all 39 (100%) had a detectable abnormal plasma cell population identified phenotypically by flow cytometry prior to ASCT. Of these patient, 18/39 (46%) had greater than 30 APC and these patients had significantly shorter PFS independent of other covariates (1-sided P=0.036, 2 sided P=0.072, logrank). Twenty-six out of 39 patients (67%) also had detectable NPC. Following ASCT, the number of patients with detectable NPC increased to 35/39 (89%), while 3/39 (8%) had no detectable NPC and 1/39 (3%) had neither NPC or APC. The proportion of APC decreased significantly after transplant (81% prior to transplant vs. 59% post-transplant, P=0.008, 2 tailed t-test). Patients with a APC to NPC ratio &lt; 1 post transplant has higher PFS rate at 2 year (54%) when compared to patients with higher APC/NPC ratio (29% PFS at 2 year), however, the difference is not statistically significant. In addition to the presence of APC, the ratio of APC to NPC, age, beta-2 microglobulin levels, and the presence of normal immunoglobulin levels were analyzed. Patients who achieved CR/VGPR after transplant had significantly longer PFS (23 months vs. 11 months, P=0.03). All other covariates were not found to be significant. Because only 10 deaths were observed, covariate analysis for OS was not feasible. In conclusion, the recovery of NPC after ASCT is seen in a substantial propotion of patients with a trend towards better PFS in patients with low APC/NPC ratio. On the other hand, the presence of a significant population of APC (&gt; 30) prior to transplant appears to correlate with poorer PFS in MM patients.

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van Hinsbergh, VW, RM Bertina, A. van Wijngaarden, NH van Tilburg, JJ Emeis, and F. Haverkate. "Activated protein C decreases plasminogen activator-inhibitor activity in endothelial cell-conditioned medium." Blood 65, no. 2 (1985): 444–51. http://dx.doi.org/10.1182/blood.v65.2.444.bloodjournal652444.

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Confluent cultures of endothelial cells from human umbilical cord were used to study the effect of activated human protein C (APC) on the production of plasminogen activators, plasminogen activator-inhibitor, and factor VIII-related antigen. Addition of APC to the cells in a serum-free medium did not affect the production of tissue-type plasminogen activator (t-PA) or factor VIII-related antigen; under all measured conditions, no urokinase activity was found. However, less plasminogen activator-inhibitor activity accumulated in the conditioned medium in the presence of APC. This decrease was dose dependent and could be prevented by specific anti-protein C antibodies. No decrease was observed with the zymogen protein C or with diisopropylfluorophosphate-inactivated APC. APC also decreased the t-PA inhibitor activity in endothelial cell-conditioned medium in the absence of cells, which suggests that the effect of APC is at least partly due to a direct effect of APC on the plasminogen activator- inhibitor. High concentrations of thrombin-but not of factor Xa or IXa-- had a similar effect on the t-PA inhibitor activity. The effect of APC on the plasminogen activator-inhibitor provides a new mechanism by which APC may enhance fibrinolysis. The data suggest that activation of the coagulation system may lead to a secondary increase of the fibrinolytic activity by changing the balance between plasminogen activator(s) and its (their) fast-acting inhibitor.

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Binder, Moritz, S. Vincent Rajkumar, Martha Q. Lacy, et al. "Prognostic Significance of Early Immune Reconstitution in Newly Diagnosed Multiple Myeloma." Blood 132, Supplement 1 (2018): 3158. http://dx.doi.org/10.1182/blood-2018-99-113970.

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Abstract Background: Peripheral blood biomarkers of tumor microenvironment and immune surveillance such as absolute lymphocyte (ALC) and monocyte (AMC) counts are independent prognostic factors in several hematologic malignancies including multiple myeloma. The timing and prognostic impact of immune reconstitution has been studied after autologous hematopoietic stem cell transplantation, less is known about its significance in newly diagnosed multiple myeloma prior to transplantation. Methods: We studied 771 patients with newly diagnosed multiple myeloma who were treated with novel agents at Mayo Clinic between 01/2004 and 12/2015. Peripheral blood absolute lymphocyte and monocyte counts were measured at the time of treatment initiation and one month thereafter in all patients (including data obtained between 14 and 42 days after treatment initiation). The outcome of interest was overall survival. The peripheral blood parameters of interest were abnormal ALC (reference range 800-2400/µL) and AMC (reference range 500-1500/µL) at baseline and at one month. Immune dysregulation was defined as both abnormal ALC and AMC. Immune reconstitution was defined as recovery of both normal ALC and AMC. The Wilcoxon signed-rank test was used to compare the peripheral blood parameters before and after the first month of treatment. Multivariable-adjusted proportional hazards regression models were used to assess the associations between changes in peripheral blood parameters and overall survival. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis was 65 years (27 - 90) and 459 patients were male (60%). The three most common first-line regimens were lenalidomide + dexamethasone, bortezomib + cyclophosphamide + dexamethasone, and bortezomib + lenalidomide + dexamethasone. Two hundred and eighty patients (36%) went on to undergo autologous hematopoietic stem cell transplantation as part of their first-line therapy. The median ALC decreased from 1100/µL (range 60 - 5590) at baseline to 850/µL (range 60 - 5590) at one month (p < 0.001). The median AMC increased from 330/µL (range 0 - 1840) at baseline to 420/µL (range 0 - 1840) at one month (p < 0.001). The median time between re-assessment of ALC and AMC was 25 days (range 15 - 42). Two hundred and thirty-four patients (31%) had evidence of immune dysregulation at baseline (both abnormal ALC and AMC). Eighty-seven of these 234 patients (37%) recovered normal ALC and AMC at one month (early immune reconstitution). One hundred and thirty-seven of the 537 patients with normal ALC and AMC at baseline (26%) developed new immune dysregulation at one month. The absence of immune dysregulation at baseline (compared to the presence thereof) was associated with better overall survival (HR 0.77, 95% CI 0.61 - 0.97, p = 0.025, n = 771). The absence of immune dysregulation at one month (compared to the persistence or development thereof) was associated with better overall survival (HR 0.63, 95% CI 0.50 - 0.80, p < 0.001, n = 771). Early immune reconstitution (compared to the persistence or development of immune dysregulation) was associated with better overall survival (HR 0.62, 95% CI 0.43 - 0.92, p = 0.016, n = 771). Both associations remained statistically significant after adjusting for age at diagnosis, sex, International Staging System stage, and eligibility for transplantation: HR 0.70 (95% CI 0.54 - 0.90, p = 0.006, n = 612) and HR 0.59 (95% CI 0.39 - 0.90, p = 0.014, n = 612), respectively. Conclusions: Peripheral blood biomarkers of immune dysregulation vary over time and have prognostic significance both at baseline and during follow-up. The presence or development of immune dysregulation in newly diagnosed multiple myeloma is an independent risk factor. The favorable impact of early immune reconstitution suggests that immune dysregulation is a potentially modifiable risk factor that may be exploited for therapeutic benefit. Figure. Figure. Disclosures Lacy: Celgene: Research Funding. Gertz:celgene: Consultancy; Medscape: Consultancy; janssen: Consultancy; Prothena: Honoraria; Apellis: Consultancy; Ionis: Honoraria; annexon: Consultancy; spectrum: Consultancy, Honoraria; Amgen: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Consultancy; Research to Practice: Consultancy; Teva: Consultancy; Alnylam: Honoraria. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Russell:Vyriad: Equity Ownership. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Seshire, Anita, Tim Beissert, Claudia Oancea, Dieter Hoelzer, Martin Ruthardt, and Elena Puccetti. "Overexpression of APC Reduces Stem Cell Capacity and Leukemogenic Potential of PLZF/RAR-Positive Leukemic Stem Cells." Blood 110, no. 11 (2007): 874. http://dx.doi.org/10.1182/blood.v110.11.874.874.

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Abstract Acute myeloid leukemia (AML)-associated fusion proteins (AAFP), such as PML/RAR, PLZF/RAR or AML1/ETO have leukemogenic potential in vivo which is related to their capacity to induce a differentiation block and aberrant self renewal in early hematopoietic progenitors. The potential of the AAFP to induce the leukemic phenotype is strictly related to their capacity to oligomerize and to form high molecular weight complexes (HMW). Furthermore we recently showed that the deregulation of the Wnt-signaling seems to be a key event for the leukemogenesis by the above mentioned AAFP because it is indispensable for the aberrant self renewal of leukemic stem cells (LSC). A „tandem affinity purification” (TAP) screen of KG1 cells expressing PLZF/RAR, PML/RAR or AML-1/ETO for elucidating the composition of the related HMW revealed the „adenomatous polyposis coli” protein (APC) as an interaction partner of PLZF/RAR. APC is a key inhibitory regulator of the Wnt-signaling and is frequently inactivated by mutations in colon carcinomas. Therefore the role of the interaction between APC and PLZF/RAR for the leukemogenesis was further investigated. Here we report that i.) only PLZF/RAR strongly interacted with APC as confirmed by co-immunoprecipitation experiments; ii.) the overexpression of APC reverted the aberrant activation of the Wnt-signaling by PLZF/RAR as revealed by a reduction of the TCF/LEF mediated transcriptional activity; iii.) the overexpression of APC also reduced the self renewal potential of PLZF/RAR-positive HSC as revealed by a reduced replating efficiency of these cells in semi solid medium, as well as by a reduction of the colony number in colony forming units spleen (CFU-S) assays; iv.) APC was able to revert the leukemogenic potential of PLZF/RAR-positive LSC as revealed by the retroviral overexpression of APC in bone marrow isolated from mice with PLZF/RAR-induced AML which were inoculated into secondary recipients. In fact until now the presence of APC significantly increased the survival of these secondary recipients with respect to mock-infected controls. Taken together these data strongly suggest that the direct interaction with PLZF/RAR is an important mechanism for the functional inactivation of APC which contributes to the aberrant activation of the Wnt-signaling in PLZF/RAR-positive cells. Furthermore our data provide further evidence that the aberrantly activated Wnt-signaling pathway represents a valid target for molecular therapy approaches.

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Blum, William, Kristie A. Blum, Cheryl Kefauver, et al. "Decitabine-Induced Differentiation Syndrome in a Patient with Acute Myeloid Leukemia: A Case Report." Blood 104, no. 11 (2004): 4528. http://dx.doi.org/10.1182/blood.v104.11.4528.4528.

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Abstract We report here for the first time a case of “decitabine-induced differentiation syndrome” in a patient (pt) with acute myeloid leukemia (AML). The cytosine analog decitabine, after incorporating into DNA, irreversibly binds DNA methyltransferase (DNMT) enzymes where cytosine residues are targeted for methylation. This allows replication of unmethylated DNA with subsequent re-expression of genes previously silenced by promoter methylation. It has been suggested that decitabine at low doses may have differentiating effects, as compared to cytotoxic effects at higher doses. A previous phase I trial demonstrated clinical activity of low dose decitabine in patients with myeloid malignancies (Issa, et al., Blood 2004). Given the close relationship of DNA methylation and histone deacetylation in modulating gene expression, we are currently conducting a phase I trial (OSU 0336) of low dose decitabine (15mg/m2 IV over 1 hour on days 1–10) alone (step 1) or in combination with escalating doses of the histone deacetylase inhibitor valproic acid (step 2) in AML. An 82 year old male pt with untreated, secondary AML (65% bone marrow blasts, 95% marrow cellularity) was enrolled on step 1 of the study and given 15mg/m2/day of decitabine for 10 consecutive days. At the time of initiation of therapy, the pt had a white blood cell (WBC) count of 8,700/uL with absolute neutrophil count (ANC) of 1,500/uL and absolute blast count (ABC) of 3,200/uL. At day 11, the pt had WBC 1,000/uL with ANC of 450/uL and ABC of 150/uL and was clinically well. However, at day 17, he presented with cough and shortness of breath, without fever. WBC had risen to 18,700/uL with ANC of 11,000/uL and ABC of 750/uL. The patient developed worsening hypoxia and required mechanical ventilation. Chest radiograph demonstrated diffuse interstitial infiltrates, but bronchoscopy and lavage (on day 18 and repeated on day 24) did not identify an infectious etiology. Due to clinical concern for a differentiation syndrome similar to the “retinoic acid syndrome” occurring in acute promyelocytic leukemia patients treated with all-trans-retinoic-acid (ATRA), the pt was started on dexamethasone 10mg IV q12 hours beginning on day 18, in addition to broad spectrum antimicrobial coverage. Peripheral blood smears during the following week showed evidence of myeloid differentiation, and by day 25 no circulating blasts were found (WBC 4,300/uL, ANC 3,000/uL) while the overall clinical condition improved. The pt was finally extubated on day 38 but within 24 hours required emergent re-intubation due to nasogastric feeding aspiration and died at day 53. In summary, these preliminary data support the biological activity of low dose decitabine in AML and suggest that clinical precautions similar to those implemented for the “retinoic acid syndrome” in ATRA-treated APL should be considered in decitabine-treated AML when myeloid differentiation and rising neutrophil counts are observed.

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Sen, Prosenjit, Sanghamitra Sahoo, Usha Pendurthi, and L. Vijaya Mohan Rao. "Zinc Binding to Protein C and Activated Protein C Modulates Their Interaction with Endothelial Cell Protein C Receptor." Blood 114, no. 22 (2009): 331. http://dx.doi.org/10.1182/blood.v114.22.331.331.

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Abstract Abstract 331 Introduction/background: Zinc is a multi-functional element that is essential for life and the second most abundant metal ion, after iron in eukaryotic organisms. Zinc deficiency has been associated with bleeding disorders and with defective platelet aggregation, suggesting it may play an important role in hemostasis. Zinc ions have been shown to enhance activation of the intrinsic pathway of coagulation but to down-regulate the extrinsic pathway of coagulation. All vitamin K-dependent coagulation proteins have calcium binding sites and may therefore to some extent, interact with other divalent metal ions, including zinc, through these sites. Recent crystallography studies identified a pair of Zn2+ binding sites in FVIIa protease domain, and with the exception of Glu220, all the side chains involved in both the Zn1 and Zn2 coordination in FVIIa are unique to FVIIa and are not present in other vitamin K-dependent clotting factors (Bajaj et al., J Biol Chem 2006; 281:24873-88). Nonetheless, Zn2+ may bind to other vitamin K-dependent clotting factors at sites different from those identified in FVIIa. Objective: The aim of the present study is to investigate the effect of zinc ions on the protein C pathway, particularly on protein C/APC binding to EPCR, protein C activation and APC catalytic activity. Methods: Protein C and APC binding to EPCR on endothelial cells was examined by radioligand binding studies. Protein C activation and APC catalytic activity were evaluated in chromogenic assays. Equilibrium dialysis was used to measure zinc binding to protein C/APC. Conformational changes in protein C/APC were monitored by intrinsic fluorescence quenching. Results: Zn2+ does not replace the Ca2+ as a mandatory cofactor for protein C/APC binding to EPCR but Zn2+ at physiologically relevant concentrations (10 to 25 μM) markedly increased Ca2+-dependent protein C and APC binding to EPCR (∼2 to 5-fold). The kinetic analysis of protein C and APC binding to EPCR suggested that Zn2+ enhanced protein C/APC binding to EPCR by increasing the binding affinity of protein C/APC to its receptor (Kd for APC: – Zn2+, 117 ± 27 nM; + Zn2+, 9.3 ± 3.3 nM; Kd, for protein C: – Zn2+, 96 ± 26 nM; + Zn2+, 21.4 ± 6.6 nM). The enhancing effect of Zn2+ on APC binding to EPCR was also observed in the presence of physiological concentrations of Mg2+, which itself increased the APC binding to EPCR, two-fold. Zn2+-mediated increased protein C binding to EPCR resulted in increased APC generation. The effect of Zn2+ was not limited to enhancing protein C and APC binding to EPCR but also affected the catalytic activity of APC. Zn2+ inhibited the amidolytic activity of APC half-maximally at 50 to 100 μM. Zn2+ also inhibited the amidolytic activity of Gla domain deleted (GD)-APC in a similar fashion. The inhibitory effect of Zn2+ was partially reversed by physiological concentrations of calcium. Addition of Zn2+ to protein C or APC quenched the intrinsic fluorescence of both APC and GD-APC. Data from the equilibrium binding studies performed with 65Zn2+ revealed that Zn2+ binds to both GD-APC and APC, but that the amount of Zn2+ bound to APC was 3 to 4-fold higher than the amount bound to GD-APC. Kinetic analysis of equilibrium binding studies suggested that two Zn2+ atoms bind to APC outside the Gla domain with relatively high affinity (∼70 μM). At least one of the Zn2+ sites may overlap with the Ca2+ binding site as the Zn2+ binding to GD-APC was inhibited by approximately 50% by saturating concentrations of Ca2+. The substantially increased Zn2+ binding to the APC compared to GD-APC suggested that the N-terminus of the Gla domain of protein C contains multiple Zn2+ binding sites. Interestingly, Zn2+ bound to APC and GD-APC with a similar high affinity suggesting that the Gla domain, as well as the protease domain, may contain high affinity binding sites for Zn2+. A majority of the Zn2+ binding sites in the Gla domain appear to be distinct from the Ca2+ binding sites as less than 40% of the maximal Zn2+ binding could be blocked by Ca2+. The putative zinc binding sites in protein C/APC appeared to be unique as no consensus canonical zinc binding sequences homologous to other known zinc binding proteins were found in protein C. Conclusions: Our present data show that Zn2+ binds to protein C/APC and induces a conformational change in these proteins, which in turn leads to higher affinity binding to their cellular receptor EPCR. Overall our results suggest that zinc ions may play an important regulatory role in the protein C pathway. Disclosures: No relevant conflicts of interest to declare.

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Censi, F., F. Tosto, G. Floridia, et al. "The Italian National External Quality Assessment Program in Molecular Genetic Testing: Results of the VII Round (2010-2011)." BioMed Research International 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/739010.

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Since 2001 the Istituto Superiore di Sanità established a quality assurance programme for molecular genetic testing that covers four pathologies: Cystic Fibrosis (CF), Beta Thalassemia (BT), Fragile X Syndrome (FX), and Familial Adenomatous Polyposis Coli (APC). Since 2009 this activity is an institutional activity and participation is open to both public and private laboratories. Seven rounds have been performed until now and the eighth is in progress. Laboratories receive 4 DNA samples with mock clinical indications. They analyze the samples using their routine procedures. A panel of assessors review the raw data and the reports; all data are managed through a web utility. In 2010 the number of participants was 43, 17, 15, 5 for CF, BT, FX, APC schemes respectively. Genotyping results were correct in 96%, 98.5%, 100%, and 100% of CF, BT, FX, and APC samples, respectively. Interpretation was correct in 74%, 91%, 88%, and 60% of CF, BT, FX, and APC reports, respectively; however in most of them it was not complete but a referral to genetic counseling was given. Reports were satisfactory in more than 60% of samples in all schemes. This work presents the 2010 results in detail comparing our data with those from other European schemes.

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Keltie, Kim, Paola Cognigni, Sam Gross, et al. "Comparison of identifiable and non-identifiable data linkage: health technology assessment of MitraClip using registry, administrative and mortality datasets." BMJ Health & Care Informatics 28, no. 1 (2021): e100223. http://dx.doi.org/10.1136/bmjhci-2020-100223.

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ObjectivesThe UK MitraClip registry was commissioned by National Health Service (NHS) England to assess real-world outcomes from percutaneous mitral valve repair for mitral regurgitation using a new technology, MitraClip. This study aimed to determine longitudinal patient outcomes by linking to routine datasets: Hospital Episode Statistics (HES) Admitted Patient Care (APC) and Office of National Statistics.MethodsTwo methods of linkage were compared, using identifiable (NHS number, date of birth, postcode, gender) and non-identifiable data (hospital trust, age in years, admission, discharge and operation dates, operation and diagnosis codes). Outcome measures included: matching success, patient demographics, all-cause mortality and subsequent cardiac intervention.ResultsA total of 197 registry patients were eligible for matching with routine administrative data. Using identifiable linkage, a total of 187 patients (94.9%) were matched with the HES APC dataset. However, 21 matched individuals (11.2%) had inconsistencies across the datasets (eg, different gender) and were subsequently removed, leaving 166 (84.3%) for analysis. Using non-identifiable data linkage, a total of 170 patients (86.3%) were uniquely matched with the HES APC dataset.Baseline patient characteristics were not significantly different between the two methods of data linkage. The total number of deaths (all causes) identified from identifiable and non-identifiable linkage methods was 37 and 40, respectively, and the difference in subsequent cardiac interventions identified between the two methods was negligible.ConclusionsPatients from a bespoke clinical procedural registry were matched to routine administrative data using identifiable and non-identifiable methods with equivalent matching success rates, similar baseline characteristics and similar 2-year outcomes.

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van Hinsbergh, VW, RM Bertina, A. van Wijngaarden, NH van Tilburg, JJ Emeis, and F. Haverkate. "Activated protein C decreases plasminogen activator-inhibitor activity in endothelial cell-conditioned medium." Blood 65, no. 2 (1985): 444–51. http://dx.doi.org/10.1182/blood.v65.2.444.444.

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Abstract Confluent cultures of endothelial cells from human umbilical cord were used to study the effect of activated human protein C (APC) on the production of plasminogen activators, plasminogen activator-inhibitor, and factor VIII-related antigen. Addition of APC to the cells in a serum-free medium did not affect the production of tissue-type plasminogen activator (t-PA) or factor VIII-related antigen; under all measured conditions, no urokinase activity was found. However, less plasminogen activator-inhibitor activity accumulated in the conditioned medium in the presence of APC. This decrease was dose dependent and could be prevented by specific anti-protein C antibodies. No decrease was observed with the zymogen protein C or with diisopropylfluorophosphate-inactivated APC. APC also decreased the t-PA inhibitor activity in endothelial cell-conditioned medium in the absence of cells, which suggests that the effect of APC is at least partly due to a direct effect of APC on the plasminogen activator- inhibitor. High concentrations of thrombin-but not of factor Xa or IXa-- had a similar effect on the t-PA inhibitor activity. The effect of APC on the plasminogen activator-inhibitor provides a new mechanism by which APC may enhance fibrinolysis. The data suggest that activation of the coagulation system may lead to a secondary increase of the fibrinolytic activity by changing the balance between plasminogen activator(s) and its (their) fast-acting inhibitor.

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McDonald, Laura, Cormac Sammon, Robert Carroll, et al. "Consistency of recording of chemotherapy cycles in the National Cancer Registration and Analysis Service Systemic Anti-Cancer Therapy database and the Hospital Episode Statistics Admitted Patient Care database." Future Oncology 16, no. 3 (2020): 4455–60. http://dx.doi.org/10.2217/fon-2019-0669.

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Aim: We assessed the extent to which chemotherapy cycles recorded in Hospital Episode Statistics (HES) Admitted Patient Care (APC) were captured in National Cancer Registration & Analysis Service Systemic Anti-Cancer Therapy (SACT) for a cohort of lung cancer patients. Methods: All chemotherapy cycles recorded for linkage eligible lung cancer patients with a National Cancer Registration & Analysis Service diagnosis between 2012 and 2015 were identified in HES APC and SACT. Results: Among a population of 4070 lung cancer patients, 6076 chemotherapy cycles were observed in HES APC data. A total of 61% of cycles were recorded in SACT on the same day, 8% on a different day and 31% were not recorded in SACT. Conclusion: Our results suggest that SACT may not capture all chemotherapy cycles administered to a patient between 2012 and 2016; however, administrative changes mean data after this period may be more complete.

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Li, Yanli, Xiaolong Shih, Zandra K. Klippel, Maureen Reiner, and John H. Page. "Relationship Between Severity and Duration of Chemotherapy Induced Neutropenia and Risk of Infection Among Patients with Non-Myeloid Malignancies." Blood 124, no. 21 (2014): 4960. http://dx.doi.org/10.1182/blood.v124.21.4960.4960.

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Abstract Introduction:Neutropenia is a common adverse effect of myelosuppressive chemotherapy and may increase the risk of infection for cancer patients. However there is limited understanding about the quantitative relationships between severity and duration of chemotherapy induced neutropenia (CIN) and the risk of infection among patients undergoing chemotherapy to treat non-myeloid malignancies. Methods: The current study is a later analysis of data from six Amgen sponsored clinical trials. We combined individual data from adult patients with non-myeloid cancer who received no granulocyte colony-stimulating factor (G-CSF) during the first cycle of myelosuppressive chemotherapy and had absolute neutrophil count (ANC) measured at least 3 times per week. The primary endpoint is occurrence of an infection related hospitalization (identified from a review of hospitalization records). The secondary endpoint is occurrence of fever (≥38.2°C) or an infection related hospitalization in combination with different grades of CIN (grade 4: ANC <0.5 x 109/L or grade 3/4: ANC<1.0 x 109/L) on the same day, -1 day, or + 2 days. Descriptive analyses were conducted to characterize the ANC nadir and time to ANC nadir. An additional variable was created to measure both the duration and severity of CIN: area over the curve (AOC) of ANC, which was calculated as the area below the threshold of 0.5 x 109/L (or 1.0 x 109/L) and above ANC-time response curve in the first chemotherapy cycle. Time-dependent Cox proportional hazards models were used to quantify the hazard of first infection associated with duration of grade 4 or grade 3/4 CIN as well as the hazard associated with AOC, all in the first chemotherapy cycle. Results: Our study analyzed data from 271 patients who had one of four cancer types: small cell lung cancer (56.1%), non-Hodgkins lymphoma (24.4%), oral cavity and pharyngeal cancer (11.4%), and breast cancer (8.1%). About 63.8% of the patients had advanced cancer and 77.5% of them received chemotherapy regimens with a high risk of developing febrile neutropenia. The ANC trajectory is shown in the figure below. The median of daily ANC reached its minimum at day 12 with a value of 0.2 x 109/L. In the first chemotherapy cycle, 18.8% had infection-related hospitalizations; 42.8% and 41.0% of patients developed grade 3/4 and grade 4 neutropenic infections, respectively. For each additional day that patients had grade 3/4 and grade 4 CIN was associated with a 28% and 30% increase in the risk of infection related hospitalization, respectively (Table 1). Each unit (day×109/L ANC) increase of AOC (below 0.5 x 109/L) was also associated with a significantly increased risk of infection related hospitalization (HR: 1.98; 95% CI: 1.35-2.90) (Table 2). Conclusions: Risk of infection increases dramatically with each additional day of grade 3 or 4 CIN. Interventions that limit the duration and extent of CIN are of critical importance to preventing infection among cancer patients receiving chemotherapy. Figure. ANC Trajectory (Median and Interquartile Range) in the First Chemotherapy Cycle Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Li: Amgen: Employment, Equity Ownership. Shih:Amgen: Consultancy. Klippel:Amgen: Employment, Equity Ownership. Reiner:Amgen: Employment, Equity Ownership. Page:Amgen Inc.: Employment, Equity Ownership.

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Ye, Xiang S., Russell R. Fincher, Alice Tang, Aysha H. Osmani, and Stephen A. Osmani. "Regulation of the Anaphase-promoting Complex/Cyclosome bybimA APC3 and Proteolysis of NIMA." Molecular Biology of the Cell 9, no. 11 (1998): 3019–30. http://dx.doi.org/10.1091/mbc.9.11.3019.

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Surprisingly, although highly temperature-sensitive, thebimA1 APC3 anaphase-promoting complex/cyclosome (APC/C) mutation does not cause arrest of mitotic exit. Instead, rapid inactivation ofbimA1 APC3 is shown to promote repeating oscillations of chromosome condensation and decondensation, activation and inactivation of NIMA and p34cdc2 kinases, and accumulation and degradation of NIMA, which all coordinately cycle multiple times without causing nuclear division. ThesebimA1 APC3-induced cell cycle oscillations require active NIMA, because a nimA5 +bimA1 APC3 double mutant arrests in a mitotic state with very high p34cdc2 H1 kinase activity. NIMA protein instability during S phase and G2 was also found to be controlled by the APC/C. The bimA1 APC3mutation therefore first inactivates the APC/C but then allows its activation in a cyclic manner; these cycles depend on NIMA. We hypothesize that bimA APC3 could be part of a cell cycle clock mechanism that is reset after inactivation ofbimA1 APC3. ThebimA1 APC3 mutation may also make the APC/C resistant to activation by mitotic substrates of the APC/C, such as cyclin B, Polo, and NIMA, causing mitotic delay. Once these regulators accumulate, they activate the APC/C, and cells exit from mitosis, which then allows this cycle to repeat. The data indicate thatbimA APC3 regulates the APC/C in a NIMA-dependent manner.

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Goss, Kathleen Heppner, and Joanna Groden. "Biology of the Adenomatous Polyposis Coli Tumor Suppressor." Journal of Clinical Oncology 18, no. 9 (2000): 1967–79. http://dx.doi.org/10.1200/jco.2000.18.9.1967.

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ABSTRACT: The adenomatous polyposis coli (APC) gene was first identified as the gene mutated in an inherited syndrome of colon cancer predisposition known as familial adenomatous polyposis coli (FAP). Mutation of APC is also found in 80% of all colorectal adenomas and carcinomas and is one of the earliest mutations in colon cancer progression. Similar to other tumor suppressor genes, both APC alleles are inactivated by mutation in colon tumors, resulting in the loss of full-length protein in tumor cells. The functional significance of altering APC is the dysregulation of several physiologic processes that govern colonic epithelial cell homeostasis, which include cell cycle progression, migration, differentiation, and apoptosis. Roles for APC in some of these processes are in large part attributable to its ability to regulate cytosolic levels of the signaling molecule beta-catenin and to affect the transcriptional profile in cells. This article summarizes numerous genetic, biochemical, and cell biologic studies on the mechanisms of APC-mediated tumor suppression. Mouse models of FAP, in which the APC gene has been genetically inactivated, have been particularly useful in testing therapeutic and chemopreventive strategies. These data have significant implications for colorectal cancer treatment approaches as well as for understanding other disease genes and cancers of other tissue types.

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Cammarota, Simona, Martina Cargiolli, Paolo Andreozzi, et al. "Increasing trend in admission rates and costs for acute diverticulitis during 2005–2015: real-life data from the Abruzzo Region." Therapeutic Advances in Gastroenterology 11 (January 2018): 175628481879150. http://dx.doi.org/10.1177/1756284818791502.

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Background: Scarce data are available on the epidemiological trend of diverticulitis and its financial burden in Italy. The aim of this work was to explore a potential variation in the rate and costs of hospital admissions for uncomplicated and complicated diverticulitis over the last decade. Methods: We selected all hospitalizations for diverticulitis of residents in the Abruzzo Region, Italy between 2005 and 2015. Age-standardized hospitalization rates (HRs) per 100,000 inhabitants for overall, uncomplicated and complicated diverticulitis were calculated. A linear model on the log of the age-standardized rates was used to calculate annual percentage changes (APC). Costs were derived from the official DRG tariff. Results: From 2005 to 2015, the HR for acute diverticulitis increased from 38.9 to 45.2 per 100,000 inhabitants (APC + 1.9%). The HR for complicated diverticulitis increased from 5.9 to 13.3 (APC + 7.6%), whereas it remained stable for uncomplicated diverticulitis. The mean hospital cost was 1.8-times higher for complicated diverticulitis compared with that for uncomplicated disease and 3.5-times higher for patients with a surgery stay compared with that for patients with a medical stay. Conclusion: During the last decade, in the Abruzzo Region, the HRs for diverticulitis and their costs increased significantly, mainly due to disease complications. Further studies are needed to explore strategies to prevent complications and to realise cost-saving policies.

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Stoddart, Angela, Jianghong Wang, Chunmei Hu, et al. "Inhibition of Canonical WNT Signaling in the Bone Marrow Niche Prevents the Development of Disease in a Mouse MDS Model with Apc Haploinsufficiency." Blood 128, no. 22 (2016): 1129. http://dx.doi.org/10.1182/blood.v128.22.1129.1129.

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Abstract The myelodysplastic syndromes (MDS) include a spectrum of clonal hematopoietic stem cell (HSC) disorders that are characterized by ineffective hematopoiesis, peripheral cytopenia(s), morphologic dysplasia, and a variable propensity to transform to acute myeloid leukemia (AML). A del(5q) is the most common recurring cytogenetic abnormality in MDS, and is observed in 10-20% of primary MDS, and 40% of therapy-related MDS and AML. Our lab has had a long-standing interest in understanding how loss of function of tumor suppressor genes on 5q, such as APC, contributes to the pathogenesis of MDS and AML. Apc is a key negative regulator of the canonical β-catenin (Ctnnb1)/WNT signaling pathway.WNT signaling has been implicated in self-renewal of HSCs and the regulation of hematopoiesis, and the deregulation of WNT signaling is associated with the development of hematological malignancies. Recent data suggests that WNT activation in the bone marrow (BM) microenvironment or niche may also contribute to the development of AML. Kode et al. (Nature 506:240, 2014) showed that expression of activated β-catenin in osteoblast cells in the BM microenvironment leads to AML in mice. Thus, aberrant WNT signaling in HSCs and/or the microenvironment that supports them may contribute to malignant transformation. We previously used a conditional mouse model (Mx1-Cre+, Apc fl/+, referred to as Apcdel/+) and showed that haploinsufficiency of Apc leads to ineffective hematopoiesis (Blood 115:3481, 2010). Interestingly, haploinsufficient loss of Apc in the niche stromal cells, but not the hematopoietic progenitors, led to the development of MDS, characterized by a severe macrocytic anemia, dyserythropoiesis, megakaryocytic proliferation, and mild granulocytic dysplasia (Blood 123:228, 2014). In this study, we sought to determine whether haploinsufficient loss of Apc, mediates this disease through modulating WNT signaling, versus other Apc functions, and whether inhibition of WNT signaling could prevent the development of MDS in Apcdel/+mice. Here, we demonstrate thatsignaling through the canonical WNT pathway mediates the development of MDS in Apc haploinsufficient mice. Specifically, loss of one copy of Ctnnb1 is sufficient to prevent the development of MDS in Apcdel/+ mice. Compared to the median survival of Apc del/+ mice, which was 255 days, all Apc del/+, Ctnnb1 del/+ mice survived until the end of the study (~400 days) (P<0.001). In addition, we showed that altered canonical WNT signaling in the BM microenvironment is responsible for the disease. Using bone marrow transplantation of wild type BM cells, we showed that Apc del/+ recipients develop MDS and die of a fatal anemia by ~4 months of age. In contrast, Apc del/+, Ctnnb1 del/+ recipients survived on average 8-10 months longer (median survival 115 vs 413 days, P <0.0001). To determine if we could prevent the development of MDS, we treated mice with the FDA-approved antihelminth drug, Pyrvinium, an inhibitor of the WNT pathway via activation of casein kinase 1 alpha and β-catenin degradation. Apc del/+mice in the control DMSO-treated group developed disease with a median survival of 227 days; however, during this time period, none of the Pyrvinium-treated mice became moribund. The mice succumbed to MDS about 100 days after Pyrvinium treatment was suspended, indicating that the drug prevented the development of disease, and must be continuously administered. We also showed that Pyrvinium treatment does not have to be administered before anemia develops; however, the drug is more effective when it is started in animals that display mild-to-moderate anemia rather than severe anemia. These studies have important implications for the treatment of certain forms of MDS. Kode et al. (Nature 506:240, 2014) showed nuclear accumulation of β-catenin in osteoblasts from ~40% of MDS/AML patients, supporting the idea that activated WNT signaling in the BM microenvironment may contribute to the development of disease. Targeting the tumor microenvironment is now recognized as a promising approach to complement current therapies, and our data highlight a potential new strategy of targeting the WNT signaling pathway for treating some forms of MDS. Disclosures No relevant conflicts of interest to declare.

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Mao, Yushan, and Mingzhao Xing. "Recent incidences and differential trends of thyroid cancer in the USA." Endocrine-Related Cancer 23, no. 4 (2016): 313–22. http://dx.doi.org/10.1530/erc-15-0445.

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Abstract The incidence rate of thyroid cancer has been rising rapidly in recent decades; however, its trend remains unclear. To investigate this, we analyzed the database of the Surveillance, Epidemiology and End Results (SEER) 13, 1992–2012 in the USA, particularly focusing on conventional papillary thyroid cancer (CPTC) and follicular variant of PTC (FVPTC). Of the 75,992 thyroid cancers, 61.3% were CPTC and 25.7% were FVPTC, and their incidence rates (IRs) were significantly increased from 1992 to 2012 (P all < 0.001), with CPTC being 2.4 times of FVPTC (P < 0.001) and the overall average annual percent change (AAPC) of incidence being 6.3% in the former and 5.3% in the latter. IRs were increased in all thyroid cancers, albeit most dramatically in PTC, in virtually all ethnic/demographic groups in recent two decades; however, the incidence trends varied among different thyroid cancers, particularly differentiable between CPTC and FVPTC. For example, Joinpoint analyses revealed that the APC of CPTC before 1996 was 1.5% (P > 0.05), which jumped to 6.8% (P < 0.05) after 1996, whereas the APC of FVPTC before 2000 was 6.6% (P < 0.05), which dropped to 4.8% (P < 0.05) after 2000. IRs and incidence trends of PTC were uneven among different ethnic/demographic groups, as exemplified by the lower IRs of both PTC variants in the Black females than in non-Hispanic White females but higher AAPCs of incidence in the former than in the latter. Interestingly, the data also suggest that the rise in the IRs of PTC is becoming plateaued in the most recent 2 years. These novel observations are helpful in understanding the incidence and incidence trends of thyroid cancer.

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Ross, Julie A., Kimberly J. Johnson, James R. Cerhan, Cindy K. Blair, John T. Soler, and Phuong L. Nguyen. "Significant Recent Declines In Adult Leukemia Incidence Rates In the United States." Blood 116, no. 21 (2010): 873. http://dx.doi.org/10.1182/blood.v116.21.873.873.

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Abstract Abstract 873 Each year in the United States, approximately 45,000 individuals are newly diagnosed with leukemia and 22,000 will die of the disease. Due to this poor survival, leukemia ranks fifth in person years of life lost among specific cancers. Little is known about causes, although exposure to solvents, radiation, pesticides and, to a modest extent, cigarette smoke has been implicated for some subtypes. The last comprehensive report of leukemia trends covered the period 1973–1998 [Xie Y et al, Cancer 2003]. Evaluation of recent leukemia incidence trends could provide important new etiologic insights. Using Surveillance, Epidemiology and End Results (SEER) Program data, we analyzed leukemia incidence trends in U.S. adults (≥ 20 years of age) by age, leukemia subtype (acute myeloid (AML), acute lymphoid (ALL), chronic myeloid (CML), chronic lymphoid (CLL)) sex, race, and ethnicity for the period 1987–2007. Frequencies, age-adjusted incidence rates (IR, per million), and trends were calculated along with annual percent change (APC) and corresponding 95% confidence intervals (CI). Joinpoint analyses were used to detect any significant directional changes in IRs over the period. Of 43,970 newly diagnosed cases identified, IRs increased with age and were consistently higher in males than females for all four subtypes. The highest IRs occurred for CLL (54.4), followed by AML (38.3), CML (20.6) and ALL (7.0). With regard to trends, IRs for CLL (APC -0.5; CI: -0.9, -0.1) and CML (APC -1.2; CI: -1.6, -0.8) declined over the time period; declines were observed in males and females, and by race and ethnicity. Male(M):Female(F) IR ratios remained relatively constant at approximately 2.0 and 1.7, respectively. For ALL, IRs decreased in males (APC -0.9; CI: -1.9, 0.2) but slightly increased in females (APC 0.4; CI: -1.0, 1.7), which was most notable in Hispanics (APC 4.0; CI: 1.2, 6.8). In contrast to CML and CLL, the overall M:F rate ratio for ALL decreased, although it did not reach statistical significance (p=0.08). For AML, IRs increased significantly for males (APC 1.0; CI: 0.3,1.6) and females (APC 1.7; CI: 0.7, 2.7) from 1987–2000 and 1987–2001, respectively. However, since then, AML IRs for males have been significantly decreasing by 4.2% per year (CI: -6.4, -2.1), while IRs for females have been decreasing by 1.6% per year (CI: -4.1, 0.9). Across the entire time period 1987–2007, there was a statistically significant negative trend (p=0.002) in the M:F IR ratio for AML. Decreasing IRs across many leukemias since 1987 are unlikely to reflect changes in screening or diagnostic coding practices. Instead, these observations may reflect temporal changes in etiologically relevant environmental exposures. Of note, the prevalence of cigarette smoking in the population has decreased and occupational safety practices (e.g., reducing solvent/radiation/pesticide exposure) have improved over the last several decades, which could contribute to the gradual decreases in some IRs observed. In contrast, the rapid and significant decrease noted for AML since 2000, especially following a significant increase, was striking and deserved additional scrutiny. We further consulted with our cancer registry colleagues to determine whether the introduction of myelodysplastic syndrome (MDS) as a new malignancy in SEER in 2001 could be influencing recent AML trends given the (apparently) coincidental overlap in time periods. Of note, approximately one third of MDS patients subsequently develop AML. We learned that AML following an MDS diagnosis from 2001–2009 was not reportable to SEER and therefore not counted. We are not aware that this has been documented in the literature. However, beginning for 2010 diagnoses, SEER changed this practice such that AML following MDS will be captured as a second malignancy. Based on these changes in AML surveillance, it will especially be important to monitor future trends for this malignancy. Overall, this study demonstrates the value of in-depth analyses of SEER cancer IRs and trends; analyses may reveal patterns of clinical and/or etiological importance, or, in the instance of AML, unpublished coding rule changes. Disclosures: No relevant conflicts of interest to declare.

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Rusbuldt, Joshua J., Andressa A. Smith, Sriram Balasubramanian, Gary Borzillo, Amy J. Johnson, and Diana Alvarez Arias. "JNJ-64457107, a CD40 Agonist, Induces Cell Death in BCL6hiIRF4neg GCB Subtype of DLBCL." Blood 132, Supplement 1 (2018): 1674. http://dx.doi.org/10.1182/blood-2018-99-114622.

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Abstract CD40 is a member of the TNF receptor family that is expressed in multiple tumor types and normal cells including antigen presenting cells (APC), endothelium and platelets. CD40-CD40L signaling is one of the pivotal mechanisms essential for robust antigen presentation and adaptive immunity. JNJ-64457107 (JNJ-107) is an anti-CD40 IgG1 agonistic antibody that is currently in a Phase 1 clinical trial (NCT02829099). JNJ-107/ADC-1013 induced significant anti-tumor activity and immunological memory (Mangsbo 2015). It was also reported that a CD40 agonist, SGN-40, induced direct cytotoxicity in diffuse large B cell lymphoma (DLBCL) cell lines (Burlington 2011), and clinical responses have been noted in this indication (Advani 2009). However, not all DLBCL patients and DLBCL cell lines respond to SGN-40. Thus, a patient selection strategy in B cell malignancies may be beneficial. Here, we investigated the mechanism of action and potential biomarkers of response to JNJ-107 in DLBCL. Here, we show that JNJ-107 induced dose-dependent APC activation measured by upregulation of co-stimulatory molecules CD86, CD54, HLA-DR and CD23 on peripheral B cells in ex vivo whole blood and in vitro generated dendritic cells by flow cytometry. The highest APC activation was at 0.1-5 µg/ml of JNJ-107. We also found that JNJ-107 induced cell death of CD40 positive DLBCL cell lines representing both, germinal center B-cell (GCB) and activated B-cell (ABC) subtypes at similar doses. Cell death was measured by the Cell Titer-Glo assay and confirmed by staining with PI/AnnexinV. JNJ-107 at 1 µg/ml induced cell death (in 30-90% of cells) in 11/20 DLBCL cell lines (called "sensitive") after 4 days of treatment, with 2 GCB lines (BJAB and SU-DHL4) showing >90% cell death. No DLBCL cell line proliferation was observed in response to JNJ-107. CD40 signals through the NF-kB pathway in DLBCL. We investigated, if basal expression of NF-kB signaling components predicts responses to JNJ-107. First, we assessed activation of the NF-kB pathway in DLBCL lines by Western blot before and after treatment with JNJ-107. We used p65 and p52 as markers of canonical and non-canonical NF-kB activation, respectively. We found that JNJ-107 predominantly activated non-canonical NF-kB signaling in DLBCL cell lines by inducing p100 cleavage and release of p52 (Figure 1). A lower rate of p52 induction was observed in JNJ-107 "sensitive" lines that had constitutive expression of p52 (Pfeiffer, OCI-Ly7). Thus, we did not observe strong correlation between p52 induction and cell death in response to JNJ-107. BCL6 and IRF4 are markers of cell of origin in DLBCL. BCL6 and IRF4 are constitutively expressed in GCB and ABC subtypes, respectively. Interestingly, "sensitive" GCB lines had higher BCL6 expression than resistant lines. BCL6 protein was rapidly degraded (within 16h) in "sensitive" GCB DLBCL lines stimulated with JNJ-107. BCL6 is a transcriptional repressor that is regulated by many factors including IRF4. IRF4 is induced downstream of CD40, and directly represses BCL6 expression by binding to its promoter (Saito 2007). Consistent with constitutive activation of NF-kB, ABC DLBCL lines constitutively expressed IRF4. Surprisingly, several GCB lines also constitutively expressed IRF4 and were unable to further upregulate IRF4 in response to JNJ-107. The latter lines showed a lower degree of cell death in response to JNJ-107 compared to lines negative for IRF4 expression (except Pfeiffer). In summary, APC activation in whole blood, direct cytotoxicity and non-canonical NF-kB activation in DLBCL cell lines were seen with CD40 agonist, JNJ-107. GCB cell lines with high BCL6 expression and negative for IRF4 (BCL6hiIRF4neg) were more sensitive to JNJ-107 induced cell death. Based on these findings, GCB DLBCL patients with functional CD40 signaling in the tumor cells (BCL6hiIRF4neg phenotype) may show enhanced anti-tumor responses. Figure 1. JNJ-107 potently induces non-canonical NF-kB signaling in DLBCL cell lines. DLBCL lines were treated with 0.1 µg/ml JNJ-107 for 15 min, then 5 µg/ml cross-linker, IgG F(ab')2 for 16h. p65 and p52 fold induction was determined by Western blot of whole lysates. Representative data of 2 independent experiments are shown. Figure 1. Figure 1. Disclosures Rusbuldt: Janssen R&D: Employment. Smith:Janssen R&D: Employment. Balasubramanian:Janssen Research & Development: Employment, Equity Ownership. Borzillo:Janssen R&D: Employment. Alvarez Arias:Janssen R&D: Employment.

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Journal articles on the topic 'AVL/APC data'

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