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Pinto-Lopes, Pedro, Francisco Adao Fonseca, Roberto Silva, Pedro von Hafe, and Elsa Fonseca. "Indolent systemic mastocytosis limited to the bone: a case report and review of the literature." Sao Paulo Medical Journal 131, no. 3 (2013): 198–204. http://dx.doi.org/10.1590/1516-3180.2013.1313460.
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CONTEXT Systemic mastocytosis is defined as a clonal disorder of mast cells and their precursor cells and is currently classified as a myeloproliferative neoplasm. Its clinical course has a wide spectrum, ranging from indolent disease, with normal life expectancy, to highly aggressive disease, associated with multisystemic involvement and poor overall survival. The aim of this study was to report a case of indolent systemic mastocytosis, focusing on the diagnostic challenges, with a review of the literature. CASE REPORT A 79-year-old Caucasian woman with osteoporosis was evaluated at the Emergency Department because of complaints of low back pain. Before this, she had consulted an orthopedist and had undergone some imaging examinations, namely a bone scan that revealed a “superscan” pattern. Due to her pain complaints and these test results, the patient was admitted to the Department of Internal Medicine. After undergoing several analytical tests and some additional imaging examinations to rule out some important differential diagnoses, she then underwent bone marrow biopsy, which made it possible to identify indolent systemic mastocytosis. CONCLUSION Systemic mastocytosis is a rare entity that is difficult to diagnose. Its symptoms are often unspecific and frequently ignored. Skeletal changes may be the first and only manifestation of the disease and in some cases, like this one, the diagnosis is made only after histological examination. The key point for the diagnosis is to contemplate the possibility of systemic mastocytosis.
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Canberk, Sule. "Precursor and borderline lesions of the thyroid (indolent lesions of epithelial origin): from theory to practice." Gland Surgery 9, no. 5 (2020): 1724–34. http://dx.doi.org/10.21037/gs-20-429.
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Lussier, Tyler, Natalie Schoebe, and Sabine Mai. "Risk Stratification and Treatment in Smoldering Multiple Myeloma." Cells 11, no. 1 (2021): 130. http://dx.doi.org/10.3390/cells11010130.
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Smoldering multiple myeloma is a heterogeneous asymptomatic precursor to multiple myeloma. Since its identification in 1980, risk stratification models have been developed using two main stratification methods: clinical measurement-based and genetics-based. Clinical measurement models can be subdivided in three types: baseline measurements (performed at diagnosis), evolving measurements (performed over time during follow-up appointments), and imaging (for example, magnetic resonance imaging). Genetic approaches include gene expression profiling, DNA/RNA sequencing, and cytogenetics. It is important to accurately distinguish patients with indolent disease from those with aggressive disease, as clinical trials have shown that patients designated as “high-risk of progression” have improved outcomes when treated early. The risk stratification models, and clinical trials are discussed in this review.
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Marchegiani, Giovanni, Stefano Andrianello, Tommaso Pollini, et al. "Natural History of Intraductal Papillary Mucinous Neoplasm of the Pancreas Reappraisal of the Indolent Precursor of Pancreatic Cancer." Journal of the American College of Surgeons 227, no. 4 (2018): e37-e38. http://dx.doi.org/10.1016/j.jamcollsurg.2018.08.099.
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Purdy, Adam, Firas Ido, and Deborah Stahlnecker. "Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH): A Case of Indolent Pulmonary Nodules Diagnosed with Robotic-Assisted Navigational Bronchoscopy." Case Reports in Pulmonology 2021 (December 10, 2021): 1–4. http://dx.doi.org/10.1155/2021/6312296.
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Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is an atypical pulmonary disorder with limited understanding. Given the rare nature of this disease, it is essential to obtain adequate tissue pathology to confirm the diagnosis. This disease is mainly diagnosed in middle-aged, nonsmoking females, and it is now accepted as a precursor lesion to pulmonary carcinoid tumors. DIPNECH presents with characteristic radiographic and histologic findings, but its diagnosis, management, and prognosis are often underrecognized and poorly understood. Those with symptoms may present with shortness of breath, wheezing, and persistent cough and are often misdiagnosed with reactive airway disease. Pulmonary function testing may reveal airflow obstruction and air trapping. Imaging is characterized by multiple lung nodules, typically less than 5 mm in size, with a background mosaic attenuation on computed tomography imaging. Histologically, DIPNECH can be suspected based on the presence of hyperplastic neuroendocrine cells. DIPNECH is considered a precursor to invasive neuroendocrine tumor, and up to 50% of patients may have a well-differentiated neuroendocrine tumor at the time of presentation. Here, we present the case of a 46-year-old female with a history of ulcerative colitis on mesalamine who presented with a 6-month history of ongoing shortness of breath, chest tightness, wheezing, and cough. She was initially diagnosed with asthma before imaging later revealed as multiple pulmonary nodules with a diffuse mosaic pattern. Using robotic-assisted navigational bronchoscopy, she underwent sampling of a dominant 1.8 cm right middle lobe pulmonary nodule and pathology was consistent with low-grade neuroendocrine tumor.
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Garcia-Montero, Andres C., Maria Jara-Acevedo, Ivan Alvarez-Twose, et al. "KIT D816V Mutation Positive Bone Marrow Mesenchymal Stem Cells in Indolent Systemic Mastocytosis Are Associated with Disease Progression." Blood 126, no. 23 (2015): 4058. http://dx.doi.org/10.1182/blood.v126.23.4058.4058.
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Abstract PURPOSE: Multilineageinvolvement of bone marrow (BM) hematopoiesis by the somatic KIT D816V mutation is present in a subset of adult indolent systemic mastocytosis (ISM) patients in association with a poorer prognosis. Here we investigated the potential involvement of BM mesenchymal stem cells (MSC) from ISM patients by the KIT D816V mutation and its potential impact on disease progression and outcome. METHODS: The KIT D816V mutation was investigated in highly-purified BM MSC and other BM cell populations from 83 ISM patients followed for a median of 116 months. MC clonality was further evaluated in female patients by the pattern of inactivation of the X chromosome (XCIP). RESULTS: KIT D816V-mutated MSC were detected in 22/83 (27%) ISM patients. All MSC-mutated patients had multilineage KIT mutation (100% vs. 30%, p=0.0001) and they more frequently showed involvement of lymphoid plus myeloid BM cells (59% vs 22%; P =.03) and a polyclonal XCIP of the KIT- mutated BM MC (64% vs 0%; P =0.01) vs other multilineage ISM cases. Moreover, presence of KIT D816V-mutated MSC was associated with more advanced disease features of ISM, a greater rate of disease progression (50% vs 17%; P =.04) and a shorter progression-free survival at 10, 20 and 30 years (P ≤.003). CONCLUSION: Overall, these results support the notion that ISM patients with mutated MSC may have acquired the KIT mutation in a common pluripotent progenitor cell, prior to differentiation into MSC and hematopoietic precursor cells, before the X-chromosome inactivation process occurs. From a clinical point of view, acquisition of the KIT mutation in an earlier BM precursor cell confers a significantly greater risk for disease progression and a poorer outcome. Disclosures No relevant conflicts of interest to declare.
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Marchegiani, Giovanni, Stefano Andrianello, Tommaso Pollini, et al. "The natural history of intraductal papillary mucinous neoplasms of the pancreas: Reappraisal of the indolent precursor of pancreatic cancer." Pancreatology 18, no. 4 (2018): S2—S3. http://dx.doi.org/10.1016/j.pan.2018.05.011.
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Marchegiani, G., S. Andrianello, T. Pollini, et al. "The natural history of intraductal papillary mucinous neoplasm of the pancreas: Reappraisal of the indolent precursor of pancreatic cancer." HPB 20 (September 2018): S195. http://dx.doi.org/10.1016/j.hpb.2018.06.051.
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López, Cristina, Pablo Mozas, Armando López-Guillermo, and Sílvia Beà. "Molecular Pathogenesis of Follicular Lymphoma: From Genetics to Clinical Practice." Hemato 3, no. 4 (2022): 595–614. http://dx.doi.org/10.3390/hemato3040041.
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Follicular lymphoma (FL), a generally indolent disease that derives from germinal center (GC) B cells, represents around 20–25% of all new lymphomas diagnosed in Western countries. The characteristic t(14;18)(q32;q21) translocation that places the BCL2 oncogene under control of the immunoglobulin heavy-chain enhancer occurs in pro- or pre-B cells. However, additional secondary alterations are required for the development of overt FL, which mainly affects genes involved in epigenetic and transcriptional regulation, signaling and B cell differentiation, the BCR/NF-κB pathway, and proliferation/apoptosis. On the other hand, new insights into the FL pathogenesis suggest that FL lacking the BCL2 translocation might be a distinct biological entity with genomic features different from the classical FL. Although FL is considered an indolent disease, around 10–20% of cases eventually transform to an aggressive lymphoma, usually a diffuse large B cell lymphoma, generally by a divergent evolution process from a common altered precursor cell acquiring genomic alterations involved in the cell cycle and DNA damage responses. Importantly, FL tumor cells require interaction with the microenvironment, which sustains cell survival and proliferation. Although the use of rituximab has improved the outlook of most FL patients, further genomic studies are needed to identify those of high risk who can benefit from innovative therapies. This review provides an updated synopsis of FL, including the molecular and cellular pathogenesis, key events of transformation, and targeted treatments.
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Khanlari, Mahsa, and Jennifer R. Chapman. "Follicular lymphoma: updates for pathologists." Journal of Pathology and Translational Medicine 56, no. 1 (2022): 1–15. http://dx.doi.org/10.4132/jptm.2021.09.29.
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Follicular lymphoma (FL) is the most common indolent B-cell lymphoma and originates from germinal center B-cells (centrocytes and centroblasts) of the lymphoid follicle. Tumorigenesis is believed to initiate early in precursor B-cells in the bone marrow (BM) that acquire the t(14;18)(q32;q21). These cells later migrate to lymph nodes to continue their maturation through the germinal center reaction, at which time they acquire additional genetic and epigeneticabnormalities that promote lymphomagenesis. FLs are heterogeneous in terms of their clinicopathologic features. Most FLs are indolent and clinically characterized by peripheral lymphadenopathy with involvement of the spleen, BM, and peripheral blood in a substantial subset of patients, sometimes accompanied by constitutional symptoms and laboratory abnormalities. Diagnosis is established by the histopathologic identification of a B-cell proliferation usually distributed in an at least partially follicular pattern, typically, but not always, in a lymph node biopsy. The B-cell proliferation is biologically of germinal center cell origin, thus shows an expression of germinal center-associated antigens as detected by immunophenotyping. Although many cases of FLs are typical and histopathologic features are straightforward, the biologic and histopathologic variability of FL is wide, and an accurate diagnosis of FL over this disease spectrum requires knowledge of morphologic variants that can mimic other lymphomas, and rarely non-hematologic malignancies, clinically unique variants, and pitfalls in the interpretation of ancillary studies. The overall survival for most patients is prolonged, but relapses are frequent. The treatment landscape in FL now includes the application of immunotherapy and targeted therapy in addition to chemotherapy.
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Zhang, QiGuo, Jian Ou-Yang, and Rong-Fu Zhou. "Clinical and Experimental Features of Natural Killer Cell Leukemias in a Chinese Population: A Single Center Experience of 10 Years." Blood 118, no. 21 (2011): 4892. http://dx.doi.org/10.1182/blood.v118.21.4892.4892.
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Abstract Abstract 4892 Leukemia of natural killer (NK) cell lineage is rare which affects Asian population preferentially. Here 10 Chinese patients with NK cell leukemia were retrospectively evaluated. Among them 7 man and 3 women, the middle age was 47 years (range 22–57 years). Aggressive NK cell leukemias were finally diagnosed in 7 patients, myeloid/NK cell precursor acute leukemias in 2 patients and NK-CLPD in 1 patient. Pronounced extramedullary involvements (breast mass, multiple subcutaneous nodes and eye rectus muscle mass) were the main manifestation in 2 myeloid/NK cell precursor acute leukemias and 1 aggressive NK-cell leukemia. Clonal cytogenetic abnormality (46, XX, 16P-) was only found in 1 myeloid/NK cell precursor acute leukemia patient. Epstein-Barr virus test was performed in 8 patients and 3 were Positive (all were aggressive NK-cell leukemias). The overall survival of 4 cases of aggressive NK-cell leukemias combined with hematophagocytic syndrome were less than 1.3 months. During following up, 8 patients died of disease, 1 NK-CLPD patient and 1 aggressive NK-cell leukemia patient treated by allo-BMT were still alive. The former NK-CLPD, who was in indolent course, survived 60+ months. The later patient was first diagnosed as NK-CLPD but with lymphoadenopathy and splenomegaly, the metabolic activity of spleen by F-18 FDG uptake was in normal range, lymph node pathology showed reactive change and PB EBV-DNA copy was negative, later hematophagocytic syndrome occurred and EBV-DNA copy became positive. The lymph node pathology were reexamined by FISH method and scattered EBV positive cells were found, so the exact diagnosis from beginning should be occult aggressive NK cell leukemia, soon matched sibling donor BMT was performed and the patient got complete remission and the EBV-DNA copy became negative and lived well for 10+ months. Natural killer cell neoplasms are rare and most in aggressive clinical course, novel therapeutic regimens including allogeneic bone marrow transplantation should be investigated to improve outcome of this disease. Disclosures: No relevant conflicts of interest to declare.
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Oben, Bénedith, Guy Froyen, Kylee H. Maclachlan, et al. "Whole-Genome Sequencing Reveals Evidence of Two Biologically and Clinically Distinct Entities: Progressive Versus Stable Myeloma Precursor Disease." Blood 136, Supplement 1 (2020): 47–48. http://dx.doi.org/10.1182/blood-2020-136403.
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Introduction Multiple myeloma (MM) is consistently preceded by an asymptomatic expansion of clonal plasma cells, clinically recognized as monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM). Here, we present the first comprehensive whole-genome sequencing (WGS) analysis of patients with MGUS and SMM. Methods To characterize the genomic landscape of myeloma precursor disease (i.e. SMM and MGUS) we performed WGS of CD138-positive bone marrow mononuclear samples from 32 patients with MGUS (N=18) and SMM (N=14), respectively. For cases with low cellularity resulting in low amounts of extracted DNA (N=15), we used the low-input enzymatic fragmentation-based library preparation method (Lee-Six et al, Nature 2019). Myeloma precursor disease samples were compared with 80 WGS of patients with MM. All WGSs (N=112) were investigated using computational tools available at the Wellcome Sanger Institute. Results After a median follow up of 29 months (range: 2-177), 17 (53%) patients with myeloma precursor disease progressed to MM (13 SMM and 4 MGUS). To interrogate the genomic differences between progressive versus stable myeloma precursor disease we first characterized the single base substitution (SBS) signature landscape. Across the entire cohort of plasma cell disorders, all main MM mutational signatures were identified: aging (SBS1 and SBS5), AID (SBS9), SBS8, SBS18, and APOBEC (SBS2 and SBS13). Interestingly, only 2/15 (13%) stable myeloma precursor disease cases showed evidence of APOBEC activity, while 14/17 (82%) and 68/80 (85%) patients with progressive myeloma precursor disease (p=0.0058) and MM (p=0.004), respectively, had APOBEC mutational activity. The two stable cases with detectable APOBEC were characterized by a high APOBEC3A:3B ratio, a feature which defines a group of MAF-translocated MM patients whose pathogenesis is characterized by intense and early APOBEC activity (Rustad et al Nat Comm 2020) and is distinct from the canonical ~1:1 APOBEC3A:3B mutational activity observed in most cases. When exploring the cytogenetic landscape, no differences were found between progressive myeloma precursor disease and MM cases. Compared to progressors and to MM, patients with stable myeloma precursor disease were characterized by a significantly lower prevalence of known recurrent MM aneuploidies (i.e. gain1q, del6q, del8p, gain 8q24, del16q) (p<0.001). This observation was validated using SNP array copy number data from 78 and 161 stable myeloma precursor disease and MM patients, respectively. To further characterize differences between progressive versus stable myeloma precursor disease, we leveraged the comprehensive WGS resolution to explore the distribution and prevalence of structural variants (SV). Interestingly, stable cases were characterized by low prevalence of SV, SV hotspots, and complex events, in particular chromothripsis and templated insertions (both p<0.01). In contrast, progressors showed a genome wide distribution and high prevalence of SV and complex events similar to the one observed in MM. To rule out that the absence of key WGS-MM defining events among stable cases would reflect a sample collection time bias, we leveraged our recently developed molecular-clock approach (Rustad et al. Nat Comm 2020). Notably, this approach is based on pre- and post-chromosomal gain SBS5 and SBS1 mutational burden, designed to estimate the time of cancer initiation. Stable myeloma precursor disease showed a significantly different temporal pattern, where multi-gain events were acquired later in life compared to progressive myeloma precursor disease and MM cases. Conclusions In summary, we were able to comprehensively interrogate for the first time the whole genome landscape of myeloma precursor disease. We provide novel evidence of two biologically and clinically distinct entities: (1) progressive myeloma precursor disease, which represents a clonal entity where most of the genomic drivers have been already acquired, conferring an extremely high risk of progression to MM; and (2) stable myeloma precursor disease, which does not harbor most of the key genomic MM hallmarks and follows an indolent clinical outcome. Disclosures Hultcrantz: Intellisphere LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding; GSK: Research Funding. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Physicians Education Resource: Consultancy; Seattle Genetics: Consultancy; Takeda: Consultancy; EUSA Pharma: Consultancy; National Cancer Institute: Research Funding; AbbVie: Consultancy. Landgren:Pfizer: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Juno: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Merck: Other; Seattle Genetics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Binding Site: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Merck: Other; Seattle Genetics: Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Karyopharma: Research Funding; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Bolli:Celgene: Honoraria; Janssen: Honoraria.
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Corinaldesi, Giorgio, and Christian Corinaldesi. "Myelodisplastic Syndrome: Is It Associated or Is It a Precursor of Myeloid Malignancies?." Blood 110, no. 11 (2007): 4592. http://dx.doi.org/10.1182/blood.v110.11.4592.4592.
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Abstract Myelodisplastic syndrome (MDS) is a clonal haematopoietic stem cells disorder considered a pre-leukemic disease (about 30% of MDS turn into acute myeloid leukaemia (AML)) which is frequently associated with cytogenetic abnormalities and chromosomal instability: monosomy 7 or 7q - syndrome, 5q- syndrome, trisomy 8, inv(16), t (8;21), t (15;17), t (12;21), t (9;11), or sub microscopic DNA mutation of gene such as RAS, p53, FLT3, HSPA9, FMS and refractory cytopenias, with dysmyelopoiesis and increased apoptosis. We have identified 15 people aged between 54/67 years with MDS and we have examined their clinical presentation and their associated disorders. RA: refractory anaemia (7 patients) RARS: refractory anaemia with ringed sideroblasts (1 patient) 5q-syndrome (1 patient) RAEB refractory anaemia with excess blast: type 1 (5–10%) (3 patients); type 2 (11–20%) (1 patient) E) RAEB-T refractory anaemia in transformation (1 patient) F) CMML chronic myelomonocytic leukemia (1 patient) The disease is characterized by chronic tiredness, headache, shortness of breath, increased susceptibility to infection especially in the lung with a prolonged fever, easy bruising, nosebleeds, pinpoint red spots, bleeding, splenomegaly, hepatomegaly, abdominal distress and pain are also common. VEGFR-1 and VEGFR-2 are strongly expressed in megakaryocytes, HLA-DR2 and HLA-DR15 are higher, immune dysfunction in MDS increases activated cytotoxic T-cells with higher percentage of CD8+CD28-, CD8+CD28- CD57+ with an increased level of CD4, and Fas ligand/Apo-1 (CD95). The RA, RARS, 5q-syndrome are more indolent disease with a lower rate of progression to AML and a prolonged clinical course; the RAEB, RAEB-T are slightly more advanced with a short course; in the CMML the progression is faster and it is frequently associated with the secondary chromosomal perturbation t(5;12), (q33;p13), or with the loss of specific portion 3p-, 7q- (7q22-7q33-). The goals of the therapy are to control symptoms and to decrease the progression to myelogenous leukaemia; our results show that a low intensity treatment in the low and intermediate groups with 5-azacitidine 75 mg/m2/day produces a high rate of response (72%, of which: complete remission: 18%, partial remission: 34%, improved: 20%), relapse 24%, disease-free survival at 3 years of 64%; with a low incidence of side effects (nausea 68%, vomiting 60%, chest pain 28%); on the other hand in the high risk group the 5-azacitidine with gentuzumab reverted to normal about 90% of the patients (complete remission: 6%, partial remission: 28%, improved: 56%), disease free survival at 3 years 52%, relapse 48%; however, the only curative treatment is stem cells transplantation from a tissue matching donor. Finally, it is very important to provide a supportive care with erythropoietin, G-CSF or GM-CSF, red cells transfusions, administration of broad-spectrum antibodies mostly for controlling symptoms, but also for preventing or treating complications.
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Ivry, Sam L., Giselle M. Knudsen, Francesco Caiazza, et al. "The lysosomal aminopeptidase tripeptidyl peptidase 1 displays increased activity in malignant pancreatic cysts." Biological Chemistry 400, no. 12 (2019): 1629–38. http://dx.doi.org/10.1515/hsz-2019-0103.
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Abstract Incidental detection of pancreatic cysts has increased dramatically over the last decade, but risk stratification and clinical management remain a challenge. Mucinous cysts are precursor lesions to pancreatic cancer, however, the majority are indolent. Current diagnostics cannot identify mucinous cysts that harbor cancer or reliably differentiate these lesions from nonmucinous cysts, which present minimal risk of malignant progression. We previously determined that activity of two aspartyl proteases was increased in mucinous cysts. Using a global protease activity profiling technology, termed multiplex substrate profiling by mass spectrometry (MSP-MS), we now show that aminopeptidase activity is also elevated in mucinous cysts. The serine aminopeptidase, tripeptidyl peptidase 1 (TPP1), was detected by proteomic analysis of cyst fluid samples and quantitation using targeted MS demonstrated that this protease was significantly more abundant in mucinous cysts. In a cohort of 110 cyst fluid samples, TPP1 activity was increased more than 3-fold in mucinous cysts relative to nonmucinous cysts. Moreover, TPP1 activity is primarily associated with mucinous cysts that harbor high-grade dysplasia or invasive carcinoma. Although only 59% accurate for differentiating these lesions, measurement of TPP1 activity may improve early detection and treatment of high-risk pancreatic cysts when used in conjunction with other promising biomarkers.
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Sarkozy, Clementine, Shaocheng Wu, Katsuyoshi Takata, et al. "Abstract A19: Integrated single cell analysis reveals co-evolution of malignant B cells and the tumor microenvironment in transformed follicular lymphoma." Blood Cancer Discovery 3, no. 5_Supplement (2022): A19. http://dx.doi.org/10.1158/2643-3249.lymphoma22-a19.
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Abstract Introduction: Histological transformation from follicular lymphoma (FL) to aggressive B-cell lymphoma (tFL) is a disease course altering event linked to poor prognosis for affected patients. From a biological point of view, it is paradigmatic of disease dynamics with distinct clinical stages that project onto genetically and phenotypically divergent states. Aim: By applying a series of high-dimensional single cell (sc)RNA and DNA profiling techniques, we aimed to characterize the clonal and phenotypic evolution of tumor B cells and to reveal dynamic interactions with components of the tumor microenvironment (TME) during transformation. Methods: We included 11 tFL patients with paired FL (tFL-FL) and DLBCL (tFL-DLBCL) timepoint biopsies, and 11 indolent FL controls (with > 6y of follow-up without evidence of progression or transformation). Single cell whole transcriptome (scWTS) and BCR sequencing was performed for all samples and single cell whole genome sequencing (scWGS) for transformation pairs. Results: In each transformation pair, BCR sequencing confirmed the clonal relationship between FL and DLBCL timepoints. Clustering of scRNA data from each pair showed an inverse correlation between transcriptional similarity and time between the two biopsies. Some tFL-FL cells could always be found within the tFL-DLBCL clusters. Therefore, we labeled these cells as presumed “early-DLBCL cells”. Phylogenetic analysis using scWGS data showed distinct FL and DLBCL clones, and “mixed-clones” composed of cells from both timepoints in most pairs. FL cells in DLBCL clones were favored to represent precursor cells of transformation. DLBCL cells in FL clones likely represent residual FL cells after transformation, and could be found in the majority of the pairs. Divergent evolution from FL to DLBCL with specific copy number abnormalities unique to each timepoint was the most common mode of evolution during transformation, and only one pair showed linear evolution. Integrative analysis of scRNA and scDNA data highlighted that samples with the fewest genomic changes showed the least transcriptomic changes and vice versa. Differential expression and gene set enrichment analysis of malignant cells identified “MYC targets V1“ as the main pathway enriched in tFL-DLBCL cells in comparison to tFL-FL cells. Cells from the indolent control FL cases had a significantly lower MYC score than cells from pre-transformed FL. In parallel to the insights into tumor cell evolution, scRNAseq analysis also revealed significant shifts in TME composition, from T cells with a TFH and central memory phenotype in tFL-FL samples, to cells with an exhausted cytotoxic phenotype in tFL-DLBCL samples. Conclusion: Applying high-dimensional scRNA and DNA profiling techniques we identified precursor cell populations of transformation at the genomic and phenotypic level and linked genomic and phenotypic evolution with shifting TME composition in a comprehensive disease evolution model of transformation. Citation Format: Clementine Sarkozy, Shaocheng Wu, Katsuyoshi Takata, Tomohiro Aoki, Susana B Neriah, Katy Milne, Brad Nelson, Andrew Weng, David Scott, Jeffrey W Craig, Christian Steidl, Andrew Roth. Integrated single cell analysis reveals co-evolution of malignant B cells and the tumor microenvironment in transformed follicular lymphoma [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A19.
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Chowdhury, Rajdip, and Abraham Mendoza. "N-Hydroxyphthalimidyl diazoacetate (NHPI-DA): a modular methylene linchpin for the C–H alkylation of indoles." Chemical Communications 57, no. 37 (2021): 4532–35. http://dx.doi.org/10.1039/d1cc01026c.
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The insertion of conventional diazocompounds into indoles are still limited by the custom carbene precursors, catalysts and manipulation of the products required. Herein, we address these shortcomings with a redox-active carbene precursor (NHPI-DA).
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Brock, Ethan J., Ryan M. Jackson, Julie L. Boerner, et al. "Sprouty4 negatively regulates ERK/MAPK signaling and the transition from in situ to invasive breast ductal carcinoma." PLOS ONE 16, no. 5 (2021): e0252314. http://dx.doi.org/10.1371/journal.pone.0252314.
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Breast ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal carcinoma (IDC). It is still unclear which DCIS will become invasive and which will remain indolent. Patients often receive surgery and radiotherapy, but this early intervention has not produced substantial decreases in late-stage disease. Sprouty proteins are important regulators of ERK/MAPK signaling and have been studied in various cancers. We hypothesized that Sprouty4 is an endogenous inhibitor of ERK/MAPK signaling and that its loss/reduced expression is a mechanism by which DCIS lesions progress toward IDC, including triple-negative disease. Using immunohistochemistry, we found reduced Sprouty4 expression in IDC patient samples compared to DCIS, and that ERK/MAPK phosphorylation had an inverse relationship to Sprouty4 expression. These observations were reproduced using a 3D culture model of disease progression. Knockdown of Sprouty4 in MCF10.DCIS cells increased ERK/MAPK phosphorylation as well as their invasive capability, while overexpression of Sprouty4 in MCF10.CA1d IDC cells reduced ERK/MAPK phosphorylation, invasion, and the aggressive phenotype exhibited by these cells. Immunofluorescence experiments revealed reorganization of the actin cytoskeleton and relocation of E-cadherin back to the cell surface, consistent with the restoration of adherens junctions. To determine whether these effects were due to changes in ERK/MAPK signaling, MEK1/2 was pharmacologically inhibited in IDC cells. Nanomolar concentrations of MEK162/binimetinib restored an epithelial-like phenotype and reduced pericellular proteolysis, similar to Sprouty4 overexpression. From these data we conclude that Sprouty4 acts to control ERK/MAPK signaling in DCIS, thus limiting the progression of these premalignant breast lesions.
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Bahrami, Armita, Jae Y. Ro, and Alberto G. Ayala. "An Overview of Testicular Germ Cell Tumors." Archives of Pathology & Laboratory Medicine 131, no. 8 (2007): 1267–80. http://dx.doi.org/10.5858/2007-131-1267-aootgc.
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Abstract Context.—More than 90% of testicular neoplasms originate from germ cells. Testicular germ cell tumors (GCTs) are a heterogeneous group of neoplasms with diverse histopathology and clinical behavior. Objective.—To help the readers distinguish various subtypes of GCTs, to highlight the clinical manifestations and pathologic features of these tumors, and to review several newly developed immunohistochemical markers for GCTs. Data Sources.—Review of the pertinent literature and our experience. Conclusions.—The etiology of GCTs is largely unknown. Cytogenetic studies suggest a different pathogenesis for each group of infantile/prepubertal GCTs, postpubertal GCTs, and spermatocytic seminoma. Unclassified intratubular germ cell neoplasia is the precursor of all GCTs, excluding spermatocytic seminoma and infantile/prepubertal GCTs. Seminoma, the most common GCT in adults, does not occur before 5 years of age. Spermatocytic seminoma, a tumor of elderly men, typically has an indolent clinical behavior, but rarely it undergoes sarcomatous transformation associated with an aggressive behavior. Embryonal carcinoma is the most common component in mixed GCTs. Eighty percent or more of embryonal carcinoma component and vascular invasion are recognized predictors of occult metastasis for clinical stage I mixed GCTs. Most patients with prepubertal yolk sac tumor, the most common pediatric GCT, have stage I disease at presentation. Most choriocarcinomas present with metastatic symptoms because of the propensity for rapid hematogenous dissemination. Teratomas in children regardless of maturity and dermoid cysts in adults are benign; in contrast, teratomas in adults have a malignant behavior. With appropriate therapy, the majority of testicular GCTs are curable.
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Gay, G., R. Rouillon, J. Bernillon, and J. Favre-Bonvin. "IAA biosynthesis by the ectomycorrhizal fungus Hebeloma hiemale as affected by different precursors." Canadian Journal of Botany 67, no. 8 (1989): 2235–39. http://dx.doi.org/10.1139/b89-285.
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The effect of different precursors, aromatic amino acids, or intermediates of the shikimate pathway (pathway for aromatic amino acids biosynthesis), on indole-3-acetic acid (IAA) synthesis by the ectomycorrhizal fungus Hebeloma hiemale was studied. This fungus did not release detectable amounts of IAA when cultivated on a medium containing no precursor or supplemented with 1 mM phenylalanine, 1 mM tyrosine or 1 mM shikimic acid. IAA accumulation in culture filtrates was low (0.5 μmol per flask) when the medium was supplemented with 1 mM anthranilic acid. The fungus released 1.6 μmol of IAA when cultivated on a medium containing 1 mM indole and 6.9 μmol in the presence of 1 mM tryptophan. These results were confirmed by studying the ability of crude enzyme extracts to convert these precursors to IAA. Specific IAA synthesizing activity was of the same order when indole or tryptophan were used as precursors. The comparison of in vivo and in vitro activity of IAA synthesizing enzymes demonstrated that a need for tryptophan concentrations higher than 0.1 mM to obtain detectable IAA synthesis is due to the low ratio of tryptophan breakdown into IAA. The inability of H. hiemale to synthesize IAA in the absence of precursors or in the presence of shikimic acid may be ascribed to a very poor endogenous tryptophan accumulation in the hyphae due to feed back inhibition of the anthranilate synthetase by tryptophan. These results indicate that precursor availability in root exudates is probably one of the main limiting factors for IAA release by ectomycorrhizal fungi under symbiotic association. Key words: ectomycorrhizal fungus, Hebeloma, indole-3-acetic acid, tryptophan, indole, shikimate pathway.
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Abdel-Hay, Karim M., Tarek S. Belal, Younis Abiedalla, et al. "Gas Chromatography–Mass Spectrometry (GC–MS) and Gas Chromatography–Infrared (GC–IR) Analyses of the Chloro-1-n-pentyl-3-(1-naphthoyl)-Indoles: Regioisomeric Cannabinoids." Applied Spectroscopy 73, no. 4 (2018): 433–43. http://dx.doi.org/10.1177/0003702818809998.
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The analytical differentiation of the indole ring regioisomeric chloro-1- n-pentyl-3-(1-naphthoyl)-indoles is described in this report. The regioisomeric chloroindole precursor compounds, N- n-pentyl chloroindole synthetic intermediates, and the target chloro-substituted naphthoylindoles showed the equivalent gas chromatographic elution order based on the position of chlorine substitution on the indole ring. The regioisomeric chloro-1- n-pentyl-3-(1-naphthoyl)-indoles yield electron ionization mass spectra having equivalent major fragments resulting from cleavage of the groups attached to the central indole nucleus. Fragment ions occur at m/z 127 and 155 for the naphthyl and naphthoyl cations common to all indoles having the naphthoyl group substituted at the indole-3 position. Fragments resulting from the loss of the naphthoyl and/or n-pentyl groups from the molecular radical cation yield the cations at m/z 318, 304, 248, and 178. The characteristic (M–17)+ fragment ion at m/z 358 resulting from the loss of OH radical is significant in the mass spectra of all these compounds with 1-naphthoyl groups substituted at the indole-3 position. The vapor phase infrared spectra provide a number of characteristic absorption bands to identify the individual isomers.
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Dutta, Ankit K., Jean-Baptiste Alberge, Elizabeth D. Lightbody, et al. "Abstract 640: Genome sequencing of circulating multiple myeloma cells for minimally invasive molecular characterization of precursor disease pathology." Cancer Research 82, no. 12_Supplement (2022): 640. http://dx.doi.org/10.1158/1538-7445.am2022-640.
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Abstract Introduction: Multiple myeloma (MM) develops from indolent stages monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Precursor conditions are incidentally diagnosed and require invasive bone marrow (BM) biopsies for complete characterization, highlighting the urgent need for improved early detection methods. Minimally invasive blood biopsies to measure circulating multiple myeloma cells (CMMCs) as markers of MM disease development are a promising solution to this unmet need. Here, we present our novel method CatchTheFISH, for whole genome sequencing (WGS) of CMMCs that enables genomic profiling and WGS based cytogenetic analyses from enriched liquid biopsy samples. Application of WGS in a cohort of 20 patients, revealed CMMCs were of tumor origin and able to faithfully match BM sequencing results and detect 100% of clinically reported events. Methods: Peripheral blood from 110 SMM patients from the PCROWD observational study (Dana-Farber Cancer Institute IRB #14-174) was collected and processed on CellSearch system (Menarini Silicon Biosystems), with enrichment and enumeration of CMMCs based on CD138+38+CD45-19- immunophenotype. In 20 patients, CMMCs and white blood cells were sorted for library construction, quantification and WGS on Illumina NovaSeq6000. Mutation analyses were performed with the cancer genome analysis pipelines of the Broad Institute. Results: CMMCs were detected in 84% of SMM patients enrolled in the study, with a median count of 13 CMMCs (range 0 to 43836). We first demonstrated the concordance of WGS results obtained from CMMCs with BM. In 100% of patients tested with paired BM and CMMCs (n = 8), we observed full agreement in structural event calling between our samples and clinical reports, including translocations and CNAs (trisomies, tetrasomy, monosomy 13 and 1q gain/amplification). Next, we showed WGS of CMMCs provided increased diagnostic yield compared to BM biopsy for the detection of structural events and MM-associated driver mutations. In 7 patients (88%) we detected additional aberrations not found by FISH. Unknown translocation events of IGH-MYC and t(14;20) were distinguished in two patients. Additionally, our method enabled detection of MM driver mutations. Three patients (38%) were found to harbor RAS mutations (KRAS and NRAS) in BM samples, which were also validated in matched CMMCs. Finally, we assessed a validation cohort of 12 SMM patients with CMMCs only. WGS detected comprehensive mutation data across all scales including clinically relevant translocations, trisomies, CNAs and mutations. Conclusion: Our findings provide proof of principle that capture and genomic profiling of CMMCs could be a robust surrogate to BM biopsy, allowing minimally invasive detection and monitoring of disease, unlocking the clinical potential of liquid biopsies for MM diagnostics. Citation Format: Ankit K. Dutta, Jean-Baptiste Alberge, Elizabeth D. Lightbody, Romanos Sklavenitis-Pistofidis, Cody J. Boehner, Tarek H. Mouhieddine, Anna Cowan, Nang Kham Su, Erica M. Horowitz, Andrew Dunford, Chip Stewart, Ziao Lin, Laura Hevenor, Hadley Barr, Amanda Cao, Ornkleaw Zepp, Thai Bui, Steve Gross, Daniel Auclair, Gad Getz, Irene M. Ghobrial. Genome sequencing of circulating multiple myeloma cells for minimally invasive molecular characterization of precursor disease pathology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 640.
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Golub, Danielle, Peter C. Pan, Benjamin Liechty, et al. "PATH-41. POLYMORPHOUS LOW-GRADE NEUROEPITHELIAL TUMOR OF THE YOUNG WITH FGFR3-TACC3 FUSION MIMICKING HIGH-GRADE GLIOMA: CASE REPORT AND SERIES OF HIGH-GRADE CORRELATES." Neuro-Oncology 23, Supplement_6 (2021): vi124. http://dx.doi.org/10.1093/neuonc/noab196.493.
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Abstract BACKGROUND Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently-described entity that can occasionally histologically and molecularly mimic high-grade glioma. The histologic and molecular features that predict aggressive behavior in FGFR3-TACC3 altered tumors are unclear. CASES We present a rare case of an indolent neuroepithelial neoplasm in a 59-year-old female with imaging initially suggestive of high-grade glioma and analyze common molecular features between this case and a series of high-grade gliomas. After total resection, pathology of the case patient revealed predominantly low-grade cytomorphology, abundant microcalcifications, unusual neovascularization, and a low proliferation index. The lesion was diffusely CD34 immunoreactive and harbored both an FGFR3-TACC3 fusion and a TERT promoter mutation. Based on the overall histologic and molecular profile, a diagnosis of PLNTY was favored. The patient was thereafter observed without adjuvant therapy with no evidence of progression at 15-month follow-up. In contrast, a series of eight adult patients with glioblastomas harboring FGFR3-TACC3 fusions and correspondingly aggressive clinical courses are also presented. Common molecular findings included IDH-wildtype status, absence of 1p19q codeletion, and CDKN2A loss. TERT promoter mutations and lack of MGMT promoter methylation were also frequently observed. These patients demonstrated a median 15-month overall survival and a 6-month progression-free survival. CONCLUSIONS PLNTY is a rare low-grade entity that can display characteristics of high-grade glioma, particularly in adults. The potential for a unique entity mimicking PLNTY which may act as a precursor lesion for a more malignant phenotype should be considered in cases with FGFR3-TACC3 fusions and other high-grade features.
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Musilova, Katerina, Jan Devan, Katerina Cerna, et al. "miR-150 downregulation contributes to the high-grade transformation of follicular lymphoma by upregulating FOXP1 levels." Blood 132, no. 22 (2018): 2389–400. http://dx.doi.org/10.1182/blood-2018-06-855502.
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Follicular lymphoma (FL) is a common indolent B-cell malignancy with a variable clinical course. An unfavorable event in its course is histological transformation to a high-grade lymphoma, typically diffuse large B-cell lymphoma. Recent studies show that genetic aberrations of MYC or its overexpression are associated with FL transformation (tFL). However, the precise molecular mechanisms underlying tFL are unclear. Here we performed the first profiling of expression of microRNAs (miRNAs) in paired samples of FL and tFL and identified 5 miRNAs as being differentially expressed. We focused on one of these miRNAs, namely miR-150, which was uniformly downmodulated in all examined tFLs (∼3.5-fold), and observed that high levels of MYC are responsible for repressing miR-150 in tFL by binding in its upstream region. This MYC-mediated repression of miR-150 in B cells is not dependent on LIN28A/B proteins, which influence the maturation of miR-150 precursor (pri-miR-150) in myeloid cells. We also demonstrated that low miR-150 levels in tFL lead to upregulation of its target, namely FOXP1 protein, which is a known positive regulator of cell survival, as well as B-cell receptor and NF-κB signaling in malignant B cells. We revealed that low levels of miR-150 and high levels of its target, FOXP1, are associated with shorter overall survival in FL and suggest that miR-150 could serve as a good biomarker measurable in formalin-fixed paraffin-embedded tissue. Overall, our study demonstrates the role of the MYC/miR-150/FOXP1 axis in malignant B cells as a determinant of FL aggressiveness and its high-grade transformation.
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Kuckländer, Uwe, and Udo Bastian. "Darstellung und Oxidation von 2-(2,5-Dihydroxy-phenyl)-ethylamin-Derivaten, II / Synthesis and Oxidation of 2-(2,5-Dihydroxyphenyl)-ethylamine Derivatives, II." Zeitschrift für Naturforschung B 42, no. 12 (1987): 1567–77. http://dx.doi.org/10.1515/znb-1987-1214.
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Abstract2,5-Dihydroxyphenylethylamine derivatives 8a,b; 14; 19a,b and 25a,b,c are synthesized and oxidized to indole 9a, indolines 15 and 18a,b as well as 24a,b,c. Quantitative oxidation of hydroquinones yields the 2-(aminoethyl)quinones 30a as free base and 30d-f; 27a,b and the hydrochlorides 28a,b. Quinone 30a is reduced to indoline 29 and acetylated to 3-acylindole 32, transformed by heating to indole 23 and in acetic acid to the dimeric indole 31. 32 is synthesized unequivocally from 33 and 34. The course of the reaction is discussed and the formation of indolines is explained by cyclisation of a semiquinone precursor (43).
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Carr, Norman J., Theresa S. Emory, and Leslie H. Sobin. "Epithelial Neoplasms of the Appendix and Colorectum." Archives of Pathology & Laboratory Medicine 126, no. 7 (2002): 837–41. http://dx.doi.org/10.5858/2002-126-0837-enotaa.
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Abstract Context.—Carcinomas of the appendix are usually well-differentiated mucinous adenocarcinomas that tend to produce pseudomyxoma peritonei and do not show metastatic spread until late in the disease process. In contrast, adenocarcinomas of the colon and rectum rarely result in pseudomyxoma peritonei and frequently metastasize, even if mucinous and well differentiated. These differences in behavior may be reflected by differences at the molecular level. Objectives.—To examine adenocarcinomas and their precursor lesions (adenomas) of the appendix and colorectum and to determine whether differences exist in the numbers of proliferating and apoptotic cells or in expression of p53, bcl-2, and the standard form of CD44 (CD44s). Design.—Retrospective analysis of surgical specimens. Setting.—Multicenter study. Patients.—Individuals treated surgically for tumors of the appendix or colorectum. Interventions.—Sections were cut from formalin-fixed surgical specimens and immunohistochemical tests were performed for Ki-67 (as a marker of proliferating cells), M30 (as a marker of apoptotic cells), p53, CD44s, and bcl-2. Main Outcome Measures.—Expression of Ki-67, M30, p53, CD44s, and bcl-2 in tumor cells. Results.—The appendiceal adenomas showed significantly lower Ki-67 counts, p53 expression, and bcl-2 expression. When compared with adenocarcinomas of the colorectum in general (mucinous and nonmucinous), the appendiceal adenocarcinomas showed significantly lower Ki-67 counts, M30 counts, and CD44s expression. However, when the analysis was confined to well-differentiated mucinous adenocarcinomas, only the M30 count was significantly different. Conclusions.—The lower proliferative and apoptotic activity of appendiceal carcinomas and the lower CD44s expression are in keeping with their more indolent behavior compared with adenocarcinomas of the colorectum. However, when only the subset of well-differentiated mucinous adenocarcinomas was compared, only the apoptotic activity was different, suggesting that the other differences were related to the morphologic structure of the lesions.
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Cortese, Matthew J., Wei Wei, and Brian T. Hill. "Outcomes of Active Surveillance Versus Initial Treatment for Nodular Lymphocyte Predominant Hodgkin Lymphoma: A National Cancer Database (NCDB) Analysis of 2,480 Patients." Blood 136, Supplement 1 (2020): 29–30. http://dx.doi.org/10.1182/blood-2020-142828.
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Introduction Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) is a unique and clinically distinct subtype of Hodgkin lymphoma (HL), comprising approximately 5% of all HL cases with an annual incidence of about 1-2 cases per million. Compared with classical HL (cHL), NLPHL is more likely to present with limited stage and a more indolent clinical course. Despite these favorable traits, systemic chemoimmunotherapies and/or radiation are often used for initial treatment. Deaths directly from NLPHL are uncommon, with mortality in these patients often attributable to treatment-related toxicities or transformation to aggressive non-Hodgkin B-cell lymphomas. There is emerging evidence that NLPHL can be treated more conservatively. Active Surveillance (AS), a strategy by which initial treatment is deferred in favor of close observation, has been evaluated in single-institution retrospective studies spanning decades. Borchmannet alreported comparable overall survival (OS) for patients managed with AS versus upfront treatment (Blood, 2019). While encouraging, additional contemporary data are needed to determine if AS is a safe option for NLPHL patients, given advances in supportive care, addition of anti-CD20 therapies, improved radiation delivery, and better diagnostic methods. This retrospective National Cancer Database (NCDB) study evaluates the effect of initial treatment modality on overall survival in a contemporary population of patients with NLPHL to determine if initial AS has comparable OS when compared with initial treatment. Methods The National Cancer Database (NCDB) is a nationwide oncology outcomes database for more than 1500 accredited cancer programs in the United States. The NCDB was queried for all patients with the diagnosis of NLPHL, defined by histology code 9659. Filters for inclusion included year of diagnosis from 2010 to 2015, B-cell/pre-B/B-precursor histologic subtype, known treatment status, and with survival data available. Demographic, socioeconomic, treatment modality, and clinical factors such as stage and Charlson-Deyo comorbidity indices were summarized. Chi-square tests were used to correlate factors with treatment status. Kaplan-Meier methods were used to estimate overall survival, and log rank test was used to compare OS between patient groups. Cox proportional hazard model was used to associate patient characteristics with OS, and backwards elimination was used to identify the final Cox model, starting from all factors in univariate analysis. Results A total of 2,480 patients with NLPHL diagnosed between 2010 and 2015 were included. Of these, 553 patients were older than 60 years (22.3%), 1,616 were male (65%), and 2,110 had a Charlson-Deyo score of 0 (85%) while 370 had a score of ≥1 (15%). 1,627 had Stage I-II disease (65.6%) while 731 had Stage III-IV disease (29.5%). Overall, 2,330 patients were alive (94%) and 150 were deceased (6%), with a median follow-up of 36.8 months (range 0.1 to 94.3 months). Initial management options included: treatment (radiation, chemo/immunotherapy, and/or surgery), no treatment (e.g. palliative care only), or AS. 2,309 patients (93.1%) were initially treated (IT), 103 (4.15%) received no treatment (NT) and 68 patients (2.74%) underwent AS. OS by treatment strategy is shown in Figure 1. In univariate analysis, there was no OS difference between IT vs AS (HR 0.71; 95% CI 0.31-1.61, P=0.41) or NT vs. AS (HR 2.03; 95% CI 0.75-5.51; P= 0.16), but there was a significant difference between NT and IT (HR 2.87; 95% CI 1.56-5.32, P=0.0008). In the final Cox multivariate analysis, there was no significant difference between three treatment groups (overall P=0.10). Age >60, male gender, those with government insurance, Charlson-Deyo score ≥1, and Stage IV were all associated with decreased OS (Table 1). Conclusion In this large NCDB outcomes analysis of 2,480 NLPHL patients, those selected for AS had no difference in overall survival compared to patients who were initially treated. This lends support to emerging evidence that AS is a viable option for a subset newly diagnosed NLPHL patients, as is routine for indolent non-Hodgkin Lymphoma. Future study is needed to identify clinical features associated with a more indolent NLPHL phenotype that may be amendable to less intense initial management. Disclosures Hill: Karyopharm:Consultancy, Honoraria, Research Funding;Takeda:Research Funding;Celgene:Consultancy, Honoraria, Research Funding;BMS:Consultancy, Honoraria, Research Funding;Novartis:Consultancy, Honoraria;Kite, a Gilead Company:Consultancy, Honoraria, Research Funding;AstraZenica:Consultancy, Honoraria, Research Funding;Beigene:Consultancy, Honoraria, Research Funding;Pharmacyclics:Consultancy, Honoraria, Research Funding;Abbvie:Consultancy, Honoraria, Research Funding;Genentech:Consultancy, Honoraria, Research Funding.
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Golantsov, Nikita, Alexey Festa, Alexey Varlamov, and Leonid Voskressensky. "Revision of the Structure and Total Synthesis of Topsentin C." Synthesis 49, no. 11 (2017): 2562–74. http://dx.doi.org/10.1055/s-0036-1588731.
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An efficient synthetic approach to access (indol-3-yl)ethane-1,2-diamines with a protecting group at the indole N atom from readily available 3-(2-nitrovinyl)indoles is reported. This approach includes solvent-free conjugate addition of O-pivaloylhydroxylamines to 1-Boc-3-(2-nitrovinyl)indoles followed by mild reduction of the adducts. The obtained (indol-3-yl)ethane-1,2-diamines are convenient synthetic precursors for several classes of marine alkaloids. The first total synthesis of racemic topsentin C, a secondary metabolite from Hexadella sp., based on this approach is reported. The initially proposed structure for topsentin C has been revised.
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Ferri-Borgogno, Sammy, Sugata Barui, Amberly M. McGee, et al. "Paradoxical Role of AT-rich Interactive Domain 1A in Restraining Pancreatic Carcinogenesis." Cancers 12, no. 9 (2020): 2695. http://dx.doi.org/10.3390/cancers12092695.
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Background & Aims: ARID1A is postulated to be a tumor suppressor gene owing to loss-of-function mutations in human pancreatic ductal adenocarcinomas (PDAC). However, its role in pancreatic pathogenesis is not clear despite recent studies using genetically engineered mouse (GEM) models. We aimed at further understanding of its direct functional role in PDAC, using a combination of GEM model and PDAC cell lines. Methods: Pancreas-specific mutant Arid1a-driven GEM model (Ptf1a-Cre; KrasG12D; Arid1af/f or “KAC”) was generated by crossing Ptf1a-Cre; KrasG12D (“KC”) mice with Arid1af/f mice and characterized histologically with timed necropsies. Arid1a was also deleted using CRISPR-Cas9 system in established human and murine PDAC cell lines to study the immediate effects of Arid1a loss in isogenic models. Cell lines with or without Arid1a expression were developed from respective autochthonous PDAC GEM models, compared functionally using various culture assays, and subjected to RNA-sequencing for comparative gene expression analysis. DNA damage repair was analyzed in cultured cells using immunofluorescence and COMET assay. Results: Retention of Arid1a is critical for early progression of mutant Kras-driven pre-malignant lesions into PDAC, as evident by lower Ki-67 and higher apoptosis staining in “KAC” as compared to “KC” mice. Enforced deletion of Arid1a in established PDAC cell lines caused suppression of cellular growth and migration, accompanied by compromised DNA damage repair. Despite early development of relatively indolent cystic precursor lesions called intraductal papillary mucinous neoplasms (IPMNs), a subset of “KAC” mice developed aggressive PDAC in later ages. PDAC cells obtained from older autochthonous “KAC” mice revealed various compensatory (“escaper”) mechanisms to overcome the growth suppressive effects of Arid1a loss. Conclusions: Arid1a is an essential survival gene whose loss impairs cellular growth, and thus, its expression is critical during early stages of pancreatic tumorigenesis in mouse models. In tumors that arise in the setting of ARID1A loss, a multitude of “escaper” mechanisms drive progression.
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Kareddula, Aparna, Daniel J. Medina, Whitney Petrosky, et al. "The role of chromodomain helicase DNA binding protein 1 (CHD1) in promoting an invasive prostate cancer phenotype." Therapeutic Advances in Urology 13 (January 2021): 175628722110224. http://dx.doi.org/10.1177/17562872211022462.
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Background: Prostate cancer (PCa) phenotypes vary from indolent to aggressive. Molecular subtyping may be useful in predicting aggressive cancers and directing therapy. One such subtype involving deletions of chromodomain helicase DNA binding protein 1 ( CHD1), a tumor suppressor gene, are found in 10–26% of PCa tumors. In this study, we evaluate the functional cellular effects that follow CHD1 deletion. Methods: CHD1 was knocked out (KO) in the non-tumorigenic, human papillomavirus 16 (HPV16)-immortalized prostate epithelial cell line, RWPE-1, using CRISPR/Cas9. In vitro assays such as T7 endonuclease assay, western blot, and sequencing were undertaken to characterize the CHD1 KO clones. Morphologic and functional assays for cell adhesion and viability were performed. To study expression of extracellular matrix (ECM) and adhesion molecules, a real-time (RT) profiler assay was performed using RWPE-1 parental, non-target cells (NT2) and CHD1 KO cells. Result: Compared to parental RWPE-1 and non-target cells (NT2), the CHD1 KO cells had a smaller, rounder morphology and were less adherent under routine culture conditions. Compared to parental cells, CHD1 KO cells showed a reduction in ECM and adhesion molecules as well as a greater proportion of viable suspension cells when cultured on standard tissue culture plates and on plates coated with laminin, fibronectin or collagen I. CHD1 KO cells showed a decrease in the expression of secreted protein acidic and rich in cysteine (SPARC), matrix metalloproteinase 2 (MMP2), integrin subunit alpha 2 (ITGA2), integrin subunit alpha 5 (ITGA5), integrin subunit alpha 6 (ITGA6), fibronectin (FN1), laminin subunit beta-3 precursor (LAMB3), collagen, tenascin and vitronectin as compared to parental and NT2 cells. Conclusion: These data suggest that in erythroblast transformation specific (ETS) fusion-negative, phosphatase and tensin homolog ( PTEN) wildtype PCa, deletion of CHD1 alters cell-cell and cell-matrix adhesion dynamics, suggesting an important role for CHD1 in the development and progression of PCa.
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Marsch, Nils, Mario Kock, and Thomas Lindel. "Study on the synthesis of the cyclopenta[f]indole core of raputindole A." Beilstein Journal of Organic Chemistry 12 (February 23, 2016): 334–42. http://dx.doi.org/10.3762/bjoc.12.36.
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The raputindoles from the rutaceous treeRaputia simulansshare a cyclopenta[f]indole partial structure the synthesis of which is subject of this investigation. An efficient route to a series of 1,5-di(indol-6-yl)pentenones was developed via Mo/Au-catalyzed Meyer–Schuster rearrangement of tertiary propargylic alcohol precursors. However, none of the enones underwent the desired Nazarov cyclization to a cyclopenta[f]indole. More suitable were 6-hydroxyallylated indolines which gave good yields of cyclopenta[f]indolines after treatment with SnCl4, as soon as sterically demanding β-cyclocitral adducts were reacted. Most successful were Pt(II) and Au(I)-catalyzed cyclizations ofN-TIPS-protected indolin-6-yl-substituted propargylacetates which provided the hydrogenated tricyclic cyclopenta[f]indole core system in high yield.
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Manoni, Elisabetta, Assunta De Nisi, and Marco Bandini. "New opportunities in the stereoselective dearomatization of indoles." Pure and Applied Chemistry 88, no. 3 (2016): 207–14. http://dx.doi.org/10.1515/pac-2016-0101.
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AbstractThe regio- and stereoselective dearomatization of indoles is realized for the first time by combining readily available indolyl precursors and electron-rich allenes, namely allenamides and aryloxyallenes. Inter- as well as intramolecular condensations were realized under gold and Brønsted acid catalysis providing a range of densely functionalized indoline and indolenine cores in high yields and excellent stereochemical outcome. Chemodivergent reaction profiles (Micheal-type addition vs. [2+2]-cycloaddition) were realized by a tailored design of both reaction conditions and functionalization of the reaction partners.
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Tschumper, Renee C., Tait D. Shanafelt, Neil E. Kay, and Diane F. Jelinek. "Characterization of Long Non-Coding RNAs in Chronic Lymphocytic Leukemia: Evidence for Association with Disease Progression in Trisomy 12 Patients." Blood 124, no. 21 (2014): 3281. http://dx.doi.org/10.1182/blood.v124.21.3281.3281.
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Abstract BACKGROUND: Chronic lymphocytic leukemia (CLL) is a heterogeneous B cell malignancy with patients being categorized into disease subsets based on several key biologic parameters, e.g., mutation status (mutated, M; or unmutated, UM) of the immunoglobulin heavy chain variable region (IGHV), acquired chromosomal abnormalities, and expression of CD38 and CD49d. Furthermore, about one third of CLL patients express stereotyped B cell receptors and/or may acquire high risk common mutations in genes such as NOTCH1 and SF3B1 suggesting ongoing genetic evolution as drivers of disease development. Critical to this concept, those CLL patients with trisomy 12 (T12) defects have a higher incidence of mutations in NOTCH1 and often have a stereotyped receptor. However, T12 patients may have a variable clinical course that appears to be unrelated to these 2 drivers suggesting an additional, possibly non-coding genetic component that may further impact disease progression in these patients. One potentially relevant genetic factor that could influence T12 clinical course is long non-coding RNAs (lncRNAs). LncRNAs are transcripts longer than 200 nucleotides that can affect a number of cellular processes. Importantly, lncRNAs have been implicated in various cancers including malignant hematopoiesis indicating they could be therapeutic targets and/or clinically useful biomarkers. METHODS: To pursue a role for lncRNAs in T12 we used v3.0 Arraystar Human LncRNA Microarrays to assess the global profile of lncRNA expression in CLL with an emphasis on patients with T12. Two cohorts of 6 patients with T12 were selected for comparison: one defined as progressive with a short time to treatment (TTT) (treatment ≤1 year after diagnosis) and one as indolent (no treatment > 5 years after diagnosis). Each cohort included 3 patients with M and 3 with UM IGHV status. RNA from normal CD5+ and CD5- B cells was included as a control. To compensate for the small sample size in each cohort, a significant difference in lncRNA expression between the groups was defined as a fold change (FC) ≥5.0, p-value ≤0.05 and false discovery rate (FDR) ≤ 0.05. RESULTS: An initial global comparison of CD5+/CD5- normal B cells vs all CLL samples found that 609 lncRNAs were differentially expressed using the criteria listed above with 158 lncRNAs having a FC>10. Notable lncRNAs in this group included: LOC541472 (down in CLL and associated with the IL-6 gene), D63785 (up in CLL and associated with TBC1D3C, an oncoprotein), CTC-459I6.1 (up in CLL and associated with RASGRF2) and AC002480.5 (down in CLL and associated with STEAP1B, shown to be overexpressed in prostate cancer). We next evaluated T12 samples and identified 90 candidate lncRNAs that may discriminate between progressive and indolent T12 cases. Within this group were 11 lncRNAs with a FC > 10, 5 of which have no known associated gene. Of those associated with known genes, 3 were ultra-conserved region encoding lncRNAs down-regulated in progressive T12 patients (TTT ≤1 yr) and linked to hephaestin-like protein 1 precursor, pannexin-1, and tubulin beta-3 chain isoform 1. Of potential high relevance we found that the lncRNA LPP-AS1 was down-regulated in progressive T12 patients (TTT ≤1 yr) and known to be associated with the LIM-containing lipoma preferred partner (LPP) gene (p=0.028; FDR=0.03 and FC=18.3). Looking specifically at IGHV M progressive T12 patients (T12M≤1 yr) vs IGHV M indolent T12 patients (T12M>5 yrs), we again found the LPP-AS1 lncRNA was highly down-regulated in T12M≤1 (p=0.00046; FDR=0.006 and FC=34.5) but it was not found to be differentially expressed in the UM T12≤1 yr vs UM T12>5 yr comparison. The LPP gene has been shown to play a role in cell-cell adhesion, motility and signaling, and is often the fusion partner for the mixed lineage leukemia (MLL) gene in secondary acute leukemia. Furthermore, LLP may play a role in breast cancer cell invasion. LPP-AS1 may be participating in IGHV M T12 progression by affecting LPP and thus influencing migration through the lymph node microenvironment. CONCLUSION: While candidate lncRNAs in T12 CLL need to be validated, the LPP-AS1 lncRNA shows promise as a possible marker and potential treatment target for those patients with T12 and M IGHV that may progress rapidly. Further studies are needed to evaluate the impact of lncRNAs on clinical outcome of T12 CLL patients. Disclosures Shanafelt: Hospiria: Research Funding; Pharmacyclics/Jannsen: Research Funding; Cephalon: Research Funding; Celgene: Research Funding; glaxoSmithKline: Research Funding; Genetech: Research Funding; Polyphenon E Int'l: Research Funding. Kay:Celgene: Research Funding.
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Nagorsen, Dirk, Gerhard Zugmaier, Peter Kufer, et al. "Transient Laboratory Findings Upon First Dosing with T-Cell Engaging BiTE® Antibody Blinatumomab in Non-Hodgkin Lymphoma Patients." Blood 114, no. 22 (2009): 4798. http://dx.doi.org/10.1182/blood.v114.22.4798.4798.
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Abstract Abstract 4798 Blinatumomab is a single-chain bispecific antibody construct with specificity for CD19 and CD3 belonging to the class of bispecific T cell engager (BiTE®). It has shown high response rates as single agent after treatment of patients with indolent and mantle cell lymphoma and B-precursor acute lymphocytic leukemia. We here report from an ongoing phase 1 trial in non-Hodgkin lymphoma patients on transient laboratory findings seen upon start of continuous i.v. infusion of blinatumomab. The vast majority of adverse events (AEs) during 4-8 weeks of infusion occurred within the first two days of treatment. Lymphopenia (up to CTCAE grade 4) was the most frequent early laboratory AE, and can be explained by rapid B cell depletion and initial redistribution of T cells. Except for B cell decline, all laboratory parameters were transient and normalized within days during continued treatment. Dose-dependent increases were seen for AST and ALT (maximally grade 1/2), CRP, and D-dimer during the first days of treatment. Dose-dependent declines during the first days of treatment were observed for platelets and hemoglobin, which normalized after a few days. Of note, no drug-related thromboembolic events were observed. Serum levels of cytokines IL-6, IL-2, IFNγ, and IL-10 showed small dose-dependent increases, which reversed to baseline within hours. No association between cytokine levels and thrombocytopenia was found. Moreover, there was no evident correlation between any laboratory abnormality and clinical adverse event observed during the first days of treatment. The laboratory AEs induced by blinatumomab appear to reflect consequences of the onset of redirected target cell lysis, T cell activation and bystander effects. In conclusion, blinatumomab causes characteristic laboratory findings during the first days of treatment, which are transient, not associated with clinically relevant AEs and do not require treatment interruption. Compared to AEs caused by chemotherapy regimens, the laboratory findings observed after start of blinatumomab treatment are considered rather mild. Disclosures: Nagorsen: Micromet: Employment, Equity Ownership. Zugmaier:Micromet: Employment, Equity Ownership. Kufer:Micromet: Employment, Equity Ownership, Patents & Royalties. Klinger:Micromet: Employment, Equity Ownership. Schmidt:Micromet: Employment, Equity Ownership. Klappers:Micromat: Employment, Equity Ownership. Wolf:Micromet: Employment, Equity Ownership. Brandl:Micromet: Employment, Equity Ownership. Baeuerle:Micromet: Employment, Equity Ownership. Bargou:Micromet: Consultancy, Patents & Royalties.
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Eiring, Anna M., Paolo Neviani, Ramasamy Santhanam, et al. "Requirement of the E2F3 Transcription Factor for BCR/ABL Leukemogenesis." Blood 110, no. 11 (2007): 33. http://dx.doi.org/10.1182/blood.v110.11.33.33.
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Abstract Several RNA binding proteins (RBPs) have been implicated in the progression of chronic myelogenous leukemia (CML) from the indolent chronic phase to the aggressively fatal blast crisis. In the latter phase, expression and function of specific RBPs are altered at transcriptional or post-translational levels by the increased constitutive kinase activity of the BCR/ABL oncoprotein, resulting in enhanced resistance to apoptotic stimuli, growth advantage and differentiation arrest of CD34+ CML blast crisis (CML-BC) progenitors. In the current study, we identified by RIP (RNA immunoprecipitation)-mediated microarray analysis that mRNA encoding the E2F3 transcription factor associates to the BCR/ABL-regulated RBP hnRNP A1. Moreover, RNA electrophoretic mobility shift and UV-crosslinking assays revealed that hnRNP A1 interacts with E2F3 mRNA through a binding site located in the 3’UTR of both human and mouse E2F3 mRNA. Accordingly, E2F3 protein levels were upregulated in BCR/ABL-transformed myeloid precursor cell lines compared to parental cells in a BCR/ABL-kinase- and hnRNP A1 shuttling-dependent manner. In fact, treatment of BCR/ABL-expressing myeloid precursors with the kinase inhibitor Imatinib (2mM, 24 hr) or introduction of a dominant-negative shuttling-deficient hnRNP A1 protein (NLS-A1) markedly reduced E2F3 protein and mRNA levels. Similarly, upregulation of BCR/ABL expression/activity in the doxycycline inducible TonB2.10 cell line resulted in increased E2F3 protein expression. BCR/ABL kinase-dependent induction of E2F3 protein levels was also detected in CML-BCCD34+ compared to CML-CPCD34+ progenitors from paired patient samples and to normal CD34+ bone marrow samples. Importantly, the in vitro clonogenic potential of primary mouse BCR/ABL+ lineage negative (Lin−) progenitors was markedly impaired in BCR/ABL+ E2F3−/− compared to BCR/ABL-transduced E2F3+/+ myeloid progenitors and upon shRNA-mediated downregulation of E2F3 expression (90% inhibition, P<0.001). Furthermore, subcutaneous injection of shE2F3-expressing BCR/ABL+ cells into SCID mice markedly impaired in vivo tumorigenesis (>80% reduction in tumor burden, P<0.01). Accordingly, BCR/ABL leukemogenesis was strongly inhibited in SCID mice intravenously injected with E2F3 shRNA-expressing 32D-BCR/ABL cells and in mice transplanted with BCR/ABL-transduced Lin− bone marrow cells from E2F3−/− mice. Specifically, we demonstrate that reduced or absent levels of E2F3 resulted in dramatically decreased numbers of circulating BCR/ABL+ cells as determined by nested RT-PCR at 4 weeks post-injection (P=0.0001), normal splenic architecture and bone marrow cellularity and the absence of infiltrating myeloid blasts into non-hematopoietic compartments (i.e. liver). By contrast, SCID mice transplanted with vector-transduced 32D-BCR/ABL cells or BCR/ABL+ E2F3+/+ Lin− BM progenitors showed signs of an overt acute leukemia-like process with blast infiltration of hematopoietic and non-hematopoietic organs. Altogether, these data outline the importance of E2F3 expression for BCR/ABL leukemogenesis and characterize a new potential therapeutic target for the treatment of patients with advanced phase CML.
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Goggiamani, Antonella, Antonia Iazzetti, Antonio Arcadi, et al. "Synthesis of Indole/Benzofuran-Containing Diarylmethanes through Palladium-Catalyzed Reaction of Indolylmethyl or Benzofuranylmethyl Acetates with Boronic Acids." Synthesis 54, no. 03 (2021): 741–53. http://dx.doi.org/10.1055/s-0041-1737275.
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AbstractThe palladium-catalyzed synthesis of indole/benzofuran-containing diarylmethanes starting from indolylmethyl or benzofuranylmethyl acetates with boronic acids has been investigated. The success of the reaction is influenced by the choice of precatalyst: with indolylmethyl acetates the reaction works well with [Pd(η3-C3H5)Cl]2/XPhos while with benzofuranylmethyl acetates Pd2(dba)3/XPhos is more efficient. The good to high yields and the simplicity of the experimental procedure make this protocol a versatile synthetic tool for the preparation of 2- and 3-substituted indoles and 2-benzo[b]furans. The methodology can be advantageously extended to the preparation of a key precursor of Zafirlukast.
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Bennis, Youssef, Yan Cluet, Dimitri Titeca-Beauport, et al. "The Effect of Sevelamer on Serum Levels of Gut-Derived Uremic Toxins: Results from In Vitro Experiments and A Multicenter, Double-Blind, Placebo-Controlled, Randomized Clinical Trial." Toxins 11, no. 5 (2019): 279. http://dx.doi.org/10.3390/toxins11050279.
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High serum levels of gut-derived uremic toxins, especially p-cresyl sulfate (pCS), indoxyl sulfate (IS) and indole acetic acid (IAA), have been linked to adverse outcomes in patients with chronic kidney disease (CKD). Sevelamer carbonate could represent an interesting option to limit the elevation of gut-derived uremic toxins. The aim of the present study was to evaluate the adsorptive effect of sevelamer carbonate on different gut-derived protein-bound uremic toxins or their precursors in vitro, and its impact on the serum levels of pCS, IS and IAA in patients with CKD stage 3b/4. For the in vitro experiments, IAA, p-cresol (precursor of pCS) and indole (precursor of IS), each at a final concentration of 1 or 10 µg/mL, were incubated in centrifugal 30 kDa filter devices with 3 or 15 mg/mL sevelamer carbonate in phosphate-buffered saline at a pH adjusted to 6 or 8. Then, samples were centrifuged and free uremic toxins in the filtrates were analyzed. As a control experiment, the adsorption of phosphate was also evaluated. Additionally, patients with stage 3b/4 CKD (defined as an eGFR between 15 and 45 mL/min per 1.73 m2) were included in a multicenter, double-blind, placebo-controlled, randomized clinical trial. The participants received either placebo or sevelamer carbonate (4.8 g) three times a day for 12 weeks. The concentrations of the toxins and their precursors were measured using a validated high-performance liquid chromatography method with a diode array detector. In vitro, regardless of the pH and concentration tested, sevelamer carbonate did not show adsorption of indole and p-cresol. Conversely, with 10 µg/mL IAA, use of a high concentration of sevelamer carbonate (15 mg/mL) resulted in a significant toxin adsorption both at pH 8 (mean reduction: 26.3 ± 3.4%) and pH 6 (mean reduction: 38.7 ± 1.7%). In patients with CKD stage 3b/4, a 12-week course of treatment with sevelamer carbonate was not associated with significant decreases in serum pCS, IS and IAA levels (median difference to baseline levels: −0.12, 0.26 and −0.06 µg/mL in the sevelamer group vs. 1.97, 0.38 and 0.05 µg/mL in the placebo group, respectively). Finally, in vitro, sevelamer carbonate was capable of chelating a gut-derived uremic toxin IAA but not p-cresol and indole, the precursors of pCS and IS in the gut. In a well-designed clinical study of patients with stage 3b/4 CKD, a 12-week course of treatment with sevelamer carbonate was not associated with significant changes in the serum concentrations of pCS, IS and IAA.
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Kreher, Richard P., та Gerald Dyker. "Struktur und Reaktivität von isoanellierten heterocyclischen Systemen mit Anπ- und (4n+2)π-Elektronen, XII [1]. 2-tert-Butyl-4-methyl-2,4-dihydropyrrolo[3,4-b]indole: Tricyclische Hetarene mit isoanellierten Pyrrolringen / Structure and Reactivity of Isoannelated Heterocyclic Systems with 4nπ- and (4n+2)π-Electrons, XII [1] 2-terr-Butyl-4-methyl-2,4-dihydropyrrolo[3,4-b]indoles: Tricyclic Hetarenes with Isoannelated Pyrrole Rings". Zeitschrift für Naturforschung B 42, № 4 (1987): 473–77. http://dx.doi.org/10.1515/znb-1987-0414.
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2-tert-Butyl-4-methyl-2,4-dihydropyrrolo[3,4-b]indole (4a) has been prepared via selective reduction of 2-rm-butyl-4-methyl-2,4-dihydropyrrolo[3,4-b]indol-l(2H)-one or -3(2H)-one 5 and 6 with diisobutylaluminiumhydride. The same precursors 5 and 6 can be transformed into 2-tert-butyl-4-methyl-2,4-dihydropyrrolo[3,4-b]indoles (4b) and (4c) bearing a methoxy group in 1- or 3-position via a two step procedure consisting in O-alkylation and CH-deprotonation. NMR Investigations afford an insight into the structure of the stable tricyclic hetarenes.
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Edlefsen, Kerstin Lara, Anneclaire De Roos, and Andrea LaCroix. "Application of the InterLymph Consortium’s Proposed Classification of Lymphoid Neoplasms for Epidemiologic Research to a Large, Nationwide Health Study: Experience in the Women’s Health Initiative." Blood 112, no. 11 (2008): 4669. http://dx.doi.org/10.1182/blood.v112.11.4669.4669.
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Abstract Large cohort studies, such as the Women’s Health Initiative, have traditionally grouped hematopoietic neoplasms (HPN) into disease categories including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and leukemia, however this may not allow for optimal distinction of biologically relevant associations. The 2001 World Health Organization (WHO) classification of HPN represents the current gold standard classification scheme, and has been incorporated into the International Classification of Disease for Oncology, Third Edition (ICD-O-3). In 2007, the International Lymphoma Epidemiology Consortium (InterLymph) proposed a classification of lymphoid neoplasms for epidemiologic research that is based upon the WHO/ICD-O-3 classification (Morton LM, et al. Blood, 2007;110:695–708). Here we report on the application of this proposed classification scheme within the Women’s Health Initiative (WHI), a large, nationwide health study. All incident cases of HPN reported by women in the WHI cohort of 161,808 women were adjudicated by SEER-trained cancer coders according to SEER criteria, including assignment of histology codes based on ICD-O-3 guidelines. Cases were simultaneously assigned to one of the four traditional categories (leukemia, NHL, HL, and MM). Histologic subtypes were then grouped according to the recommendations of InterLymph. A total of 1534 women with incident HPN were identified within the WHI cohort. This included 405 within the general category of leukemia, 853 NHL, 237 MM, and 39 HL. Within the leukemia category, 221 are of lymphoid origin. See Table 1 for the InterLymph classification of the lymphoid neoplasms. These findings highlight the critical importance of appropriately classifying HPN for epidemiologic research. The traditional classification of all blood-based HPN as “leukemias” is particularly problematic, as this grouping includes neoplasms from both the myeloid and lymphoid lineages. In addition, disorders with both leukemic and solid disease phases, such as CLL/SLL, are split between those two traditional categories (leukemia and NHL). These groups also include entities with both indolent and aggressive clinical behaviors. HPN are a heterogeneous group of neoplasms that are known to have distinct phenotypes, presentations, and natural progressions, and they are increasingly recognized to be etiologically heterogeneous. The traditional grouping of these neoplasms into leukemia, NHL, HL, and MM is problematic, and may limit the interpretation of research findings. Classification of these neoplasms according to the recommendations of InterLymph should allow for improved detection of biologically relevant associations. TABLE 1. All incident lymphoid neoplasms since WHI enrollment, by ICD-0-3 histologic subtype (first column) and by traditional categorization as leukemia (leuk), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and multiple myeloma (MM). TOTAL NHL Leuk* MM HL *Leukemia category includes 405 total participants, 177 with myeloid leukemias (116 AML, 40 CML, 14 CMML, 7 other/unclassified) and 7 with leukemias of ambiguous/unspecified lineage ^Chronic lymphocytic leukemia/small lymphocytic lymphoma/pro-lymphocytic leukemia/mantle cell lymphoma Lymphoid neoplasms TOTAL 1350 853 221 237 39 Hodgkin (HL) TOTAL 39 0 0 0 39 Classical Hodgkin (HL, C) 23 23 Hodgkin, not otherwise specified (HL, NOS) 10 10 Nodular lymphocyte-predominant (HL, NLP) 6 6 Non-Hodgkin (NHL) B lineage: TOTAL B-NHL 1259 811 211 237 0 Precursor B-acute lymphoblastic leukemia/lymphoma (B-ALL) 7 7 Mature CLL/SLL/PLL/MCL^ 294 106 188 Lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM) 32 23 9 Burkitt lymphoma (BL) 7 6 1 Follicular lymphoma (FL) 208 208 Marginal zone lymphoma (MZL) 88 88 Hairy cell leukemia (HCL) 6 6 Diffuse large B cell (DLBCL) 275 275 Plasma cell neoplasm (PCN) 237 237 B-NHL, not otherwise specified (NOS) 105 105 T lineage: TOTAL T-NHL 47 41 6 0 0 Precursor T-acute lymphoblastic leukemia/lymphoma (T-ALL) 2 2 Mature Mycosis Fungoides(MF)/Sezary syndrome (SS) 7 7 Peripheral T cell lymphoma (PTCL) 30 30 Natural Killer/T cell lymphoma (NK/T) 1 1 Large granular lymphocyte leukemia (T-LGL) 5 5 T-prolymphocytic lymphoma (T-PLL) 2 1 1 Unknown lineage: TOTAL UKNOWN/UNSPECIFIED NHL 5 1 4 0 0 Precursor Acute lymphoblastic leukemia (U-ALL) 1 1 Mature NHL, not other specified (U-NHL) 4 1 3
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Nadel, Bertrand. "Early Steps of Follicular Lymphoma Pathogenesis." Blood 128, no. 22 (2016): SCI—5—SCI—5. http://dx.doi.org/10.1182/blood.v128.22.sci-5.sci-5.
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Abstract Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in the Western world, generally characterized by a disseminated disease at diagnosis, an indolent clinical course and recurrent, increasingly chemo-resistant relapses. Overt FL is preceded by an insidious phase of asymptomatic growth and might emerge from common precursor clones (CPCs), evolving over decades, and which might participate to subsequent relapses. Consequently, the cell of origin remains ambiguous. From the clinical standpoint, morphological, histological and molecular evidences all indicate that FL results from the malignant transformation of germinal center (GC) B-cells. Nevertheless, it is now clear that the natural history of FL does not initiate in the GC, and that FL precursors emerge much earlier in B-cell ontogeny. The hallmark t(14;18)(q32;q21) translocation, present in 85-90% of FL patients, results from repair failures during V(D)J recombination in bone marrow pre-B cells, and the ensuing constitutive expression of the BCL2 oncogene is thus considered the necessary early first hit to transformation. However, BCL2 as such is a very weak driver, as evidenced by the detection of t(14;18)in peripheral blood from a large fraction of the adult healthy population, and the long latency and low penetrance observed in various BCL2 mouse models. Intriguingly, circulating t(14;18)+-carrying cells in healthy individuals are mostly clonally expanded GC-experienced B cells, and show imprints of early illegitimate genomic events. Recent data of clonal dynamics in human and mouse models strongly suggest that such illegitimate events likely accumulated over iterative passages through successive GC reactions. Because GCs constitute a very particular environment, highly and purposely prone to genomic reshuffling and somatic mutations, such chronic "GC addiction" combined with BCL2-mediated decoupling from the GC selection checkpoint would create a highly mutagenic dynamics linked with slow oncogenic progression. Thus, the path to transformation appears as a complex multi-hit process occurring along B cell ontogeny, escalating along successive derailments of B cell receptor diversification mechanisms, and subversion of specific immunological properties of B cells. Combined with the power of next generation sequencing, molecular interrogations of t(14;18)+ clones in healthy individuals and FL patients recently provided new insights into CPCs, their commitment to malignant development years ahead disease manifestation, and into candidate genes paving the transformation process. Intriguingly, it is now envisioned that some of the recurrent alterations found in FL patients (such as KMT2D loss of-function) might occur in CPCs or earlier in B cell ontogeny and might even precede and/or condition t(14;18) occurrence or BCL2-mediated transformation. An exciting era is now opening in deciphering the kinetics of transformation and in decrypting the genomic status of FL CPC. With the prospective arrival of the chemo-free era in hematology and a flourishing landscape of novel therapeutic agents, it is today more important than ever to correctly understand the underlying FL biology in order to deliver efficient tailored therapies at the right time and in the right patients. Disclosures No relevant conflicts of interest to declare.
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Pirog, T. P., D. V. Piatetska, N. O. Klymenko, and G. O. Iutynska. "Ways of Auxin Biosynthesis in Microorganisms." Mikrobiolohichnyi Zhurnal 84, no. 2 (2022): 57–72. http://dx.doi.org/10.15407/microbiolj84.02.057.
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Among plant hormones, auxins, in particular indole-3-acetic acid (IAA), are the most studied and researched. Almost all groups of soil microorganisms, both plant-associated and non-plant-associated bacteria, fungi, and phytopathogenic microorganisms are capable of producing auxins. The development of preparations for crop production is directly related to the production of bacterial strains with high auxin-synthesizing potential, which is possible only with a full understanding of the ways of regulation and synthesis of auxins in bacteria. The synthesis of auxins in microorganisms can take place in two ways: by the gradual conversion of tryptophan to IAA (tryptophan-dependent pathway) or by the use of other intermediates (tryptophan-independent pathway). The latter is poorly clarified, and in the literature available today, there is only a small amount of information on the functioning of this pathway in microorganisms. The review presents literature data on the ways of auxin biosynthesis in different groups of microorganisms, as well as approaches to the intensification of indole-3-acetic acid synthesis. The formation of IAA from tryptophan can be carried out in the following ways: through indole-3-pyruvate, through indole-3-acetamide, and through indole-3-acetonitrile. The vast majority of available publications are related to the assimilation of tryptophan through the formation of indole-3-pyruvate as this pathway is the most common among microorganisms. Thus, it functions in rhizospheric, symbiotic, endophytic, and free-living bacteria. The concentration of synthesized IAA among natural strains is in the range from 260 to 1130 μg/mL. Microorganisms in which the indole-3-acetamide pathway functions are characterized by lower auxin-synthesizing ability compared to those that assimilate tryptophan through indole-3-pyruvate. These include bacteria of the genera Streptomyces, Pseudomonas, and Bradyrhizobium and fungi of the genus Fusarium. The level of synthesis of IAA in such microorganisms is from 1.17×10−4 to 255.6 μg/mL. To date, only two strains that assimilate tryptophan via the indole-3-acetonitrile pathway and form up to 31.5 μg/mL IAA have been described in the available literature. To intensify the synthesis of indole-3-acetic acid, researchers use two main approaches: the first consists in introducing into the culture medium of exogenous precursors of biosynthesis (usually tryptophan, less often indole-3-pyruvate, indole-3-acetamide, and indole-3-acetonitrile); the second — in increasing the expression of the corresponding genes and creating recomindolebinant strains-supersynthetics of IAA. The largest number of publications is devoted to increasing the synthesis of IAA in the presence of biosynthesis precursors. Depending on the type of bacteria, the composition of the nutrient medium, and the amount of exogenously introduced precursor, the synthesis of the final product was increased by 1.2—27 times compared to that before the intensifi cation. Thus, in the presence of 11 g/L tryptophan, Enterobacter sp. DMKU-RP206 synthesized 5.56 g/L, while in a medium without the precursor, it yielded only 0.45 g/L IAA. Recombinant strains Corynebacterium glutamicum ATCC 13032 and Escherichia coli MG165 formed 7.1 and 7.3 g/L IAA, respectively, when tryptophan (10 g/L) was added to the culture medium. The level of auxin synthesis in microorganisms may be increased under stress conditions (temperature, pH, biotic and abiotic stress factors), but in this case, the IAA concentration does not exceed 100 mg/L, and therefore this method of intensification cannot compete with the others above.
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Sholihin, H. Hayat. "SINTESIS 7-FORMILINDOL SEBAGAI BAHAN DASAR PEMBENTUK KATALIS EPOKSIDASI BARU (SYNTHESIS OF 7-FORMYLINDOLE AS PRECURSOR OF NEW EPOXIDATION CATALYSTS)." Jurnal Pengajaran Matematika dan Ilmu Pengetahuan Alam 2, no. 1 (2015): 78. http://dx.doi.org/10.18269/jpmipa.v2i1.396.
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Manganese (III) salen complexes have been reported as epoxidation catalysts. It is caused a major breakthrough in the enantioselective epoxidation of alkenes into epoxide compounds. This catalyst was synthesized from salicylaldehyde derivatives. Based on the structure, salicylaldehyde is an isosteric nature of 7-folmylindole, consequently opened the door to an array of fascinating and versatile ligand systems, and offer tremendous scope for molecular designe, because of the greatly enhanced capacity for substitution of indoles compared with phenols. Initial target of the project to synthesize of 7-formylindole. There are numerous strategies and methodes to achieve the target molecules. Further study of reaction mechanism of a useful target compound could be explanated and developed as a new class of catalyst. Key word: Epoxidation catalyst, indole, organometal catalyst.
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Bettanin, Luana, Filipe Penteado, Luiz H. Dapper, and Eder J. Lenardão. "Selenocyanation of Indoles Promoted by Visible Light." Chemistry Proceedings 2, no. 1 (2020): 29. http://dx.doi.org/10.3390/eccs2020-07562.
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We developed a promising synthetic methodology for the regioselective photocatalyzed 3-selenocyanation of indoles, employing potassium selenocyanate (KSeCN) and a blue LED light. The 3-selanylindoles have been emerging as a potentially bioactive class of compounds and already have demonstrated anti-inflammatory, antinociceptive and anticancer properties. There are in the literature several methodologies for their preparation; for example, applying intermolecular cyclization with Se-based electrophilic species. Therefore, it is of interest to seek innovative and effective methodologies to selectively access this class of molecules. Furthermore, the photocatalytically formed NCSe· radical can react directly with the N-heterocycle unsaturated substrates, affording the desired compound more effectively than other electrophilic selenium species. In addition, the 3-selenocyanato-1H-indole derivatives can be employed as precursor to obtaining diselenides, through a reduction–oxidation reaction sequence. The new method employs indole as unsaturated N-heterocycle substrate, and 1.3 equiv. of potassium selenocyanate as a selenium source, in the presence of 5.0 mol% of eosin Y, an organic photocatalyst, and 1.0 mL of acetonitrile. The system was stirred and irradiated with a blue LED light for 5 h, and the crude was purified using column chromatography. Thus, as a result, we developed an efficient and smoothly methodology to prepare 3-selenocyanato-1H-indole derivatives, in good yields.
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Audrito, Valentina, Sara Serra, Davide Brusa, et al. "Extracellular Nicotinamide Phosphoribosyltransferase (NAMPT) Shapes the CLL Microenvironment Promoting Macrophage M2 Polarization Via a Non-Enzymatic Mechanism." Blood 124, no. 21 (2014): 3316. http://dx.doi.org/10.1182/blood.v124.21.3316.3316.
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Abstract Cancer-associated microenvironment provides to malignant cells the right cocktail of signals to increase survival, reprogram their metabolism and escape the control of the immune system. Nicotinamide phosphoribosyltransferase (NAMPT) is the only human enzyme that metabolizes nicotinamide, the main NAD precursor, in a rate-limiting step in NAD biosynthesis. Beside this canonical activity, NAMPT can be secreted in the extracellular milieu (eNAMPT), where it exerts cytokine/adipokine-like actions in different tumor models, as well as in acute and chronic inflammatory-metabolic diseases. Here we investigated the functional role of eNAMPT in the microenvironment of chronic lymphocytic leukemia (CLL), an indolent lymphoproliferative disorder, strongly dependent on a growth supportive environment. Results indicate that: i) B-CLL lymphocytes express higher levels of NAMPT mRNA and intracellular protein than normal circulating B lymphocytes obtained from age- and sex-matched donors; ii) plasma levels of eNAMPT are also significantly higher in CLL patients (n=95) compared to controls (n=20) and iii) eNAMPT is produced by CLL lymphocytes upon B-cell receptor, toll-like receptor and NF-KB signaling pathway activation. We then asked whether this cytokine plays an active role in the leukemic microenvironment. Data shows that eNAMPT acts on resting monocytes, polarizing them towards tumor-supporting M2 macrophages, known as nurse-like cells (NLC) in CLL. These cells express high levels of the scavenger receptor CD163, mannose receptor CD206 and indoleamine 2,3-dioxygenase (IDO), and secrete immunosuppressive (IL-10, CCL18) and tumor-promoting (IL-6, IL-8) cytokines. NAMPT-primed NLCs activate ERK1/2, STAT3 and NF-kB signaling, promote leukemic cell survival and reduce T cell responses. These effects are independent of the enzymatic activity of NAMPT, as inferred from the use of an enzymatically inactive mutant. From the translational point of view, drugs interfering with CLL signaling, such as Ibrutinib, can efficiently suppress NAMPT transcription, reducing NAMPT protein levels. Furthermore, NLCs differentiated in the presence of the immunomodulatory drug lenalidomide express lower levels of NAMPT, again suggesting that drugs that restore immune functions interfere with the production of eNAMPT. To conclude, we propose that a vicious circle based on CLL cell activation through antigen and accessory signals increase eNAMPT and CCL3 production. CCL3 serves as an attractant for circulating monocytes, which - in the presence of high levels of eNAMPT - differentiate into NLC, with an enhanced M2 phenotype and increased functional characteristics, contributing to CLL survival, activation and proliferation and inhibition of T cell responses. Disclosures No relevant conflicts of interest to declare.
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Chen, Qing-An, Wei-Song Zhang, and Yan-Cheng Hu. "Isoprene: A Promising Coupling Partner in C–H Functionalizations." Synlett 31, no. 17 (2020): 1649–55. http://dx.doi.org/10.1055/s-0040-1707172.
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Five-carbon dimethylallyl units, such as prenyl and reverse-prenyl, are widely distributed in natural indole alkaloids and terpenoids. In conventional methodologies, these valuable motifs are often derived from substrates bearing leaving groups, but these processes are accompanied by the generation of stoichiometric amounts of by-products. From an economical and environmental point of view, the basic industrial feedstock isoprene is an ideal alternative precursor. However, given that electronically unbiased isoprene might undergo six possible addition modes in the coupling reactions, it is difficult to control the selectivity. This article summarizes the strategies we have developed to achieve regioselective C–H functionalizations of isoprene under transition-metal and acid catalysis.1 Introduction2 Catalytic Coupling of Indoles with Isoprene3 Catalytic Coupling of Formaldehyde, Arenes and Isoprene4 Catalytic Coupling of 4-Hydroxycoumarins with Isoprene5 Catalytic Coupling of Cyclic 1,3-Diketones with Isoprene6 Conclusion and Outlook
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Bodemann, René Roberto, Peter Rahfeld, Magdalena Stock, et al. "Precise RNAi-mediated silencing of metabolically active proteins in the defence secretions of juvenile leaf beetles." Proceedings of the Royal Society B: Biological Sciences 279, no. 1745 (2012): 4126–34. http://dx.doi.org/10.1098/rspb.2012.1342.
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Allomones are widely used by insects to impede predation. Frequently these chemical stimuli are released from specialized glands. The larvae of Chrysomelina leaf beetles produce allomones in gland reservoirs into which the required precursors and also the enzymes are secreted from attached gland cells. Hence, the reservoirs can be considered as closed bio-reactors for producing defensive secretions. We used RNA interference (RNAi) to analyse in vivo functions of proteins in biosynthetic pathways occurring in insect secretions. After a salicyl alcohol oxidase was silenced in juveniles of the poplar leaf beetles, Chrysomela populi , the precursor salicyl alcohol increased to 98 per cent, while salicyl aldehyde was reduced to 2 per cent within 5 days. By analogy, we have silenced a novel protein annotated as a member of the juvenile hormone-binding protein superfamily in the juvenile defensive glands of the related mustard leaf beetle, Phaedon cochleariae . The protein is associated with the cyclization of 8-oxogeranial to iridoids (methylcyclopentanoid monoterpenes) in the larval exudates made clear by the accumulation of the acylic precursor 5 days after RNAi triggering. A similar cyclization reaction produces the secologanin part of indole alkaloids in plants.
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Tahri, Sabrin, Tarek H. Mouhieddine, Robert A. Redd, et al. "Clonal Hematopoiesis Is Associated with Increased Risk of Progression of Asymptomatic Waldenström Macroglobulinemia." Blood 138, Supplement 1 (2021): 2678. http://dx.doi.org/10.1182/blood-2021-149711.
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Abstract Introduction Clonal hematopoiesis (CH) is associated with adverse outcomes in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma undergoing autologous stem cell transplantation. Still, its implications for patients with indolent NHL have not been well studied. Here, we report the prevalence of CH in patients with Waldenström Macroglobulinemia (WM) and its association with clinical outcomes. Methods We retrospectively reviewed clinical data of 602 patients with IgM monoclonal gammopathy of undetermined significance (MGUS), smoldering WM (SWM), and WM who had clinical next-generation sequencing (NGS) performed on bone marrow aspirates or peripheral blood obtained between October 2014 and February 2020 at the Dana-Farber Cancer Institute. An Illumina Truseq amplicon-based NGS assay of 95 genes recurrently mutated in myeloid and lymphoid neoplasms was utilized. Each specimen yielded ~2 million reads and ~1500X average coverage, with 90% of amplicons having &gt;200X coverage. Pathogenic driver variants were identified based on mutation type, position, and frequency in published reports and public databases. To unambiguously differentiate CH mutations from those in the WM clone, CH was defined by the presence of somatic mutations in DNMT3A, TET2, or ASXL1 (DTA). Results The cohort included 147 patients with MGUS or asymptomatic WM and 453 patients with symptomatic WM, with a median age of 66 years (range = 40-89) and 68 years (range = 33-93), respectively, at the time of first NGS assay. The prevalence of CH-DTA was 14% in symptomatic WM patients and did not differ significantly in MGUS (13%) or SWM (14%). Among precursor patients, there was an increased risk of progression to symptomatic WM for those with CH-DTA [7/20 patients with vs. 11/116 without CH-DTA progressed over a median of 54 months (P = 0.002)]. In symptomatic WM patients, CH-DTA was positively associated with older age (P &lt; 0.001) at the time of NGS, with a median age of 72 vs. 67 years for patients with versus those without CH-DTA. CH-DTA was not associated with inferior overall survival (OS) with a relatively short median follow-up from diagnosis and NGS assay. OS was 6.7 years (95% CI = 6.1-7.6) for patients with CH-DTA and 2.5 years for patients without DH-DTA (95% CI = 2.2-2.8). The most common cause of death was disease progression, with no significant difference between those with or without CH-DTA. Patients with CH-DTA had an increased risk of cardiovascular disease (30% vs. 18%, P = 0.036). Conclusions We demonstrate that CH is common in WM patients and is associated with an increased risk of progression from precursor states but not with inferior survival. Further work is needed to determine how the presence of CH might promote progression to WM and whether it can be incorporated into future risk stratification models. Importantly, our data do not support changes in clinical management or alterations in therapy for patients with WM and coexistent CH and reinforce the need to interpret NGS results within their specific clinical context. Disclosures Steensma: Novartis: Current Employment. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding. Treon: X4: Research Funding; Dana Farber Cancer Institute: Current Employment; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; BMS: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy. Sperling: Adaptive: Consultancy.
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Kaur, Banni Preet, Jasneet Kaur, and Swapandeep Singh Chimni. "Arenesulfonyl indole: new precursor for diversification of C-3 functionalized indoles." RSC Advances 11, no. 4 (2021): 2126–40. http://dx.doi.org/10.1039/d0ra09133b.
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Arenesulfonyl indole has emerged as an efficient scaffold to provide direct access to C-3 substituted indole derivativesviavinylogous imine intermediate generated by elimination of arenesulfinic group under basic conditions.
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Kaur, Banni Preet, Jasneet Kaur, and Swapandeep Singh Chimni. "Arenesulfonyl indole: new precursor for diversification of C-3 functionalized indoles." RSC Advances 11, no. 4 (2021): 2126–40. http://dx.doi.org/10.1039/d0ra09133b.
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Arenesulfonyl indole has emerged as an efficient scaffold to provide direct access to C-3 substituted indole derivatives via vinylogous imine intermediate generated by elimination of arenesulfinic group under basic conditions.
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Manoharan, Dhinesh kumar. "Synthesis, Characterization and Evaluation of Anti-inflammatory Activity of Novel Indoline Derivatives." JOURNAL OF ADVANCES IN CHEMISTRY 12, no. 12 (2016): 4557–63. http://dx.doi.org/10.24297/jac.v12i12.4826.
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Series of indoline derivatives were synthesized using N-(4-aminophenyl) indoline-1-carbothiamide as a precursor. The structures of synthesized compounds were confirmed by FT-IR, 1H-NMR, 13C-NMR and LC-MS. The in vitro anti-inflammatory activity of synthesized indoline derivatives were examined by standard anti-denaturation assay. The compounds 4a (IC50 = 62.2 µg/ml) and 4b (IC50 = 60.7 µg/ml) showed potent inhibition on protein denaturation. The compounds 5a (IC50 = 97.8 µg/ml) exhibits moderate inhibition on protein denaturation
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Vincent, Guillaume, Natacha Denizot, Régis Guillot, and Cyrille Kouklovsky. "N-Iodosuccinimide-Mediated Oxidative Coupling of Indoles and Phenols: A Synthetic Study toward the Benzofuroindoline Moiety of Bipleiophylline." Synthesis 50, no. 24 (2018): 4823–28. http://dx.doi.org/10.1055/s-0036-1592002.
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We report our efforts to apply an N-iodosuccinimide-mediated dearomative oxidative coupling of indoles and phenols to benzofuroindoline-containing polycyclic scaffolds related to the natural product bipleiophylline. Suitable conditions from N-substituted indoles are developed and applied to the synthesis of a hexacyclic model starting from a tetracyclic ABCE precursor.