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Lakhwani, Sunil, Laura Rosiñol, Noemi Puig, Miguel Angel Pico Picos, Laura Medina-González, Joaquin Martinez Lopez, Bruno Paiva, et al. "Sustained Recovery of Uninvolved Heavy/Light Chain Pair Immunoparesis during Maintenance Discriminates Patients with Sustained Negative Minimal Residual Disease." Blood 142, Supplement 1 (November 28, 2023): 1958. http://dx.doi.org/10.1182/blood-2023-179452.
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Introduction. Immunoparesis (IP) or the suppression of uninvolved immunoglobulins (Ig) is a very common finding in multiple myeloma (MM) patients at diagnosis that confers worse prognosis. In addition to classic total Ig, IP can be measured by the uninvolved heavy/light chain pair of the same immunoglobulin (uHLC). Previously, we have reported that recovery of uHLC IP in a single time point (at first year of maintenance) is an independent prognostic factor in newly diagnosed MM transplant eligible (NDMM-TE) patients with intensive treatment within a clinical trial, without significant prognostic value for recovery from classic IP in that setting. Moreover, recovery of uHLC IP affords complementary information to single time point minimal residual disease (MRD) for risk stratification. Although, negative sustained MRD is the most important evolutive favorable prognostic factor in MM, some patients relapse despite achieving negative sustained MRD. Aim. To evaluate the prognostic value of sustained uHLC IP recovery during maintenance treatment, measured by progression free survival (PFS), within a clinical trial of NDMM TE patients with intensive treatment and its potential association with sustained MRD. Patients & Methods. Patients with newly diagnosed MM enrolled in the PETHEMA/GEM2012MENOS65 trial received six cycle VRD-GEM induction, autologous hematopoietic stem cell transplantation conditioned by melphalan or busulfan plus melphalan and consolidation with two more cycles of VRD-GEM. Afterwards, patients were enrolled in the PETHEMA/GEM2014MAIN clinical trial that randomly assigned them to maintenance with lenalidomide and low-dose dexamethasone (Rd) or Rd plus ixazomib for two years. After two years, patients who achieved negative MRD stopped the treatment and patients who did not achieve MRD negativity received three more years of Rd. We analyzed uHLC in a central laboratory at diagnosis and at the first and second year of maintenance. We consider IP at diagnosis when uHLC were under lower limit of normality (LLN) and recover IP when suppressed uHLC at diagnosis reach at least LLN plus 10%. Sustained uHLC IP recovery was defined as IP recovery in the first year of maintenance that persists in the second year of maintenance. MRD was analyzed by next generation flow cytometry (sensitivity level 2x10 -6) after consolidation and at the first and second year of maintenance. Sustained MRD was defined as a negative MRD for at least 12 months that remains negative at the second year of maintenance. In the PETHEMA/GEM2012MENOS65 trial, 458 patients were included of which 332 patients entered the PETHEMA/GEM2014MAIN clinical trial. We included in this study 137 patients, those who reached the second year of maintenance without relapse and had samples available at any of the three time points for the uHLC analysis. Results. We found uHLC IP in 93.7% of patients (119/127) at diagnosis, 28.1% of patients (34/121) at first year of maintenance and 46.8% of patients (51/109) at second year of maintenance. After the second year of maintenance, we found recovery from uHLC IP present at diagnosis in 48.4% of patients (46/95). Patients that recovered from uHLC IP after second year of maintenance had better PFS (p=0.015) with hazard ratio (HR) 0.27 (CI95% 0.09 - 0.84). Patients with sustained recovery from uHLC IP had better prognosis than patients without recovery at first year of maintenance [p=0.010; HR 0.16 (CI95% 0.03 - 0.78)] and patients with IP recovery at first year who lose it at second year of maintenance [p=0.002: HR 0.12 (CI95% 0.02 - 0.59)] ( Figure 1). Only five patients without recovery at first year had uHLC IP recovery at second year of maintenance, but with similar PFS than patients without recovery at both time points (p=0.441). Sustained negative MRD for at least 12 months was present in 87/136 (64%) of patients, however we had data of IP recovery evolution in only 54 of these patients, of which 28 had sustained IP recovery. Patients with sustained negative MRD and sustained IP recovery had longer PFS than patients with sustained negative MRD without sustained IP recovery [p=0.025; HR 0.13 (CI95% 0.02 - 0.98)] ( Figure 2). Conclusions. Sustained recovery of uHLC IP during maintenance in NDMM-TE patients with intensive treatment is a prognostic factor complementary to sustained negative MRD. Combination of both factors identify patients with very good prognosis.
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Campbell, Lauren, Karthik Ramasamy, and Ross Sadler. "Non-Invasive MRD Monitoring in Multiple Myeloma Patients By Heavy/Light Chain Analysis." Blood 142, Supplement 1 (November 28, 2023): 4716. http://dx.doi.org/10.1182/blood-2023-190487.
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Introduction The majority of multiple myeloma (MM) patients are now achieving very deep responses. The most sensitive disease detection techniques are currently bone marrow assays. However, as bone marrow sampling is invasive and unpleasant for patients it is important to investigate whether blood-based assays could be equally or more informative of disease status. The heavy/light chain assay (Hevylite TM, The Binding Site, UK) evaluates serum heavy/light chains (HLC) for IgG, IgA and IgM M-proteins. This study assessed whether the HLC assay could act as an effective marker for disease in the bone marrow of treated MM patients and evaluated the prognostic utility of HLC measurements at best response and relapse time points. Methods 104 IgG and IgA MM patients were recruited either prior to transplant or during chemotherapy. Median follow up was 18 months. Routine M-protein tests were performed alongside HLC testing with parameters including involved HLC (iHLC), uninvolved HLC (uHLC) and kappa/lambda HLC ratio (HLCr). A bone marrow flow cytometry (NGF) assay was performed up to a sensitivity of 10 -6 and was considered to be the gold standard assay. Disease response was determined according to the IMWG criteria. Results and Discussion At pre- and post-transplant time points there was significant agreement between HLC measurements and NGF, with uHLC being the most sensitive measurement (86%) and HLCr the most specific (100%). Both uHLC and HLCr show substantial agreement with the bone marrow NGF method whilst iHLC cannot be used to indicate bone marrow status. Survival analysis showed significantly inferior progression free survival (PFS) in patients with an abnormal uHLC (p=0.01) (Figure A) or HLCr (p=0.02) result post-transplant but no survival difference based on iHLC status (p=0.78) (Figure B). Interestingly, performing survival analysis on these same samples using serum immunofixation (IFE) status (positive or negative) did not produce a significant PFS difference between participants (p=0.21). During long term follow up, HLC values showed a correlation with depth of response, with uHLC being abnormal in 60% of complete response (CR) patients. This suggests that those participants currently grouped as CR may be able to be further subdivided according to uHLC level and this could have a prognostic value in the monitoring and treatment of these patients. At best response uHLC was the only HLC or free light chain (FLC) measurement which gave a significant difference in PFS for all patients in partial response (PR) or better (p=0.005), remaining true when analysing patients in ≥CR only (p=0.002). The addition of free light chain measurements into the HLC analysis did not improve the significance of these survival differences. In relapsed patients, paired comparisons of M-protein and disease activity markers at best response vs. prior to clinical relapse were performed. uHLC was the only marker which was significantly different between the two time points in IgG and IgA patients. The significance of this was confirmed by showing that those patients in stable disease did not experience a significant change in uHLC levels. For other M-protein variables such as total immunoglobulin, IFE status and FLC values there was an increase in levels or abnormality between best response and pre-relapse but these were not significant. The paired comparison suggests that monitoring an individual using HLC could help to detect relapse earlier than conventional methods. In all analyses performed the HLC assay showed increased sensitivity and utility over the IFE technique. Conclusion This study suggests that the HLC assay can be used prior to bone marrow analysis to help influence decisions and improve the patient and laboratory experience. These results can be put into practice during patient follow up post initial treatment in the following ways: At deepest response an abnormal uHLC or HLCr suggests a positive MRD status, meaning a possible reduction or delay in the requirement for bone marrow assessment.All patients in ≥VGPR should have HLC performed alongside conventional assays during follow up.If uHLC values become abnormal during follow up then it should be assumed that the patient is about to undergo relapse. The measurement of HLC values have been shown to be a significant marker in this study, for sensitively detecting the M-protein, giving further clarification of response status and predicting early relapse.
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AGUERO, R. R., C. KORZENOWSKI, J. R. Y. AGUIRRE, A. CAMPOS FILHO, L. C. P. da SILVA FILHO, and C. S. MALLMANN. "Experimental study of concrete mixtures to produce UHPRC using sustainable brazilians materials." Revista IBRACON de Estruturas e Materiais 12, no. 4 (August 2019): 766–89. http://dx.doi.org/10.1590/s1983-41952019000400004.
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Abstract An experimental study is presented to produce Ultra High Performance Reinforced Concrete (UHPRC) with sustainable materials produced in Brazil. A complete factorial arrangement was defined and five controllable factors were selected based on the literature review. Cylindrical specimens were tested at 7, 14 and 28 days of curing, with and without heat treatment. The residual deviations of the results were determined and an analysis of variance using ANOVA was applied to know the contribution of each controllable factor on the compressive strength, which reached a maximum value of 138.12 MPa. Finally, a mix design is proposed to obtain UHPRC by applying a simple manufacturing procedure using commercial materials, with which a high performance concrete can be obtained, reaching at least 70% of its strength in seven days.
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Cobzac, Vitalie, Mariana Jian, Tatiana Globa, and Viorel Nacu. "Joint cartilage experimental defect regeneration by hierarchic biphasic combined grafts." Moldovan Medical Journal 65, no. 2 (December 2022): 20–29. http://dx.doi.org/10.52418/moldovan-med-j.65-2.22.03.
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Background: The existing surgical techniques used to regenerate articular cartilage fail. Utilisation of hierarchical, biphasic structures obtained from osteochondral tissue, through demineralisation, decellularization, longitudinal perforation and combination with chondroprogenitor cells, presents a high potential in cartilage defects regeneration. Material and methods: The research was performed on 36 rabbits, separated equally in two experimental and one control group. In the experimental groups, the experimental osteochondral defects of 4-4.5 mm in depth, were performed with a 3.7 drill bit at the level of weight bearing surface of the medial femoral condyle. In the 1st group the defects were treated with grafts combined with autologous chondrocytes, and in the 2nd group with grafts combined with autologous mesenchymal stem cells. In the control group, cartilaginous defects were treated by transferring the osteochondral plugs taken from the trochlear groove. The rabbits were removed from the experiment at 6 and 12 weeks. The results were evaluated by Unified Histological Score of Regenerated Cartilage (UHSRC). Results: At 6 weeks, according to UHSRC, the 1st group had 28.33±1.53 points, the 2nd group –27.67±2.08 points and the control group –26.33±1.53 points (p˃0.1; p˃0.2). At 12 weeks the 1st group had 18.68±5 points, the 2nd group –14.89±3.76 points and the control group –17.22 ±4.84 points (p˃0.5; p˃0.2). Conclusions: According to UHSRC, the experimental groups don’t show a significant difference compared to the control group at 6 and 12 weeks, also the quality of regenerated cartilage is poor.
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Govender, Ireshyn Selvan, Rethabile Mokoena, Stoyan Stoychev, and Previn Naicker. "Urine-HILIC: Automated Sample Preparation for Bottom-Up Urinary Proteome Profiling in Clinical Proteomics." Proteomes 11, no. 4 (September 28, 2023): 29. http://dx.doi.org/10.3390/proteomes11040029.
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Urine provides a diverse source of information related to a patient’s health status and is ideal for clinical proteomics due to its ease of collection. To date, most methods for the preparation of urine samples lack the throughput required to analyze large clinical cohorts. To this end, we developed a novel workflow, urine-HILIC (uHLC), based on an on-bead protein capture, clean-up, and digestion without the need for bottleneck processing steps such as protein precipitation or centrifugation. The workflow was applied to an acute kidney injury (AKI) pilot study. Urine from clinical samples and a pooled sample was subjected to automated sample preparation in a KingFisher™ Flex magnetic handling station using the novel approach based on MagReSyn® HILIC microspheres. For benchmarking, the pooled sample was also prepared using a published protocol based on an on-membrane (OM) protein capture and digestion workflow. Peptides were analyzed by LCMS in data-independent acquisition (DIA) mode using a Dionex Ultimate 3000 UPLC coupled to a Sciex 5600 mass spectrometer. The data were searched in Spectronaut™ 17. Both workflows showed similar peptide and protein identifications in the pooled sample. The uHLC workflow was easier to set up and complete, having less hands-on time than the OM method, with fewer manual processing steps. Lower peptide and protein coefficient of variation was observed in the uHLC technical replicates. Following statistical analysis, candidate protein markers were filtered, at ≥8.35-fold change in abundance, ≥2 unique peptides and ≤1% false discovery rate, and revealed 121 significant, differentially abundant proteins, some of which have known associations with kidney injury. The pilot data derived using this novel workflow provide information on the urinary proteome of patients with AKI. Further exploration in a larger cohort using this novel high-throughput method is warranted.
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Lampropoulos, Andreas, Demetris Nicolaides, Spyridon Paschalis, and Ourania Tsioulou. "Experimental and Numerical Investigation on the Size Effect of Ultrahigh-Performance Fibre-Reinforced Concrete (UHFRC)." Materials 14, no. 19 (September 30, 2021): 5714. http://dx.doi.org/10.3390/ma14195714.
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In the last few years, there has been increasing interest in the use of Ultrahigh-Performance Fibre-Reinforced Concrete (UHPFRC) layers or jackets, which have been proved to be quite effective in strengthening applications. However, to facilitate the extensive use of UHPFRC in strengthening applications, reliable numerical models need to be developed. In the case of UHPFRC, it is common practice to perform either direct tensile or flexural tests to determine the UHPFRC tensile stress–strain models. However, the geometry of the specimens used for the material characterization is, in most cases, significantly different to the geometry of the layers used in strengthening applications which are normally of quite small thickness. Therefore, and since the material properties of UHPFRC are highly dependent on the dimensions of the examined specimens, the so called “size effect” needs to be considered for the development of an improved modelling approach. In this study, direct tensile tests have been used and a constitutive model for the tensile behaviour of UHPFRC is proposed, taking into consideration the size of the finite elements. The efficiency and reliability of the proposed approach has been validated using experimental data on prisms with different geometries, tested in flexure and in direct tension.
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Aiemcharoen, Piyapat, Santad Wichienchot, and Decha Sermwittayawong. "Antioxidant and anti-diabetic activities of crude ethanolic extract from the banana inflorescence of musa (ABB group) namwa maliong." Functional Foods in Health and Disease 12, no. 4 (April 5, 2022): 161. http://dx.doi.org/10.31989/ffhd.v12i4.909.
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Background: Banana inflorescence is one of the edible parts of banana. It is well-known to have antioxidants and anti-diabetic potential health benefits. Methods: In this study, the banana inflorescence from Musa (ABB group) Namwa Mali-Ong was prepared using ethanol extraction and investigated for its biochemical compositions and biological activities. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging, ferric reducing antioxidant power (FRAP), and 2,2’-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) free radical scavenging activity assays were performed. The phytochemical composition of the extract was analyzed using the ultra-high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UHLC-ESI-QTOF/MS) technique. Additionally, the ability of the extract to stimulate glucose in C2C12 myotube was investigated. Results: The ethanolic extract of banana inflorescence contained carbohydrate, protein, phenolic, and flavonoid compounds. The results show that the extract exhibited low-level antioxidant activities. For example, the half-maximal inhibitory concentration (IC50) in the DPPH and ABTS assays was at 27.89 ± 0.054 and 21.33 ± 0.87 mg/mL, respectively. Although the extract possesses low-level antioxidant activities, it stimulated glucose uptake in C2C12 myotubes in a dose- and time-dependent fashion. Consistently, the UHLC-ESI-QTOF/MS analysis in both positive and negative electrospray ionization modes reveals several components in the extract such as phytosphingosine and α-linolenic acid that have previously been shown to exhibit an anti-diabetic activity.Conclusion: The results show that the inflorescence ethanolic extract possesses antioxidant and anti-diabetic activities and may potentially be developed into a health-promoting product such as an anti-diabetic drug. Keywords: antioxidant activity; banana inflorescence; glucose uptake; anti-diabetic; C2C12 myotubes
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Vaishnav, Arti, Abdullah Khan, Qiuhong Zhao, Naresh Bumma, Francesca Cottini, Elvira Umyarova, Nidhi Sharma, Ashley E. Rosko, Don Benson, and Srinivas Devarakonda. "Deletion 1p at Time of Diagnosis of Multiple Myeloma Portends Inferior Outcomes." Blood 142, Supplement 1 (November 28, 2023): 1974. http://dx.doi.org/10.1182/blood-2023-182845.
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Background: Multiple myeloma (MM) is associated with several cytogenetic abnormalities (CA) that influence the disease course, response to treatment and survival. Trisomies and immunoglobulin H chain translocations are primary CA while del(17p), gain(1q), del(1p) and others are secondary CA. Gain (3 copies) and amplification (>3 copies) 1q have been recognized as adverse prognostic markers and incorporated into the second revision of the International Staging System (R2-ISS). However, the role of del(1p) is less well defined, especially in the era of modern myeloma therapeutics. We aimed to analyze the outcomes of newly diagnosed MM (NDMM) patients (pts) with chromosome 1 abnormalities, mainly del 1p, treated with autologous hematopoietic cell transplant (AHCT) consolidation at The Ohio State University. Methods: We identified and reviewed the medical records of all NDMM pts who were treated with AHCT from 1/1/2015-2/13/2019 (n=511). High-risk cytogenetics (HRC) was defined by the presence of del(17p), t(4;14), or t(14;16) similar to R-ISS; standard-risk cytogenetics (SRC) were defined as the absence of HRC. Modified HR cytogenetics (mHRC) included gain/amp 1q and/or t(14;20) in addition to HRC, while ultra high-risk (uHRC) included 2 or more mHRC risk factors. Results: The baseline pt characteristics are presented in Table 1. Of 511 pts transplanted, 453 had cytogenetic data from diagnosis. SRC were seen in 353 pts (77.9%), while 100 (22.1%) had HRC, 156 (34.4%) had mHRC, and 43 (9.5%) had uHRC. Thirty-two (7.1%) pts had del(1p) while 105 (23.2%) had gain 1q and 30 (6.6%) had amp 1q. As expected, compared to SRC pts, pts with HRC, mHRC and uHRC had higher risk of relapse or death. Patients with gain and amp 1q had inferior outcomes in terms of PFS (HR 1.35; 95% CI 1.06-1.73, p=0.016), TTNT (HR 1.84; 95% CI 1.40-2.42, p<0.001) and OS (HR 1.47; 95% CI 1.06-2.02, p=0.02), consistent with published literature. The median PFS, TTNT and OS from AHCT in pts with gain/amp 1q was 3.17 years (y), 3.95y and 7.13y, respectively, compared to 4.01y, 7.60y and 8.21y in pts without gain/amp 1q. Pts with del(1p) had inferior PFS (median 2.43y versus 3.98y; HR 1.75; 95% CI 1.16-2.64, p=0.008), TTNT (median 2.72y versus 6.17y; HR 1.96; 95% CI 1.22-3.14, p=0.005) and OS (median 4.11y versus 8.38y; HR 2.19; 95% CI 1.34-3.58, p=0.002) from AHCT compared to those without del(1p). (Figure 1). Conclusions: In this cohort of NDMM pts that underwent AHCT, del(1p) at diagnosis was an independent predictor of shorter PFS, TTNT and OS. Despite advances in induction regimens, AHCT consolidation and maintenance therapy, del(1p) continues to portend inferior outcomes. Larger analyses are needed to validate the prognostic value of del(1p) and investigate its role in predicting outcomes in MM.
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Baharuddin, Nur Khaida, Fadzli Mohamed Nazri, Ramadhansyah Putra Jaya, and Badorul Hisyam Abu Bakar. "Evaluation of bond strength between fire-damaged normal concrete substance and ultra-high-performance fiber-reinforced concrete as a repair material." World Journal of Engineering 13, no. 5 (October 3, 2016): 461–66. http://dx.doi.org/10.1108/wje-06-2016-0014.
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Purpose This study aims to investigate and compare the interfacial bond characteristics between fire-damaged normal concrete substrate and ultra-high-performance fiber-reinforced concrete (UHPFRC) as a repair material. Design/methodology/approach First, fire-damaged normal concrete was prepared. Then, with a cast surface, the substrate was subjected to different surface moisture conditions. Three types of moisture conditions were set, namely, air dry, saturated surface dry (SSD) and wet. Slant shear and splitting cylinder tests were conducted to determine the interfacial bond strength of the composite. Findings In general, results indicate that surface moisture conditions significantly influence bond strength. The substrate under SSD condition exhibited the highest bond strength. The findings suggest that UHPFRC is a promising material for the repair and reuse of fire-damaged concrete structures. Originality/value This study compares the bond strength between fire-damaged normal concrete and UHPRC.
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Osgouei, Younes Baghaei, Shahriar Tavousi Tafreshi, and Masoud Pourbaba. "Experimental and Numerical Characterization of Non-Proprietary UHPFRC Beam—Parametric Analyses of Mechanical Properties." Buildings 13, no. 6 (June 20, 2023): 1565. http://dx.doi.org/10.3390/buildings13061565.
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Fabrication of ultra-high-performance concrete (UHPC) is costly, especially when commercial materials are used. Additionally, in contrast to conventional concrete, numerical procedures to simulate the behaviour of ultra-high-performance fibre-reinforced concrete (UHPFRC) are very limited. To contribute to the foregoing issues in this field, local materials were used in the fabrication process, while accounting for environmental issues and costs. Micro steel fibres (L: 13 mm, d: 0.16 mm, and ft: 2600 MPa; L: length, d: diameter, ft: tensile strength) were used in 2% volumetric ratios. Compression and indirect tests were carried out on cylindrical and prismatic beams according to international standards. To further enrich the research and contribute to the limited simulation data on UHPFRC, and better comprehension of the parameters, numerical analyses were performed using the ATENA software. Finally, nonlinear regression analyses were employed to capture the deflection-flexural response of the beams. The results were promising, indicating cost-effective fabrication using local materials that met the minimum requirements of UHFRC in terms of compressive strength. Furthermore, inverse analysis proved to be an easy and efficient method for capturing the flexural response of UHPFRC beams.
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Frost, Scott, Larry Lerno, Jerry Zweigenbaum, Hildegarde Heymann, and Susan Ebeler. "Characterization of Red Wine Proanthocyanidins Using a Putative Proanthocyanidin Database, Amide Hydrophilic Interaction Liquid Chromatography (HILIC), and Time-of-Flight Mass Spectrometry." Molecules 23, no. 10 (October 18, 2018): 2687. http://dx.doi.org/10.3390/molecules23102687.
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Proanthocyanidins are complex polymers of flavan-3-ol monomers and play a key sensory and health role in foods and beverages. We describe here a novel method for characterizing wine proanthocyanidins using a theoretical database comprised of the chemical formula and exact mass of 996 compounds. The database was constructed using the four primary grape and wine proanthocyanidin monomers: (epi)catechin, (epi)catechin-3-O-gallate, (epi)gallocatechin, and (epi)gallocatechin-3-O-gallate, each combined in all possible combinations up to a polymerization of 10. The database was queried against spectra collected using ultrahigh performance liquid chromatography (UHLPC) with a hydrophilic interaction liquid chromatography (HILIC) column and coupled to a high-resolution accurate mass quadrupole time-of-flight mass spectrometer (Q-TOF MS). Two wine samples produced with different post fermentation maceration were analyzed using the presented method to demonstrate application for analysis of diverse proanthocyanidins. The first sample was pressed immediately at the end of fermentation when all sugar had been utilized and the second received eight weeks of post fermentation maceration. The HILIC column combined with high resolution tandem mass spectrometry and database matching provided tentative identification of 89 compounds with excellent resolution and without the need for two-dimensional separations. The identified compounds were visualized with Kendrick mass analysis, a simple technique allowing for rapid visualization of which compounds are present in a given sample.
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Safi, Brahim, Amel Aboutair, Mohammed Saidi, Youcef Ghernouti, and Chahrazade Oubraham. "Effect of the heat curing on strength development of ultra-high performance fiber reinforced concrete (UHPFRC) containing dune sand and ground brick waste." Journal of Building Materials and Structures 1, no. 2 (June 6, 2014): 40–46. http://dx.doi.org/10.34118/jbms.v1i2.7.
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This work aims to investigate the strength development of ultra-high performance fiber reinforced concrete (UHPFRC) containing ground dune sand (GDS) and ground brick waste (GWB) as a substitutions of cement and dune sand (DS) as an aggregate. The variables are the nature of addition (GDS and GWB) in the binder and the heat curing at different temperatures (20°C and 60°C) at 7 days of curing. Two temperatures 20°C and 60 °C were applied to samples with intermediate levels for 8 hours in total. In this study, two types of cements (CEMI and CEMII) were used to prepare UHPFRC. The GWB was replaced by GDS at levels of 10, 20 and 30% by weight. The results show that the obtained concretes develop a high mechanical performance with a suitable heat treatment according to the cement type and the used fiber. The compressive strength at 7 days of UHPFRC has increased with heat curing (at 60 °C) compared to that obtained at 28 days and measured at 20 °C. Results show also that values of compressive strength of concrete containing DS are close to those obtained by the control concrete. This study has showed that the dune sand can be used in UHPRC, and that the substitution of the GWB by GDS can provide concretes with acceptable mechanical performance.
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Ma, Liyuan, Qiaoling Yu, Meng Zhuang, Chen Yang, Yuan Liu, Yuling Li, Cheng Liu, Xiaoyan Shen, and Yan Chang. "UHPLC-MS/MS Assay for Quantification of Legubicin, a Novel Doxorubicin-Based Legumain-Activated Prodrug, and Its Application to Pharmacokinetic and Tissue Distribution Studies." Molecules 29, no. 4 (February 8, 2024): 775. http://dx.doi.org/10.3390/molecules29040775.
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Legubicin, a novel prodrug based on doxorubicin, has both albumin-binding and legumain-activating properties. The aim of this study was to develop and validate a UHPLC-MS/MS method for investigating the in vivo pharmacokinetics and tissue distribution profiles of legubicin in rats and tumor-bearing mice following intravenous administration, and to compare this prodrug with the positive control drug doxorubicin. The study employed a UHLC-MS/MS method to determine the levels of albumin-bound of legubicin and two metabolites (free Leu-DOX and DOX) in plasma, tumor, and tissue samples. This method was validated for good selectivity, high sensitivity, excellent extraction recovery, and short run time. The results showed that legubicin was present in the circulation in vivo mainly in a protein-bound form with larger AUC values and lower clearance and distribution, and essentially released small amounts of doxorubicin. Compared to administration of equimolar doses of doxorubicin, legubicin showed increased exposure of the active drug in the tumor and decreased the level of the active drug in the heart and kidney. This study provides valuable information on the pharmacokinetics and tissue distribution of legubicin, implicating its potential as a novel and effective drug candidate for anti-cancer therapies.
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Murillo, Ilda, Marcio M. Andrade, Anel Montes, Jose M. Grasa, and Pilar Giraldo. "Are IgM Hevylite® Immunoglobulin Heavy Chain/Light Chain Analysis a Useful Tool to Differentiate IgM MGUS From Waldenström Macroglobulinemia?" Blood 120, no. 21 (November 16, 2012): 5097. http://dx.doi.org/10.1182/blood.v120.21.5097.5097.
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Abstract Abstract 5097 Background: Monoclonal IgM is the biomarker that characterize to Waldenstrom's macroglobulinemia (WM), a rare low grade B-cell lymphoma derived of the lymphoplasmacytic cell, even serum IgM component also is presented in MGUS. Recently new determinations of heavy chain/light chain immunoglobulins pairs (HLC) have been developed as biomarkers to apply to every day clinical practice. The diagnostic and prognostic potential of these biomarkers is under investigation. The aim of this study is to present our experience in the use of free light chain assay (sFLC) and HLC as biomarkers at diagnostic in order to discriminate between MGUS and WM, and to evaluate their potential prognostic value during disease course. Patients and Methods: A total of 43 patients (pts) were detected as having a serum monoclonal IgM in the Hematology Department of MSUH. Pts were classified as MGUS or WM according to the morphological, immunophenotype characteristics of lymphoplasmacitic bone marrow cells and CT-scan data. Pts were examined every 3–6 months following our clinical protocol in order to detect progression or transformation. Serum samples were collected prior and during treatment and were kept frozen at −70°C since collection and incorporate to our regional Biobank. Analysis of IgM were performed with the sFLC, (Freelite® test, the Binding Site, Birmingham, UK) and the HLC (Hevylite® immunoassay the Binding Site). Freelite® test is a nephelometric measurement of kappa and lambda light chains that circulate not bound to immunoglobulin heavy chain. Hevylite® immunoassay is based on specific polyclonal antibodies that recognize epitopes spanning the junction of the heavy and light chains of the individual immunoglobulin isotypes, it measures specifically IgMkappa and IgMlambda, separately. A normal range of IgM Hevylite assay was produced from normal (blood donor) sera, median (CI 95%) were: IgMkappa, 0. 634 g/L (0. 29–1. 82); IgMlambda, 0. 42g/L (0. 17–0. 94); HLC ratio (HLCR), 1. 6 (0. 95–2. 3). For ease of comparison IgM HLCR was expressed as the involved monoclonal immunoglobulin (iHLC)/uninvolved polyclonal immunoglobulin (uHLC). Results: The study included a series of 25 WM, 18 IgM-MGUS (included 2 IgM-cryoglobulinemia), 36 at diagnosis and 7 at relapse/refractory. The median age was 67. 1 years (13–85); IgM HLCR was 114. 68 (1. 02 – 353) in WM symptomatic, 71. 55 (1. 02 – 286. 43) in WM asymptomatic and 9. 5 (0. 45 – 50. 74) in IgM MGUS (p=0. 003). HLCR was higher in WM patients requiring treatment (n=13) at diagnosis than in pts (n=30) not requiring treatment (113 v 15. 77 p=0. 019) and also HLCR was significantly higher at relapse/refractory (n=9) than in pts (n=34) not relapse (113 v 17. 17 p=0. 012) uHLC was significantly higher in IgM-MGUS than WM to IgMkappa (n=28) and IgMlambda (n=15) iHLC: 0. 37 g/L (0. 11–1. 25) v 0. 1 g/L (0. 02–4. 03), p=0. 022; and 0. 69 g/L (0. 08–4. 09) v 0. 32 g/L (0. 22–0. 63), p=0. 05 respectively. sFLC level was 64 mg/L (10. 88–993) in WM and 31. 7 mg/L (6. 08–141) in IgM MGUS (p=0. 05). sFLC level was higher in WM requiring treatment at diagnosis than in pts not requiring treatment (73. 7 v 36. 85 p=0. 039). sFLC level was not significative in relapse/refractory (p=0. 168), it was not separate between WM asymptomatic and WM symptomatic (p=0. 092). There was a good correlation between HLCR and sFLC ratio (r=0. 3, p=0. 044) but not with sFLC level, HLCR, sFLC level and sFLC ratio did not predict for overall survival (OS) and progression free survival (PFS) in our study. Mean estimated OS was 78. 3 months (95% CI: 53. 67–102. 94) and PFS 69. 7 months (95% CI: 47. 28–92. 13). Conclusion: It seems that HLCR and sFLC could be good biomarkers to differentiate between IgM-MGUS and WM at diagnostic. High levels of HLC and sFLC were also seen in pts requiring treatment. HLCR discriminates WM symptomatic/asymptomatic and progressing pts uHLC levels were significantly higher in IgM-MGUS than WM pts showing that IgM-MGUS have a more robust immune system. Further studies are needed to evaluate their prognostic value. This work has been partially sponsored by a grant from FEHHA Disclosures: No relevant conflicts of interest to declare.
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Napodano, Cecilia, Laura Ioannilli, Valerio Basile, Francesca Gulli, Valeria Carnazzo, Stefano Pignalosa, Luigi Di Biase, et al. "Laboratory and Clinical Settings of Heavy/Light Chain (HLC) Assays in the Management of Monoclonal Gammopathies and Multiple Myeloma." Journal of Personalized Medicine 13, no. 5 (April 27, 2023): 743. http://dx.doi.org/10.3390/jpm13050743.
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The antibody-related immune response is mediated by immunoglobulins (Igs), soluble circulating glycoproteins produced by activated B cells that, upon the recognition of specific epitopes on pathogen surfaces, activate, proliferate, and differentiate into antibody-secreting plasma cells. Although the antibodies are effectors of the humoral immune adaptive response, their overproduction in response to a dysregulated proliferation of clonal plasma cell production in tumoral conditions (i.e., multiple myeloma), enriches the serum and urinary matrices, assuming the crucial role of biomarkers. Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the expansion and accumulation of clonally activated plasma cells in bone marrow, determining the release of high amounts of monoclonal component (MC) that can be detected as intact immunoglobulin (Ig), immunoglobulin fragments, or free light chains (FLCs). The importance of detecting biomarkers for the diagnosis, monitoring, and prognosis of diseases is highlighted by the international guidelines that recommend specific assays for the analysis of intact Igs and FLC. Moreover, a developed assay called Hevylite® allows for the quantification of immunoglobulins that are both involved (iHLC) and not involved (uHLC) in the tumor process; this is a fundamental aspect of following up the patient’s workup and evaluating the progression of disease, together with the treatments response. We here summarize the major points of the complex scenario involving monoclonal gammopathies and MM clinical management in view of advantages derived for the use of Hevylite®.
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Campbell, Lauren, Fotios Panitsas, Supratik Basu, Francis Anyanu, Sophie Lee, Berne Ferry, and Karthik Ramasamy. "Hevylite and Freelite Normalisation Is a Surrogate Marker for MRD Negativity Post-ASCT." Blood 128, no. 22 (December 2, 2016): 4633. http://dx.doi.org/10.1182/blood.v128.22.4633.4633.
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Abstract Introduction Evaluation of minimal residual disease (MRD) in multiple myeloma (MM) by multi-parameter flow cytometry (MFC) is a biomarker for risk of relapse. Applicability of MFC in routine practice has been challenging with suboptimal marrow samples and sampling needed at multiple time points. Sensitive serological assays which can detect MRD and have prognostic utility are needed to optimize the management of MM patients. The HevyliteTM assay (The Binding Site, UK) evaluates serum heavy/light chain ratios for IgG, IgA and IgM. We hypothesised the normalisation of serological markers is a good surrogate for plasma cell reconstitution in a healthy bone marrow (BM) microenvironment. The aim of this study was to prospectively compare Hevyliteand FreeliteTM assays with MFC of BM plasma cells from patients receiving autologous stem cell transplants (ASCT). We wanted to investigate if a correlation exists between MFC MRD negativity and the serological normalisation of Hevylite plus Freelite assays. Methods Hevylite, Freelite, SPEP, IFE on serum and MFC on bone marrow were performed on 23 patients post induction therapy and at a median of 90 days post-ASCT. Serological tests were performed again in available patients at 275 days post-ASCT. The combination of Freelite and Hevylite, which measures involved (iHLCr) and uninvolved (uHLCr) heavy light chain (HLC)-pairs, allows investigation of plasma cell reconstitution and its prognostic value in transplant patients. Six-colour MFC was performed as previously published (Rawstron et al. JCO 2013). IMWG uniform response criteria were used to categorise patients. Kaplan Meier estimates of Progression Free Survival (PFS) from time of transplantation until disease progression or death (whichever came first) were calculated and log-rank test was used for comparisons across groups. Sensitivity, specificity and ROC area analysis were used to assess performance of serologic response tests against flow MRD negativity, which is considered gold standard. Results Total of 23 patients were recruited to the study, 8 female (34.8%), 15 male (65.2%), with median age 61 (46-71). Isotype and ISS distribution were as follows; 11 IgG (47.8%), 4 IgA (17.4%), 1 IgM (4.35%), 7 LC only (30.4%) and 8 ISS1 (34.8%), 6 ISS2 (26.1%), 9 ISS3 (39.1%). Median marrow PC involvement at diagnosis was 45%, (20-90%) (N=18). At diagnosis, median LDH levels 192 IU/L, (153-475), median Hb 109.5 g/l, (72-152), with renal impairment noted in 6/23 (26.1%) and abnormal skeletal survey 15/23 (65.2%). High risk MM FISH was reported in 1/23 (4.35%), unknown 11/23 (47.8%) with rest determined to have standard risk. Median time from start of induction to HDM/ASCT 8 months (6.5-20) and median number of lines of treatment before HDM/ASCT was 1. Two deaths were noted on study. Median follow-up of surviving patients from diagnosis was 31 months (10-42). VGPR or better was achieved in 18/23 (88%) patients post-transplant by IMWG criteria. Hevylite ratio (iHLCr and uHLCr) normalised in 11/23 (48%) patients, with Freelite ratio (FLCr) normalisation in 14/23 (61%). MFC MRD negativity at 3 months post-ASCT was noted in 6/23 (26%) patients, in whom the post-ASCT Hevylite ratio and FLCr were also normalised. Comparing response assessments post-ASCT using standard IMWG criteria, MFC MRD, HLCr normalisation and FLCr normalisation, we found that MFC MRD is more sensitive to pick up residual disease over other tests. MFC MRD positivity correlates with early disease progression as MRD negativity significantly improves PFS outcomes (not reached vs 21 months) p=0.01 (Figure 1a). Patients with both HCLr and FLCr normalisation have significantly better PFS outcomes (not reached vs 21 months) p=0.04 (Figure 1b). ROC curve comparison of MFC MRD negativity and HLCr and FLCr normalisation tests, shows a 100% (95% CI 54.1% - 100%) sensitivity and 82% specificity (95% CI 56.6 - 96.2%) for serological normalisation. This demonstrates that HLCr and FLCr normalisation serves as a useful surrogate marker for MFC MRD negativity in our study. Conclusions We report the first prospective study demonstrating HLCr and FLCr normalisation post-transplant is a useful surrogate marker for flow MRD negativity, which is a widely accepted gold standard. This data requires further validation in a larger cohort of post-ASCT MM patients. Disclosures Ramasamy: Celgene: Honoraria, Research Funding.
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Jiménez Jiménez, Juana, Tiago Pais, Luisa Campos, and Carmen Hernando de Larramendi. "Effect of Different Integration Approaches to the M-Spike Quantification in Serum Protein Electrophoresis and How It Correlates to the New Heavy/Light Chain Assay." Blood 126, no. 23 (December 3, 2015): 5345. http://dx.doi.org/10.1182/blood.v126.23.5345.5345.
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Abstract Introduction To measure the Monoclonal Protein (MP) is essential in monoclonal gammopathies (MG) for both diagnosis and response assessment. However, the M-spike quantification may be affected by the inherent subjectivity and by the opted integration method to determine the area under the M-spike corresponding to the MP in a serum protein electrophoresis (SPE). Co-migration with other serum proteins and strong polyclonal background may also affect the MP accurate measurement. Due to its pivotal role in managing MG, and since new automatized techniques have been developed for the MP quantification, this study aims at compare different M-spike integration methods on the measurement of MP, and compare it to the new Heavy/Light chain assay (HLC/ Hevylite®), which allows to separately quantify, by automated nephelo/turbidimetry, the serum levels of IgG-K, IgG-L, IgA-K, IgA-L, IgM-K and IgM-L. Material and Methods 147 samples from 143 MGUS and MM patients were included. All the samples were analyzed by SPE (SEBIA- HYDRASYS 2) and two integration methods were used for quantifying the MP: MP1: peak defined until baseline; MP2: peak defined excluding the polyclonal part. The size of the paraprotein measured by the MP1 method was used to divide the samples in MP<10g/L and MP>10g/L. Statistical analysis included Passing-Bablok (PB) and Bland-Altman (Analyse-It®) and Mann-Whitney test (GraphPad Prism). Results The MP quantification by the MP1 and MP2 methods was significantly different (medians: 7.4 g/L vs 4.1 g/L, P<0.0001), with a relative difference of -64.36%. When dividing samples according to the MP size, the mean relative difference found was higher in samples with MP<10g/L than MP>10g/L (MP1:-85.02% vs MP2:-28.23%; medians: 5.4g/L vs 2.2g/L, P<0.0001; and 18.45g/L vs 14.65g/L, P=0.0253; respectively). Likewise, the correlation between MP1 and MP2 was good (r=0.991) but it weakened to r=0.864 in samples with MP< 10g/L. Therefore, the two integration methods diverged more in the quantification of small MP. In all analysis, MP1 correlated better than the MP2 method with the involved HLC (iHLC) (r=0.886 and r=0.87, respectively) and the total Ig (r=0.924 and r=0.9, respectively), with lower mean relative differences. The MP1 correlation with iHLC was considerably better in samples with MP>10g/L in respect to MP<10g/L (r=0.837 and r=0.55, respectively). PB analysis further revealed an agreement between MP1 and iHLC quantification in samples with MP>10g/L: iHLC=2.096+1.045PM1 (95%CI: Intercept -3.978 to 5.719; Slope: 0.8568 to 1.320), confirming that Hevylite is a useful tool for the MP quantification. Moreover, PB analysis on the summation of Heavy/Light pairs of the same immunoglobulin isotype resulted in an agreement with the levels of total Immunoglobulin (tIg) (r=0.857. PB: ∑HLC=0.1819+0.9211tIg; 95%CI: Intercept -0.9733 to 1.331; Slope: 0.8454 to 1.006), being slightly better in MP<10g/L than >10g/L, indicating the HLC analysis is valid for small MP measurements. HLC analysis also allows measuring the uninvolved-HLC pair (uHLC), a new immunoparesis parameter than has been suggested to have prognostic value. In this study, 32/34 MM and 49/109 MGUS samples had suppressed levels of uHLC. Interestingly, the MP1 and MP2 correlation with iHLC was better in MM than in GMSI samples (r=0,864 and r=0,857, versus, r=0,678 and r=0,606, respectively), which may be due both to generally higher levels of MP or lower polyclonal background in MM samples. Furthermore, 2/109 MGUS samples resulted in a different risk-of-progression category depending on the method of M-spike integration, with the iHLC being in agreement with the MP1 in one of the samples and discordant with the other. Conclusions The MP measurement by M-spike integration until baseline correlated with the iHLC and total immunoglobulin measurement better than when the M-spike integration excludes the polyclonal part. The good agreement between the iHLC and SPE in the quantification of the monoclonal protein puts this assay as an alternative method especially relevant at low concentration levels, which may help correcting for methodology associated variability within clinical laboratories. Finally, HLC may be easier to standardize than the SPE analysis and could eliminate the need for total Ig quantification. Disclosures Pais: The Binding Site Spain: Employment. Campos:The Binding Site Spain: Employment.
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Rukundo, PM, JK Kikafunda, and A. Oshaug. "Roles and capacity of duty bearers in the realization of the human right to adequate food in Uganda." African Journal of Food, Agriculture, Nutrition and Development 11, no. 48 (December 28, 2011): 5493–509. http://dx.doi.org/10.18697/ajfand.48.10100.
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The right to adequate food recognised under international law provides a strong foundation for eradicating hunger and malnutrition in all nations. Uganda ratified the International Covenant on Economic, Social, and Cultural Rights (ICESCR) in 1987 and thereby committed itself to ensure the realization of the right to adequate food recognised under Article 11 of the Covenant. This study analysed the roles and capacity of duty bearers in the realization of the right to adequate food in Uganda. Structured interviews were held with purposefully selected duty bearers from 11 districts in the country between February and July 2007. Districts were selected by criterion based sampling. Relevant policies, budgets, and legislation were also reviewed, particularly with state obligations on human rights, and capacity of duty bearers in mind. Although this right is expressly recognised in the Food and Nutrition Policy of 2003 in which a multi-sectoral approach is proposed, sector-specific roles are not explicitly defined in Uganda’s institutional and policy framework. Most duty bearer (63%) considered the Ministry of Agriculture, Animal Industry and Fisheries (MAAIF) as being responsible for the delays in implementing the relevant actions for the right to food. The Uganda Human Rights Commission (UHRC) reported receiving inadequate budget resources to support the right to food. Only 20% of duty bearers had knowledge of the General Comment 12, which is an important United Nations instrument that defines and elaborates on the human right to adequate food. Duty bearer’s knowledge of the right to food in the national Constitution had a significant (X2 = 0.003; P<0.05) positive correlation (R=0.283) with membership status to an ad hoc Uganda Food and Nutrition Council (UFNC). A proposed Food and Nutrition Bill had taken over 10 years without being presented to the National Parliament for the process of enactment into law. As such, most of the support for this right came from development partners. Whereas the ministry of health and MAAIF are line ministries in the implementation of food and nutrition policy, the right to food roles of the various duty bearers in Uganda need to be well defined. Capacity development is also needed, particularly related to integrating right to food sector-specific roles into the theoretical development and practical implementation of food and nutrition security programmes at all levels in the country.
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Puig, Noemi, Cristina Agullo, Teresa Contreras, Bruno Paiva, Maria Teresa Cedena Romero, José Juan Pérez, Irene Aires, et al. "Isolated and Dynamic Peripheral Blood Residual Disease Status Characterized By Mass Spectrometry Predicts Outcome in Patients with High Risk Smoldering Multiple Myeloma Treated in the GEM-CESAR Trial." Blood 142, Supplement 1 (November 28, 2023): 645. http://dx.doi.org/10.1182/blood-2023-182964.
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Background: GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the rate of minimal residual disease (MRD) negativity in the bone marrow (BM) assessed by next generation flow (NGF) after autologous stem cell transplantation (ASCT) and sustained 3 and 5 years afterwards. Here, we update the preliminary results presented at ASH2019 about the clinical value of quantitative immunoprecipitation mass spectrometry to assess treatment response in this group of patients. Methods: Pts received induction with six 4-week cycles of KRd (K: 36mg/m 2 twice weekly, R: lenalidomide 25mg po od days 1-21 and d: dexamethasone 40mg po weekly), high-dose melphalan followed by ASCT, consolidation with two further cycles of KRd and up to 2 years of maintenance with Rd (R: 10mg po od, d: 20mg po weekly). Peripheral blood Residual Disease(PRD) was analyzed post-ASCT and at treatment completion (after 2 years of maintenance) using Quantitative Immunoprecipitation Mass Spectrometry with anti IgG/A/M, total k and total l beads using the EXENT ® Solution (The Binding Site, part of Thermo Fisher Scientific). From the 90 pts enrolled in the trial, 61 were analyzed post-ASCT and 35 at the end of treatment. Isotype-matched immunoparesia (IMI) was also evaluated post-ASCT using the heavy/light chain pairs. Kaplan-Meier curves were plotted either from the specific time point investigated or from the last one if dynamics were analyzed. Results: First,PRD was analyzed post-ASCT and at treatment completion and deemed to be positive in 54% (33/61) and 20% (7/35) of patients, respectively. At both time points, PRD assessment discriminated two groups of patients with a very significantly different prognosis: median PFS in PRD+cases post-ASCT was 4.27 years vs not reached in PRD- cases (p=0.0071) (Fig 1A) and after 2 years of maintenance, the median PFS in PRD- cases was not reached vs 1.43 years in PRD+ cases (p=0.0011) (Fig 1B). Importantly, standard response criteria and, more specifically, the achievement of complete response (CR) or better, was not associated with disease outcome. And further, among samples in ³CR, PRD+ was also able to discriminate a group of patients with poorer outcome, with a median PFS of 4.42 years vs not reached in PRD- cases (p=0.0136) Interestingly, when we combined the analysis of the M-protein by mass spectrometry with the identification of severe isotype-matched suppression (uHLC < 50%), PRD+ patients post-ASCT could be further stratified in two subgroups with significantly different median PFS (not reached in those with no severe IMI vs 3.85 years in those with severe IMI, p=0.0384) (Fig 1C). A similar tendency was observed among PRD+cases after 2 years of maintenance (mPFS in those with no severe IMI of 2.5 years vs 9 months in those with severe IMI) although the difference did not reach statistical significance. Then, we analyzed PRD dynamics after ASCT and at the end of treatment. Sustained PRDnegativity during this period was observed in 12 pts (33.3%), and sustained positivity in 6 (16.6%). In 5 pts (13.8%) PRD converted from positive to negative, and in 1 (2.7%) from negative to positive. Whereas sustained PRD+ was associated with a very short median PFS of 1.66 years, patients with sustained PRD- or who converted from PRD+ to PRD- displayed a very favorable outcome with median PFS not reached and significantly different compared to the sustained PRD+ group (p<0,0001) (Fig 1D). Interestingly, the only patient that converted from PRD-to PRD+ had a very poor outcome with a mPFS 3.8 months. By contrast, sustained CR or better according to standard response criteria was not significantly associated with clinical outcome. Conclusion: In this cohort of high-risk smoldering MM patients treated intensively with a curative intention, whereas standard CR or better was not associated with clinical outcome, PRD status defined by mass-spectrometry segregated two groups of patients with different PFS at the 2 time points analyzed. Furthermore, this outcome was better predicted when PRD dynamics were analyzed and/or with the evaluation of severe IMI on PRD+ patients, highlighting once again the relevance of immune recovery as a determinant factor in the evolution of the disease.
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Lakhwani, Sunil, Laura Rosiñol, Noemí Puig, Miguel-Angel Pico-Picos, Laura Medina-González, Joaquín Martínez-López, Bruno Paiva, et al. "Recovery of uninvolved heavy/light chain pair immunoparesis in newly diagnosed transplant-eligible myeloma patients complements the prognostic value of minimal residual disease detection." Haematologica, November 30, 2023. http://dx.doi.org/10.3324/haematol.2023.284154.
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Immunoparesis (IP) in multiple myeloma (MM) patients can be measured by classic assessment of immunoglobulin (Ig) levels or by analysis of the uninvolved heavy/light chain pair of the same immunoglobulin (uHLC) by the Hevylite® assay. In this study we evaluate the prognostic value of recovery from IP measured by classic total Ig and uHLC assessment in newly diagnosed MM transplant-eligible (NDMM-TE) patients with intensive treatment and its association with Minimal Residual Disease (MRD). Patients were enrolled and treated in the PETHEMA/GEM2012MENOS65 trial and continued in the PETHEMA/GEM2014MAIN trial. Total Ig (IgG, IgA and IgM) and uHLC were analyzed in a central laboratory at diagnosis, after consolidation treatment and after the first year of maintenance. MRD was analyzed by next generation flow cytometry after consolidation (sensitivity level 2x10-6). We found no differences in progression free survival (PFS) between patients who recovered and patients who didn’t recover from IP after consolidation when examining classic total Ig and uHLC. However, after the first year of maintenance, in contrast to patients with classic IP, patients with recovery from uHLC IP had longer PFS than patients without recovery, with hazard ratio of 0.42 (CI95% 0.21–0.81; p=0.008). Multivariate analysis with Cox proportional-hazards regression models confirmed recovery from uHLC IP after the first year of maintenance as an independent prognostic factor for PFS, with an increase in C-statistic of 0.05 (-0.04–0.14; p<0.001) when adding uHLC IP recovery. Moreover, we observed that MRD status and uHLC IP recovery affords complementary information for risk stratification. In conclusion, recovery from uHLC IP after one year of maintenance is an independent prognostic factor for PFS in NDMM-TE patients who receive intensive treatment. Immune reconstitution, measured as recovery from uHLC IP, provides complementary prognostic information to MRD assessment.
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Behne, S., L. Myrrhe, and P. Winterhalter. "Entwicklung einer UHLPC‐DAD‐Methode zur Charakterisierung von Carotinoiden in Kartoffeln." Lebensmittelchemie 75, S2 (August 2021). http://dx.doi.org/10.1002/lemi.202158058.
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Agarwal, S., S. Verma, K. Kothiwal, N. Verma, and K. Vishvakarma. "Local solutions by slum communities to deal with summer water scarcity: Learning from Indore, India." European Journal of Public Health 30, Supplement_5 (September 1, 2020). http://dx.doi.org/10.1093/eurpub/ckaa166.150.
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Abstract Issue Government of India's, NITI Aayog reports that 600 million people in India face extreme water stress. Slums and similarly vulnerable urban populations face huge challenges in accessing water for basic needs, increasing in summers. Indore is an extreme water stressed city in India. Methods During Urban Health Resource Centre's (UHRC) program work in slums, including women's groups UHRC forms and trains in 2018 we learnt of acute water scarcity in summers. Women in 16 slums were motivated to evolve and implement possible solutions. Most slum dwellers provide services on low wages to the city. With public bore-wells drying-up, in Feb.- May 2019 UHRC helped women's groups' submit community requests, reminders to elected ward representatives and Municipal offices for free water tankers. UHRC motivated slum families to collectively negotiate with private providers to reduce cost, systematise water supply for more families. In 4 peri-urban slums we strengthened water access relationship between farmers and slum dwellers. Results During Feb.-May 2019 10 of the 16 slums received free water tankers from Municipal Corporation. More population of 4 peri-urban slums accessed water from farmer's tube-well. Slum families evolved coping mechanisms of storing more general use water in underground tanks or many cans. Families with larger storage shared water with needy families demonstrating social cooperation. Lessons Trained and mentored slum women's groups gently negotiating with elected ward-level politicians and municipal officials helps in provision of free water tankers in summers. This strategy to get govt. water supply in slums is adaptable in fast growing Indian cities. Owing to geographical proximity, rural-urban cooperation can help slums in city's fringes obtain water from farmer tube-wells used for irrigation. Fostering community cooperation helps more needy families get water. Key messages Slum communities develop local mechanisms to access and store water which need to be understood by civil society organisations and Government to improve solutions for water supply in summer months. Slum women emerge as dynamic actors to improve the lives of both women and men (Sen, 2000). In this case women help negotiate for and foster community cooperation for water, store more water.
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Andrade-Campos, Marcio, Ilda Murillo-Flórez, Ramón García-Sanz, and Pilar Giraldo. "Immunoparesis in IgM gammopathies as a useful biomarker to predict disease progression." Clinical Chemistry and Laboratory Medicine (CCLM) 55, no. 10 (January 1, 2017). http://dx.doi.org/10.1515/cclm-2016-0748.
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AbstractBackground:The management of IgM monoclonal gammopathies undetermined significance (IgM-MGUS) and Waldenstrom’s macroglobulinemia (WM) may be challenging. Modern immunoassays that quantify specific monoclonal heavy and light chain immunoglobulins are promising for their use in these applications.Methods:Ninety consecutive patients (39 IgM-MGUS, 32 indolent WM [iWM], and 19 WM) seen between January 2007 and March 2014 were analyzed. Heavy/light chain (HLC) and serum free light chains assays (FLC) were determined at diagnosis to study their utility as biomarkers in IgM monoclonal gammopathies.Results:The HLC involved to uninvolved IgM ratios (iHLC/uHLC) showed a progressive increase when going from IgM-MGUS, to iWM and to WM (p=0.002). Furthermore, an iHLC/uHLC>62 identified a group of iWM patients with a shorter time-to-progression (TTP) (108 vs. 133 months, p=0.033). Separate analysis of the involved and uninvolved components showed that only the suppression of the uninvolvedimmunoglobulin was predictive of shorter TTP (HR=3.04, p=0.03) suggesting that it could be the majorcontributor to the prognostic value of the Hevylite assay. Additionally, a multivariate analysis showed that immunosuppression (either classical immunoparesis or Hevylite immunosuppression) was an independent prognostic factor (p=0.016) reinforcing its relevance in the disease mechanism. Finally, monoclonal sFLC levels were highest in WM patients, with 83% presenting values>60 mg/L.Conclusions:The results suggest that the levels of immunosuppression and/or the iHLC/uHLC ratio of IgM immunoglobulins measured by Hevylite are associated with greater disease activity which significantly impacts in the outcome of WM patients and may also help in the differentiation of IgMMGUS from iWM.
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Tanna, Nikunj, Robert S. Plumb, Billy J. Molloy, Paul D. Rainville, and Ian D. Wilson. "Enhanced Chromatographic Efficiency Obtained with Vacuum Jacketed Columns Facilitates the Rapid UHLPC/MS/MS-Based Analysis of Fasiglifam in Rat Plasma." SSRN Electronic Journal, 2022. http://dx.doi.org/10.2139/ssrn.4225414.
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Levy-Booth, David J., Laura E. Navas, Morgan M. Fetherolf, Li-Yang Liu, Thomas Dalhuisen, Scott Renneckar, Lindsay D. Eltis, and William W. Mohn. "Discovery of lignin-transforming bacteria and enzymes in thermophilic environments using stable isotope probing." ISME Journal, May 2, 2022. http://dx.doi.org/10.1038/s41396-022-01241-8.
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AbstractCharacterizing microorganisms and enzymes involved in lignin biodegradation in thermal ecosystems can identify thermostable biocatalysts. We integrated stable isotope probing (SIP), genome-resolved metagenomics, and enzyme characterization to investigate the degradation of high-molecular weight, 13C-ring-labeled synthetic lignin by microbial communities from moderately thermophilic hot spring sediment (52 °C) and a woody “hog fuel” pile (53 and 62 °C zones). 13C-Lignin degradation was monitored using IR-GCMS of 13CO2, and isotopic enrichment of DNA was measured with UHLPC-MS/MS. Assembly of 42 metagenomic libraries (72 Gb) yielded 344 contig bins, from which 125 draft genomes were produced. Fourteen genomes were significantly enriched with 13C from lignin, including genomes of Actinomycetes (Thermoleophilaceae, Solirubrobacteraceae, Rubrobacter sp.), Firmicutes (Kyrpidia sp., Alicyclobacillus sp.) and Gammaproteobacteria (Steroidobacteraceae). We employed multiple approaches to screen genomes for genes encoding putative ligninases and pathways for aromatic compound degradation. Our analysis identified several novel laccase-like multi-copper oxidase (LMCO) genes in 13C-enriched genomes. One of these LMCOs was heterologously expressed and shown to oxidize lignin model compounds and minimally transformed lignin. This study elucidated bacterial lignin depolymerization and mineralization in thermal ecosystems, establishing new possibilities for the efficient valorization of lignin at elevated temperature.
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Hakim, Lukman, and Vici Handalusia. "Management of Local Community-Based Tourism in West Sekotong Village – West Lombok Regency." JOURNAL OF ECONOMICS, FINANCE AND MANAGEMENT STUDIES 06, no. 06 (June 26, 2023). http://dx.doi.org/10.47191/jefms/v6-i6-50.
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The concept of CBT (community base tourism) in the management of a tourism object is a rational choice and answer to various weaknesses with the G + B (government and business world) approach. In CBT's view, management is also carried out by the local community/local community, so the pattern becomes G+B+C. This study aims to describe forms of tourism management by local communities, and their relationship with G+B. Besides that, the research seeks to explore the operationalization of one aspect of Sapta Pesona into programs/activities that have been carried out by the local community. The research location is in West Sekotong Village, West Lombok Regency, with key informants as respondents. The survey was also conducted on domestic tourists to get their opinion in the form of an assessment of the implementation of the Cleanliness Program, and as feedback (feed back) on the CBT management model. Full data analysis using qualitative data. The participation of the private sector. Important indicators in the CBT model are decision-making costs (DMC) and financing of the use of local human resources (utilization of human resource cost, UHRC) in building community participation. Based on a survey of domestic tourists on the Cleaning Program (from Sapta Pesona) in Sekotong Barat Village, it was shown that in general they thought the program was 2839relatively good, with a score of 4.104 from the range 1 (=very bad) – 5 (=very good).
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Raman, Maitreyi, Ramana Vishnubhotla, Hena R. Ramay, Maria C. B. Gonçalves, Andrea S. Shin, Dhanashri Pawale, Balachundhar Subramaniam, and Senthilkumar Sadhasivam. "Isha yoga practices, vegan diet, and participation in Samyama meditation retreat: impact on the gut microbiome & metabolome – a non-randomized trial." BMC Complementary Medicine and Therapies 23, no. 1 (April 5, 2023). http://dx.doi.org/10.1186/s12906-023-03935-8.
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Abstract Background Growing evidence suggests a role for gut bacteria and their metabolites in host-signaling responses along the gut-brain axis which may impact mental health. Meditation is increasingly utilized to combat stress, anxiety, and depression symptoms. However, its impact on the microbiome remains unclear. This study observes the effects of preparation and participation in an advanced meditation program (Samyama) implemented with a vegan diet including 50% raw foods, on gut microbiome and metabolites profiles. Methods There were 288 subjects for this study. Stool samples were collected at 3-time points for meditators and household controls. Meditators prepared for 2 months for the Samyama, incorporating daily yoga and meditation practices with a vegan diet including 50% raw foods. Subjects were requested to submit stool samples for 3 time points – 2 months before Samyama (T1), right before Samyama (T2), and 3 months following Samyama (T3). 16 s rRNA sequencing was used to study participants' microbiome. Alpha and beta diversities along with short-chain fatty acid (SCFA) were assessed. Metabolomics were performed on a mass spectrometer coupled to a UHLPC system and analyzed by El-MAVEN software. Results Alpha diversity showed no significant differences between meditators and controls, while beta diversity showed significant changes (padj = 0.001) after Samyama in meditators’ microbiota composition. After the preparation phase, changes in branched short-chain fatty acids, higher levels of iso-valerate (padj = 0.02) and iso-buytrate (padj = 0.019) were observed at T2 in meditators. Other metabolites were also observed to have changed in meditators at timepoint T2. Conclusion This study examined the impact of an advanced meditation program combined with a vegan diet on the gut microbiome. There was an increase in beneficial bacteria even three months after the completion of the Samyama program. Further study is warranted to validate current observations and investigate the significance and mechanisms of action related to diet, meditation, and microbial composition and function, on psychological processes, including mood. Trial registration Registration number: NCT04366544; Registered on 29/04/2020.
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Wone, Bernard W. M., Jason M. Kinchen, and David L. Swanson. "Seasonal Metabotypes in Small Birds." FASEB Journal 31, S1 (April 2017). http://dx.doi.org/10.1096/fasebj.31.1_supplement.874.2.
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Seasonal changes present challenges to free living birds, such as alterations to food availability and type, as well as metabolic adjustments to cold conditions. To better understand the mechanistic basis of this metabolic flexibility, we conducted a large‐scale metabolic profiling of pectoralis muscle in black‐capped chickadees (BCCH) and American goldfinches (AMGO) during summer and winter seasons. These muscle samples were analyzed using non‐biased, global metabolomics profiling technology based on UHLC/MS/MS2 and GC/MS platforms. A total of 582 metabolites were characterized for summer and winter seasons. Comparison of global biochemical profiles in avian muscle revealed several metabolomic differences. Notably, BCCH showed greater than 2‐fold enrichment in advanced glycation end‐product, ceramides, creatine, branched fatty acid, ketone, and purine and pyrimidine metabolic pathways, whereas AMGO showed greater than 2‐fold enrichment in advanced glycation end‐product, ceramides, disaccharides and oligosaccharides, ascorbate and alderate, glutamate, lysine, and alanine and aspartate metabolic pathways. Declined levels in amino acids might reflect decreasing dietary protein intake and/or protein sparing to conserve muscle for thermogenesis in both bird species during winter. Concomitant decreased abundances in TCA cycle metabolites suggest faster cycling of the oxidative phosphorylation pathway to meet the metabolic demands of thermogenesis during winter. Accordingly, BCCH displayed shifts toward lipid oxidation with seasonal change, whereas AMGO showed declines in ketone bodies suggesting increased energy demands or subtle changes in substrate availability with seasonal change. Interestingly, increased levels of tryptophan metabolites, such as serotonin and tryptophan betaine, were observed for both species during winter season. Collectively, our results provide an unprecedented view into the complex biochemical regulatory events orchestrating seasonal metabolic phenotypes.Support or Funding InformationThis material is based upon work supported by the University of South Dakota start up funds.
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Wone, Bernard W. M., and David L. Swanson. "Metabolic Profiling and Integration of Metabolomic and Transcriptomic Data From Pectoralis Muscle Reveal Winter-Adaptive Metabolic Responses of Black-Capped Chickadee and American Goldfinch." Frontiers in Ecology and Evolution 10 (April 12, 2022). http://dx.doi.org/10.3389/fevo.2022.866130.
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Seasonal changes, such as alterations in food availability or type and cold conditions, present challenges to free-living birds living in highly seasonal climates. Small birds respond to such challenges through seasonal metabolic flexibility, which better matches seasonal metabolic phenotypes to environmental conditions and can improve fitness. To better understand the mechanistic basis of this metabolic flexibility, we conducted a large-scale metabolic profiling of pectoralis muscle in black-capped chickadees (Poecile atricapillus) and American goldfinches (Spinus tristis), which are small, year-round bird species of temperate-zones. We analyzed muscle samples using non-biased, global metabolomics profiling technology based on UHLC/MS/MS2 platforms. A total of 582 metabolites was characterized for summer and winter season samples. Chickadees showed greater seasonal separation of global metabolite profiles than goldfinches, which is consistent with previous transcriptomic studies of pectoralis muscle in these two species. Reduced levels of amino acids during winter occurred in both species and might reflect decreasing dietary protein intake, amino acid shuttling to other pathways for thermogenesis and/or elevated rates of protein turnover in the pectoralis muscle. Concomitant decreased abundances in tricarboxylic acid cycle (TCA) metabolites suggest faster cycling of the oxidative phosphorylation pathway in winter to meet the metabolic demands of thermogenesis. Accordingly, chickadees displayed shifts toward lipid oxidation in winter, whereas goldfinches showed winter declines in ketone bodies, which suggests increased energy demand or subtle changes in substrate availability. Beyond the winter-specific changes in metabolite abundances, integration of the metabolomic and the transcriptomic data revealed a landscape of gene–metabolite associations related to the winter-adaptive metabolic response. This landscape of gene–metabolite pairs was overrepresented by pathways associated with transport of small molecules, metabolism of amino acids and derivatives, activation and biosynthesis of fatty acid derivatives, and biosynthesis and metabolism of nicotinate and nicotinamide derivatives. Collectively, our results suggest that increased levels of NADH and its derivatives in the pectoralis muscle are a potential novel mechanism for increasing winter metabolic output, fueled by lipids, for thermogenesis during winter.
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Agarwal, S., N. Verma, S. Verma, K. Vishvakarma, and K. Kothiwal. "Vegetable gardening in slum homes for food security especially in COVID-19 and well-being in India." European Journal of Public Health 31, Supplement_3 (October 1, 2021). http://dx.doi.org/10.1093/eurpub/ckab165.277.
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Abstract Issue With livelihood loss, uncertain earning, slum families are often food insecure, at risk of undernutrition particularly during COVID-19 in Indian and other LMIC cities. While wheat flour was provided free during lockdown, later at subsidized costs and during non-COVID times, vegetables need to be bought at market price. Methods UHRC provided seeds, encouraged families to grow vegetables in slums of Indore, India for five years. In 2019-20 and 20-21, data was gathered through interviews, observations in 20 slums (where >15 families grew vegetables). Results Uptake of seeds increased from 900 families in 2019-20 to 1200 in 20-21. With sharing of surplus harvest, 70,000 persons benefited in 2020-21. Families overcame food insecurity by arranging just wheat flour and cooked a vegetable for a meal. Used paint tubs, broken buckets and small spaces were used. Creepers were made to climb on roofs, walls, trees. Green cover increased to > 8 acres in 2021. The practice saves valuable family resources particularly in COVID-19 distress through provision of vegetables for family consumption. Lessons Perseverant efforts are key and help build a ‘fairer, healthier world'. Yield per family increased as they grow with incremental confidence. Despite small spaces slum families creatively grew vegetables. Children and youth help overcome constraints and are key actors. Early adopters serve as motivators and champions for subsequent adopters who begin growing vegetables on observing neighbours, friends grow vegetables and share with them. Nurturing plants, seeing vegetables grow fostered positivity, hope, motivation to grow every year, enhanced self-worth, and a positive feeling about their abode. People particularly children and youth learn how eating home-grown vegetables reduces carbon footprint of purchased vegetables transported to urban markets, save cost and overcome food insecurity. They reduce ambient air temperature to cool urban spaces. Key messages Despite small spaces, slum families grow, share vegetables, feel accomplished, enable food security, social cooperation, all crucial to well-being of slum populations. Methods used and lessons learnt of perseveringly motivating slum families have the potential of replication/adaptation in cities of India and other LMICs.