PINT: Protein–protein Interactions Thermodynamic Database

The first release of Protein–protein Interactions Thermodynamic Database (PINT) contains >1500 data of several thermodynamic parameters along with sequence and structural information, experimental conditions and literature information. Each entry contains numerical data for the free energy change, dissociation constant, association constant, enthalpy change, heat capacity change and so on of the interacting proteins upon binding, which are important for understanding the mechanism of protein–protein interactions. PINT also includes the name and source of the proteins involved in binding, their Protein Information Resource, SWISS-PROT and Protein Data Bank (PDB) codes, secondary structure and solvent accessibility of residues at mutant positions, measuring methods, experimental conditions, such as buffers, ions and additives, and literature information. A WWW interface facilitates users to search data based on various conditions, feasibility to select the terms for output and different sorting options. Further, PINT is cross-linked with other related databases, PIR, SWISS-PROT, PDB and NCBI PUBMED literature database. The database is freely available a

Candidate genes of Waldenström’s macroglobulinemia: current evidence and research

Waldenström’s macroglobulinemia (WM) is a relatively uncommon, indolent malignancy of immunoglobulin M-producing B cells. The World Health Organization classifies it as a lymphoplasmacytic lymphoma and patients typically present with anemia, hepatosplenomegaly and diffuse lymphadenopathies. Historically, the genetic characterization of the disease has been hampered by the relatively low proliferative rate of WM cells, thus making karyotyping challenging. The use of novel technologies such as fluorescence in situ hybridization, gene array, and whole genome sequencing has contributed greatly to establishing candidate genes in the pathophysiology of WM and to identifying potential treatment targets, such as L265P MYD88. The discovery of microRNAs and the recognition of epigenetics as a major modulatory mechanism of oncogene expression and/or oncosuppressor silencing have aided in further understanding the pathogenesis of WM. Once thought to closely resemble multiple myeloma, a cancer of terminally differentiated, immunoglobulin-secreting plasma cells, WM appears to genetically cluster with other indolent B-cell lymphomas such as chronic lymphocytic leukemia/small cell lymphoma. The relative high incidence of familial cases of WM and other B-cell malignancies has been helpful in identifying high-risk gene candidates. In this review, we focus on the established genes involved in the pathogenesis of WM, with special emphasis on the key role of derangement of the nuclear factor kappa B signaling pathway and epigenetic mechanisms

Large refrigerant capacity in superparamagnetic iron nanoparticles embedded in a thin film matrix

A magnetocaloric effect (MCE) with sizable isothermal entropy change (ΔS) maintained over a broad range of temperatures above the blocking temperature is reported for a rare earth-free superparamagnetic nanoparticle system comprising of Fe–TiN heterostructure. Superparamagnetic iron (Fe) particles were embedded in a titanium nitride (TiN) thin film matrix in a TiN/Fe/TiN multilayered pattern using a pulsed laser deposition method. High angle annular dark-field images in conjunction with dispersive energy analysis, recorded using scanning transmission electron microscopy, show a clear presence of alternating layers of Fe and TiN with a distinct atomic number contrast between Fe particles and TiN. Quantitative information about the isothermal entropy change (ΔS) and the magnetocaloric effect in the multilayer Fe–TiN system has been obtained by applying Maxwell relation to the magnetization vs temperature data at various fields. With the absence of a dynamic magnetic hysteresis above the blocking temperature, the negative ΔS as high as 4.18 × 103 J/Km3 (normal or forward MCE) is obtained at 3 T at 300 K

A prospective, open label clinical study to evaluate the safety, efficacy and tolerability of azadvir herbal steam inhaler in asymptomatic, mildly symptomatic COVID-19 patients and health care workers posted to covid wards

Background: COVID-19 patients experience cytokine storm which cause pulmonary and extra-pulmonary complications even with currently available of standard of care. Additional antiviral and immune boosters are the need of hour to treat COVID-19 and to prevent post covid complications.Methods: In this study we enrolled 40 asymptomatic to mild COVID-19 patients to receive azadvir herbal steam inhaler along with standard of care. We evaluated the benefits of azadvir herbal steam inhaler by assessing RT-PCR conversion, clinical outcomes and improvement in immune markers (LDH, CRP, D-DIMER).Results: At the end of the study the immune markers improved significantly in study patients. In mild symptomatic cases IL-6 was 23.2 pg/ml on day 0 and 21.8 pg/ml on day 14. Reduction in IL-6 in mild symptomatic patients was statistically highly significant (p=0.0056). Mean IL-6 in asymptomatic patients was 22.3 pg/ml on day 0 and 21.1 pg/ml on day 14. Reduction in IL-6 in asymptomatic patients was statistically highly significant (p=0.0035).  Mean D-dimer was showing decreasing trend from day 0 to day 14 in mild symptomatic patients. In asymptomatic patients D dimer was 0.8 µg/ml on day 0 and 0.6 µg/ml on day 14. D-dimer decreased significantly from day 0 to day 14 (p value =0.0013). Mean LDH values on day 0 in mild symptomatic patients was 319.4 U/l and 219.3 on day 14. The reduction in LDH values in mild symptomatic patients is statistically significant (p value <0.0122). In asymptomatic patients mean LDH values on day 0 was 237 U/l and 194 U/l on day 14. The reduction in LDH values in asymptomatic group was statistically significant. Mean CRP values in mild symptomatic patients on day 0 was 12.2 mg/l and 3.8 mg/l on day 14. There was significant reduction in CRP values in mild symptomatic group which was statistically significant (p value =0.0546). Mean CRP values in asymptomatic patients on day 0 was 4.9 mg/l and 2.8 mg/l on day 14. There was significant reduction in mean CRP in asymptomatic patients which was statistically significant (p value =0.0446). In the present study all 40 patients (100%) cleared the virus and became negative for RT PCR test within 6 days. None of the patients progressed to severe COVID-19 and none of the patients succumbed to the disease.Conclusions: Azadvir accelerated recovery of COVID-19 patients by RT-PCR conversion, early improvement in clinical symptoms and immune markers in this study. This study results clearly indicates that azadvir has antiviral, immune booster activity and has definitive role in the management of asymptomatic to mild COVID-19 patients along with standard of care (CTRI no. CTRI/2020/06/026181)

Extensional collapse of the Gondwana orogen: evidence from Cambrian mafic magmatism in the Trivandrum Block, southern India

The assembly of Late Neoproterozoic–Cambrian supercontinent Gondwana involved prolonged subduction and accretion generating arc magmatic and accretionary complexes, culminating in collision and formation of high grade metamorphic orogens. Here we report evidence for mafic magmatism associated with post-collisional extension from a suite of gabbroic rocks in the Trivandrum Block of southern Indian Gondwana fragment. Our petrological and geochemical data on these gabbroic suite show that they are analogous to high Fe tholeiitic basalts with evolution of the parental melts dominantly controlled by fractional crystallization. They display enrichment of LILE and LREE and depletion of HFSE with negative anomalies at Zr–Hf and Ti corresponding to subduction zone magmatic regime. The tectonic affinity of the gabbros coupled with their geochemical features endorse a heterogeneous mantle source with collective melt contributions from sub-slab asthenospheric mantle upwelling through slab break-off and arc-related metasomatized mantle wedge, with magma emplacement in subduction to post-collisional intraplate settings. The high Nb contents and positive Nb–Ta anomalies of the rocks are attributed to inflow of asthenospheric melts containing ancient recycled subducted slab components and/or fusion of subducted slab materials owing to upwelling of hot asthenosphere. Zircon grains from the gabbros show magmatic crystallization texture with low U and Pb content. The LA-ICPMS analyses show 206Pb/238U mean ages in the range of 507–494 Ma suggesting Cambrian mafic magmatism. The post-collisional mafic magmatism identified in our study provides new insights into mantle dynamics during the waning stage of the birth of a supercontinent.Qiong-Yan Yang, Sohini Ganguly, E.Shaji, Yunpeng Dong, V. Nanda-Kuma

Guidelines for non-transplant chemotherapy for treatment of systemic AL amyloidosis: EHA-ISA working group

Background: This guideline has been developed jointly by the European Society of Haematology and International Society of Amyloidosis recommending non-transplant chemotherapy treatment for patients with AL amyloidosis. / Methods: A review of literature and grading of evidence as well as expert recommendations by the ESH and ISA guideline committees. / Results and Conclusions: The recommendations of this committee suggest that treatment follows the clinical presentation which determines treatment tolerance tempered by potential side effects to select and modify use of drugs in AL amyloidosis. All patients with AL amyloidosis should be considered for clinical trials where available. Daratumumab-VCD is recommended from most untreated patients (VCD or VMDex if daratumumab is unavailable). At relapse, the two guiding principles are the depth and duration of initial response, use of a class of agents not previously exposed as well as the limitation imposed by patients’ fitness/frailty and end organ damage. Targeted agents like venetoclax need urgent prospective evaluation. Future prospective trials should include advanced stage patients to allow for evidence-based treatment decisions. Therapies targeting amyloid fibrils or those reducing the proteotoxicity of amyloidogenic light chains/oligomers are urgently needed

A gene expression signature distinguishes innate response and resistance to proteasome inhibitors in multiple myeloma

Extensive interindividual variation in response to chemotherapy is a major stumbling block in achieving desirable efficacy in the treatment of cancers, including multiple myeloma (MM). In this study, our goal was to develop a gene expression signature that predicts response specific to proteasome inhibitor (PI) treatment in MM. Using a well-characterized panel of human myeloma cell lines (HMCLs) representing the biological and genetic heterogeneity of MM, we created an in vitro chemosensitivity profile in response to treatment with the four PIs bortezomib, carfilzomib, ixazomib and oprozomib as single agents. Gene expression profiling was performed using next-generation high-throughput RNA-sequencing. Applying machine learning-based computational approaches including the supervised ensemble learning methods Random forest and Random survival forest, we identified a 42-gene expression signature that could not only distinguish good and poor PI response in the HMCL panel, but could also be successfully applied to four different clinical data sets on MM patients undergoing PI-based chemotherapy to distinguish between extraordinary (good and poor) outcomes. Our results demonstrate the use of in vitro modeling and machine learning-based approaches to establish predictive biomarkers of response and resistance to drugs that may serve to better direct myeloma patient treatment options

Phase I/randomized phase II trial of TRC105 plus bevacizumab versus bevacizumab in recurrent glioblastoma: North Central Cancer Treatment Group N1174 (Alliance)

Background Patients with glioblastoma (GBM) have a poor prognosis and limited effective treatment options. Bevacizumab has been approved for treatment of recurrent GBM, but there is questionable survival benefit. Based on preclinical and early clinical data indicating that CD105 upregulation may represent a mechanism of resistance to bevacizumab, we hypothesized that combining bevacizumab with the anti-CD105 antibody TRC105 may improve efficacy in recurrent GBM.Methods Phase I dose-escalation/comparative randomized phase II trial in patients with GBM. During phase I, the maximum tolerated dose (MTD) of TRC105 in combination with bevacizumab was determined. In phase II, patients were randomized 1:1 to TRC105 and bevacizumab or bevacizumab monotherapy. Patients receivedTRC105 (10 mg/kg) weekly and bevacizumab (10 mg/kg) every 2 weeks. Efficacy, as assessed by progression-free survival (PFS), was the primary endpoint; safety, quality of life, and correlative outcomes were also evaluated.Results In total, 15 patients were enrolled in phase I and 101 in phase II; 52 patients were randomized to TRC105 with bevacizumab and 49 to bevacizumab monotherapy. The MTD was determined to be 10 mg/kg TRC105 weekly plus bevacizumab 10 mg/kg every 2 weeks. An increased occurrence of grade &gt;= 3 adverse events was seen in the combination arm, including higher incidences of anemia. Median PFS was similar in both treatment arms: 2.9 months for combination versus 3.2 months for bevacizumab monotherapy (HR = 1.16, 95% CI = 0.75-1.78, P = .51). Quality of life scores were similar for both treatment arms.Conclusions TRC105 in combination with bevacizumab was well tolerated in patients with recurrent GBM, but no difference in efficacy was observed compared to bevacizumab monotherapy

Post-Transplant Outcomes in High-Risk Compared with Non-High-Risk Multiple Myeloma: A CIBMTR Analysis.

Conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) identify high-risk multiple myeloma (HRM) populations characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM populations after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma identified by FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (-Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 HRM patients (17.5%), induction with bortezomib and immunomodulatory agents (imids) was higher compared with non-HRM (56% versus 43%, P \u3c .001) with similar pretransplant complete response (CR) rates (14% versus 16%, P .1). At day 100 post-transplant, at least a very good partial response was 59% in HRM and 61% in non-HRM (P = .6). More HRM patients received post-transplant therapy with bortezomib and imids (26% versus 12%, P = .004). Three-year post-transplant progression-free (PFS) and overall survival (OS) rates in HRM versus non-HRM were 37% versus 49% (P \u3c .001) and 72% versus 85% (P \u3c .001), respectively. At 3 years, PFS for HRM patients with and without post-transplant therapy was 46% (95% confidence interval [CI], 33 to 59) versus 14% (95% CI, 4 to 29) and in non-HRM patients with and without post-transplant therapy 55% (95% CI, 49 to 62) versus 39% (95% CI, 32 to 47); rates of OS for HRM patients with and without post-transplant therapy were 81% (95% CI, 70 to 90) versus 48% (95% CI, 30 to 65) compared with 88% (95% CI, 84 to 92) and 79% (95% CI, 73 to 85) in non-HRM patients with and without post-transplant therapy, respectively. Among patients receiving post-transplant therapy, there was no difference in OS between HRM and non-HRM (P = .08). In addition to HRM, higher stage, less than a CR pretransplant, lack of post-transplant therapy, and African American race were associated with worse OS. In conclusion, we show HRM patients achieve similar day 100 post-transplant responses compared with non-HRM patients, but these responses are not sustained. Post-transplant therapy appeared to improve the poor outcomes of HRM