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

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

Interpreting clinical trial data in multiple myeloma: translating findings to the real-world setting

Substantial improvements in survival have been seen in multiple myeloma (MM) over recent years, associated with the introduction and widespread use of multiple novel agents and regimens, as well as the emerging treatment paradigm of continuous or long-term therapy. However, these therapies and approaches may have limitations in the community setting, associated with toxicity burden, patient burden, and other factors including cost. Consequently, despite improvements in efficacy in the rigorously controlled clinical trials setting, the same results are not always achieved in real-world practice. Furthermore, the large number of different treatment options and regimens under investigation in various MM settings precludes the feasibility of obtaining head-to-head clinical trial data, and there is a temptation to use cross-trial comparisons to evaluate data across regimens. However, multiple aspects, including patient-related, disease-related, and treatment-related factors, can influence clinical trial outcomes and lead to differences between studies that may confound direct comparisons between data. In this review, we explore the various factors requiring attention when evaluating clinical trial data across available agents/regimens, as well as other considerations that may impact the translation of these findings into everyday MM management. We also investigate discrepancies between clinical trial efficacy and real-world effectiveness through a literature review of non-clinical trial data in relapsed/ refractory MM on novel agent−based regimens and evaluate these data in the context of phase 3 trial results for recently approved and commonly used regimens. We thereby demonstrate the complexity of interpreting data across clinical studies in MM, as well as between clinical studies and routine-care analyses, with the aim to help clinicians consider all the necessary issues when tailoring individual patients’ treatment approaches

Clinical predictors of long-term survival in newly diagnosed transplant eligible multiple myeloma - an IMWG Research Project

Purpose: multiple myeloma is considered an incurable hematologic cancer but a subset of patients can achieve long-term remissions and survival. The present study examines the clinical features of long-term survival as it correlates to depth of disease response. Patients & Methods: this was a multi-institutional, international, retrospective analysis of high-dose melphalan-autologous stem cell transplant (HDM-ASCT) eligible MM patients included in clinical trials. Clinical variable and survival data were collected from 7291 MM patients from Czech Republic, France, Germany, Italy, Korea, Spain, the Nordic Myeloma Study Group and the United States. Kaplan–Meier curves were used to assess progression-free survival (PFS) and overall survival (OS). Relative survival (RS) and statistical cure fractions (CF) were computed for all patients with available data. Results: achieving CR at 1 year was associated with superior PFS (median PFS 3.3 years vs. 2.6 years, p < 0.0001) as well as OS (median OS 8.5 years vs. 6.3 years, p < 0.0001). Clinical variables at diagnosis associated with 5-year survival and 10-year survival were compared with those associated with 2-year death. In multivariate analysis, age over 65 years (OR 1.87, p = 0.002), IgA Isotype (OR 1.53, p = 0.004), low albumin < 3.5 g/dL (OR = 1.36, p = 0.023), elevated beta 2 microglobulin ≥ 3.5 mg/dL (OR 1.86, p < 0.001), serum creatinine levels ≥ 2 mg/dL (OR 1.77, p = 0.005), hemoglobin levels < 10 g/dL (OR 1.55, p = 0.003), and platelet count < 150k/μL (OR 2.26, p < 0.001) appeared to be negatively associated with 10-year survival. The relative survival for the cohort was ~0.9, and the statistical cure fraction was 14.3%. Conclusions: these data identify CR as an important predictor of long-term survival for HDM-ASCT eligible MM patients. They also identify clinical variables reflective of higher disease burden as poor prognostic markers for long-term survival

Mitigation of quorum sensing mediated virulence factors of Pseudomonas aeruginosa: the role of Meldrum’s acid activated furan

The rapid emergence of drug resistant pathogens is a major threat which has warranted the development of alternative strategies to combat infectious diseases. In this work, we have tested the anti-virulent activity of Meldrum’s acid activated furan (MAF) and 1,3-dimethyl barbituric acid activated furan (BAF) against Chromobacterium violaceum and Pseudomonas aeruginosa. It was found that MAF significantly reduced the violacein production and biofilm formation of C. violaceum at sub-inhibitory concentrations. The quorum sensing (QS) regulated virulence factors of P. aeruginosa including biofilm formation, motility, pigment production, and elastase activity were also found to be reduced considerably at sub-inhibitory concentrations of MAF. Additionally, MAF downregulated the expression of genes in the QS circuitry of P. aeruginosa, demonstrating the potential of MAF in lowering the pathogenicity of P. aeruginosa. In silico studies demonstrated the potential of MAF to compete with the signaling molecules of C. violaceum and P. aeruginosa for the QS receptor interaction. In vivo studies using Caenorhabditis elegans demonstrated the anti-pathogenicity of MAF by enhancing the survival of P. aeruginosa-infected C. elegans. These results suggest that activated furan compounds could be potential inhibitors of QS-mediated virulence factors in C. violaceum and P. aeruginosa, encouraging their use in combating multidrug-resistant pathogens

International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM)

Smoldering multiple myeloma (SMM) is an asymptomatic precursor state of multiple myeloma (MM). Recently, MM was redefined to include biomarkers predicting a high risk of progression from SMM, thus necessitating a redefinition of SMM and its risk stratification. We assembled a large cohort of SMM patients meeting the revised IMWG criteria to develop a new risk stratification system. We included 1996 patients, and using stepwise selection and multivariable analysis, we identified three independent factors predicting progression risk at 2 years: serum M-protein >2 g/dL (HR: 2.1), involved to uninvolved free light-chain ratio >20 (HR: 2.7), and marrow plasma cell infiltration >20% (HR: 2.4). This translates into 3 categories with increasing 2-year progression risk: 6% for low risk (38%; no risk factors, HR: 1); 18% for intermediate risk (33%; 1 factor; HR: 3.0), and 44% for high risk (29%; 2–3 factors). Addition of cytogenetic abnormalities (t(4;14), t(14;16), +1q, and/or del13q) allowed separation into 4 groups (low risk with 0, low intermediate risk with 1, intermediate risk with 2, and high risk with ≥3 risk factors) with 6, 23, 46, and 63% risk of progression in 2 years, respectively. The 2/20/20 risk stratification model can be easily implemented to identify high-risk SMM for clinical research and routine practice and will be widely applicable

Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis

Immunoglobulin light-chain (AL) amyloidosis is a rare, incurable plasma cell disorder. Its therapy has benefited immensely from the expanding drug armamentarium available for multiple myeloma. Pomalidomide in combination with weekly dexamethasone (Pom/dex) is active among patients with relapsed myeloma. In the present study, we explored the Pom/dex combination in patients with previously treated AL. Patients were eligible for this prospective phase 2 trial if they had had at least one prior regimen and if they had reasonably preserved organ function. Patients were treated with oral Pom/dex. Thirty-three patients were enrolled. The median age was 66 years. Median time from diagnosis to on-study was 37 months. Eighty-two percent had cardiac involvement. The confirmed hematologic response rate was 48%, with a median time to response of 1.9 months. Organ improvement was documented in 5 patients. The median overall and progression-free survival rates were 28 and 14 months, respectively; the 1-year overall and progression-free survival rates were 76% and 59%, respectively. There was a discordance between the hematologic response and the N-terminal probrain natriuretic peptide response. The most common grade 3-5 adverse events, regardless of attribution, were neutropenia and fatigue. We conclude that pomalidomide appears to be a valuable drug covering an unmet clinical need in patients with previously treated AL. The trial is registered at www.clinicaltrials.gov as NCT00558896. (Blood. 2012;119(23): 5397-5404