Retrospective Study of Carfilzomib-Pomalidomide-Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients in a Tertiary Care Hospital in India

Carfilzomib is a second-in class Proteosome Inhibitor and has been approved for Relapsed/Refractory Multiple Myeloma (RRMM). We retrospectively retrieved and analyzed data of KPd combination both biweekly and weekly regimens at our centre from 1 st August 2017 and 31 st May 2020. Sixty-nine patients were treated with KPd with median age of 58 years. Median prior lines of chemotherapy were 2(1-15). Twenty-eight (40.5%) patients underwent autoSCT. Median no. of cycles was 4(1-12) and 3(1-13) with median time to response of 4(2-12) and 2(2-6) months in biweekly and once weekly regimen cohorts respectively. At last follow-up, overall response rate (ORR) was 65.2%{CR-n = 10 (14.5%), VGPR-n = 19 (27.5%), PR-n = 16 (23.2%)} with n = 13(18.8%) patients had PD and relapse was observed in n = 24(34.8%). Thirty (43.4%) patients received maintenance therapy {n = 21(70%)} or autoSCT {n = 9(30%)}. Common toxicities were anemia {n = 11(15.9 %)}, thrombocytopenia (n = 15(21.7%) and neutropenia (n = 16 (23.2%)}, hypertension {n = 28(40.5%)}, peripheral neuropathy (grade1/2) {n = 15(21.7%)}, infections [n = 18(26%) {bacterial [n = 9(13%),viral n = 7(10.1%), fungal n = 8(11.6%)}]. At a median follow-up of 18 months, the estimated median PFS was 11.3 months (95%C.I. 8.3– 14.2) whereas the estimated median OS was 28 months (95%C.I. 20.4-35.5) for the entire cohort. Mortality rate of 2.5% and 10% in two cohorts respectively. Commonest cause of death was PD and sepsis. KPD is a well-tolerated regimen for RRMM, which can be a bridge to ASCT, however with significant side effects.     

Exploring the therapeutic mechanisms of Cassia glauca in diabetes mellitus through network pharmacology,molecular docking and molecular dynamics

Cassia glauca is reported as anti-diabetic medicinal plant and is also used as an ethnomedicine. However, its mode of action as an anti-diabetic agent has not been clearly elucidated. Hence, the present study investigated the probable mechanism of action of C. glauca to manage diabetes mellitus via network pharmacology and molecular docking and simulations studies. The reported bioactives from C. glauca were retrieved from an open-source database, i.e. ChEBI, and their targets were predicted using SwissTargetPrediction. The proteins involved in the pathogenesis of diabetes were identified from the therapeutic target database. The targets involved in diabetes were enriched in STRING, and the pathways involved in diabetes were identified concerning the KEGG. Cytoscape was used to construct the network among bioactives, proteins, and probably regulated pathways, which were analyzed based on edge count. Similarly, molecular docking was performed using the Glide module of the Schrodinger suite against majorly targeted proteins with their respective ligands. Additionally, the drug-likeness score and ADMET profile of the individual bioactives were predicted using MolSoft and admetSAR2.0 respectively. The stability of these complexes were further studied via molecular dynamics simulations and binding energy calculations. Twenty-three bio-actives were retrieved from the ChEBI database in which cassiarin B was predicted to modulate the highest number of proteins involved in diabetes mellitus. Similarly, GO analysis identified the PI3K-Akt signaling pathway to be primarily regulated by modulating the highest number of gene. Likewise, aldose reductase (AKR1B1) was majorly targeted via the bioactives of C. glauca. Similarly, docking study revealed methyl-3,5-di-O-caffeoylquinate (docking score −9.209) to possess the highest binding affinity with AKR1B1. Additionally, drug-likeness prediction identified cassiaoccidentalin B to possess the highest drug-likeness score, i.e. 0.84. The molecular dynamics simulations and the MMGBSA indicate high stability and greater binding energy for the methyl-3,5-di-O-caffeoylquinate (ΔG_bind = −40.33 ± 6.69 kcal mol⁻¹) with AKR1B1, thus complementing results from other experiments. The study identified cassiarin B, cassiaoccidentalin B, and cinnamtannin A2 as lead hits for the anti-diabetic activity of C. glauca. Further, the PI3K-Akt and AKR1B1 were traced as majorly modulated pathway and target, respectively.

Cassia glauca is reported for anti-diabetic action and is also used as an ethnomedicine.     

Gender differences,outcomes and trends among nonagenarian with atrial fibrillation: insight from National Inpatient Sample database

BACKGROUND Nonagenarians(NG),individuals aged≥90 years,constitute an increasing proportion of hospitalizations presenting with atrial fibrillation(AF).However,not much is known about demographics,clinical outcomes,and trends of hospitalizations.Therefore,we analyzed data about hospitalizations and clinical outcomes among NGs with AF over ten years from 2005 to 2014 using a publically available database,the National Inpatient Sample.METHODS All hospitalizations and major outcomes of subjects≥90 years with a primary diagnosis of AF(ICD-9-CM code 427.31)over a ten-year period were assessed in this study by multivariate logistic regression analysis.RESULTS There were more females than males(176,268 females,51,384 males)in this analysis.The number of hospitalizations for AF among NG increased by 50%(17,295 in 2005 to 25,830 in 2014).Males were more likely to undergo cardioversion(6.14%of males vs.5.06%of females,P<0.0001).Over this period,in-hospital mortality declined from 3.21%in 2005 to 2.38%in 2014(P=0.0041),with higher in-hospital mortality in males(3.23%in males vs.2.76%in females,P=0.0138),mean length of hospitalization decreased from 4.53 days to 4.13 days(P<0.0001),the prevalence of congestive heart failure fell from 0.48%to 0.23%(P=0.0257),and the use of anticoagulation increased from 6.09%to 14.54%(P<0.0001).In a multivariate analysis,hospital admission on the weekend,Elixhauser comorbidity index,CHA2DS2VASc score,acute respiratory failure,and the length of hospital stay were associated with a higher risk of in-hospital mortality.CONCLUSIONS From 2005 to 2014,AF-related hospitalizations among NGs increased,more so in in females population,mortality trends improved,rates of anticoagulation increased,and cardioversions increased.Despite the decreasing trend of in-hospital mortality since 2005,the relatively high mortality rate in males warrants further studies.     

Clinical outcomes following proton therapy for adult craniopharyngioma: a single-institution cohort study

Journal of Neuro-Oncology - Craniopharyngioma is a benign tumor that commonly develops within the suprasellar region. The tumor and treatment can have debilitating consequences for pediatric and...     

Ductal paucity and Warkany syndrome in a patient with congenital extrahepatic portocaval shunt

An eleven-year-old clinically dysmorphic and devel-opmentally retarded male child presenting with com-plaints of 5 episodes of recurrent cholestatic jaundice since 3 years of age was evaluated. Imaging revealed features consistent with congenital extrahepatic porto-caval shunt(Abernethy type 1b), multiple regenerative liver nodules and intrahepatic biliary radical dilatation. The presence of ductal paucity and trisomy 8 were con-firmed on liver biopsy and karyotyping. The explanation for unusual and previously unreported features in the present case has been proposed.     

CEACAM-1 Induced CSF3-receptor Downregulation in Bone Marrow Associated With Refractory Neutropenia in Advanced Cirrhosis

Background and Aims: Cirrhosis patients exhibit cyto-penia, and, at times refractory neutropenia to granulocyte colony-stimulating factor (G-CSF), which acts th...     

Incretin Response to a Standard Test Meal in a Rat Model of Sleeve Gastrectomy with Diet-Induced Obesity

Background

Currently, the most effective treatment for obesity is bariatric surgery. Gastroduodenal bypass surgery produces sustained weight loss and improves glycemic control and insulin sensitivity. Previous studies have shown that sleeve gastrectomy (SG) produces similar results and implicate changes in incretin hormone release in these effects.

Methods

Male Sprague–Dawley rats were divided into four groups; lean control (lean), diet-induced obesity (DIO), DIO animals that had undergone SG (SG), and DIO animals that had undergone a sham operation (sham).

Results

After a 2-week recovery period, the incretin response to a standard test meal was measured. Blood sampling was performed in free-moving rats at various time points using chronic vascular access to the right jugular vein. There was a significant increase in the bodyweight of DIO animals fed a high-fat/high-sugar diet compared with the lean animals, which was reversed by SG. DIO caused an impairment of the GLP-1 response to a standard test meal, but not the GIP response. SG resulted in a dramatic increase in the GLP-1 response to a standard test meal but had no effect on the GIP response.

Conclusions

A rapid rise in blood sugar was observed in the SG group following a standard test meal that was followed by reactive hypoglycemia. SG dramatically increases the GLP-1 response to a standard test meal but has no effect on GIP in a rat model of DIO.