A multicenter phase I study of cabazitaxel,mitoxantrone, and prednisone for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer: A department of defense prostate cancer clinical trials consortium study

Background

Cabazitaxel plus prednisone has significant activity in patients with chemotherapy-naïve and pretreated metastatic castration-resistant prostate cancer (mCRPC). Mitoxantrone has antitumor activity in mCRPC and nonoverlapping mechanism of action and toxicity profile.

Brief Report: Estimates from 31 countries show the significant impact of COVID-19 excess mortality on the incidence of family bereavement

Excess mortality associated with the COVID-19 pandemic has led many to experience the loss of family members, with significant negative outcomes. We quantify the extent to which these population-wide rates of kin loss represent a departure from levels expected in the absence of COVID-19 excess mortality and consider which demographic groups are most likely to be affected. Results for biological kin in 31 countries indicate dramatic increases in excess kin loss associated with excess mortality and follow a generational pattern consistent with COVID-19 mortality risk by age. During periods of high excess mortality, the number of younger individuals losing a grandparent increased by up to 845 per 100,000, or 1.2 times expected levels (for individuals aged 30 to 44 y in the United Kingdom in April 2020), while the number of older individuals losing a sibling increased by up to 511 per 100,000 or 1.15 times (for individuals aged 65 y and over in Poland in November 2020). Our monthly multicountry estimates of excess kin loss complement existing point estimates of the number of individuals bereaved by COVID-19 mortality [Verdery et al., Proc. Natl. Acad. Sci. U.S.A. 117, 17695–17701 (2020); Kidman et al., JAMA Pediatr. 175, 745–746 (2021); Hillis et al., Lancet 398, 391–402 (2021)] and highlight the role of heterogeneous excess mortality in shaping country experiences.     

Discovery and Structure Optimization of a Series of Isatin Derivatives as Mycobacterium tuberculosis Chorismate Mutase Inhibitors

In this study, the crystal structure of the Mycobacterium tuberculosis (MTB) enzyme chorismate mutase (CM) bound to transition state analogue (PDB: 2FP2) was used as a framework for virtual screening of the BITS‐Pilani in‐house database (2500 compounds) to identify new scaffold. We identified isatin as novel small molecule MTB CM inhibitors; further twenty‐four isatin derivatives were synthesized and evaluated in vitro for their ability to inhibit MTB CM, and activity against M. tuberculosis as steps towards the derivation of structure–activity relationships (SAR) and lead optimization. Compound 3‐(4‐nitrobenzylidene)indolin‐2‐one, 24 emerged as the most promising lead with an IC₅₀ of 1.01 ± 0.22 μm for purified CM and MIC of 23.5 μm for M. tuberculosis, with little or no cytotoxicity.     

Trends in Place of Death for Individuals With Deaths Attributed to Advanced Chronic or End-Stage Kidney Disease in the United States

ContextAn important aspect of end-of-life care, place of death is understudied in advanced chronic (CKD) and end-stage kidney disease (ESKD).ObjectiveWe sought to examine trends and factors associated with where advanced CKD/ESKD patients die.MethodsWe conducted a retrospective cross-sectional study using mortality data from 2003 to 2017 for deaths attributed primarily to advanced CKD/ESKD in the United States.ResultsBetween 2003 and 2017, 222,247 deaths were attributed to advanced CKD/ESKD. From 2003 to 2017, deaths occurring in hospitals declined from 56.0% (n = 5356) to 35.6% (n = 7764), whereas increases occurred in deaths at home (13.5% [n = 1292] to 24.3% [n = 5306]), nursing facilities (18.6% [n = 1776] to 19.3% [n = 4221]), and hospice facilities (0.3% [n = 29] to 13.4% [n = 2917]). Nonwhite race was associated with increased odds of hospital death (Black [OR = 1.59; 95% CI = 1.55, 1.62]; Native American [OR = 1.47; 95% CI = 1.32, 1.63]; Asian [OR = 1.43; 95% CI = 1.32, 1.55] and reduced odds of nursing facility (Black [OR = 0.622; 95% CI = 0.600, 0.645]; Native American [OR = 0.638; 95% CI = 0.572, 0.712]; Asian [OR = 0.574; 95% CI = 0.533, 0.619], or hospice facility death (Black [OR = 0.843; 95% CI = 0.773, 0.918]; Native American [OR = 0.380; 95% CI = 0.289, 0.500]; Asian [OR = 0.609; 95% CI = 0.502, 0.739]). Older age was associated with reduced odds of hospital death (≥85 [OR = 0.334; 95% CI = 0.312, 0.358]) and increased odds of home (≥85 [OR = 1.55; 95% CI = 1.43, 1.68]), nursing facility (≥85 [OR = 3.09; 95% CI = 2.76, 3.45]) or hospice facility death (≥85 [OR = 1.60; 95% CI = 1.49, 1.72]).ConclusionsHospitals remain the most common place of death from advanced CKD/ESKD; however, the proportion of home, nursing facility, and hospice facility deaths have increased.     

Stepwise acquisition of pyrimethamine resistance in the malaria parasite

The spread of high-level pyrimethamine resistance in Africa threatens to curtail the therapeutic lifetime of antifolate antimalarials. We studied the possible evolutionary pathways in the evolution of pyrimethamine resistance using an approach in which all possible mutational intermediates were created by site-directed mutagenesis and assayed for their level of drug resistance. The coding sequence for dihydrofolate reductase (DHFR) from the malaria parasite Plasmodium falciparum was mutagenized, and tests were carried out in Escherichia coli under conditions in which the endogenous bacterial enzyme was selectively inhibited. We studied 4 key amino acid replacements implicated in pyrimethamine resistance: N51I, C59R, S108N, and I164L. Using empirical estimates of the mutational spectrum in P. falciparum and probabilities of fixation based on the relative levels of resistance, we found that the predicted favored pathways of drug resistance are consistent with those reported in previous kinetic studies, as well as DHFR polymorphisms observed in natural populations. We found that 3 pathways account for nearly 90% of the simulated realizations of the evolution of pyrimethamine resistance. The most frequent pathway (S108N and then C59R, N51I, and I164L) accounts for more than half of the simulated realizations. Our results also suggest an explanation for why I164L is detected in Southeast Asia and South America, but not at significant frequencies in Africa.     

Clinical,Biochemical, Tumoural and Mutation Profile of VHL- and MEN2A-Associated Pheochromocytoma: A Comparative Study

World Journal of Surgery - To compare clinical, biochemical, tumoural and mutational characteristics of Von Hippel Lindau Syndrome (VHL)-associated pheochromocytoma (PCC) to multiple endocrine...     

Novel point mutations in the dihydrofolate reductase gene of Plasmodium vivax: evidence for sequential selection by drug pressure

Mutations in the dihydrofolate reductase (dhfr) genes of Plasmodium falciparum and P. vivax are associated with resistance to the antifolate antimalarial drugs. P. vivax dhfr sequences were obtained from 55 P. vivax isolates (isolates Belem and Sal 1, which are established lines originating from Latin America, and isolates from patient samples from Thailand [n = 44], India [n = 5], Iran [n = 2], and Madagascar [n = 2]) by direct sequencing of both strands of the purified PCR product and were compared to the P. vivax dhfr sequence from a P. vivax parasite isolated in Pakistan (isolate ARI/Pakistan), considered to represent the wild-type sequence. In total, 144 P. vivax dhfr mutations were found at only 12 positions, of which 4 have not been described previously. An F-->L mutation at residue 57 had been observed previously, but a novel codon (TTA) resulted in a mutation in seven of the nine mutated variant sequences. A new mutation at residue 117 resulted in S-->T (S-->N has been described previously). These two variants are the same as those observed in the P. falciparum dhfr gene at residue 108, where they are associated with different levels of antifolate resistance. Two novel mutations, I-->L at residue 13 and T-->M at residue 61, appear to be unique to P. vivax. The clinical, epidemiological, and sequence data suggest a sequential pathway for the acquisition of the P. vivax dhfr mutations. Mutations at residues 117 and 58 arise first when drug pressure is applied. Highly mutated genes carry the S-->T rather than the S-->N mutation at residue 117. Mutations at residues 57 and 61 then occur, followed by a fifth mutation at residue 13.     

Patient Willingness to Pay for Reductions in Chronic Low Back Pain and Chronic Neck Pain

Many recommended nonpharmacologic therapies for patients with chronic spinal pain require visits to providers such as acupuncturists and chiropractors. Little information is available to inform third-party payers’ coverage policies regarding ongoing use of these therapies. This study offers contingent valuation-based estimates of patient willingness to pay (WTP) for pain reductions from a large (n = 1,583) sample of patients using ongoing chiropractic care to manage their chronic low back and neck pain. Average WTP estimates were $45.98 (45.8) per month per 1-point reduction in current pain for chronic low back pain and $37.32 (38.0) for chronic neck pain. These estimates met a variety of validity checks including that individuals’ values define a downward-sloping demand curve for these services. Comparing these WTP estimates with patients’ actual use of chiropractic care over the next 3 months indicates that these patients are likely “buying” perceived pain reductions from what they believe their pain would have been if they didn't see their chiropractor—that is, they value maintenance of their current mild pain levels. These results provide some evidence for copay levels and their relationship to patient demand, but call into question ongoing coverage policies that require the documentation of continued improvement or of experienced clinical deterioration with treatment withdrawal.PerspectiveThis study provides estimates of reported WTP for pain reduction from a large sample of patients using chiropractic care to manage their chronic spinal pain and compares these estimates to what these patients do for care over the next 3 months, to inform coverage policies for ongoing care.     

Suppression of the nitric oxide pathway in metastatic renal cell carcinoma patients receiving vascular endothelial growth factor-signaling inhibitors

Therapies that target the vascular endothelial growth factor (VEGF) pathway cause hypertension, but the mechanism remains unknown. This cross-sectional study tested the hypothesis that VEGF inhibition causes hypertension by suppressing VEGF-mediated vasodilatory pathways. Urine was collected from 80 patients with metastatic renal cell carcinoma from 2002 to 2009, 40 at baseline and 40 while on VEGF inhibitors. Measured urinary biomarkers include albumin, metabolites of the nitric oxide (NO) pathway and its downstream effector cGMP, and prostaglandin pathway biomarkers prostaglandin E2, 6-keto prostaglandin F1α, and cAMP, all normalized to urinary creatinine. The mean age in both groups was 61.8 years, 76% were men, and urinary albumin was higher in patients receiving VEGF inhibitors (median: 18.4 versus 4.6 mg/g; P = 0.009). cGMP/creatinine was suppressed in patients on VEGF inhibitors (0.28 versus 0.39 pmol/μg; P = 0.01), with a trend toward suppression of nitrate/creatinine (0.46 versus 0.62 μmol/mg; P = 0.09). Both comparisons were strengthened when patients on bevacizumab were excluded, and only those receiving small molecule tyrosine kinase inhibitors were analyzed (cGMP/creatinine: P = 0.003; nitrate/creatinine: P = 0.01). Prostaglandin E2, 6-keto prostaglandin F1α, and cAMP did not differ between groups. These results suggest that hypertension induced by VEGF inhibitors is mediated by suppression of NO production. Prospective studies are needed to explore whether these biomarkers may be useful predictors of efficacy in patients receiving VEGF-targeted therapies.     

Helicobacter species and pathogenesis of gallbladder cancer

BACKGROUND:Gallbladder cancer(GBC)is a rare disease but a leading cause of cancer-related death worldwide.A number of etiological factors have been implicated in the causation of GBC and pathogenic infection by bacteria is one of these. DATA SOURCES:A PubMed search onhelicobacter,gall- bladder cancer,andbiliary tract malignancieswas done on the topic,and the relevant data were collected,reviewed,and analyzed. RESULTS:Helicobacter is an epsilon proteobacterium that infects the mucosal lining of the human gas...