Concise review: Clinical relevance of drug drug and herb drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein).

Learning Objectives After completing this course, the reader will be able to: Identify important sources of variability in drug exposure caused by drug interactions mediated by P-glycoprotein.Describe how unwanted drug–drug interactions may lead to unexpected serious toxicity or undertreatment.Prevent these interactions by individualizing pharmacotherapy; this means selecting noninteracting drugs or adapting the dose of (the) interacting drug(s). CME Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.co

Loss-of-rescue of Ryr1I4895T-related pathology by the genetic inhibition of the ER stress response mediator CHOP

RYR1 is the gene encoding the ryanodine receptor 1, a calcium release channel of the endo/sarcoplasmic reticulum. I4898T in RYR1 is one of the most common mutations that give rise to central core disease (CCD), with a variable phenotype ranging from mild to severe myopathy to lethal early-onset core-rod myopathy. Mice with the corresponding I4895T mutation in Ryr1 present mild myopathy when the mutation is heterozygous while I4895T homozygous is perinatal-lethal. Here we show that skeletal muscles of I4895T homozygous mice at birth present signs of stress of the endoplasmic reticulum (ER stress) and of the related unfolded protein response (UPR) with increased levels of the maladaptive mediators CHOP and ERO1. To gain information on the role of CHOP in the pathogenesis of RYR1I4895T-related myopathy, we generated compound Ryr1I4895T, Chop knock-out (-/-) mice. However, the genetic deletion of Chop, although it attenuates ER stress in the skeletal muscle of the newborns, does not rescue any phenotypic or functional features of Ryr1I4895T in mice: neither the perinatal-lethal phenotype nor the inability of Ryr1I4895T to respond to its agonist caffeine, but protects from ER stress-induced apoptosis. These findings suggest that genetic deletion of the ER stress response mediator CHOP is not sufficient to counteract the pathological Ryr1I4895T phenotype

Parenting-Related Exhaustion During the Italian COVID-19 Lockdown

Worldwide, the coronavirus disease 2019 (COVID-19) pandemic has generated significant worry, uncertainty, anxiety, sadness, and loneliness. In Italy, these effects have been particularly pronounced. While research on the COVID-19 outbreak has mainly focused on the clinical features of infected patients and the psychological impact on the general population and health professionals, no investigation has yet assessed the psychological impact of the pandemic on parents. In the present research, we conducted a web-based survey of Italian parents to examine the prevalence of parenting-related exhaustion-and to identify its associated risk and protective factors-4 weeks into the lockdown

Heptad stereotypy, S/Q layering, and remote origin of the SARS-CoV-2 fusion core

The fusion of the SARS-CoV-2 virus with cells, a key event in the pathogenesis of Covid-19, depends on the assembly of a six-helix fusion core (FC) formed by portions of the spike protein heptad repeats (HRs) 1 and 2. Despite the critical role in regulating infectivity, its distinctive features, origin, and evolution are scarcely understood. Thus, we undertook a structure-guided positional and compositional analysis of the SARS-CoV-2 FC, in comparison with FCs of related viruses, tracing its origin and ongoing evolution. We found that clustered amino acid substitutions within HR1, distinguishing SARS-CoV-2 from SARS-CoV-1, enhance local heptad stereotypy and increase sharply the FC serine-to-glutamine (S/Q) ratio, determining a neat alternate layering of S-rich and Q-rich subdomains along the post-fusion structure. Strikingly, SARS-CoV-2 ranks among viruses with the highest FC S/Q ratio, together with highly syncytiogenic respiratory pathogens (RSV, NDV), whereas MERS-Cov, HIV, and Ebola viruses display low ratios, and this feature reflects onto S/Q segregation and H-bonding patterns. Our evolutionary analyses revealed that the SARS-CoV-2 FC occurs in other SARS-CoV-1-like Sarbecoviruses identified since 2005 in Hong Kong and adjacent regions, tracing its origin to >50 years ago with a recombination-driven spread. Finally, current mutational trends show that the FC is varying especially in the FC1 evolutionary hotspot. These findings establish a novel analytical framework illuminating the sequence/structure evolution of the SARS-CoV-2 FC, tracing its long history within Sarbecoviruses, and may help rationalize the evolution of the fusion machinery in emerging pathogens and the design of novel therapeutic fusion inhibitors

Potent in vitro antiproliferative properties for a triplatinum cluster toward triple negative breast cancer cells

The trinuclear platinum cluster [Pt3(μ-PBut2)3(CO)3]CF3SO3 (I) was designed featuring the presence of a nearly equilateral platinum triangle bridged by three di-tert-butylphosphide ligands; in addition, each platinum center bears a terminal carbonyl ligand. This triplatinum cluster was initially developed in view of applications in the field of cluster-containing innovative materials. Yet, due to the large success of platinum complexes in cancer treatment, we also decided to explore its cytotoxic and anticancer properties. Accordingly, the solubility profile of this compound in several solvents was preliminarily investigated, revealing a conspicuous solubility in DMSO and DMSO/buffer mixtures; this makes the biological testing of I amenable. UV–Vis measurements showed that the triplatinum cluster is stable for several hours under a variety of conditions, within aqueous environments. No measurable reactivity was observed for I toward two typical model proteins, i.e. lysozyme and cytochrome c. On the contrary, a significant reactivity was evidenced when reacting I with small sulfur-containing ligands. In particular, a pronounced reactivity with reduced glutathione and cysteine emerged from ESI-MS experiments, proving complete formation of I-GSH and I-Cys derivatives, with the loss of a single carbonyl ligand. Starting from these encouraging results, the cytotoxic potential of I was assayed in vitro against a panel of representative cancer cell lines, and potent cytotoxic properties were disclosed. Of particular interest is the finding that the triplatinum species manifests potent antiproliferative properties toward Triple Negative Breast Cancer Cells, often refractory to most anticancer drugs. Owing to the reported encouraging results, a more extensive biological and pharmacological evaluation of this Pt cluster is now warranted to better elucidate its mode of action

Evolution of clinical trials in ovarian cancer management over the past 20 years: never settle down, always go beyond

Purpose. A practice synthesis of available evidence-based medicine data in ovarian cancer (OC), aiming to provide directions for future research. Materials and Methods. We performed a systematic review. PubMed was searched for relevant OC trials between January 2000 and December 2019. Results. Out of 865 references screened, 199 trials were found eligible for inclusion. Most trials were multicenter (83.9%). There was a trend reduction in the number of patients enrolled/per study over the years. Studies testing targeted/biological therapies dominated the second decade (60 trials in 2010-2019 versus 2 trials in 2000-2009). The proportion of trials with positive survival and clinical outcomes significantly increased from 23.8% in early 2000s to 54.1% in the last 5 years. Trials with histology/molecular biomarker criteria were more likely to meet progression-free survival endpoint than those without these selection criteria (69.2% versus 32.6%). Conclusion. This systematic review suggests a trend of increased positive studies, mainly linked to precision medicine

Survival and Prognostic Factors in Patients with Hepatocellular Carcinoma Treated by Percutaneous Ethanol Injection: A 10-Year Experience

The treatment of early and intermediate stage hepatocellular carcinoma (HCC) is still debated. Surgical treatments are considered to be the only curative procedures available, and only for a minority of patients. Percutaneous ethanol injection (PEI) is an established technique for the ablation of HCC nodules, and shows survival rates similar to those of resection. The efficacy of PEI in patients with biopsy-proven viral cirrhosis and small to intermediate inoperable HCC was evaluated. One hundred twenty-seven patients (85 men, 42 women, mean age 63 years, range 51 to 92 years, 115 hepatitis C virus-positive, 12 hepatitis B virus-positive) were enrolled between January 1993 and December 2002. They all underwent a standard PEI procedure and were prospectively followed-up. Overall median survival rate was 28 months (range six to 112 months). The following parameters were associated with a significantly longer survival: nodule diameter smaller than 30 mm (P=0.0480), the presence of a perinodular boundary (P=0.0008), serum alpha-fetoprotein less than 20 ng/mL (P=0.0104), a Child-Pugh A class score (PÃ0.0001) or a Cancer of the Liver Italian Program score of 0 (PÃ0.0001) and the presence or absence of small esophageal varices (P=0.013). The 19 patients with all these favourable characteristics showed an overall median survival of 61 months. An alpha-fetoprotein below 20 ng/mL was associated with significantly longer disease-free survival (P=0.0009). The Child-Pugh and Cancer of the Liver Italian Program scores were effective in predicting prognosis of these patients. In conclusion, PEI still represents a safe and economically sound treatment for HCC

The Energy Landscape of Human Serine Racemase

Human serine racemase is a pyridoxal 5′-phosphate (PLP)-dependent dimeric enzyme that catalyzes the reversible racemization of L-serine and D-serine and their dehydration to pyruvate and ammonia. As D-serine is the co-agonist of the N-methyl-D-aspartate receptors for glutamate, the most abundant excitatory neurotransmitter in the brain, the structure, dynamics, function, regulation and cellular localization of serine racemase have been investigated in detail. Serine racemase belongs to the fold-type II of the PLP-dependent enzyme family and structural models from several orthologs are available. The comparison of structures of serine racemase co-crystallized with or without ligands indicates the presence of at least one open and one closed conformation, suggesting that conformational flexibility plays a relevant role in enzyme regulation. ATP, Mg2+, Ca2+, anions, NADH and protein interactors, as well as the post-translational modifications nitrosylation and phosphorylation, finely tune the racemase and dehydratase activities and their relative reaction rates. Further information on serine racemase structure and dynamics resulted from the search for inhibitors with potential therapeutic applications. The cumulative knowledge on human serine racemase allowed obtaining insights into its conformational landscape and into the mechanisms of cross-talk between the effector binding sites and the active site

Break-apart interphase fluorescence in situ hybridization assay in papillary thyroid carcinoma: on the road to optimizing the cute-off level for RET/PTC rearrangements.

Objective: Chromosomal rearrangements of the RET proto-oncogene is one of the most common molecular events in papillary thyroid carcinoma (PTC). However, their pathogenic role and clinical significance are still debated. This study aimed to investigate the prevalence of RET/PTC rearrangement in a cohort of BRAF WT PTCs by fluorescence in situ hybridization (FISH) and to search a reliable cut-off level in order to distinguish clonal or non-clonal RET changes. Design: Forty BRAF WT PTCs were analyzed by FISH for RET rearrangements. As controls, six BRAFV600E mutated PTCs, 13 follicular adenomas (FA), and ten normal thyroid parenchyma were also analyzed. Methods: We performed FISH analysis on formalin-fixed, paraffin-embedded tissue using a commercially available RET break-apart probe. A cut-off level equivalent to 10.2% of aberrant cells was accepted as significant. To validate FISH results, we analyzed the study cohort by qRT-PCR. Results: Split RETsignals above the cut-off level were observed in 25% (10/40) of PTCs, harboring a percentage of positive cells ranging from 12 to 50%, and in one spontaneous FA (1/13, 7.7%). Overall, the data obtained by FISH matched well with qRTPCR results. Challenging findings were observed in five cases showing a frequency of rearrangement very close to the cut-off. Conclusions: FISH approach represents a powerful tool to estimate the ratio between broken and non-broken RET tumor cells. Establishing a precise FISH cut-off may be useful in the interpretation of the presence of RET rearrangement, primarily when this strategy is used for cytological evaluation or for targeted therapy