BCL2 G quadruplex-binding small molecules: Current status and prospects for the development of next-generation anticancer therapeutics

B cell lymphoma 2 (BCL2) overexpression in a range of human tumors is often related to chemotherapy resistance and poor prognosis. GC-rich regions upstream of the P1 promoter in human BCL2 can form G-quadruplex (G4) structures through the stacking of four Hoogsteen-paired guanine bases. Stabilizing the G4 fold implies the inhibition of BCL2 expression and, thus, small molecules that selectively bind to the G4 are promising anticancer candidates. In this review, we discuss the structural aspects, binding affinity, selectivity, and biological activity of well-characterized BCL2 G4 binding ligands in vitro and in vivo. We also explore future directions in the research and development of G4-based anticancer therapeutics.     

Improving knowledge and trust in vaccines: A survey-based assessment of the potential of the European Union Clinical Trial Regulation No 536/2014 plain language summary to increase health literacy

The European Clinical Trial Regulation No 536/2014 is the first mandate for a non-technical, publicly disclosed, plain language summary (PLS) of clinical trial results. This easy-to-understand summary has the potential to inform the public about clinical trial results and thereby improve health literacy in vaccines.To investigate the utility of the PLS, we undertook 2 online surveys (July/October 2020) in the United Kingdom, the United States and India. Participants were selected by quota sampling to ensure representation of gender, age and parental status. Those lacking interest in vaccine clinical research were excluded. In survey 1, participants were questioned about their interest in and expectations of vaccine trial results. In survey 2, the perceptions of participants to a range of written communication styles used in publicly available PLSs were evaluated.A total of 66 (13%) and 122 (29%) individuals were excluded solely due to lack of interest in vaccine clinical research in surveys 1 and 2, respectively; 450 respondents (150/country) completed survey 1 and 300 (100/country) completed survey 2. In survey 1, there was a correlation (p < 0.01) between claimed knowledge of and trust in vaccines. Healthcare professionals were the most trusted source for vaccine information, while vaccine companies were ranked relatively low. In survey 2, infographic PLS formats were considered easiest to understand, most engaging and the strongest communicators. Emphasizing the main points of the infographics in the text did not improve comprehension or recall. Most respondents (86%) indicated that they would like to see this type of communication in the future.Overall, this research suggests that the PLS, by optimizing content and format, has a potential to increase health literacy, and thereby, as part of a wider integrated communication strategy, build vaccine knowledge and confidence.     

Antigenic cartography using sera from sequence-confirmed SARS-CoV-2 variants of concern infections reveals antigenic divergence of Omicron

1. Download : Download high-res image (182KB)
2. Download : Download full-size image

     

Cholinergic hyperactivity in patients with myasthenia gravis with MuSK antibodies: A neurophysiological study

ObjectivePatients with myasthenia gravis associated with muscle-specific tyrosine kinase antibodies (MuSK-MG) often manifest signs of cholinergic hyperactivity with standard doses of acetylcholinesterase inhibitors (AChE-Is). Aim of the study was to investigate whether repetitive compound muscle action potential (R-CMAP), the neurophysiological correlate of cholinergic hyperactivity, was present in MuSK-MG irrespective of AChE-I treatment.MethodsPatients with confirmed diagnosis of MuSK-MG were consecutively enrolled during follow-up visits, from January 2019 to April 2020. All these subjects underwent the same neurophysiological protocol, including motor nerve conduction studies and repetitive nerve stimulation. In patients taking pyridostigmine, neurophysiological testing was performed at least 12 hours after the last dose. For comparison, the presence of R-CMAP was investigated in 20 consecutive acetylcholine receptor antibody positive myasthenia gravis (AChR-MG) patients.ResultsWe enrolled 25 MuSK-MG patients (20 females), aged 16–79 years at the study time, with disease duration ranging 0.6–48.8 years (median: 17.7 years). R-CMAP was detected in 12/25 (48%) MuSK-MG cases and in none of the AChR-MG controls (p = 0.0003). In the MuSK-MG population, a history of muscle cramps and fasciculations, during low-dose pyridostigmine therapy, was significantly more frequent in R-CMAP positive than in R-CMAP negative patients (100% vs 31%, p = 0.001). At the time of the study, the proportion of patients still symptomatic for MG was higher among R-CMAP positive cases (92% vs 23%, p = 0.0005).ConclusionsCholinergic hyperactivity is a relatively common finding in MuSK-MG patients, independent of AChE-I treatment, and may constitute an intrinsic feature of the disease.SignificanceR-CMAP detection can represent a useful diagnostic clue for MuSK-MG and predicts poor tolerance to AChE-Is.     

Is dose modification or discontinuation of nilotinib necessary in nilotinib-induced hyperbilirubinemia?

Nilotinib is a specific breakpoint cluster region-Abelson leukemia virus-tyrosine kinase inhibitor that is used as an effective first- or second-line treatment in imatinib-resistant chronic myelogenous leukemia (CML) patients. Hepatotoxicity due to nilotinib is a commonly reported side effect; however, abnormal liver function test (LFT) results have been reported in asymptomatic cases. When alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are more than five-fold the upper limit of the normal (ULN) or when the serum total bilirubin level is more than three-fold the ULN, dose modification or discontinuation of nilotinib is recommended, resulting in decreased levels of hematological indicators in certain patients with CML. Nilotinib-induced hyperbilirubinemia typically manifests as indirect bilirubinemia without elevated ALT or AST levels. Such abnormal liver functioning is thus not attributed to the presence of a true histologic lesion of the liver. The underlying mechanism may be related to the inhibition of uridine diphosphate glucuronosyltransferase activity. Therefore, nilotinib dose adjustment is not recommended for this type of hyperbilirubinemia, and in the absence of elevated liver enzyme levels or presence of abnormal LFT findings, physicians should consider maintaining nilotinib dose intensity without modifications.