Recent progress towards development of effective systemic chemotherapy for the treatment of malignant brain tumors

Systemic chemotherapy has been relatively ineffective in the treatment of malignant brain tumors even though systemic chemotherapy drugs are small molecules that can readily extravasate across the porous blood-brain tumor barrier of malignant brain tumor microvasculature. Small molecule systemic chemotherapy drugs maintain peak blood concentrations for only minutes, and therefore, do not accumulate to therapeutic concentrations within individual brain tumor cells. The physiologic upper limit of pore size in the blood-brain tumor barrier of malignant brain tumor microvasculature is approximately 12 nanometers. Spherical nanoparticles ranging between 7 nm and 10 nm in diameter maintain peak blood concentrations for several hours and are sufficiently smaller than the 12 nm physiologic upper limit of pore size in the blood-brain tumor barrier to accumulate to therapeutic concentrations within individual brain tumor cells. Therefore, nanoparticles bearing chemotherapy that are within the 7 to 10 nm size range can be used to deliver therapeutic concentrations of small molecule chemotherapy drugs across the blood-brain tumor barrier into individual brain tumor cells. The initial therapeutic efficacy of the Gd-G5-doxorubicin dendrimer, an imageable nanoparticle bearing chemotherapy within the 7 to 10 nm size range, has been demonstrated in the orthotopic RG-2 rodent malignant glioma model. Herein I discuss this novel strategy to improve the effectiveness of systemic chemotherapy for the treatment of malignant brain tumors and the therapeutic implications thereof

SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Search for gravitational waves associated with gamma-ray bursts detected by Fermi and Swift during the LIGO–Virgo run O3b

We search for gravitational-wave signals associated with gamma-ray bursts (GRBs) detected by the Fermi and Swift satellites during the second half of the third observing run of Advanced LIGO and Advanced Virgo (2019 November 1 15:00 UTC–2020 March 27 17:00 UTC). We conduct two independent searches: a generic gravitational-wave transients search to analyze 86 GRBs and an analysis to target binary mergers with at least one neutron star as short GRB progenitors for 17 events. We find no significant evidence for gravitational-wave signals associated with any of these GRBs. A weighted binomial test of the combined results finds no evidence for subthreshold gravitational-wave signals associated with this GRB ensemble either. We use several source types and signal morphologies during the searches, resulting in lower bounds on the estimated distance to each GRB. Finally, we constrain the population of low-luminosity short GRBs using results from the first to the third observing runs of Advanced LIGO and Advanced Virgo. The resulting population is in accordance with the local binary neutron star merger rate

Efficacy of absolute alcohol injection compared with band ligation in the eradication of esophageal varices Eficácia da injeção de álcool absoluto comparada com ligadura elástica na erradicação de varizes de esôfago

BACKGROUND: Endoscopic sclerotherapy is an absolute indication for treating esophageal varices. Re-bleeding is common during the treatment period, before all varices become eradicated. AIM: To compare two techniques of endoscopic esophageal varices eradication: sclerotherapy with absolute alcohol and banding ligation. PATIENTS AND METHOD: Forty-six patients with liver cirrhosis and esophageal varices were prospectively randomized into two treatment groups: endoscopic sclerotherapy with absolute alcohol and banding ligation. Patients were included if they had large varices with signs of high bleeding risk. Informed writing consent was obtained from every patient and the Ethics Committee of Federal University of São Paulo, SP, Brazil, approved the study. After eradication, all patients were followed up to 1 year to look for re-bleeding episodes and variceal recurrence. RESULTS: Both groups were similar except that male gender was more common in the sclerotherapy group. There was no statistical difference regarding variceal eradication (78.3% in sclerotherapy group vs 73.9% in the ligation group), recurrence (26.7% vs 42.9%, respectively) and death related to any cause (21.7% vs 13.9%). In the sclerotherapy group more sessions were need to obtain complete variceal eradication. In this group we did observe a high re-bleeding rate (34.8%) and more ulcers associated with retrosternal pain right after the procedure. There was no difference regarding overall morbidity and mortality. CONCLUSIONS: Banding ligation requires fewer sessions than sclerotherapy with absolute alcohol to eradicate esophageal varices. Both methods are equally efficient regarding variceal eradication and recurrence during a short follow-up period.<br>RACIONAL: Escleroterapia endoscópica tem indicação absoluta no tratamento das varizes de esôfago. Ressangramento é comum durante o período de tratamento, antes que as varizes sejam erradicadas. OBJETIVO: Comparar duas técnicas de erradicação endoscópica de varizes de esôfago: escleroterapia com álcool absoluto e ligadura elástica. PACIENTES E MÉTODOS: Quarenta e seis pacientes com cirrose hepática e varizes de esôfago foram prospectivamente randomizados em dois grupos de tratamento: escleroterapia endoscópica com álcool absoluto e ligadura elástica. Os pacientes foram incluídos no estudo se tivessem varizes de grosso calibre com sinais de alto risco de sangramento. Consentimento informado por escrito foi obtido de cada paciente e o estudo foi aprovado pelo Comitê de Ética da instituição onde o estudo foi realizado. Após a erradicação, todos os pacientes foram seguidos durante 1 ano para avaliar a taxa de ressangramento e a recidiva das varizes. RESULTADOS: Ambos os grupos foram parecidos exceto no que se refere ao sexo masculino, mais comum no grupo da escleroterapia. Não houve diferença estatisticamente significante em relação a erradicação das varizes (78,3% no grupo da escleroterapia vs. 73,9% no grupo da ligadura), recidiva (26,7% vs. 42,9%, respectivamente) e mortalidade relacionada a qualquer causa (21,7% vs. 13,9%). No grupo da escleroterapia houve necessidade de maior número de sessões para obtenção da erradicação completa das varizes. Neste mesmo grupo observou-se alta taxa de ressangramento (34,8%) e presença de mais úlceras associadas com dor retroesternal logo após o procedimento. Não houve diferença na morbimortalidade global. CONCLUSÕES: O tratamento com ligadura elástica requer menos sessões do que a escleroterapia com álcool absoluto para erradicar as varizes de esôfago. Ambos os métodos são igualmente eficazes, a curto prazo, no que diz respeito à taxa de erradicação e recidiva das varizes