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Activation of G_s signaling at mitochondria by mitoDREADD-G_s increases mitochondrial metabolism, leading to better memory in mouse models of dementia, directly linking brain mitochondrial deficits to cognitive symptoms of neurodegenerative diseases.

Several toxicities are associated with molecular-targeted drugs including gastrointestinal adverse effects. These adverse effects need to be considered carefully because they can lead to the discontinuation of oral treatment and subsequently compromise cancer control. The authors of this Review discuss the incidence and clinical patterns of the gastrointestinal toxic effects induced by these agents and propose some hypotheses for each adverse event.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

DNA repair as a therapeutic target has received considerable attention in the treatment of non-small-cell lung cancer (NSCLC). In this Review, Postel-Vinay et al. discuss how optimizing treatment of NSCLC according to DNA-repair biomarkers, such as ERCC1, BRCA1 or RRM1, may aid clinical decision making and improve the outcome of patients with NSCLC.

The majority of patients with cancer do not die as a result of the primary tumour, rather from the metastases that arise from that tumour. The mechanisms and markers of metastasis have, therefore, been a main focus of both clinical and preclinical research. This Perspectives article discusses the hurdles that need to be overcome to successfully translate the preclinical metastasis research into the clinic.

Modern challenges in oncology, in particular the advent of targeted therapies and personalized medicine, highlight the need for developing a consortium of comprehensive cancer centers to run clinical trials in rare, molecularly-defined populations, and implement high-throughput technologies for daily practice.

KRASmutations can be predictive of resistance to anti-EGFR monoclonal-based therapy in patients with colorectal cancer. Only limited studies, however, have assessed the predictive value ofKRAS mutations in response to conventional chemotherapy. In this Review, the authors assess the available literature and propose that KRASmutations have no value in response prediction to conventional chemotherapy in colorectal cancer, non-small-cell cancer and other solid tumors.

Barlesi and colleagues describe the determinants of severe COVID-19 outcomes in patients with cancer managed at the Gustave Roussy Cancer Centre.

The rapid pace of research in cancer biology, and the advent of molecular targeted therapies has made personalized medicine a reality. This knowledge has generated a vast panel of molecular biomarkers. This Review presents the molecular, prognostic and predictive factors for the six solid tumors associated with the highest mortality. The authors discuss the key biomarkers for each disease site according to its associated clinicopathological presentation and specific associated molecular interactions.

Some molecular targeted therapies can confer radiation response and minimize toxicity compared with chemoradiation regimens. Many of these molecular targeted drugs are being tested in clinical trials in combination with radiotherapy; however, for the optimal translation of these drugs in the clinical setting, their safety must be demonstrated in phase I clinical trials. The combination of new molecular targeted therapies and radiation might not necessarily be equivalent to the toxicity of the targeted drug plus the usual toxicity of radiation. Deutschet al. discuss the need for specific and long-term clinical evaluation and the necessity to reassess phase I strategies, toxicity endpoints, and trial concepts in order to fully optimize these regimens.

Forest carbon source and sink processes may have contrasting climatic sensitivities. This analysis on 177 coniferous forest sites shows that carbon fluxes and wood formation are coupled but not fully synchronous at intra-annual scales, with peaks in cambial activity preceding those in photosynthesis and respiration.

Understanding the emergence, evolution, and transmission of antibiotic resistance genes (ARGs) is essential to combat antimicrobial resistance. Here, Munk et al. analyse ARGs in hundreds of sewage samples from 101 countries and describe regional patterns, diverse genetic environments of common ARGs, and ARG-specific transmission patterns.

In a large multicentric study of patients with advanced NSCLC undergoing anti-PD-1 therapy, the relative abundance of intestinal Akkermansia spp. was shown to associate with changes in the gut microbiome ecosystem and clinical outcomes.

The use of tumour molecular profiles for therapeutic decision making requires that molecular diagnostics be introduced into routine clinical practice. To this end, the French National Cancer Institute and French Ministry of Health have set up a national network of 28 regional molecular genetics centres. In this Perspectives article, the authors look at the 4-year history of the French initiative and discuss its success in rapidly implementing molecular tests for new tumour biomarkers.

Prospective analysis of transcriptomic and genomic alterations increases the proportion of patients with solid cancer who are eligible for receiving matched therapies and shows promise in improving clinical outcomes.

An integrated analysis of de novo and inherited coding variants in 42,607 individuals with autism spectrum disorder identifies 60 risk genes of which five have not previously been associated with neurodevelopmental disorders.

Immune checkpoint inhibition is a novel approach to cancer treatment with enormous potential to improve the outcomes of patients with a range of malignancies. However, owing to this novel approach, a range of adverse events have emerged with different aetiologies to those of more conventional cancer treatments. In this Review, the authors describe the occurrence, and optimal management of adverse events resulting from use of immune checkpoint inhibitors.

Tumours can escape CD8 T-cell immunity by down-regulating antigen presentation machinery components, such as TAP. Here the authors describe tumour antigenic peptides processed by TAP-independent and -dependent pathways and show in mouse models that these peptides can be exploited to induce antitumor T-cell activity when TAP expression is downregulated.

Our understanding of the pathogenesis of tobacco-related lung carcinogenesis is improving but the molecular mechanisms of neoplastic transformation in never-smokers have not yet been elucidated. Mountzios et al. describe the best characterized signaling pathways that are implicated in the transduction of proliferative signals, and discuss the differences in the molecular characteristics of smokers and never-smokers.

A new ultraluminous X-ray source has been discovered in M 31, whose variability and associated bright, compact radio emission identify it as a stellar-mass black hole accreting close to the Eddington limit.

Italiano and colleagues demonstrate the utility of mature tertiary lymphoid structures to predict response to immunotherapy, with pathologic analysis in three independent patient cohorts spanning multiple tumor types.

Patient data from six clinical trials are used to compare the genomic landscapes of breast cancer metastases with those of primary tumours, revealing an increase in mutational burden and clonal diversity.

Clinical and correlative biomarker results from a phase 1 clinical trial in patients with different solid tumours are presented; the findings indicate that PD-L1 expression on tumour-infiltrating immune cells is associated with clinical response to MPDL3280A (anti-PD-L1).

A deterioration of disease can occur upon treatment with anti-PD-1/PD-L1 monoclonal antibodies; this paradoxical phenomenon is defined as hyperprogression. The authors discuss the pathophysiological hypotheses that might explain hyperprogressive disease and the resulting challenges for patient management, with a focus in clinical decisions involving immune-checkpoint inhibitors.

Roman Thomas and colleagues report exome sequencing of 29 small-cell lung cancers (SCLCs), 2 SCLC genomes and transcriptomes of 15 SCLCs. They identify recurrent mutations in the CREBBP, EP300 and MLL genes encoding histone modifiers. They identify mutations in SLIT2 and EPHA7, which have a role in axon guidance and cell migration, and focal amplifications of FGFR1.

Several trials are testing immune-checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, in patients with resectable non-small-cell lung cancer as an adjuvant, neoadjuvant or perioperative approach. However, the optimal use of ICIs with curative intent in patients with early stage non-small-cell lung cancer remains unclear. The authors of this Review discuss the current trial landscape and discuss challenges and opportunities.

The Cancer Core Europe centers share their experience on caring for patients with cancer during the COVID-19 pandemic ― a time of challenges and opportunities for cancer health professionals, researchers and patients alike.

This Review describes the dynamic interplay between the DNA damage response and anticancer immunity, and highlights challenges and recent developments towards harnessing this interaction for therapeutic benefit.

Oncolytic viruses are currently seen as a potential therapeutic option for patients with cancer who do not respond to immune checkpoint inhibitors. This Review discusses the different therapeutic approaches to develop oncolytic viruses, delivery modalities and methods for assessing their biological activity.