Explore the vast range of titles available.

Among patients with cancers bearing the KRAS G12C mutation who received divarasib at a 400-mg dose, 56% with lung cancer, 36% with colorectal cancer, and 36% with other tumor types had a confirmed response.

In this randomized, placebo-controlled trial, treatment with nintedanib, an intracellular inhibitor of multiple tyrosine kinases, led to a reduced rate of loss of forced vital capacity in patients with idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis is a fatal lung disease characterized by worsening dyspnea and progressive loss of lung function. 1 A decline in forced vital capacity (FVC) is consistent with disease progression and is predictive of reduced survival time. 1 – 6 Idiopathic pulmonary fibrosis is believed to arise from an aberrant proliferation of fibrous tissue and tissue remodeling due to the abnormal function and signaling of alveolar epithelial cells and interstitial fibroblasts. 7 The activation of cell-signaling pathways through tyrosine kinases such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) has been implicated in the pathogenesis of . . .

Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal. In order to find a general treatment for cancer, this study found that MTH1 activity is essential for the survival of transformed cells, and isolated two small-molecule inhibitors of MTH1, TH287 and TH588 — in the presence of these inhibitors, damaged nucleotides are incorporated into DNA only in cancer cells, causing cytotoxicity and eliciting a beneficial response in patient-derived mouse xenograft models. MTH1 is Ras-linked target for cancer therapy Mutations in the Ras oncogene are associated with poor prognosis. It was known that overexpression of MTH1, a protein involved in preventing the incorporation of damaged bases into DNA, prevents Ras-induced senescence. In seeking to understand how damaged deoxynucleotides (dNTPs) promote cancer, Thomas Helleday and colleagues found that MTH1 activity is essential for the survival of transformed cells, and isolated two small-molecule MTH1 inhibitors, TH287 and TH588. In the presence of these hydrolase inhibitors, damaged nucleotides are incorporated into DNA only in cancer cells, causing cytotoxicity and eliciting a beneficial response in mouse xenograft cancer models. In a second study, Giulio Superti-Furga and colleagues sought to identify the target of a small molecule, SCH51344, that had been developed for use against Ras -dependent cancers and found that it inactivates MTH1. This allowed them to identify a new potent inhibitor of MTH1 that is enantiomer-selective, ( S )-crizotinib. In the presence of this drug, tumour growth is suppressed in animal models of colon cancer.

In a randomized trial, patients with brain amyloid deposition but no dementia who received a β-site amyloid precursor protein–cleaving enzyme 1 inhibitor had no benefit with respect to clinical outcomes and worsening on some measures of cognition and daily function.

Among patients with recent MI, therapy with a polypill containing aspirin, ramipril, and atorvastatin led to a lower incidence of major adverse cardiovascular events at a median of 3 years than usual care.

In this randomized trial, the discontinuation of renin–angiotensin system inhibitors in patients with advanced chronic kidney disease did not lead to a significant between-group difference in the long-term rate of decline in the eGFR.

WHO has targeted that medicines to prevent recurrent cardiovascular disease be available in 80% of communities and used by 50% of eligible individuals by 2025. We have previously reported that use of these medicines is very low, but now aim to assess how such low use relates to their lack of availability or poor affordability. We analysed information about availability and costs of cardiovascular disease medicines (aspirin, β blockers, angiotensin-converting enzyme inhibitors, and statins) in pharmacies gathered from 596 communities in 18 countries participating in the Prospective Urban Rural Epidemiology (PURE) study. Medicines were considered available if present at the pharmacy when surveyed, and affordable if their combined cost was less than 20% of household capacity-to-pay. We compared results from high-income, upper middle-income, lower middle-income, and low-income countries. Data from India were presented separately given its large, generic pharmaceutical industry. Communities were recruited between Jan 1, 2003, and Dec 31, 2013. All four cardiovascular disease medicines were available in 61 (95%) of 64 urban and 27 (90%) of 30 rural communities in high-income countries, 53 (80%) of 66 urban and 43 (73%) of 59 rural communities in upper middle-income countries, 69 (62%) of 111 urban and 42 (37%) of 114 rural communities in lower middle-income countries, eight (25%) of 32 urban and one (3%) of 30 rural communities in low-income countries (excluding India), and 34 (89%) of 38 urban and 42 (81%) of 52 rural communities in India. The four cardiovascular disease medicines were potentially unaffordable for 0·14% of households in high-income countries (14 of 9934 households), 25% of upper middle-income countries (6299 of 24 776), 33% of lower middle-income countries (13 253 of 40 023), 60% of low-income countries (excluding India; 1976 of 3312), and 59% households in India (9939 of 16 874). In low-income and middle-income countries, patients with previous cardiovascular disease were less likely to use all four medicines if fewer than four were available (odds ratio [OR] 0·16, 95% CI 0·04–0·57). In communities in which all four medicines were available, patients were less likely to use medicines if the household potentially could not afford them (0·16, 0·04–0·55). Secondary prevention medicines are unavailable and unaffordable for a large proportion of communities and households in upper middle-income, lower middle-income, and low-income countries, which have very low use of these medicines. Improvements to the availability and affordability of key medicines is likely to enhance their use and help towards achieving WHO's targets of 50% use of key medicines by 2025. Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, AstraZeneca (Canada), Sanofi-Aventis (France and Canada), Boehringer Ingelheim (Germany and Canada), Servier, GlaxoSmithKline, Novartis, King Pharma, and national or local organisations in participating countries.

There is concern that patients taking renin–angiotensin–aldosterone system inhibitors have an increased risk of Covid-19, because angiotensin-converting enzyme 2 is a receptor for the virus. This study showed no increase in likelihood of a positive Covid-19 test or severe Covid-19 in patients taking any of five common classes of antihypertensive drugs.

For cancer cells to survive and proliferate, they must escape normal immune destruction. One mechanism by which this is accomplished is through immune suppression effected by up-regulation of indoleamine 2,3-dioxygenase (IDO1), a heme enzyme that catalyzes the oxidation of tryptophan to N-formylkynurenine. On deformylation, kynurenine and downstream metabolites suppress T cell function. The importance of this immunosuppressive mechanism has spurred intense interest in the development of clinical IDO1 inhibitors. Herein, we describe the mechanism by which a class of compounds effectively and specifically inhibits IDO1 by targeting its apo-form. We show that the in vitro kinetics of inhibition coincide with an unusually high rate of intrinsic enzyme–heme dissociation, especially in the ferric form. X-ray crystal structures of the inhibitor–enzyme complexes show that heme is displaced from the enzyme and blocked from rebinding by these compounds. The results reveal that apo-IDO1 serves as a unique target for inhibition and that heme lability plays an important role in posttranslational regulation.

Patients with interstitial lung disease associated with systemic sclerosis were treated with usual care plus placebo or nintedanib. The annual rate of change in forced vital capacity assessed over a 52-week period was −52.4 ml per year with nintedanib and −93.3 ml per year with placebo. There were no differences in other measures of systemic sclerosis.