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Cancer cells acquire distinct metabolic preferences based on their tissue of origin, genetic alterations and degree of interaction with systemic hormones and metabolites. These adaptations support the increased nutrient demand required for increased growth and proliferation. Diet is the major source of nutrients for tumours, yet dietary interventions lack robust evidence and are rarely prescribed by clinicians for the treatment of cancer. Well-controlled diet studies in patients with cancer are rare, and existing studies have been limited by nonspecific enrolment criteria that inappropriately grouped together subjects with disparate tumour and host metabolic profiles. This imprecision may have masked the efficacy of the intervention for appropriate candidates. Here, we review the metabolic alterations and key vulnerabilities that occur across multiple types of cancer. We describe how these vulnerabilities could potentially be targeted using dietary therapies including energy or macronutrient restriction and intermittent fasting regimens. We also discuss recent trials that highlight how dietary strategies may be combined with pharmacological therapies to treat some cancers, potentially ushering a path towards precision nutrition for cancer.This Review discusses the metabolic alterations and vulnerabilities across multiple types of cancer, and describes how these could potentially be targeted using diet in conjunction with pharmacologic therapies.

Alpelisib is a α-selective phosphatidylinositol 3-kinase (PI3K) inhibitor approved for treatment of postmenopausal women, and men, with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–), PIK3CA-mutated, advanced breast cancer (ABC). Hyperglycemia is a common, on-target adverse effect that impairs treatment efficacy and increases the rate of treatment delays, dose reductions, and discontinuation. Currently, there are no clear guidelines on how to manage hyperglycemia due to alpelisib when metformin is not effective. In this case series, we review 3 subjects with ABC that developed hyperglycemia during alpelisib-fulvestrant therapy and were successfully managed with dietary and pharmacologic interventions. These cases provide anecdotal evidence to support the use of sodium-glucose co-transporter-2 inhibitors (SGLT2i) and very low carbohydrate diets to minimize hyperglycemia during alpelisib therapy.

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease affecting at least a quarter of the world’s population. NAFLD is commonly associated with other metabolic conditions such as insulin resistance, type 2 diabetes, obesity, and dyslipidemia. Given the liver’s prominent role in regulating glucose and lipid homeostasis, we hypothesized that subjects with NAFLD have a distinct profile of blood analytes. This investigation examines the association between NAFLD and circulating markers of glucose and lipid metabolism in order to identify a NAFLD-specific metabolite panel that can be used as a predictive biomarker in future studies. We are performing a cross-sectional study in 500 subjects to identify genetic and hormonal factors that correlate with the presence of NAFLD. This abstract reports a preliminary analysis of the results from the first 45 subjects enrolled. Fasting blood samples were collected from 31 subjects with NAFLD and 14 subjects with other metabolic diseases (‘Other’) and without radiologic evidence of NAFLD. The following analytes were measured: serum alanine aminotransferase (ALT), total cholesterol, direct-LDL, HDL, triglycerides, ApoB, small dense LDL-C (sdLDL), VLDL, Lp(a), cholesterol absorption/production markers (beta-sitosterol, campesterol, lathosterol, and desmosterol), glucose, insulin, hemoglobin A1C, adiponectin, hs-CRP, and fatty acids (saturated and unsaturated). Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from glucose and insulin levels, and fatty acids were batched together by structural similarity and reported as indices. The groups were compared using multiple t-tests or the Kolmogorov-Smirnov test when data were non-parametric. The NAFLD group had a mean age 48.4 ± 12.9 yrs and BMI 32.9 ± 6.6 kg/m2. These participants were 61% female and 58% had dyslipidemia, 25% pre-diabetes, and 25% type 2 diabetes. The Other group had a mean age 49.9 ± 12.9 yrs and BMI 39.1 ± 15.6 kg/m2. They were 64% female and 57% had dyslipidemia, 14% pre-diabetes, and 21% type 2 diabetes. ALT was higher in the NAFLD group (55 ± 40 vs 27 ± 22 IU/L, P<0.001). Intriguingly, the saturated fatty acid index was elevated in the NAFLD group (32.5 ± 1.9 vs 30.1 ± 2.2 %, P<0.05), and the omega-6 fatty acid index was elevated in the Other group (42.9 ± 3.7 vs 38.5 ± 4.7 %, P<0.05). These changes led to an unsaturated/saturated fatty acid ratio that was significantly lower in the NAFLD group (2.0 ± 0.1 vs 2.3 ± 0.2, P<0.01). There were no other significant differences in the blood metabolites and hormones. In this small sample comparing subjects with metabolic disease with and without NAFLD, levels of ALT and the ratio of circulating unsaturated/saturated fatty acids are distinguishing features of NAFLD. These may be helpful measures to identify subjects with metabolic disease that require further evaluation for NAFLD.

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci ( n  = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy. Multiancestry genome-wide association analyses identify new risk loci for stroke and stroke subtypes. Fine mapping and bioinformatics analyses of these risk loci point to mechanisms not previously implicated in stroke pathophysiology.

Patients with type 2 diabetes at high risk for cardiovascular disease who were already taking a renin–angiotensin system blocker were randomly assigned to the direct renin inhibitor aliskiren or placebo. The study was discontinued early for no benefit, or even possible harm. Mortality associated with type 2 diabetes remains nearly twice that when diabetes is absent. 1 Complications of diabetes, particularly renal and cardiovascular disease, substantially increase the risk of subsequent severe illness and death. When a patient has both renal and cardiovascular disease, the risk is magnified further. 2 , 3 Blood-pressure lowering is beneficial in slowing renal-disease progression, reducing cardiovascular disease events, and preventing premature death. 4 Renin–angiotensin–aldosterone system (RAAS) blockers are highly effective, with apparent benefits extending beyond simple blood-pressure lowering 5 – 8 ; such agents have become the preferred first-line interventions in high-risk persons with diabetes. Theoretically, dual RAAS blockade should be more . . .

Researchers can investigate many aspects of animal ecology through noninvasive photo–identification. Photo–identification is becoming more efficient as matching individuals between photos is increasingly automated. However, the convolutional neural network models that have facilitated this change need many training images to generalize well. As a result, they have often been developed for individual species that meet this threshold. These single‐species methods might underperform, as they ignore potential similarities in identifying characteristics and the photo–identification process among species. In this paper, we introduce a multi‐species photo–identification model based on a state‐of‐the‐art method in human facial recognition, the ArcFace classification head. Our model uses two such heads to jointly classify species and identities, allowing species to share information and parameters within the network. As a demonstration, we trained this model with 50,796 images from 39 catalogues of 24 cetacean species, evaluating its predictive performance on 21,192 test images from the same catalogues. We further evaluated its predictive performance with two external catalogues entirely composed of identities that the model did not see during training. The model achieved a mean average precision (MAP) of 0.869 on the test set. Of these, 10 catalogues representing seven species achieved a MAP score over 0.95. For some species, there was notable variation in performance among catalogues, largely explained by variation in photo quality. Finally, the model appeared to generalize well, with the two external catalogues scoring similarly to their species' counterparts in the larger test set. From our cetacean application, we provide a list of recommendations for potential users of this model, focusing on those with cetacean photo–identification catalogues. For example, users with high quality images of animals identified by dorsal nicks and notches should expect near optimal performance. Users can expect decreasing performance for catalogues with higher proportions of indistinct individuals or poor quality photos. Finally, we note that this model is currently freely available as code in a GitHub repository and as a graphical user interface, with additional functionality for collaborative data management, via Happywhale.com.

Pathophysiological defects in water homeostasis can lead to renal failure. Likewise, common genetic disorders associated with abnormal cytoskeletal dynamics in the kidney collecting ducts and perturbed calcium and cAMP signaling in the ciliary compartment contribute to chronic kidney failure. We show that collecting ducts in mice lacking the A-Kinase anchoring protein AKAP220 exhibit enhanced development of primary cilia. Mechanistic studies reveal that AKAP220-associated protein phosphatase 1 (PP1) mediates this phenotype by promoting changes in the stability of histone deacetylase 6 (HDAC6) with concomitant defects in actin dynamics. This proceeds through a previously unrecognized adaptor function for PP1 as all ciliogenesis and cytoskeletal phenotypes are recapitulated in mIMCD3 knock-in cells expressing a phosphatase-targeting defective AKAP220-ΔPP1 mutant. Pharmacological blocking of local HDAC6 activity alters cilia development and reduces cystogenesis in kidney-on-chip and organoid models. These findings identify the AKAP220-PPI-HDAC6 pathway as a key effector in primary cilia development.

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4 . LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans. Carotid intima-media thickness (cIMT) and plaque are associated with subclinical atherosclerosis and coronary heart disease (CHD). Here, the authors identify and prioritize genetic loci for cIMT and plaque by GWAS and colocalization approaches and further demonstrate genetic correlation with CHD and stroke.

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.

Despite heterogeneity, an increased prevalence of psychological comorbidity and an altered pronociceptive gut microenvironment have repeatedly emerged as causative pathophysiology in patients with irritable bowel syndrome (IBS). Our aim was to study these phenomena by comparing gut-related symptoms, psychological scores, and biopsy samples generated from a detailed diarrhea-predominant IBS patient (IBS-D) cohort before their entry into a previously reported clinical trial. Data were generated from 42 patients with IBS-D who completed a daily 2-week bowel symptom diary, the Hospital Anxiety and Depression score, and the Patient Health Questionnaire-12 Somatic Symptom score and underwent unprepared flexible sigmoidoscopy. Sigmoid mucosal biopsies were separately evaluated using immunohistochemistry and culture supernatants to determine cellularity, mediator levels, and ability to stimulate colonic afferent activity. Pain severity scores significantly correlated with the daily duration of pain (r = 0.67, P < 0.00001), urgency (r = 0.57, P < 0.0005), and bloating (r = 0.39, P < 0.05), but not with psychological symptom scores for anxiety, depression, or somatization. Furthermore, pain severity scores from individual patients with IBS-D were significantly correlated (r = 0.40, P < 0.008) with stimulation of colonic afferent activation mediated by their biopsy supernatant, but not with biopsy cell counts nor measured mediator levels. Peripheral pronociceptive changes in the bowel seem more important than psychological factors in determining pain severity within a tightly phenotyped cohort of patients with IBS-D. No individual mediator was identified as the cause of this pronociceptive change, suggesting that nerve targeting therapeutic approaches may be more successful than mediator-driven approaches for the treatment of pain in IBS-D.