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Background Accurate assessment of health disparities requires unbiased knowledge of genetic risks in different populations. Unfortunately, most genome-wide association studies use genotyping arrays and European samples. Here, we integrate whole genome sequence data from global populations, results from thousands of genome-wide association studies (GWAS), and extensive computer simulations to identify how genetic disease risks can be misestimated. Results In contrast to null expectations, we find that risk allele frequencies at known disease loci are significantly different for African populations compared to other continents. Strikingly, ancestral risk alleles are found at 9.51% higher frequency in Africa, and derived risk alleles are found at 5.40% lower frequency in Africa. By simulating GWAS with different study populations, we find that non-African cohorts yield disease associations that have biased allele frequencies and that African cohorts yield disease associations that are relatively free of bias. We also find empirical evidence that genotyping arrays and SNP ascertainment bias contribute to continental differences in risk allele frequencies. Because of these causes, polygenic risk scores can be grossly misestimated for individuals of African descent. Importantly, continental differences in risk allele frequencies are only moderately reduced if GWAS use whole genome sequences and hundreds of thousands of cases and controls. Finally, comparisons between uncorrected and corrected genetic risk scores reveal the benefits of considering whether risk alleles are ancestral or derived. Conclusions Our results imply that caution must be taken when extrapolating GWAS results from one population to predict disease risks in another population.

Constrictor agonists set arterial tone through two coupling processes, one tied to (electromechanical), the other independent (pharmacomechanical) of, membrane potential (V M ). This dual arrangement raises an intriguing question: is the contribution of each mechanism (1) fixed and proportionate, or (2) variable and functionally biased. Examination began in mouse mesenteric arteries with a vasomotor assessment to a classic G q/11 (phenylephrine) or G q/11 /G 12/13 (U46619) agonist, in the absence and presence of nifedipine, to separate among the two coupling mechanisms. Each constrictor elicited a concentration response curve that was attenuated and rightward shifted by nifedipine, findings consistent with functional bias. Electromechanical coupling preceded pharmacomechanical, the latter’s importance rising with agonist concentration. In this regard, ensuing contractile and phosphorylation (CPI-17 & MYPT1 (T-855 & T-697)) measures revealed phenylephrine-induced pharmacomechanical coupling was tied to protein kinase C (PKC) activity, while that enabled by U46619 to PKC and Rho-kinase. A complete switch to pharmacomechanical coupling arose when agonist superfusion was replaced by pipet application to a small portion of artery. This switch was predicted, a priori, by a computer model of electromechanical control and supported by additional measures of V M and cytosolic Ca 2+ . We conclude that the coupling mechanisms driving agonist-induced constriction are variable and functionally biased, their relative importance set in accordance with agonist concentration and manner of application. These findings have important implications to hemodynamic control in health and disease, including hypertension and arterial vasospasm.

Gastrointestinal neuroendocrine tumors are increasingly common. Practitioners should examine these lesions carefully found on routine endoscopy. Obtaining accurate neuroendocrine tumors stage and grade is critical to patient assessment and management, and assistance from advanced endoscopists may be needed.

Glioma resection is associated with prolonged survival, but neuro-oncological trials have frequently refrained from quantifying the extent of resection. The Response Assessment in Neuro-Oncology (RANO) resect group is an international, multidisciplinary group that aims to standardise research practice by delineating the oncological role of surgery in diffuse adult-type gliomas as defined per WHO 2021 classification. Favourable survival effects of more extensive resection unfold over months to decades depending on the molecular tumour profile. In tumours with a more aggressive natural history, supramaximal resection might correlate with additional survival benefit. Weighing the expected survival benefits of resection as dictated by molecular tumour profiles against clinical factors, including the introduction of neurological deficits, we propose an algorithm to estimate the oncological effects of surgery for newly diagnosed gliomas. The algorithm serves to select patients who might benefit most from extensive resection and to emphasise the relevance of quantifying the extent of resection in clinical trials.

Key Points Brain tumours, such as gliomas, in adults and children are morphologically similar, but harbour different genomic alterations, both across and within histological subtypes, that affect prognosis and treatment response Many of these genomic alterations lead to reprogramming of cellular metabolism, including glucose, amino acid, and lipid metabolism The metabolic reprogramming in brain tumours can be visualized and assessed using various non-invasive clinical imaging modalities Metabolic imaging shows great promise as a means to non-invasively evaluate some of the genomic alterations in order to guide the clinical management of patients Many of the molecular pathways that are aberrant in brain tumours result in reprogramming of metabolism, which creates opportunities for in vivo metabolic imaging to improve diagnosis, patient stratification, and disease monitoring. Herein, the molecular basis and strategies for non-invasive metabolic imaging of brain tumours are reviewed. The revolution in cancer genomics has uncovered a variety of clinically relevant mutations in primary brain tumours, creating an urgent need to develop non-invasive imaging biomarkers to assess and integrate this genetic information into the clinical management of patients. Metabolic reprogramming is a central hallmark of cancer, including brain tumours; indeed, many of the molecular pathways implicated in the pathogenesis of brain tumours result in reprogramming of metabolism. This relationship provides the opportunity to devise in vivo metabolic imaging modalities to improve diagnosis, patient stratification, and monitoring of treatment response. Metabolic phenomena, such as the Warburg effect and altered mitochondrial metabolism, can be leveraged to image brain tumours using techniques including PET and MRI. Moreover, genetic alterations, such as mutations affecting isocitrate dehydrogenase, are associated with unique metabolic signatures that can be detected using magnetic resonance spectroscopy. The need to translate our understanding of the molecular features of brain tumours into imaging modalities with clinical utility is growing; metabolic imaging provides a unique platform to achieve this objective. In this Review, we examine the molecular basis for metabolic reprogramming in brain tumours, and examine current non-invasive metabolic imaging strategies that can be used to interrogate these molecular characteristics with the ultimate goal of guiding and improving patient care.

BackgroundCurrent success in transplant oncology for select liver tumors, such as hepatocellular carcinoma, has ignited international interest in liver transplantation (LT) as a therapeutic option for nonresectable colorectal liver metastases (CRLM). In the United States, the CRLM LT experience is limited to reports from a handful of centers. This study was designed to summarize donor, recipient, and transplant center characteristics and posttransplant outcomes for the indication of CRLM.MethodsAdult, primary LT patients listed between December 2017 and March 2022 were identified by using United Network Organ Sharing database. LT for CRLM was identified from variables: “DIAG_OSTXT”; “DGN_OSTXT_TCR”; “DGN2_OSTXT_TCR”; and “MALIG_TY_OSTXT.”ResultsDuring this study period, 64 patients were listed, and 46 received LT for CRLM in 15 centers. Of 46 patients who underwent LT for CRLM, 26 patients (56.5%) received LTs using living donor LT (LDLT), and 20 patients received LT using deceased donor (DDLT) (43.5%). The median laboratory MELD-Na score at the time of listing was statistically similar between the LDLT and DDLT groups (8 vs. 9, P = 0.14). This persisted at the time of LT (8 vs. 12, P = 0.06). The 1-, 2-, and 3-year, disease-free, survival rates were 75.1, 53.7, and 53.7%. Overall survival rates were 89.0, 60.4, and 60.4%, respectively.ConclusionsThis first comprehensive U.S. analysis of LT for CRLM suggests a burgeoning interest in high-volume U.S. transplant centers. Strategies to optimize patient selection are limited by the scarce oncologic history provided in UNOS data, warranting a separate registry to study LT in CRLM.

INTRODUCTION:The incidence of esophagogastric junction adenocarcinoma (EGJAC) has been rising. Intestinal metaplasia of the esophagogastric junction (EGJIM) is a common finding in gastroesophageal reflux (irregular Z-line) and may represent an early step in the development of EGJAC in the West. Worldwide, EGJIM may represent progression along the Correa cascade triggered by Helicobacter pylori. We sought to evaluate the cost-effectiveness of endoscopic surveillance of EGJIM.METHODS:We developed a decision analytic model to compare endoscopic surveillance strategies for 50-year-old patients after diagnosis of non-dysplastic EGJIM: (i) no surveillance (standard of care), (ii) endoscopy every 3 years, (iii) endoscopy every 5 years, or (iv) 1-time endoscopy at 3 years. We modeled 4 progression scenarios to reflect uncertainty: A (0.01% annual cancer incidence), B (0.05%), C (0.12%), and D (0.22%).RESULTS:Cost-effectiveness of endoscopic surveillance depended on the progression rate of EGJIM to cancer. At the lowest progression rate (scenario A, 0.01%), no surveillance strategies were cost-effective. In moderate progression scenarios, 1-time surveillance at 3 years was cost-effective, at $30,989 and $16,526 per quality-adjusted life year for scenarios B (0.05%) and C (0.12%), respectively. For scenario D (0.22%), surveillance every 5 years was cost-effective at $77,695 per quality-adjusted life year.DISCUSSION:Endoscopic surveillance is costly and can cause harm; however, low-intensity longitudinal surveillance (every 5 years) is cost-effective in populations with higher EGJAC incidence. No surveillance or 1-time endoscopic surveillance of patients with EGJIM was cost-effective in low-incidence populations. Future studies to better understand the natural history of EGJIM, identify risk factors of progression, and inform appropriate surveillance strategies are required.