Identifying new targeted therapies that kill tumor cells while sparing normal tissue is a major challenge of cancer research. Using a high-throughput chemical synthetic lethal screen, we sought to ...identify compounds that exploit the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in about 80% of renal cell carcinomas (RCCs). RCCs, like many other cancers, are dependent on aerobic glycolysis for ATP production, a phenomenon known as the Warburg effect. The dependence of RCCs on glycolysis is in part a result of induction of glucose transporter 1 (GLUT1). Here, we report the identification of a class of compounds, the 3-series, exemplified by STF-31, which selectively kills RCCs by specifically targeting glucose uptake through GLUT1 and exploiting the unique dependence of these cells on GLUT1 for survival. Treatment with these agents inhibits the growth of RCCs by binding GLUT1 directly and impeding glucose uptake in vivo without toxicity to normal tissue. Activity of STF-31 in these experimental renal tumors can be monitored by (18)Ffluorodeoxyglucose uptake by micro-positron emission tomography imaging, and therefore, these agents may be readily tested clinically in human tumors. Our results show that the Warburg effect confers distinct characteristics on tumor cells that can be selectively targeted for therapy.
Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of ...protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.
Recent advancements in next-generation sequencing have greatly expanded the use of multi-gene panel testing for hereditary cancer risk. Although genetic testing helps guide clinical diagnosis and ...management, testing recommendations are based on personal and family history of cancer and ethnicity, and many carriers are being missed. Herein, we report the results from 23,179 individuals who were referred for 30-gene next-generation sequencing panel testing for hereditary cancer risk, independent of current testing guidelines—38.7% of individuals would not have met National Comprehensive Cancer Network criteria for genetic testing. We identified a total of 2811 pathogenic variants in 2698 individuals for an overall pathogenic frequency of 11.6% (9.1%, excluding common low-penetrance alleles). Among individuals of Ashkenazi Jewish descent, three-quarters of pathogenic variants were outside of the three common BRCA1 and BRCA2 founder alleles. Across all ethnic groups, pathogenic variants in BRCA1 and BRCA2 occurred most frequently, but the contribution of pathogenic variants in other genes on the panel varied. Finally, we found that 21.7% of individuals with pathogenic variants in genes with well-established genetic testing recommendations did not meet corresponding National Comprehensive Cancer Network criteria. Taken together, the results indicate that more individuals are at genetic risk for hereditary cancer than are identified by current testing guidelines and/or use of single-gene or single-site testing.
Effective analgesia is an important element of enhanced recovery after surgery (ERAS), but the clinical impact of regional anesthesia and analgesia for colorectal surgery remains unclear.
We aimed to ...determine the impact of regional anesthesia following colorectal surgery in the setting of ERAS.
We performed a systematic review of nine databases up to June 2020, seeking randomized controlled trials comparing regional anesthesia versus control in an ERAS pathway for colorectal surgery. We analyzed the studies with successful ERAS implementation, defined as ERAS protocols with a hospital length of stay of ≤5 days. Data were qualitatively synthesized. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool.
Of the 29 studies reporting ERAS pathways, only 13 comprising 1170 patients were included, with modest methodological quality and poor reporting of adherence to ERAS pathways. Epidural analgesia had limited evidence of outcome benefits in open surgery, while spinal analgesia with intrathecal opioids may potentially be associated with improved outcomes with no impact on length of stay in laparoscopic surgery, though dosing must be further investigated. There was limited evidence for fascial plane blocks or other regional anesthetic techniques.
Although there was variable methodological quality and reporting of ERAS, we found little evidence demonstrating the clinical benefits of regional anesthetic techniques in the setting of successful ERAS implementation, and future studies must report adherence to ERAS in order for their interventions to be generalizable to modern clinical practice.
CRD42020161200.
Sexual minority adolescents face mental health disparities relative to heterosexual adolescents. We evaluated temporal changes in US adolescent reported sexual orientation and suicide attempts by ...sexual orientation.
We used Youth Risk Behavioral Surveillance data from 6 states that collected data on sexual orientation identity and 4 states that collected data on sex of sexual contacts continuously between 2009 and 2017. We estimated odds ratios using logistic regression models to evaluate changes in reported sexual orientation identity, sex of consensual sexual contacts, and suicide attempts over time and calculated marginal effects (MEs).
The proportion of adolescents reporting minority sexual orientation identity nearly doubled, from 7.3% in 2009 to 14.3% in 2017 (ME: 0.8 percentage points pp per year; 95% confidence interval CI: 0.6 to 0.9 pp). The proportion of adolescents reporting any same-sex sexual contact increased by 70%, from 7.7% in 2009 to 13.1% in 2017 (ME: 0.6 pp per year; 95% CI: 0.4 to 0.8 pp). Although suicide attempts declined among students identifying as sexual minorities (ME: -0.8 pp per year; 95% CI: -1.4 to -0.2 pp), these students remained >3 times more likely to attempt suicide relative to heterosexual students in 2017. Sexual minority adolescents accounted for an increasing proportion of all adolescent suicide attempts.
The proportion of adolescents reporting sexual minority identity and same-sex sexual contacts increased between 2009 and 2017. Disparities in suicide attempts persist. Developing and implementing approaches to reducing sexual minority youth suicide is critically important.
Background and Aims
The transcription factor nuclear factor erythroid 2‐related factor 2 (Nrf2) regulates an array of cytoprotective genes, yet studies in transgenic mice have led to conflicting ...reports on its role in liver regeneration. We aimed to test the hypothesis that pharmacological activation of Nrf2 would enhance liver regeneration.
Approach and Results
Wild‐type and Nrf2 null mice were administered bardoxolone methyl (CDDO‐Me), a potent activator of Nrf2 that has entered clinical development, and then subjected to two‐thirds partial hepatectomy. Using translational noninvasive imaging techniques, CDDO‐Me was shown to enhance the rate of restoration of liver volume (MRI) and improve liver function (multispectral optoacoustic imaging of indocyanine green clearance) in wild‐type, but not Nrf2 null, mice following partial hepatectomy. Using immunofluorescence imaging and whole transcriptome analysis, these effects were found to be associated with an increase in hepatocyte hypertrophy and proliferation, the suppression of immune and inflammatory signals, and metabolic adaptation in the remnant liver tissue. Similar processes were modulated following exposure of primary human hepatocytes to CDDO‐Me, highlighting the potential relevance of our findings to patients.
Conclusions
Our results indicate that pharmacological activation of Nrf2 is a promising strategy for enhancing functional liver regeneration. Such an approach could therefore aid the recovery of patients undergoing liver surgery and support the treatment of acute and chronic liver disease.
Neuromyelitis optica (NMO) is an inflammatory autoimmune disease of the central nervous system that preferentially targets the optic nerves and spinal cord. The clinical presentation may suggest ...multiple sclerosis (MS), but a highly specific serum autoantibody against the astrocytic water channel aquaporin-4 present in up to 80% of NMO patients enables distinction from MS. Optic neuritis may occur in either condition resulting in neuro-anatomical retinal changes. Optical coherence tomography (OCT) has become a useful tool for analyzing retinal damage both in MS and NMO. Numerous studies showed that optic neuritis in NMO typically results in more severe retinal nerve fiber layer (RNFL) and ganglion cell layer thinning and more frequent development of microcystic macular edema than in MS. Furthermore, while patients’ RNFL thinning also occurs in the absence of optic neuritis in MS, subclinical damage seems to be rare in NMO. Thus, OCT might be useful in differentiating NMO from MS and serve as an outcome parameter in clinical studies.
Although causality is yet to be confirmed, a considerable volume of research has explored the relationships between cow milk consumption, type II diabetes, and cardiovascular disease. Contrastingly, ...it has not been comprehensively examined whether milk of non-bovine origin can provide cardiometabolic protection. This narrative review outlines the marked differences in macronutrient composition, particularly protein and lipid content, and discusses how whole milk product (and individual milk ingredients) from different species could impact cardiometabolic health. There is some data, although primarily from compositional analyses, animal studies, and acute clinical trials, that non-bovine milk (notably sheep and goat milk) could be a viable substitute to cow milk for the maintenance, or enhancement, of cardiometabolic health. With a high content of medium-chain triglycerides, conjugated linoleic acid, leucine, and essential minerals, sheep milk could assist in the prevention of metabolic-related disorders. Similarly, albeit with a lower content of such functional compounds relative to sheep milk, goat and buffalo milk could be plausible counterparts to cow milk. However, the evidence required to generate nutritional recommendations for 'non-bovine milk' is currently lacking. Longer-term randomised controlled trials must assess how the bioactive ingredients of different species' milks collectively influence biomarkers of, and subsequently incidence of, cardiometabolic health.
It is unclear whether universal access to primary percutaneous coronary intervention (pPCI) may reduce sex differences in 1-year rehospitalization for heart failure (HF) and myocardial infarction ...(MI) after ST-elevation myocardial infarction (STEMI). We studied 7,597 consecutive STEMI patients (13.8% women, n = 1,045) who underwent pPCI from January 2007 to December 2013. Cox regression models adjusted for competing risk from death were used to assess sex differences in rehospitalization for HF and MI within 1 year from discharge. Compared with men, women were older (median age 67.6 vs 56.0 years, p < 0.001) with higher prevalence of co-morbidities and multivessel disease. Women had longer median door-to-balloon time (76 vs 66 minutes, p < 0.001) and were less likely to receive drug-eluting stents (19.5% vs 24.1%, p = 0.001). Of the medications prescribed at discharge, fewer women received aspirin (95.8% vs 97.6%, p = 0.002) and P2Y12 antagonists (97.6% vs 98.5%, p = 0.039), but there were no significant sex differences in other discharge medications. After adjusting for differences in baseline characteristics and treatment, sex differences in risk of rehospitalization for HF attenuated (hazard ratio HR 1.05, 95% confidence interval CI 0.79 to 1.40), but persisted for MI (HR 1.68, 95% CI 1.22 to 2.33), with greater disparity in patients aged ≥60 years (HR 1.83, 95% CI 1.18 to 2.85) than those aged <60 years (HR 1.45, 95% CI 0.84 to 2.50). In conclusion, in a setting of universal access to pPCI, the adjusted risk of 1-year rehospitalization for HF was similar in both sexes, but women had significantly higher adjusted risk of 1-year rehospitalization for MI, especially older women.
PDF
