Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms

Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. Video Abstract [Figure presented] Keywords: type 2 diabetes (T2D); genetics; disease mechanism; SLC16A11; MCT11; solute carrier (SLC); monocarboxylates; fatty acid metabolism; lipid metabolism; precision medicin

Pharmaceutical pollution of the world's rivers

Environmental exposure to active pharmaceutical ingredients (APIs) can have negative effects on the health of ecosystems and humans. While numerous studies have monitored APIs in rivers, these employ different analytical methods, measure different APIs, and have ignored many of the countries of the world. This makes it difficult to quantify the scale of the problem from a global perspective. Furthermore, comparison of the existing data, generated for different studies/regions/continents, is challenging due to the vast differences between the analytical methodologies employed. Here, we present a global-scale study of API pollution in 258 of the world's rivers, representing the environmental influence of 471.4 million people across 137 geographic regions. Samples were obtained from 1,052 locations in 104 countries (representing all continents and 36 countries not previously studied for API contamination) and analyzed for 61 APIs. Highest cumulative API concentrations were observed in sub-Saharan Africa, south Asia, and South America. The most contaminated sites were in low- to middle-income countries and were associated with areas with poor wastewater and waste management infrastructure and pharmaceutical manufacturing. The most frequently detected APIs were carbamazepine, metformin, and caffeine (a compound also arising from lifestyle use), which were detected at over half of the sites monitored. Concentrations of at least one API at 25.7% of the sampling sites were greater than concentrations considered safe for aquatic organisms, or which are of concern in terms of selection for antimicrobial resistance. Therefore, pharmaceutical pollution poses a global threat to environmental and human health, as well as to delivery of the United Nations Sustainable Development Goals

Relationship between degree of cellular differentiation in colorectal cancer and topographical distribution.

Objetivos: intentar establecer la relación existente entre el grado diferenciación celular del cáncer colon y su distribución topográfica: en 215 pacientes diagnosticados de cáncer colorrectal entre los años 1997 y 2000. Material y métodos: se estudiaron de forma prospectiva 215 pacientes (129 hombres y 86 mujeres) de edades comprendidas entre 23 y 84 años, con edad media de 64 años. En todos se realizó colonoscopia completa con varias tomas de biopsia. En los casos de estenosis tumoral con imposibilidad para sobrepasar la lesión se realizó enema opaco. Los estudios de extensión incluyeron TAC y ecografía abdominal, hemograma, perfil bioquímico completo y marcadores tumorales Ca 19-9 y alfafetoproteina). La distribución topográfica de los cánceres colorrectales fue la siguiente: recto 78 (35%), sigrna 66 (31%), descendente 21 (10%), transverso 12 (6%), ascendente 19 (9%), ciego 11 (5%), y anorrectal 8 (4%). Resultados: siendo el objetivo de nuestro estudio el establecer la relación entre el asentamiento tumoral en el colon y su grado de diferenciación celular encontramos: a) bien diferenciados 101/215 (47%); b) moderadamente diferenciados 98/215 y c) pobremente diferenciados 16/215 (7 El cáncer bien diferenciado lo encontramos en 49% de los hombres y en el 43% de las mujeres, el moderadamente diferenciado fue del 43% entre los hombres y del 49% entre las mujeres, el pobremente diferenciado fue del 7,5% entre los hombres y de 7,2% entre las mujeres. Según su distribución: en el colon izquierdo,80 adenocarcinomas eran bien diferenciados, 77 moderadamente diferenciados y 8 pobremente diferenciados; en el colon transverso; 7 adenocarcinomas eran bien diferenciados 3 moderadamente diferenciados y 2 pobremente diferenciados, en el colon derecho 11 adenocarcinomas eran bien diferenciados, 15 moderadamente diferenciados y 4 pobremente diferenciados. De los 8 cánceres recto-anales, 3 eran bien diferenciados, 3 moderadamente diferenciados y 2 pobremente diferenciados, habiendo observado que dicho grado de diferenciación no tiene un significado estadístico de relación con la distribución topográfica del tumor. Según la clasificación fueron más frecuentes en los estadios, los bien diferenciados (101/215) fueron más frecuentes en los estadios BI (32,6%) y C2 (20, los moderadamente diferenciados (98/215) lo fueron en los estadios Bi y C2 el de los estadios C2 fueron tumores pobremente diferenciados. No apreciamos diferencias estadísticamente significativas en la distribución de los grados de diferenciación estadios (p—ns). Conclusiones: nuestros resultados, no hemos observado que el grado de diferenciación celular del cáncer colorrectal se relacione con su localización inicial en el colon y es, independiente del sexo y de la edad. En cuanto a su posible relación con la estadios de Dukes y Astler-Coller tampoco hemos demostrarla.To demonstrate the relationship between degree of cellular differentiation in colorectal cancer and topographical distribution in 215 patients diagnosed with colorectal cancer from 1997 to 2000. MATERIAL AND METHODS: 215 patients (129 men and 86 women) were studied prospectively with a mean age of 64 years (range: 23-84 years). In all patients we performed a full colonoscopy with several biopsies (in patients with colon stenosis we used barium enema), radiographic studies (CT, abdominal ultrasounds), and laboratory tests for serum tumour markers (CEA, Ca 19-9, alpha-fetoprotein). The topographic location of colorectal cancer was: rectum 35%, sigmoid colon 31%, descending colon 10%, transverse colon 6%, ascending colon 9%, caecum 5%, and we included anorectal cancer 4%. RESULTS: According to histological differentiation we found: A) well-differentiated tumours 101/215 (47%); B) moderately-differentiated tumours 98/215 (45.5%), and C) poorly-differentiated tumours 16/215 (7.5%). We found no significant association among histological differentiation, topographic location, stage according to the Astler-Coller classification, sex or age (p = ns). The prevalence of well-differentiated tumours in men was 49% and 43% in women; of moderately-differentiated cancers in men was 43%, and 49% in women; for poorly-differentiated tumours in men was 7.5%, and 7.2% in women. Regarding tumour location, 165 cancers were found in the left colon: 80 were well differentiated, 77 moderately differentiated and 8 poorly differentiated. In the transverse colon we found 12 tumours: 7 well differentiated, 3 moderately differentiated and 2 poorly differentiated. 30 cancers were localized in the right colon: 11 well differentiated, 15 moderately differentiated and 4 poorly differentiated. In the anorectum 8 tumours were found: 3 well differentiated, 3 moderately differentiated and 2 poorly differentiated. According to staging classification, well differentiated tumours (101/215) were more common in Dukes' C2 (20.7%) and B1 (32.6%), moderately differentiated cancers (98/215) were in B1 (28.5%) and C2 (20.4%), and poorly differentiated tumours (16) were more common in Dukes' C2 (25%), without differences among other stages (p = ns). CONCLUSIONS: According to our results we have found that histological differentiation of colorectal cancer has no association with topographic location, and it is independent of sex or age. We have not found any relationship either between histological differentiation and stage in the Astler-Coller classification, but well differentiated cancers were more common at any location, age or sex

Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer

International audienc