High Efficacy of Two Artemisinin-Based Combinations (Artesunate + Amodiaquine and Artemether + Lumefantrine) in Caala, Central Angola.

In April 2004, 137 children 6-59 months of age with uncomplicated Plasmodium falciparum (Pf) malaria (Caala, Central Angola) were randomized to receive either artemether-lumefantrine (Coartem) or artesunate + amodiaquine (ASAQ). After 28 days of follow-up, there were 2/61 (3.2%) recurrent parasitemias in the Coartem group and 4/64 (6.2%) in the ASAQ group (P = 0.72), all classified as re-infections after PCR genotyping (cure rate = 100% [95%CI: 94-100] in both groups). Only one patient (ASAQ group) had gametocytes on day 28 versus five (Coartem) and three (ASAQ) at baseline. Compared with baseline, anemia was significantly improved after 28 days of follow-up in both groups (Coartem: from 54.1% to 13.4%; ASAQ: from 53.1% to 15.9%). Our findings are in favor of a high efficacy of both combinations in Caala. Now that Coartem has been chosen as the new first-line anti-malarial, the challenge is to insure that this drug is available and adequately used

Vitamin D status of pregnant women with obesity in the United Kingdom and its association with pregnancy outcomes: a secondary analysis of the UPBEAT study

Prenatal vitamin D deficiency is widely reported and may affect perinatal outcomes. In this secondary analysis of the UK Pregnancies Better Eating and Activity Trial (UPBEAT), we examined vitamin D status and its relationship with selected pregnancy outcomes in women with obesity (BMI≥30kg/m2) from multi-ethnic inner-city settings in the UK. Determinants of vitamin D status at a mean of 17±1 weeks' gestation were assessed using multivariable linear regression and reported as percent differences in serum hydroxyvitamin D (25(OH)D). Associations between 25(OH)D and clinical outcomes were examined using logistic regression. Among 1089 participants, 67% had 25(OH)D &lt;50nmol/L and 26% had concentrations &lt;25nmol/L. In fully adjusted models accounting for socio-demographic and anthropometric characteristics, 25(OH)D was lower among women of Black (% difference = -33; 95%CI: -39 to -27), Asian (% difference= -43; 95%CI: -51 to -35) and other non-White (% difference= -26; 95%CI: -35 to -14) ethnicity compared to women of White ethnicity (n=1086; P&lt;0.001 for all). In unadjusted analysis, risk of gestational diabetes was greater in women with 25(OH)D &lt;25nmol/L compared to ≥50nmol/L (OR=1.58; 95%CI: 1.09 to 2.31), but the magnitude of effect estimates was attenuated in the multivariable model (OR=1.33; 95%CI: 0.88 to 2.00). There were no associations between 25(OH)D and risk of preeclampsia, preterm birth, or SGA or LGA delivery. These findings demonstrate low 25(OH)D among pregnant women with obesity and highlight ethnic disparities in vitamin D status in the UK. However, evidence for a greater risk of adverse perinatal outcomes among women with vitamin D deficiency was limited.</p

Micro-RNA-215 and -375 regulate thymidylate synthase protein expression in pleural mesothelioma and mediate epithelial to mesenchymal transition

The standard front-line treatment for pleural mesothelioma (PM) is pemetrexed-based chemotherapy, whose major target is thymidylate synthase (TS). In several cancer models, miR-215 and miR-375 have been shown to target TS, while information on these miRNAs in PM are still limited although suggest their role in epithelial to mesenchymal transition. Seventy-one consecutive PM tissues (4 biphasic, 7 sarcomatoid, and 60 epithelioid types) and 16 commercial and patient-derived PM cell lines were screened for TS, miR-215, and miR-375 expression. REN and 570B cells were selected for miR-215 and miR-375 transient transfections to test TS modulation. ZEB1 protein expression in tumor samples was also tested. Moreover, genetic profile was investigated by means of BAP1 and p53 immunohistochemistry. Expression of both miR-215 and miR-375 was significantly higher in epithelioid histotype. Furthermore, inverse correlation between TS protein and both miR-215 and miR-375 expression was found. Efficiently transfected REN and 570B cell lines overexpressing miR-215 and miR-375 showed decreased TS protein levels. Epithelioid PM with a mesenchymal component highlighted by reticulin stain showed significantly higher TS and ZEB1 protein and lower miRNA expression. A better survival was recorded for BAP1 lost/TS low cases. Our data indicate that miR-215 and miR-375 are involved in TS regulation as well as in epithelial-to-mesenchymal transition in PM. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00428-022-03321-8

Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

Malignant pleural mesothelioma (MPM) is a rare and fatal disease of the pleural lining. Up to 80% of the MPM cases are linked to asbestos exposure. Even though its use has been banned in the industrialized countries, the cases continue to increase. MPM is a lethal cancer, with very little survival improvements in the last years, mirroring very limited therapeutic advances. Platinum-based chemotherapy in combination with pemetrexed and surgery are the standard of care, but prognosis is still unacceptably poor with median overall survival of approximately 12 months. The genomic landscape of MPM has been widely characterized showing a low mutational burden and the impairment of tumor suppressor genes. Among them, BAP1 and BLM are present as a germline inactivation in a small subset of patients and increases predisposition to tumorigenesis. Other studies have demonstrated a high frequency of mutations in DNA repair genes. Many therapy approaches targeting these alterations have emerged and are under evaluation in the clinic. High-throughput technologies have allowed the detection of more complex molecular events, like chromotripsis and revealed different transcriptional programs for each histological subtype. Transcriptional analysis has also paved the way to the study of tumor-infiltrating cells, thus shedding lights on the crosstalk between tumor cells and the microenvironment. The tumor microenvironment of MPM is indeed crucial for the pathogenesis and outcome of this disease; it is characterized by an inflammatory response to asbestos exposure, involving a variety of chemokines and suppressive immune cells such as M2-like macrophages and regulatory T cells. Another important feature of MPM is the dysregulation of microRNA expression, being frequently linked to cancer development and drug resistance. This review will give a detailed overview of all the above mentioned features of MPM in order to improve the understanding of this disease and the development of new therapeutic strategies

Integrated Assessment of Shallow-Aquifer Vulnerability to Multiple Contaminants and Drinking-Water Exposure Pathways in Holliston, Massachusetts

Half of U.S. drinking water comes from aquifers, and very shallow ones (table) are especially vulnerable to anthropogenic contamination. We present the case of Holliston, a Boston, Massachusetts suburb that draws its drinking water from very shallow aquifers, and where metals and solvents have been reported in groundwater. Community concerns focus on water discolored by naturally occurring manganese (Mn), despite reports stating regulatory aesthetic compliance. Epidemiologic studies suggest Mn is a potentially toxic element (PTE) for children exposed by the drinking-water pathway at levels near the regulatory aesthetic level. We designed an integrated, community-based project: five sites were profiled for contaminant releases; service areas for wells were modeled; and the capture zone for one vulnerable well was estimated. Manganese, mercury, and trichloroethylene are among 20 contaminants of interest. Findings show that past and/or current exposures to multiple contaminants in drinking water are plausible, satisfying the criteria for complete exposure pathways. This case questions the adequacy of aquifer protection and monitoring regulations, and highlights the need for integrated assessment of multiple contaminants, associated exposures and health risks. It posits that community-researcher partnerships are essential for understanding and solving complex problems

Gas-phase dehydration of glycerol over thermally-stable SAPO-40 catalyst

SAPO-40 was used as catalyst for the gas-phase dehydration of glycerol towards acrolein. At 350 ºC the catalyst attained full conversion of glycerol with a negligible deactivation in the first 48 h, a glycerol conversion above 50 % after 120 h on stream and a nearly constant selectivity to acrolein above 70%. This catalyst proved to be highly resistant under the experimental conditions used and can be regenerated without loss of activity or significant structural damage. The comparison of SAPO-40 with SAPO-34 and SAPO-11 illustrates the importance of the porous structure and emphasizes the good catalytic performance of this material