Clear-cell Renal Cell Carcinoma: Molecular Characterization of IMDC Risk Groups and Sarcomatoid Tumors

IntroductionRecent trials have suggested predictive biomarkers in advanced clear-cell renal cell carcinoma (accRCC): International Metastatic RCC Database Consortium (IMDC) good risk or angiogenic gene signature for sunitinib and IMDC intermediate/poor risk for ipilimumab-nivolumab and T-effector cell signature or sarcomatoid dedifferentiation for atezolizumab-bevacizumab. We hypothesized that earlier described molecular subtypes, ccrcc1 to ccrcc4, could provide similar information as a single generic biomarker and molecularly characterize the heterogeneous intermediate-risk group.Patients and MethodsPatients with accRCC treated with systemic therapies were included. We assessed associations between the 5 biomarkers and their impact on progression-free survival (PFS) and response rate (RR) on first-line sunitinib or pazopanib. The cutoff percentage of sarcomatoid dedifferentiation with optimal discriminative value was determined.ResultsIn total, 430 patients were included (163 with molecular data). The molecular ccrcc2 subtype identified tumors with higher angiogenic gene expression across IMDC risk groups: prevalence was high in IMDC good risk and low in IMDC poor risk (P < .001). Molecular subtype, IMDC, and angiogenic gene expression had comparable C-indices to predict PFS and RR (range, 60%-66%). The ccrcc2 subtype and angiogenic gene expression were positive predictors of PFS in IMDC intermediate-risk patients (P = .006; P = .04). Immune signature did not differ between IMDC groups, but was strongly correlated with molecular subtype (P = .8 and P = .0007). A cutoff value of 25% sarcomatoid differentiation discriminated tumors with distinct molecular characteristics and therapeutic sensitivity.ConclusionIn accRCC, molecular subtypes can explain differences in IMDC risk group, expression of angiogenesis and immune response genes, and sarcomatoid dedifferentiation. They can identify molecularly different patient populations within the heterogeneous IMDC intermediate group and select patients for systemic therapies.     

Modifications in dietary and alcohol intakes between before and after cancer diagnosis: Results from the prospective population‐based NutriNet‐Santé cohort

Postdiagnosis diet and alcohol consumption may be associated with cancer prognosis, recurrence and mortality. Our aim was to investigate food, nutrient and alcohol intake variations between before and after cancer diagnosis and their determinants in a prospective cohort. Subjects (n = 696) were incident cancer cases diagnosed in the NutriNet‐Santé cohort between 2009 and 2016. Food, nutrient and alcohol intakes were prospectively collected using repeated nonconsecutive 24‐hr dietary records since subjects' inclusion (i.e. an average of 2 y before diagnosis). Mean number of dietary records per subject was 5.9 before and 8.1 after diagnosis. All dietary data before and after diagnosis were compared by mixed models. Factors associated with the main dietary changes observed were also investigated using multivariable logistic regressions. We observed a decrease in intakes of vegetables (mean decrease in intake in patients who decreased their intake=‐102.4 ± 79.8 g/d), dairy products (–93.9 ± 82.8 g/d), meat/offal (–35.5 ± 27.8/d), soy products (–85.8 ± 104.1 g/d), sweetened soft drinks (–77.9 ± 95.4 g/d), and alcoholic drinks (–92.9 ± 119.9 g/d), and an increase in broths (42.1 ± 34.9 g/d) and fats/sauces (18.0 ± 13.4 g/d). We observed a decrease in energy intake (–377.2 ± 243.5 kcal/d) and in intakes of alcohol (–7.6 ± 9.4 g/d) proteins (–17.4 ± 12.5 g/d), and several vitamins (p < 0.05) and micronutrients (p < 0.05). Conversely, lipid (19.4 ± 14.6 g/d), SFA (9.3 ± 7.0 g/d), MUFA (8.3 ± 6.3 g/d) and vitamin E (3.9 ± 3.3 mg/d) intakes increased after diagnosis. This large prospective study suggests that cancer diagnosis is a key period for nutritional changes. It highlights some healthy behaviors such as a decrease in alcohol and sweetened drink consumption, but also less favorable trends, such as a decrease in vegetable consumption and in many vitamin and mineral intakes. These results provide insights to identify and target recommendations to put forward for better nutritional care of cancer survivors.     

Secondary Hardening of a High-N Ni-Free Stainless Steel

High-N Ni-free stainless steels are used for their excellent mechanical properties combined with their high corrosion resistance, especially for biomedical applications. Even though it is well-known that secondary hardening during annealing after cold working has been observed in many materials, this phenomenon was not reported for these materials, one of the best known being Biodur108©, although numerous efforts have been made to increase its hardness. In this work, thermomechanical treatments at low temperature of cold-deformed Biodur108© were conducted to increase the hardness. Hardness as high as 830 Hv was obtained. For this material, the annealing of a deformed sample at intermediate temperature leads to a secondary hardening phenomenon. The mechanisms responsible for this secondary hardening were analyzed. It was found that for deformed samples, annealing at 575 °C leads to the formation of small Cr₂N precipitates along grain boundaries and sub-grain boundaries, and simultaneously with a new body-centered cubic (BCC) phase that possesses a super structure. The newly formed phases have sub-micrometric grain sizes.     

SARS-CoV-2 Transmission in Belgian French-Speaking Primary Schools: An Epidemiological Pilot Study

Schools have been a point of attention during the pandemic, and their closure one of the mitigating measures taken. A better understanding of the dynamics of the transmission of SARS-CoV-2 in elementary education is essential to advise decisionmakers. We conducted an uncontrolled non-interventional prospective study in Belgian French-speaking schools to describe the role of attending asymptomatic children and school staff in the spread of COVID-19 and to estimate the transmission to others. Each participant from selected schools was tested for SARS-CoV-2 using a polymerase chain reaction (PCR) analysis on saliva sample, on a weekly basis, during six consecutive visits. In accordance with recommendations in force at the time, symptomatic individuals were excluded from school, but per the study protocol, being that participants were blinded to PCR results, asymptomatic participants were maintained at school. Among 11 selected schools, 932 pupils and 242 school staff were included between January and May 2021. Overall, 6449 saliva samples were collected, of which 44 came back positive. Most positive samples came from isolated cases. We observed that asymptomatic positive children remaining at school did not lead to increasing numbers of cases or clusters. However, we conducted our study during a period of low prevalence in Belgium. It would be interesting to conduct the same analysis during a high prevalence period.     

Serum and Urine Metabolites in Healthy Men after Consumption of Acidified Milk and Yogurt

The identification of molecular biomarkers that can be used to quantitatively link dietary intake to phenotypic traits in humans is a key theme in modern nutritional research. Although dairy products (with and without fermentation) represent a major food group, the identification of markers of their intake lags behind that of other food groups. Here, we report the results from an analysis of the metabolites in postprandial serum and urine samples from a randomized crossover study with 14 healthy men who ingested acidified milk, yogurt, and a non-dairy meal. Our study confirms the potential of lactose and its metabolites as markers of lactose-containing dairy foods and the dependence of their combined profiles on the fermentation status of the consumed products. Furthermore, indole-3-lactic acid and 3-phenyllactic acid are two products of fermentation whose postprandial behaviour strongly discriminates yogurt from milk intake. Our study also provides evidence of the ability of milk fermentation to increase the acute delivery of free amino acids to humans. Notably, 3,5-dimethyloctan-2-one also proves to be a specific marker for milk and yogurt consumption, as well as for cheese consumption (previously published data). These molecules deserve future characterisation in human interventional and observational studies.     

Preclinical evaluation and structural optimization of anti-BCMA CAR to target multiple myeloma

Chimeric antigen receptor (CAR) T-cell based immunotherapy has become a promising treatment mainly for hematological malignancies. Following the major success of CD19-targeted CAR, new potential targets for other malignancies are required. As such, B-cell maturation antigen (BCMA) is an attractive tumor-associated antigen to be targeted in multiple myeloma (MM). Herein, we aimed at assessing the function and optimal configuration of different BCMA-specific CAR, based on the same targeting moiety but with a different hinge and co-stimulatory domain. We compared their function to that of a previously characterized BCMA-CAR used in clinical trials. All constructs were expressed at high levels by primary human T cells and could trigger cytokine production and cytotoxicity upon co-culture with multiple myeloma targets. Nonetheless, critical differences were observed in off-target activation, exhaustion, and activation marker expression and in vivo anti-tumoral activity mediated by these different constructs. Interestingly, we noted that CD8-based hinge, combined with a 4-1BB intracellular domain, proved superior compared to IgG4-connecting regions, and/or a CD28-signaling moiety respectively. Overall, this study emphasizes the influence of CAR primary structure on its function and led to the identification of a highly efficient BCMA-specific CAR, namely H8BB, which displayed superior anti-tumoral activity both in vitro and long-term in vivo efficacy.     

Impact of Stagnation on the Diversity of Cyanobacteria in Drinking Water Treatment Plant Sludge

Health-related concerns about cyanobacteria-laden sludge of drinking water treatment plants (DWTPs) have been raised in the past few years. Microscopic taxonomy, shotgun metagenomic sequencing, and microcystin (MC) measurement were applied to study the fate of cyanobacteria and cyanotoxins after controlled sludge storage (stagnation) in the dark in a full-scale drinking water treatment plant within 7 to 38 days. For four out of eight dates, cyanobacterial cell growth was observed by total taxonomic cell counts during sludge stagnation. The highest observed cell growth was 96% after 16 days of stagnation. Cell growth was dominated by potential MC producers such as Microcystis, Aphanocapsa, Chroococcus, and Dolichospermum. Shotgun metagenomic sequencing unveiled that stagnation stress shifts the cyanobacterial communities from the stress-sensitive Nostocales (e.g., Dolichospermum) order towards less compromised orders and potential MC producers such as Chroococcales (e.g., Microcystis) and Synechococcales (e.g., Synechococcus). The relative increase of cyanotoxin producers presents a health challenge when the supernatant of the stored sludge is recycled to the head of the DWTP or discharged into the source. These findings emphasize the importance of a strategy to manage cyanobacteria-laden sludge and suggest practical approaches should be adopted to control health/environmental impacts of cyanobacteria and cyanotoxins in sludge.     

Protein/Fiber Index Modulates Uremic Toxin Concentrations in Hemodialysis Patients

Background: Indoxyl sulfate (IS) and p-cresyl sulfate (PCS), two uremic toxins (UTs), are associated with increased mortality in patients with chronic kidney disease (CKD). These toxins are produced by the microbiota from the diet and excreted by the kidney. The purpose of this study was to analyze the effect of diet on IS and PCS concentration in hemodialysis (HD) patients. Methods: We performed a prospective monocentric study using a seven-day diet record and determination of serum IS and PCS levels in HD patients. We tested the association between toxin concentrations and nutritional data. Results: A total of 58/75 patients (77%) completed the diet record. Mean caloric intake was 22 ± 9.2 kcal/kg/day. The protein/fiber index was 4.9 ± 1.8. No correlation between IS or PCS concentration and protein/fiber index was highlighted. In the 18 anuric patients (31%) in whom residual renal function could not affect toxin concentrations, IS and PCS concentrations were negatively correlated with fiber intake and positively correlated with the protein/fiber index. In a multivariate analysis, IS serum concentration was positively associated with the protein/fiber index (p = 0.03). Conclusions: A low protein/fiber index is associated with low concentrations of uremic toxins in anuric HD patients. Diets with an increased fiber intake must be tested to determine whether they reduce PCS and IS serum concentrations.