Ketogenic diet enhances the anti-cancer effects of PD-L1 blockade in renal cell carcinoma.

Introduction: Clear cell renal cell carcinoma (ccRCC) is characterized by a predominant metabolic reprogramming triggering energy production by anaerobic glycolysis at the expense of oxydative phosphorylation. Ketogenic diet (KD), which consists of high fat and low carbohydrate intake, could bring required energy substrates to healthy cells while depriving tumor cells of glucose. Our objective was to evaluate the effect of KD on renal cancer cell tumor metabolism and growth proliferation. Methods: Growth cell proliferation and mitochondrial metabolism of ACHN and Renca renal carcinoma cells were evaluated under ketone bodies (KB) exposure. In vivo studies were performed with mice (nude or Balb/c) receiving a xenograft of ACHN cells or Renca cells, respectively, and were then split into 2 feeding groups, fed either with standard diet or a 2:1 KD ad libitum. To test the effect of KD associated to immunotherapy, Balb/c mice were treated with anti-PDL1 mAb. Tumor growth was monitored. Results: In vitro, KB exposure was associated with a significant reduction of ACHN and Renca cell proliferation and viability, while increasing mitochondrial metabolism. In mice, KD was associated with tumor growth reduction and PDL-1 gene expression up-regulation. In Balb/c mice adjuvant KD was associated to a better response to anti-PDL-1 mAb treatment. Conclusion: KB reduced the renal tumor cell growth proliferation and improved mitochondrial respiration and biogenesis. KD also slowed down tumor growth of ACHN and Renca in vivo. We observed that PDL-1 was significantly overexpressed in tumor in mice under KD. Response to anti-PDL-1 mAb was improved in mice under KD. Further studies are needed to confirm the therapeutic benefit of adjuvant KD combined with immunotherapy in patients with kidney cancer.

[Impact of delay before partial nephrectomy of a localized kidney tumor]. / Impact du délai avant prise en charge par néphrectomie partielle d'une tumeur du rein localisée.

INTRODUCTION: Partial nephrectomy is the treatment of choice for small localized renal tumors. In case of doubt, a biopsy can confirm the diagnosis. The aim of this study was to evaluate the impact of a delayed time to partial nephrectomy on cancer development. MATERIALS AND METHODS: Our single center study enrolled localized renal tumor patients who underwent a partial nephrectomy between 2015 and 2020; the collected data were included in the uroCCR prospective database. The histopathological stage of the tumors and the recurrence rate in patients treated with surgery >90 days after diagnosis were investigated. The impact a preoperative biopsy on was also explored. Statistical significance was tested using Student's t-test and Chi-squared test (SPSS software). RESULTS: The cohort consisted of 179 patients, among which 41 (23 %) received a preoperative biopsy. 89 patients (50 %) were treated surgically >3 months after diagnosis. The median time to nephrectomy was 86 days (13-1 037). A delayed time to surgery did not lead to significantly higher recurrence rates (P=0.66). Preoperative biopsy led to a doubling time to surgery (P<0.001) but was neither correlated to a more severe tumor stage (P=0.944) nor to a higher recurrence rate (P=0.08). Tumor growth was not significantly different with or without the presence of a biopsy (P=0.122). CONCLUSION: Our data evidence that a substantial delayed time to partial nephrectomy does not result in a negative impact on cancer prognosis in localized renal tumor patients.

Antibiotic therapy impact on intravesical BCG therapy efficacy for high-risk localized bladder cancer treatment.

Intravesical Bacillus Calmettes-Guerin (BCG) instillations is the gold standard adjuvant treatment for high and very high-risk non-muscle-invasive bladder cancer (NMIBC). Antibiotics may be required to treat asymptomatic bacteriuria before instillations or to prevent side effects. By modifying the bladder microbiota and through its bactericidal action, it could modify the efficacy of BCG. This study evaluates the impact of antibiotics received during BCG-induction treatment on the oncological outcomes for high and very high risk NMIBC. We retrospectively included all patients who received a full induction regimen of BCG therapy between January 2017 and June 2022. Clinical and tumor characteristics as well as tolerability were collected. Recurrence-free survival (RFS) and progression-free survival (PFS) were compared according to the prescription of antibiotics, its type and duration. A total of 126 patients were included, 86.5% of the tumors were high risk and 13.5% very high risk. The median follow-up was 31 months (7-60). 36% of the patients received antibiotics during BCG-induction treatment (among which 44% received fluoroquinolones). 21.4% of patients had tumor recurrence. There was no difference in RFS (p=0.902) or PFS (p=0.88) according to the duration or the type of antibiotics received. The use of a prolonged antibiotic treatment (> 7 days) significantly increased the duration of the BCG-induction treatment from 35 to 41,5 days (p=0,049) and the median number of delayed treatments by 1,5 [0-4]. Neither the use of antibiotics nor their duration modified the risk of recurrence or the intensity of side effects in multivariate analysis. Antibiotics received during BCG-induction immunotherapy did not influence oncological short-term outcomes or intensity of side effects.

Voter conformism and inefficient policies.

A reelection-seeking politician makes a policy decision that can reveal her private information. This information bears on whether her political orientation and capabilities will be a good fit to future circumstances. We study how she may choose inappropriate policies to hide her information, even in the absence of specific conflicts of interests, and how voters' conformism affects her incentives to do so. Conformism is independent from policies and from voters' perceptions. Yet we identify a 'conformism advantage' for the incumbent that exists only when there is also an incumbency advantage. Conformism changes the incentives of the incumbent and favors the emergence of an efficient, separating equilibrium. It may even eliminate the pooling equilibrium (that can consist in inefficient persistence). Conformism has a mixed impact on social welfare however: it improves policy choices and the information available to independent voters, but fosters inefficient reelection in the face of a stronger opponent. When the incumbent is 'altruistic' and values social welfare even when not in power, she partly internalizes this latter effect. The impact of conformism is then non monotonous.

The relative power of individual distancing efforts and public policies to curb the COVID-19 epidemics.

Lockdown curbs the COVID-19 epidemics but at huge costs. Public debates question its impact compared to reliance on individual responsibility. We study how rationally chosen self-protective behavior impacts the spread of the epidemics and interacts with policies. We first assess the value of lockdown in terms of mortality compared to a counterfactual scenario that incorporates self-protection efforts; and second, assess how individual behavior modify the epidemic dynamics when public regulations change. We couple an SLIAR model, that includes asymptomatic transmission, with utility maximization: Individuals trade off economic and wellbeing costs from physical distancing with a lower infection risk. Physical distancing effort depends on risk aversion, perceptions of the epidemics and average distancing effort in the population. Rational distancing effort is computed as a Nash Equilibrium. Equilibrium effort differs markedly from constant, stochastic or proportional contacts reduction. It adjusts to daily incidence of hospitalization in a way that creates a slightly decreasing plateau in epidemic prevalence. Calibration on French data shows that a business-as-usual benchmark yields an overestimation of the number of deaths by a factor of 10 compared to benchmarks with equilibrium efforts. However, lockdown saves nearly twice as many lives as individual efforts alone. Public policies post-lockdown have a limited impact as they partly crowd out individual efforts. Communication that increases risk salience is more effective.

Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension.

The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor1. Although some MRAP2 mutations have been described in people with obesity1-3, their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, hyperglycemia and hypertension. This contrasts with other monogenic forms of obesity characterized by excessive hunger, including melanocortin-4 receptor deficiency, that present with low blood pressure and normal glucose tolerance4. The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets.