The conserved dileucine- and tyrosine-based motifs in MLV and MPMV envelope glycoproteins are both important to regulate a common Env intracellular trafficking

BACKGROUND: Retrovirus particles emerge from the assembly of two structural protein components, Gag that is translated as a soluble protein in the cytoplasm of the host cells, and Env, a type I transmembrane protein. Because both components are translated in different intracellular compartments, elucidating the mechanisms of retrovirus assembly thus requires the study of their intracellular trafficking. RESULTS: We used a CD25 (Tac) chimera-based approach to study the trafficking of Moloney murine leukemia virus and Mason-Pfizer monkey virus Env proteins. We found that the cytoplasmic tails (CTs) of both Env conserved two major signals that control a complex intracellular trafficking. A dileucine-based motif controls the sorting of the chimeras from the trans-Golgi network (TGN) toward endosomal compartments. Env proteins then follow a retrograde transport to the TGN due to the action of a tyrosine-based motif. Mutation of either motif induces the mis-localization of the chimeric proteins and both motifs are found to mediate interactions of the viral CTs with clathrin adaptors. CONCLUSION: This data reveals the unexpected complexity of the intracellular trafficking of retrovirus Env proteins that cycle between the TGN and endosomes. Given that Gag proteins hijack endosomal host proteins, our work suggests that the endosomal pathway may be used by retroviruses to ensure proper encountering of viral structural Gag and Env proteins in cells, an essential step of virus assembly

The Effect of Foot Reflexology on Chemotherapy-Induced Nausea and Vomiting in Patients With Digestive or Lung Cancer: Randomized Controlled Trial

BackgroundCancer is a chronic disease with an incidence of 24.5 million and 9.6 million deaths worldwide in 2017. Lung and colorectal cancer are the most common cancers for both sexes and, according to national and international recommendations, platinum-based chemotherapy is the reference adjuvant treatment. This chemotherapy can be moderately to highly emetogenic. Despite antiemetic therapy, chemotherapy-induced nausea and vomiting (CINV) may persist. Moreover, cancer patients are increasingly interested in alternative and complementary medicines and have expressed the desire that nonpharmacological treatments be used in hospitals. Among alternative and complementary medicines, foot reflexology significantly decreases the severity of CINV in patients with breast cancer. ObjectiveThe primary aim of this study was to assess the benefits of foot reflexology as a complement therapy to conventional treatments regarding the severity of acute CINV in patients with digestive or lung cancer. The secondary objectives assessed were the frequency and severity of delayed CINV, quality of life, anxiety, and self-esteem. MethodsThis study was conducted between April 2018 and April 2020 in the Hospices Civils de Lyon, France. This was an open-label randomized controlled trial. Participants were randomized into two groups: the intervention group (ie, conventional care with foot reflexology; n=40) and the control group (ie, conventional care without foot reflexology; n=40). Foot reflexology sessions (30 minutes each) were performed on outpatients or inpatients. Eligible participants were patients with lung or digestive cancer with an indication for platinum-based chemotherapy. ResultsThe severity of acute nausea and vomiting was assessed with a visual analog scale during the second cycle of chemotherapy. A significant increase of at least 2 points was observed for the control group (7/34, 21%; P=.001). Across all cycles, the foot reflexology group showed a trend toward less frequent delayed nausea (P=.28), a significantly less frequent consumption of antiemetic drugs (P=.04), and no significant difference for vomiting (P=.99); there was a trend toward a perception of stronger severity for delayed nausea in the control group (P=.39). Regarding quality of life and anxiety, there was no significant difference between the intervention group and the control group (P=.32 and P=.53, respectively). ConclusionsThis study’s results indicate that foot reflexology provides significantly better management of acute nausea severity and decreased consumption of antiemetic drugs in patients with lung or digestive cancer. In order to fulfill patients’ desires to use nonpharmacological treatments and complementary and alternative medicines in hospitals, foot reflexology could be provided as a complementary intervention to conventional antiemetic drugs. Foot reflexology did not result in adverse effects. To assess the benefits of foot reflexology in routine practice, a larger study with several health care centers would be needed with a cluster randomized controlled trial. Trial RegistrationClinicalTrials.gov NCT03508180; https://clinicaltrials.gov/ct2/show/NCT03508180 International Registered Report Identifier (IRRID)RR2-10.2196/1723

The Effects of Foot Reflexology on Chemotherapy-Induced Nausea and Vomiting in Patients with Digestive System or Lung Cancer: Protocol for a Randomized Controlled Trial

International audienceBackground The side effects of chemotherapy, specifically chemotherapy-induced nausea and vomiting, are a concern for patients. To relieve these side effects, antiemetic drugs are recommended. However, some patients report that these drugs are not sufficiently effective. Moreover, patients with chronic disease, including cancer, are increasingly interested in complementary and alternative medicines, and express the desire for nonpharmacological treatments to be used in hospitals. Foot reflexology is a holistic approach that is reported to significantly reduce the severity of chemotherapy-induced nausea and vomiting in patients with breast cancer. Some of the chemotherapy treatments for patients with lung and digestive system cancer are moderately or highly emetic. Objective The primary objective of this study is to assess the benefits of foot reflexology, together with conventional treatments, on the severity and frequency of chemotherapy-induced nausea and vomiting in patients with lung or digestive system cancer. The secondary objectives to be assessed are quality of life, anxiety, and self-esteem. Methods This study is an open-label randomized controlled trial conducted over 22 months (18 months intervention and 4 months follow-up). Eligible participants are patients with a lung or digestive system cancer with an indication for platinum-based chemotherapy. Participants are randomized into two groups: conventional care with foot reflexology and conventional care without foot reflexology. Foot reflexology sessions (30 minutes) are performed on an outpatient or inpatient basis. It was estimated that 40 participants per group will be required. The benefits of foot reflexology will be assessed by comparing the relative change in the severity of nausea and vomiting, as assessed by a visual analogue scale, and the frequency of these side effects between the two groups. The secondary objectives will be assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; Hospital and Anxiety Depression Scale; and Body Image Questionnaire. Results This study was approved by the regional ethics committee (Île de France X CPP) on April 3, 2018 (No. ID RCB 2018-A00571-54). Enrollment started in June 2018. Data analysis will be performed during the second quarter of 2020 and results will be published in the last quarter of 2020. Conclusions The lack of knowledge regarding the efficacy and safety of foot reflexology limits oncologists to recommend it for this use. This study will provide evidence of the benefits of foot reflexology. If efficacy is confirmed, foot reflexology may be a promising complement to conventional antiemetic drugs. Trial Registration Clinicaltrials.gov NCT03508180; https://www.clinicaltrials.gov/ct2/show/NCT03508180. International Registered Report Identifier (IRRID) DERR1-10.2196/1723

Ibrutinib in very elderly patients with relapsed/refractory chronic lymphocytic leukemia: A real-world experience of 71 patients treated in France: A study from the French Innovative Leukemia Organization (FILO) group

International audienc

SMAD2/3 mediate oncogenic effects of TGF-β in the absence of SMAD4

International audienceTGF-β signaling is involved in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis, representing one of the four major pathways genetically altered in 100% of PDAC cases. TGF-β exerts complex and pleiotropic effects in cancers, notably via the activation of SMAD pathways, predominantly SMAD2/3/4. Though SMAD2 and 3 are rarely mutated in cancers, SMAD4 is lost in about 50% of PDAC, and the role of SMAD2/3 in a SMAD4-null context remains understudied. We herein provide evidence of a SMAD2/3 oncogenic effect in response to TGF-β1 in SMAD4-null human PDAC cancer cells. We report that inactivation of SMAD2/3 in SMAD4-negative PDAC cells compromises TGF-β-driven collective migration mediated by FAK and Rho/Rac signaling. Moreover, RNA-sequencing analyses highlight a TGF-β gene signature related to aggressiveness mediated by SMAD2/3 in the absence of SMAD4. Using a PDAC patient cohort, we reveal that SMAD4-negative tumors with high levels of phospho-SMAD2 are more aggressive and have a poorer prognosis. Thus, loss of SMAD4 tumor suppressive activity in PDAC leads to an oncogenic gain-of-function of SMAD2/3, and to the onset of associated deleterious effects

Early clindamycin for bacterial vaginosis in pregnancy (premeva): a multicentre, double-blind, randomised controlled trial

International audienceBackground: Preterm delivery during pregnancy (<37 weeks' gestation) is a leading cause of perinatal mortality and morbidity. Treating bacterial vaginosis during pregnancy can reduce poor outcomes, such as preterm birth. We aimed to investigate whether treatment of bacterial vaginosis decreases late miscarriages or spontaneous very preterm birth.Methods: PREMEVA was a double-blind randomised controlled trial done in 40 French centres. Women aged 18 years or older with bacterial vaginosis and low-risk pregnancy were eligible for inclusion and were randomly assigned (2:1) to three parallel groups: single-course or triple-course 300 mg clindamycin twice-daily for 4 days, or placebo. Women with high-risk pregnancy outcomes were eligible for inclusion in a high-risk subtrial and were randomly assigned (1:1) to either single-course or triple-course clindamycin. The primary outcome was a composite of late miscarriage (16-21 weeks) or spontaneous very preterm birth (22-32 weeks), which we assessed in all patients with delivery data (modified intention to treat). Adverse events were systematically reported. This study is registered with ClinicalTrials.gov, number NCT00642980.Findings: Between April 1, 2006, and June 30, 2011, we screened 84 530 pregnant women before 14 weeks' gestation. 5630 had bacterial vaginosis, of whom 3105 were randomly assigned to groups in the low-risk trial (n=943 to receive single-course clindamycin, n=968 to receive triple-course clindamycin, and n=958 to receive placebo) or high-risk subtrial (n=122 to receive single-course clindamycin and n=114 to receive triple-course clindamycin). In 2869 low-risk pregnancies, the primary outcome occurred in 22 (1·2%) of 1904 participants receiving clindamycin and 10 (1·0%) of 956 participants receiving placebo (relative risk [RR] 1·10, 95% CI 0·53-2·32; p=0·82). In 236 high-risk pregnancies, the primary outcome occurred in 5 (4·4%) participants in the triple-course clindamycin group and 8 (6·0%) participants in the single-course clindamycin group (RR 0·67, 95% CI 0·23-2·00; p=0·47). In the low-risk trial, adverse events were more common in the clindamycin groups than in the placebo group (58 [3·0%] of 1904 vs 12 [1·3%] of 956; p=0·0035). The most commonly reported adverse event was diarrhoea (30 [1·6%] in the clindamycin groups vs 4 [0·4%] in the placebo group; p=0·0071); abdominal pain was also observed in the clindamycin groups (9 [0·6%] participants) versus none in the placebo group (p=0·034). No severe adverse event was reported in any group. Adverse fetal and neonatal outcomes did not differ significantly between groups in the high-risk subtrial.Interpretation: Systematic screening and subsequent treatment for bacterial vaginosis in women with low-risk pregnancies shows no evidence of risk reduction of late miscarriage or spontaneous very preterm birth. Use of antibiotics to prevent preterm delivery in this patient population should be reconsidered.French Ministry of Health

A fixed-duration, measurable residual disease–guided approach in CLL: follow-up data from the phase 2 ICLL-07 FILO trial

International audienceAbstract Trials assessing first-line, fixed-duration approaches in chronic lymphocytic leukemia (CLL) are yielding promising activity, but few long-term data are available. We report follow-up data from a phase 2 trial (ICLL07 FILO) in previously untreated, medically fit patients (N = 135). Patients underwent obinutuzumab-ibrutinib induction for 9 months; then, following evaluation (N = 130 evaluable), those in complete remission and with bone marrow measurable residual disease (BM MRD) &lt;0.01% (n = 10) received ibrutinib for 6 additional months; those in partial remission and/or with BM MRD ≥0.01%, the majority (n = 120), also received 4 cycles of immunochemotherapy (fludarabine/cyclophosphamide-obinutuzumab). Beyond end of treatment, responses were assessed every 3 month and peripheral blood MRD every 6 months. At median follow-up 36.7 months from treatment start, progression-free and overall survival rates (95% confidence interval) at 3 years were 95.7% (92.0% to 99.5%) and 98% (95.1% to 100%), respectively. Peripheral blood MRD &lt;0.01% rates were 97%, 96%, 90%, 84%, and 89% at months 16, 22, 28, 34, and 40, respectively. No new treatment-related or serious adverse event occurred beyond end of treatment. Thus, in previously untreated, medically fit patients with CLL, a fixed-duration (15 months), MRD-guided approach achieved high survival rates, a persistent MRD benefit beyond the end of treatment, and low long-term toxicity. This trial was registered at www.clinicaltrials.gov as #NCT02666898