A new one-pot solvent-less reaction to convert benzylic, allylic, ferrocenyl or tertiary alcohols into S-thioesters, bench-stable and less odorous precursors of the corresponding thiols, which is based on reactions in neat thioacetic acid in the presence of tetrafluoroboric acid, is presented. Reaction monitoring by NMR and GC of the benzyl alcohol conversion indicated the intermediate formation of benzyl acetate and benzyl thionoacetate (PhCH2 OC(S)CH3 ) prior to the slower conversion to the final S-benzyl thioacetate product. Increasing the HBF4 concentration enhanced the reaction rate, giving good to excellent yield (up to 99 %) for a large scope of alcohols. Control experiments, with support of DFT calculations, have revealed a thermodynamically favorable, though requiring HBF4 -activation, disproportionation of CH3 C(O)SH to CH3 C(O)OH and CH3 C(S)SH, the latter immediately decomposing to H2 S and (MeC)4 S6 but also generating the hitherto unreported [MeC(O)C(Me)S]2 (μ-S)2 . Kinetic investigations demonstrated that the rate of benzyl alcohol conversion is second-order in [PhCH2 OH] and second order in [HBF4 ], while the rate of conversion of the benzyl acetate intermediate to S-benzyl thioacetate is second order in [PhCOOMe] and fourth order in [HBF4 ]. The DFT calculations rationalize the need to two alcohol molecules and two protons to generate the reactive benzyl cation.

BackgroundColorectal cancer (CRC) can be classified into four molecular subtypes (CMS) among which CMS1 is associated with the best prognosis, while CMS4, the mesenchymal subtype, has the worst outcome. Although mitochondria are considered to be hubs of numerous signaling pathways, the study of mitochondrial metabolism has been neglected for many years. Mitochondrial Complex I (CI) plays a dual role, both in energy and reactive oxygen species (ROS) production. However, the possible contribution of CI to tumorigenesis in cancer remains unclear. The purpose of this study was to investigate the CI under the prism of the CMS classification of CRC in ex vivo models.MethodsBiochemical dosages, bioenergetics analysis and western-blot were used to characterize CI expression, function and redox balance in LoVo and MDST8 cell lines, belonging to CMS1 and CMS4 subgroups, respectively. Cell proliferation and migration were assessed by xCELLigence technology. Overproduction or scavenging of mitochondrial ROS (mtROS) were performed to analyze the effect of mtROS on proliferation, migration, and mesenchymal markers. Focal adhesion kinase (FAK) and its activation were analyzed by immunofluorescence. We assessed the distribution of two CI scores in CRC cohorts according to CMS classification and their relevance for patient survival.ResultsWe found that CI is downregulated in CMS4 cells and is associated with elevated mtROS. We establish for the first time that in these migrating cells, mtROS production is maintained at optimal levels not only through changes in CI activity but also by inactivation/acetylation of superoxide dismutase 2 (SOD2), a major mitochondrial antioxidant enzyme. We show that promoting or scavenging mtROS both mitigate CMS4 cells’ migration. Our results also point to a mtROS-mediated focal adhesion kinase (FAK) activation, which likely sustains their migratory phenotype. Using cohorts of CRC patients, we document that the expression of CI is downregulated in the CMS4 subgroup, and that low CI expression is associated with poor prognosis. Patients’ datasets reveal an inverse correlation between CI and the epithelial-mesenchymal transition (EMT) pathway.ConclusionWe showed that inhibition of CI contributes to heighten mtROS, which likely foster MDST8 migration and might account for the specific EMT signature of CMS4 tumors. These data reveal a novel role of mitochondrial CI in CRC, with biological consequences that may be targeted with anti- or pro-oxidant drugs in clinical practice.

Although patients with microsatellite instable metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single-arm, phase 1b/2 MEDITREME trial evaluated the safety and efficacy of durvalumab plus tremelimumab combined with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable metastatic CRC. Safety was the primary objective of phase Ib; no safety issue was observed. The phase 2 primary objective of efficacy in terms of 3-month progression-free survival (PFS) in patients with MSS tumors was met, with 3-month PFS of 90.7% (95% confidence interval (CI): 79.2-96%). For secondary objectives, response rate was 64.5%; median PFS was 8.2 months (95% CI: 5.9-8.6); and overall survival was not reached in patients with MSS tumors. We observed higher tumor mutational burden and lower genomic instability in responders. Integrated transcriptomic analysis underlined that high immune signature and low epithelial-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor-specific T cell response associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC. Clinicaltrials.gov identifier: NCT03202758 .

Abstract Background: Treatment options for patients (pts) with heavily pretreated mCRPC are limited. Augmenting endocrine therapy by targeting CDK4/6 with abemaciclib has dramatically improved outcomes in HR+ breast cancer. Similar to ER, AR signaling activates CDK4 & 6 and abemaciclib showed preclinical anti-tumor activity in prostate cancer (PC). This signal seeking single arm Phase 2 study evaluated the safety and clinical activity of abemaciclib monotherapy in pts with heavily pretreated poor prognosis mCRPC who progressed after both a novel hormonal agent (NHA) and two taxanes. Methods: Eligible pts had progressive mCRPC, measurable disease by RECIST1.1, and previously received ≥1 NHA, docetaxel, and cabazitaxel for metastatic PC. Abemaciclib was administered at 200 mg BID on a continuous 28-day dosing schedule. The primary endpoint was investigator-assessed objective response rate without concurrent bone progression (ORR). A target ORR of ≥12.5% was deemed suitable to support further evaluation of abemaciclib monotherapy in this refractory mCRPC setting. Key secondary endpoints included disease control rate (DCR), time to PSA progression, radiographic progression-free survival (rPFS), overall survival (OS), and safety. Results: Forty-four pts (median age 68 yrs; 75% ECOG PS 1, median PSA of 96 ng/mL) were enrolled. In total, 46.5% had visceral metastasis, including 27.9% with liver metastases. Median time from development of mCRPC to study entry was 2.1 yrs and the median number of prior systemic regimens for mCRPC was 3. Median number of treatment cycles was 3 (1-13). Five pts (11.8%) had soft tissue response. The ORR without concurrent bone progression was 6.8%. Eighteen pts (40.9%) had stable disease, of which 6 (13.6%) lasted ≥6 months (mos); DCR was 47.7%. Median rPFS was 2.7 mos (95% CI 1.9, 3.7); 6-mos rPFS rate was 24.9% (95% CI 12.4, 39.5); median time to PSA progression was 6.5 mos. Median OS was 7.6 mos (95% CI 5.6, NE). Any grade (G) TRAEs experienced by ≥50% of pts were diarrhea (79.5%), decreased appetite (52.3%) and fatigue (50%); majority were G1/2. G3 TRAEs in ≥ 5% of pts were neutropenia (22.7%), anemia (6.8%), fatigue (6.8%) and diarrhea (6.8%). There were no G4 or G5 TRAEs. Discontinuation rate due to AE was 13.6%. Conclusions: Abemaciclib demonstrated modest but objective single-agent clinical activity in pts with very heavily pretreated progressive mCRPC. The safety profile of abemaciclib was consistent with the experience in breast cancer. Although the primary endpoint was not formally met, the single agent activity observed in this late line mCRPC setting validates CDK4/6 as a therapeutic target in advanced PC. The CYCLONE 2 and CYCLONE 3 studies are currently evaluating abemaciclib in combination with abiraterone/prednisone to leverage synergy of combined CDK4/6 and hormonal inhibition in first line mCRPC and mHSPC settings, respectively. Citation Format: Neeraj Agarwal, Daniel Castellano Guana, Teresa A. Gordoa, Jose A. Arija, Emeline Colomba, Gwenaelle Gravis, Loic Mourey, Stephanie Oudard, Aude Flechon, Macarena Gonzalez, Pablo Maroto-Rey, Michael Schweizer, Enrique Gallardo, Karim Nacerddine, Adams K. Appiach, Arjun Balar, Erica Johnston, José M. Piulats. CYCLONE 1: abemaciclib in men with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT159.

Presbycusis is the physiological decrease in hearing due to advancing age and begins well before the sixth decade. These recommendations recall the principles of early diagnosis of presbycusis and the means of optimal rehabilitation as soon as the first symptoms appear. The recommendations are based on a systematic analysis of the literature carried out by a multidisciplinary group of doctors and audioprosthetists from all over France. They are graded A, B, C or expert opinion according to decreasing level of scientific evidence. The diagnosis of presbycusis is more difficult at the beginning of its evolution but a certain number of tools are available for its early diagnosis and its management in face-to-face or even distance learning. In case of a clinical profile suggestive of presbycusis in a young subject, especially if there are several family cases, it is recommended to propose a genetic investigation. It is recommended to perform free-field speech audiometry in noise to measure intelligibility in an environment as close as possible to reality. Questionnaires can be used in addition to audiometry to best assess the patient's disability. It is recommended that hearing rehabilitation with a hearing aid or cochlear implant may slow or prevent cognitive decline. Combined auditory and cognitive rehabilitation should be offered regardless of the time elapsed since the fitting. It is recommended to integrate programs accessible via smartphones, tablets or the Internet, integrating different training domains in addition to face-to-face sessions.

AbstractBackgroundHearing and vision impairments are highly prevalent in people with dementia (PwD) and may have a negative impact on quality of life and other dementia‐related outcomes. Intervening to optimize sensory function improve these outcomes. The SENSE‐cog Trial evaluated whether a home‐based multi‐part ‘sensory support’ intervention (SSI) is effective in improving quality of life and other key outcomes in PwD (including hearing and/or vision problems), and their care partners.MethodsThis was a pan‐European, multi‐centre, observer blind, randomized controlled trial (RCT), of PwD with hearing and/or vision impairment and their companions. We compared ‘care as usual’ (CAU) to a multi‐part complex intervention of hearing and vision rehabilitation (SSI) tailored to each participant dyad. The SSI included: assessment and correction of hearing and/or vision impairments; home‐based, therapist‐delivered sensory support (i.e., adherence with devices; improving the sensory environment, communication training, and signposting to other support agencies). Outcomes were collected at baseline, intervention end (18 weeks) and post‐intervention (36 weeks – the primary endpoint) and included: quality of life, sensory and cognitive functional ability, relationship satisfaction, neuropsychiatric symptoms, and mental well‐being. Health resource utilization was measured to estimate cost‐effectiveness of the intervention.ResultsAcross 7 European centers (UK, France, Cyprus, Greece), 252 participants with dementia (median age 80 years, 53% female, 59% hearing impairment only, 4% visual impairment only and 37% both impairments) were randomized from May 2018 to May 2021 to receive either CAU or SSI (10 visits over 18 weeks). Mitigating strategies to adapt study procedures to the COVID‐19 pandemic were implemented. Over 75% of participants completed the primary outcome, the DEM‐QoL scale, at 36 weeks. An initial feasibility study yielded positive results for this outcome revealing an average improvement in the DEM‐QoL of 4.9 points (> minimum important clinical change).ConclusionsHearing and vision support in PwD is a potentially important and cost‐effective means of improving the lived experience of dementia, representing a critical step in the diagnostic and care pathway. Main RCT results will be available in May 2022. Trial registration: ISRCTN17056211

ABSTRACT Children with Attentional Deficit Hyperactivity Disorder (ADHD) frequently have low self-awareness and attentional deficits on which therapeutic hypnosis can have a positive impact. Here we investigated the contribution of therapeutic hypnosis in the treatment of written language disorders in a child with ADHD. This study is a Single-Case Experimental Design (SCED) using repeated measures. The participant is 11 years old. We assessed reading performance and verbal fluency for four weeks before starting the intervention, as well as during the therapeutic window when four hypnosis sessions were administered over an 8-week timeframe. We assessed written language through a regular and irregular word reading test, a spelling choice test, a phonological analysis test, and a fast serial naming test pre- and post-intervention. We assessed attention and self-esteem pre- and post-intervention. The patient’s scores on text reading improved during the intervention compared to the baseline (p = .028). Reading fluency improved, but the pre-post comparison did not reach statistical significance. A progression in scores and response times in phonological tests was observed, with the participant moving from pathological scores in the pre-intervention to normative scores in the post-intervention. Attention and self-esteem significantly improved after the treatment (p = .031, and p = .002 respectively). These results indicate that hypnosis-based therapy might be beneficial to children with specific written language disorders. If these results are confirmed in future studies, therapeutic hypnosis may become part of the recommendations for treatment of ADHD.

Viscothermal acoustic propagation in gases contained in rigid straight or conical tubes is considered. Under the assumption that the wavelength is much larger than both the boundary layer thickness and the tube radius, pressure and flow are shown to be solutions of a pair of coupled 1D differential equations, formulated as transmission line equations involving complex loss coefficients. The derivation of these loss coefficients, which is usually accomplished in cylinders, is generalized here to conical geometries. In the well-known case of circular cylinders, the Zwikker–Kosten (ZK) theory is recovered. For circular cones, the expression of the loss coefficients is derived. It involves complex-order spherical harmonics, instead of Bessel functions for circular cylinders, and makes the hydraulic radius appear as a natural relevant geometrical parameter. We show that replacing the classical radius by the hydraulic radius in the ZK theory provides an affordable and accurate approximation of the analytic model derived for cones. The proposed formulas are used to compute the input impedance of a cone, and compared with a 3D reference. In an ideal setting, using the spherical harmonics or the hydraulic radius in the 1D method accurately approximates the full 3D method, and allows to increase accuracy by approximately two orders of magnitude compared to the ZK theory.

In heart transplantation, antibody-mediated rejection (AMR) is a major contributor to patient morbidity and mortality. Multiple routine endomyocardial biopsies (EMB) remain the gold standard to detect AMR, but this invasive procedure suffers from many limitations. We aimed to develop and validate an AMR risk model to improve individual risk stratification of AMR. Heart recipients from 2 referral transplant centers, Cedars-Sinai (US) and Pitié-Salpêtrière (France), were included from 2012 to 2019. Database included detailed clinical, immunologic, imaging, and histological parameters. The US cohort was randomly distributed in a derivation (2/3) and in a test set (1/3). The primary end point was biopsy-proven AMR. A mixed effect logistic regression model with a random intercept was applied to identify variables independently associated with AMR. Simulation analyzes were performed. The US and French cohorts comprised a total of 1341 patients, representing 12 864 EMB. Overall, 490 AMR episodes were diagnosed (3.8% of EMB). Among the 26 potential determinants of AMR, 5 variables showed independent association: time post-transplant (P<0.001), pretransplant sensitizing event (P=0.001), circulating donor-specific anti-human leukocyte antigen antibody (P=0.001), graft dysfunction (P=0.004), and prior history of definite AMR (P<0.001). In the US test set, the calibration and the discrimination of the model were accurate (area under the curve, 0.79 [95% CI, 0.78-0.81]). Those results were confirmed in the external validation cohort (area under the curve, 0.78 [95% CI, 0.77-0.79]) and reinforced by various sensitivity analyses. The model also showed good performance to predict overall cause of rejection. Simulation models revealed that the AMR risk model could safely reduce the number of EMB. Our results support the use of the AMR risk model as a clinical decision tool to minimize the number of routine EMB after heart transplantation.