DOK1 and DOK2 regulate CD8 T cell signaling and memory formation without affecting tumor cell killing.

Targeting intracellular inhibiting proteins has been revealed to be a promising strategy to improve CD8+ T cell anti-tumor efficacy. Here, we are focusing on intracellular inhibiting proteins specific to TCR signaling: DOK1 and DOK2 expressed in T cells. We hypothesized that depletion of intracellular inhibition checkpoint DOK1 and DOK2 could improve CD8+ T-cell based cancer therapies. To evaluate the role of DOK1 and DOK2 depletion in physiology and effector function of CD8+ T lymphocytes and in cancer progression, we established a transgenic T cell receptor mouse model specific to melanoma antigen hgp100 (pmel-1 TCR Tg) in WT and Dok1/Dok2 DKO (double KO) mice. We showed that both DOK1 and DOK2 depletion in CD8+ T cells after an in vitro pre-stimulation induced a higher percentage of effector memory T cells as well as an up regulation of TCR signaling cascade- induced by CD3 mAbs, including the increased levels of pAKT and pERK, two major phosphoproteins involved in T cell functions. Interestingly, this improved TCR signaling was not observed in naïve CD8+ T cells. Despite this enhanced TCR signaling essentially shown upon stimulation via CD3 mAbs, pre-stimulated Dok1/Dok2 DKO CD8+ T cells did not show any increase in their activation or cytotoxic capacities against melanoma cell line expressing hgp100 in vitro. Altogether we demonstrate here a novel aspect of the negative regulation by DOK1 and DOK2 proteins in CD8+ T cells. Indeed, our results allow us to conclude that DOK1 and DOK2 have an inhibitory role following long term T cell stimulations.

Hepatic round ligament necrosis: A report of two cases managed differently.

INTRODUCTION AND IMPORTANCE: Hepatic round ligament necrosis is a rare condition that has atypical clinical presentation. Its diagnosis; however, being a combination of clinical and biological signs, is very dependent on the computed topography scan. CASE PRESENTATION: This report demonstrates 2 cases that had different presentations. Case 1 was an elderly female with multiple comorbidities presenting with signs of sepsis, perturbation of liver enzymes and presence of thrombosis of portal vein as well as dilatation of bile ducts. On the other hand, case 2 was a younger male patient presenting with inflammatory syndrome, no other biological abnormalities and only an evident fatty stranding in his radiological workup. CLINICAL DISCUSSION: Our 2 cases had different presentations in severity and were thus treated differently. The first patient had clinical, biological and radiological signs of severity; thus, he was treated surgically. On the other hand, the other patient with benign presentation was treated medically with antibiotics. CONCLUSION: In the absence of recommendations concerning the management of hepatic round ligament necrosis, we suggest that treatment choice be based on the severity signs being: clinical, biological or radiological.

Symptomatic Gallbladder Adenomyomatosis: A rare clinical presentation.

INTRODUCTION AND IMPORTANCE: Gallbladder Adenomyomatosis (GA) is a benign rare condition that is mostly asymptomatic but can present as abdominal pain. GA usually occurs in the middle-aged population with an equal sex distribution. CASE PRESENTATION: A case of a 49-years-old female who sought medical care several times due to abrupt abdominal pain. She underwent echography, Computed Tomography (CT) scan and Magnetic Resonance Imaging (MRI) before performing laparoscopic cholecystectomy for symptomatic GA. The pathology report confirmed acalculous cholecystitis in the presence of GA. CLINICAL DISCUSSION: In fact, echography can reveal the "comet- tail" sign, the CT can show the "rosary sign"; and MRI shows the "pearl necklace" sign. These signs, in the absence of gallstones, can justify the abdominal pain hence the diagnosis of symptomatic GA. CONCLUSION: GA is being increasingly reported; however, symptomatic cases remain the exception. We believe that awareness to this entity should be raised so that healthcare professionals can establish the diagnosis efficiently.

Viscosity of Suspensions of Strongly Bonded Spherical Particles of Nickel-Manganese-Cobalt Mixed Oxides (NMC) in Molten Poly(Ethylene Carbonate) for Batteries.

Ionically conductive polymers highly filled with active materials, such as metal oxides are increasingly studied for their potential use in all solid-state batteries. They offer the desirable processing ease of polymers for mass production despite interfacial issues that remain to be solved. In this study, it is shown that spherical particles of transition metal oxides can be introduced in co-polymers of alkene carbonate and ethylene oxide at loading close to the maximum packing fraction, without imparting the processability in the melt of the material. In particular, the viscosity does not show any yield stress and the increase of viscosity shows that the intrinsic viscosity of the filler does not match with the usual 2.5 value in the limit of the Einstein's equation. Conversely, rheological data show that the value is rather close to unity consistently with theoretical arguments that predicted that this scaling factor should be unity when particle rotation is precluded. In the present case, this behavior is attributed to strong bonding between polymer and filler that is proved by electronic microscopy and by dynamical mechanical spectroscopy showing a relaxation due to bound polymer.

The impact of exercise on Alzheimer's disease progression.

INTRODUCTION: The preventive effects of chronic physical exercise (CPE) on Alzheimer's disease (AD) are now admitted by the scientific community. Curative effects of CPE are more disputed, but they deserve to be investigated, since CPE is a natural non-pharmacological alternative for the treatment of AD. AREAS COVERED: In this perspective, the authors discuss the impact of CPE on AD based on an exhaustive literature search using the electronic databases PubMed, ScienceDirect and Google Scholar. EXPERT OPINION: Aerobic exercise alone is probably not the unique solution and needs to be complemented by other exercises (physical activities) to optimize the slowing down of AD. Anaerobic, muscle strength and power, balance/coordination and meditative exercises may also help to slow down the AD progression. However, the scientific evidence does not allow a precise description of the best training program for patients with AD. Influential environmental conditions (e.g. social relations, outdoor or indoor exercise) should also be studied to optimize training programs aimed at slowing down the AD progression.

[Anti-fall plan for the elderly in France 2022-2024: objectives and methodology]. / Plan antichute des personnes âgées France 2022-2024 : objectifs et méthodologie1.

BACKGROUND: Falls and fall-related injuries are a major public health problem in industrialized countries. Faced with this challenge, a French national plan was launched in 2022 aiming to reduce by 20% the incidence of falls-related hospitalizations or deaths. OBJECTIVES: To describe the main pillars of the 2022-2024 French national plan against falls in older persons. Methods and assessment: The six pillars of the plan are: 1) screening and monitoring risks of falls and alert health and care workers; 2) home safety assessment and getting out safely; 3) developing technical aids for mobility and the use of assistive technologies at home; 4) appropriate physical activity, best weapon against falls; 5) tele-assistance devices for all older persons; 6) a cross-cutting pillar: Informing, raising awareness, training, and involving local actors. The plan, deployed in the 18 French regions, will provide a unique opportunity to determine the best strategies to achieve the objectives and the barriers encountered. CONCLUSIONS: The deployment of the French national plan will bring useful data for considering a long-term strategy in France and helping countries or regions wishing to implement a fall prevention plan on their territory.

[Synthesis in French of the 2022 global recommendations for the management and prevention of falls in the elderly]. / Synthèse en langue française des recommandations mondiales 2022 pour la prise en charge et la prévention des chutes chez les personnes âgées.

BACKGROUND: Falls and fall-related injuries are common in older adults, have negative effects on functional independence and quality of life and are associated with increased morbidity, mortality and health related costs. OBJECTIVE: To synthesize evidence-based and expert consensus-based 2022 world guidelines for the management and prevention of falls in older adults. These recommendations consider a person-centred approach that includes the preferences of the patient, caregivers and other stakeholders, gaps in previous guidelines, recent developments in e-health and both local context and resources. RECOMMENDATIONS: All older adults should be advised on falls prevention and physical activity. Opportunistic case finding for falls risk is recommended for communitydwelling older adults. An algorithm is proposed to stratify falls risk and interventions for persons at low, moderate or high risk. Those considered at high risk should be offered a comprehensive multifactorial falls risk assessment with a view to co-design and implement personalised multidomain interventions. Other recommendations cover details of assessment and intervention components and combinations, and recommendations for specific settings and populations. CONCLUSIONS: The core set of recommendations provided will require flexible implementation strategies that consider both local context and resources.

Negative intracellular regulators of T-cell receptor (TCR) signaling as potential antitumor immunotherapy targets.

Immunotherapy strategies aim to mobilize immune defenses against tumor cells by targeting mainly T cells. Co-inhibitory receptors or immune checkpoints (ICPs) (such as PD-1 and CTLA4) can limit T cell receptor (TCR) signal propagation in T cells. Antibody-based blocking of immune checkpoints (immune checkpoint inhibitors, ICIs) enable escape from ICP inhibition of TCR signaling. ICI therapies have significantly impacted the prognosis and survival of patients with cancer. However, many patients remain refractory to these treatments. Thus, alternative approaches for cancer immunotherapy are needed. In addition to membrane-associated inhibitory molecules, a growing number of intracellular molecules may also serve to downregulate signaling cascades triggered by TCR engagement. These molecules are known as intracellular immune checkpoints (iICPs). Blocking the expression or the activity of these intracellular negative signaling molecules is a novel field of action to boost T cell-mediated antitumor responses. This area is rapidly expanding. Indeed, more than 30 different potential iICPs have been identified. Over the past 5 years, several phase I/II clinical trials targeting iICPs in T cells have been registered. In this study, we summarize recent preclinical and clinical data demonstrating that immunotherapies targeting T cell iICPs can mediate regression of solid tumors including (membrane associated) immune-checkpoint inhibitor refractory cancers. Finally, we discuss how these iICPs are targeted and controlled. Thereby, iICP inhibition is a promising strategy opening new avenues for future cancer immunotherapy treatments.

Observational, Multicenter Study of the Efficacy and Safety of Cervical Disk Arthroplasty With Mobi-C in the Treatment of Cervical Degenerative Disk Disease. Results at 10 years Follow-Up.

BACKGROUND: Cervical disk arthroplasty replacement (CDA) was developed to avoid specific disadvantages of cervical fusion. The purpose of this paper is to provide 10-year follow-up results of an ongoing prospective study after CDA. METHODS: Three hundred eighty-four patients treated using the Mobi-C (ZimVie, Troyes, France) were included in a prospective multicenter study. Routine clinical and radiologic examinations were reported preoperatively and postoperatively with up to 10-year follow-up. Complications and revision surgeries were also documented. RESULTS: At 10 years showed significant improvement in all clinical outcomes [Neck Disability Index, visual analog scale (VAS) for arm and neck pain, physical component summary of SF36, and mental component summary of SF36). Motion at the index level increased significantly over baseline (mean range of motion=7.6 vs. 8 degrees at five years and 6.0 degrees preoperatively; P <0.001) and 71.3% of the implanted segments remained mobile (range of motion>3 degrees). Adjacent disks were also mobile at 10 years with the same mobility as preoperatively. At 10 years, 20.9% of the implanted segments demonstrated no heterotopic ossification. Thirty-four patients (8.9%) experienced 41 adverse events, with or without reoperation during the first five years. We found only two additional surgeries after five years. We observed an increased percentage of working patients and a decrease in medication consumption. Regarding the overall outcome, 94% of patients were satisfied. CONCLUSIONS: Our 10-year results showed significant improvement in all clinical outcomes, with low rates of revision or failure. This experience in patients with long-term follow-up after CDA endorses durable, favorable outcomes in properly selected patients.

High-throughput mass cytometry staining for deep phenotyping of human natural killer cells.

This protocol details the step-by-step procedure for in-depth immune phenotyping of peripheral blood natural killer (NK) cells from clinical samples by mass cytometry. The protocol consists of three main steps: PBMC incubation with a mix of metal-conjugated antibodies for extracellular phenotyping followed by fixation, permeabilization and incubation with a mix of metal-conjugated antibodies for staining of intracellular proteins, and sample acquisition on a mass cytometer. High-dimensional analysis enables the visualization of NK cell subsets and their phenotypical characteristics. For complete details on the use and execution of this protocol, please refer to Chretien et al. (2021).

Barriers and Expectations of Adolescents Regarding the Identification and Management of Their Psychoactive Substance Use by Their General Practitioner.

AIMS: General practitioners (GPs), who are the most frequently consulted health professionals by adolescents, play a key role in screening for psychoactive substance (PAS) use. The purpose of our study was to determine the barriers and expectations of adolescents regarding the identification and management of their PAS use by their general practitioner. METHODS: Descriptive, cross-sectional study of a population of adolescents aged 12 to 17 years, followed up in general practice in France. Adolescents were recruited from general practice offices by open-access questionnaires. An opaque box was provided to ensure the anonymity of the adolescents. RESULTS: A total of 277 adolescents were included: 155 girls, mean age 14.5 ± 1.7 years, 113 adolescents (41%) had used a PAS at least once in the past 12 months. Alcohol was the most used PAS, followed by tobacco and cannabis. Three groups were identified: the nonusers group (n = 134); the group of moderate users (n = 71); the group of users at risk of substance abuse or misusing (n = 38). Regardless of group, adolescents felt that their GP was attentive, responsive, competent, understanding, and took the time to ask the appropriate questions in their role. The at-risk group was less confident and less comfortable, and they felt more judged and more afraid of the GP telling their parents. Despite this, the at-risk group was the most willing to talk to their GP about their PAS. Almost half of the adolescents surveyed found it useful to use a questionnaire to discuss PAS. CONCLUSIONS: Reminding each consultation of the principles of the relationship of trust and confidentiality while maintaining an empathetic attitude would make it easier for GPs to remove adolescents' inhibitions about communicating about their PAS use.

[Falls prévention in older persons]. / Comment évaluer le risque de chute chez le sujet âgé ?

"Falls prévention in older persons Falls in persons aged 65 or older are a major public health problem. Some simple questions (have you experienced any fall in the previous year ? Do you have a fear of falling when walking ?) And a few simple examinations (one-leg stance, timed up and go, chair-rising, stop walking when talking test) allow to differentiate between patients at low risk of falling, for whom education and risk reassessment at 12 months are offered, patients at moderate risk of falling, for whom a physical examination and a prescription review to modify the cause of instability, and referral to a adapted physical exercise program are offered, the effect of which will be evaluated at 3-6months, and patients at high risk of falls, for whom a standardized geriatric assessment shoud be offered, at best carried out by a geriatric team, allowing the establishment of an individualized program targeting all risk factors for falls, the effectiveness of which will be reassessed at 1-3 months."

"Prévention des chutes chez le sujet âgé Les chutes après 65ans constituent un important problème de santé publique. L'entretien médical (à la recherche d'antécédents de chute, d'une peur de tomber) et quelques examens simples (temps d'appui unipodal, timed up and go test, test de relever de chaise, stop walking when talking test) permettent au médecin de distinguer trois types de profils de risque. Pour les patients à risque faible, une éducation thérapeutique et une réévaluation du risque à 12mois sont proposées. Les patients à risque modéré sont examinés (et leur ordonnance révisée) à la recherche de causes d'instabilité, puis orientés vers un programme d'activités physiques adaptées dont l'effet sera évalué à 3-6mois. Les patients à haut risque de chute doivent bénéficier d'une évaluation gérontologique standardisée, dans l'idéal effectuée par une équipe gériatrique, pour mettre en place un programme individualisé ciblant tous les facteurs de risque de chute, dont l'efficacité doit être réévaluée à 1-3mois."

Targeting CISH enhances natural cytotoxicity receptor signaling and reduces NK cell exhaustion to improve solid tumor immunity.

BACKGROUND: The success and limitations of current immunotherapies have pushed research toward the development of alternative approaches and the possibility to manipulate other cytotoxic immune cells such as natural killer (NK) cells. Here, we targeted an intracellular inhibiting protein 'cytokine inducible SH2-containing protein' (CISH) in NK cells to evaluate the impact on their functions and antitumor properties. METHODS: To further understand CISH functions in NK cells, we developed a conditional Cish-deficient mouse model in NK cells (Cishfl/flNcr1Ki/+ ). NK cells cytokine expression, signaling and cytotoxicity has been evaluated in vitro. Using intravenous injection of B16F10 melanoma cell line and EO711 triple negative breast cancer cell line, metastasis evaluation was performed. Then, orthotopic implantation of breast tumors was performed and tumor growth was followed using bioluminescence. Infiltration and phenotype of NK cells in the tumor was evaluated. Finally, we targeted CISH in human NK-92 or primary NK cells, using a technology combining the CRISPR(i)-dCas9 tool with a new lentiviral pseudotype. We then tested human NK cells functions. RESULTS: In Cishfl/flNcr1Ki/+ mice, we detected no developmental or homeostatic difference in NK cells. Global gene expression of Cishfl/flNcr1Ki/+ NK cells compared with Cish+/+Ncr1Ki/+ NK cells revealed upregulation of pathways and genes associated with NK cell cycling and activation. We show that CISH does not only regulate interleukin-15 (IL-15) signaling pathways but also natural cytotoxicity receptors (NCR) pathways, triggering CISH protein expression. Primed Cishfl/flNcr1Ki/+ NK cells display increased activation upon NCR stimulation. Cishfl/flNcr1Ki/+ NK cells display lower activation thresholds and Cishfl/flNcr1Ki/+ mice are more resistant to tumor metastasis and to primary breast cancer growth. CISH deletion favors NK cell accumulation to the primary tumor, optimizes NK cell killing properties and decreases TIGIT immune checkpoint receptor expression, limiting NK cell exhaustion. Finally, using CRISPRi, we then targeted CISH in human NK-92 or primary NK cells. In human NK cells, CISH deletion also favors NCR signaling and antitumor functions. CONCLUSION: This study represents a crucial step in the mechanistic understanding and safety of Cish targeting to unleash NK cell antitumor function in solid tumors. Our results validate CISH as an emerging therapeutic target to enhance NK cell immunotherapy.

Intra-amniotic levothyroxine infusions in a case of fetal goiter due to novel Thyroglobulin gene variants.

Indications and administration of intra-amniotic infusions of L-thyroxine in the context of non-immune fetal hypothyroidism with goiter lack of standardization. Systematic follow-up of clinical features related to thyroid hormonal homeostasis may be useful to evaluate their efficiency and develop standardized management guidelines.

Controversies in the management of bowel obstruction in pregnant woman.

.

Role of non-pharmacological interventions for healthy ageing.

The range of non-pharmacological interventions (NPIs) available for people over 60 years of age is continuously expanding, both in terms of prevention and therapy. They have been empirically selected for centuries and more recently developed through epigenetic studies, clinical trials and technological innovations, and their development has increased and diversified around the world. Residual questions concern: 1) the scope of such treatments which appears to overlap with alternative medicines, 2) their evaluation, which some researchers say is impossible, and 3) their implementation in the elderly, which appears to be overly complicated. This article addresses these three questions and presents digital tools developed by the CEPS University Platform facilitating the evaluation of NPIs in the field of healthy aging. The transformation of the health system, which has become necessary to meet the needs of baby boomers, will widen the arsenal of health-related solutions. The combination of approaches to medicine and health has become personalised, comprehensive and integrative. NPIs will play a major role in the coming century. These practices differ from alternative medicines, general public health messages and socio-cultural approaches through continuous research, a quality approach and traceability of use. NPIs today constitute a complementary ecosystem for biomedical treatments which are increasingly becoming economically and legally consolidated.

Antenatal diagnosis of CHARGE syndrome: Prenatal ultrasound findings and crucial role of fetal dysmorphic signs. About a series of 10 cases and review of literature.

Although the prognosis of CHARGE syndrome can be highly variable from mild until severe, final diagnosis is difficult to establish in utero. The aim of our study is to compare antenatal and postnatal findings in a retrospective cohort of 10 successive patients with a positive CHD7 gene variant in order to identify the specific prenatal features for CHARGE syndrome diagnosis. Fetal ultrasound, follow-up and supplementary investigations are collected and compared to postnatal findings. Congenital heart defect (7/10), choanal atresia (7/10) and tracheoesophageal atresia (4/10) are the most frequent fetal anomalies found. Inner and external ear anomalies appear as the keystone (constant features) for prenatal diagnosis of CHARGE syndrome in fetuses with multiple anomalies and normal microarray karyotype. External ear malformations are identified in all cases by 3D ultrasound when carefully evaluated. MRI and temporal bone CT-Scan are second line useful tools to assess the diagnosis when looking for semicircular canal agenesis, arhinencephaly and/or choanal atresia. Before availability of prenatal exome sequencing in clinical routine, present findings lead to the recommendation that fetuses, with congenital heart defect (mainly septal and conotruncal), cleft lip/palate or unexplained polyhydramnios should carefully be screened for clues suggesting CHARGE syndrome using 2D and 3D ultrasound, MRI and temporal bone CT-Scan. When CHARGE syndrome is suspected with normal molecular karyotype, CHD7 gene sequencing must be offered.