How green is my reusable bronchoscope?

INTRODUCTION: Single-use bronchoscopes have replaced reusable ones in many institutions. This study aimed to evaluate the environmental and financial impacts of both strategies: reusable and single-use bronchoscopes. MATERIAL AND METHODS: We conducted a pragmatic study in a 21-bed polyvalent ICU, in Saint-Brieuc, Bretagne, France. The eco-audit consisted of estimating greenhouse gas (GHG) emissions, considering the life cycle of each strategy. Greenhouse gas (GHG) emissions related to construction, packaging, transport and waste elimination were compared between 2 devices: the reusable bronchoscope, a Pentax® FI-16RBS that was disinfected twice daily; and the single-use bronchoscope, the bronchoflex agile® from TSC. RESULTS: For the reusable bronchoscope, GHG emissions were marginally impacted by the number of bronchoscopies performed (from 185 kg eq.CO2 per year to 192 kg eq.CO2 for 10 or 110 bronchoscopies per year). For the reusable device, GHG emissions directly depended on the number of bronchoscopies performed with 3.82 kg eq.CO2 emitted per bronchoscopy. The breakeven point for the reusable bronchoscope was estimated at 50 bronchoscopies in terms of GHG emissions and 96 bronchoscopies for financial considerations. CONCLUSION: Considering current practice in our ICU, reusable bronchoscopes have lower GHG emissions when used more than 50 times a year and a lower cost when used more than 96 times a year as compared with single-use bronchoscopes.

Automated Bio-AFM Generation of Large Mechanome Data Set and Their Analysis by Machine Learning to Classify Cancerous Cell Lines.

Mechanobiological measurements have the potential to discriminate healthy cells from pathological cells. However, a technology frequently used to measure these properties, i.e., atomic force microscopy (AFM), suffers from its low output and lack of standardization. In this work, we have optimized AFM mechanical measurement on cell populations and developed a technology combining cell patterning and AFM automation that has the potential to record data on hundreds of cells (956 cells measured for publication). On each cell, 16 force curves (FCs) and seven features/FC, constituting the mechanome, were calculated. All of the FCs were then classified using machine learning tools with a statistical approach based on a fuzzy logic algorithm, trained to discriminate between nonmalignant and cancerous cells (training base, up to 120 cells/cell line). The proof of concept was first made on prostate nonmalignant (RWPE-1) and cancerous cell lines (PC3-GFP), then on nonmalignant (Hs 895.Sk) and cancerous (Hs 895.T) skin fibroblast cell lines, and demonstrated the ability of our method to classify correctly 73% of the cells (194 cells in the database/cell line) despite the very high degree of similarity of the whole set of measurements (79-100% similarity).

NK cells with adhesion defects and reduced cytotoxic functions are associated with a poor prognosis in Multiple Myeloma.

The promising results obtained with immunotherapeutic approaches for multiple myeloma (MM) call for a better stratification of patients based on immune components. The most pressing being cytotoxic lymphocytes such as Natural Killer (NK) cells that are mandatory for MM surveillance and therapy. In this study, we performed a single cell RNA sequencing analysis of NK cells from 10 MM patients and 10 age/sex matched healthy donors (HD) that revealed important transcriptomic changes in NK cell landscape affecting both the bone marrow and peripheral blood compartment. The frequency of mature cytotoxic "CD56dim" NK cell subsets was reduced in MM patients at the advantage of late-stage NK cell subsets expressing NFB and IFN-I inflammatory signatures. These NK cell subsets accumulating in MM patients were characterized by a low CD16 and CD226 expression and poor cytotoxic functions. MM CD16/CD226Lo NK cells also had adhesion defects with reduced LFA-1 integrin activation and actin polymerization that may account for their limited effector functions in vitro. Finally, analysis of BM infiltrating NK cells in a retrospective cohort of 177 MM patients from the IFM 2009 trial demonstrated that a high frequency of NK cells and their low CD16 and CD226 expression were associated with a shorter overall survival. Thus, CD16/CD226Lo NK cells with reduced effector functions accumulate along MM development and negatively impact patients' clinical outcome. Given the growing interest in harnessing NK cells to treat myeloma, this improved knowledge around MM-associated NK cell dysfunction will stimulate the development of more efficient immunotherapeutic drugs against MM.

Investigating the discrimination ability of 3D convolutional neural networks applied to altered brain MRI parametric maps.

Convolutional neural networks (CNNs) are gradually being recognized in the neuroimaging community as a powerful tool for image analysis. Despite their outstanding performances, some aspects of CNN functioning are still not fully understood by human operators. We postulated that the interpretability of CNNs applied to neuroimaging data could be improved by investigating their behavior when they are fed data with known characteristics. We analyzed the ability of 3D CNNs to discriminate between original and altered whole-brain parametric maps derived from diffusion-weighted magnetic resonance imaging. The alteration consisted in linearly changing the voxel intensity of either one (monoregion) or two (biregion) anatomical regions in each brain volume, but without mimicking any neuropathology. Performing ten-fold cross-validation and using a hold-out set for testing, we assessed the CNNs' discrimination ability according to the intensity of the altered regions, comparing the latter's size and relative position. Monoregion CNNs showed that the larger the modified region, the smaller the intensity increase needed to achieve good performances. Biregion CNNs systematically outperformed monoregion CNNs, but could only detect one of the two target regions when tested on the corresponding monoregion images. Exploiting prior information on training data allowed for a better understanding of CNN behavior, especially when altered regions were combined. This can inform about the complexity of CNN pattern retrieval and elucidate misclassified examples, particularly relevant for pathological data. The proposed analytical approach may serve to gain insights into CNN behavior and guide the design of enhanced detection systems exploiting our prior knowledge.

Albumin influences leucocyte FcRn expression in the early days of kidney transplantation.

FcRn, a receptor originally known for its involvement in IgG and albumin transcytosis and recycling, is also important in the establishment of the innate and adaptive immune response. Dysregulation of the immune response has been associated with variations in FcRn expression, as observed in cancer. Recently, a link between autophagy and FcRn expression has been demonstrated. Knowing that autophagy is strongly involved in the development of reperfusion injury in kidney transplantation and that albuminemia is transiently decreased in the first 2 weeks after transplantation, we investigated variations in FcRn expression after kidney transplantation. We monitored FcRn levels by flow cytometry in leukocytes from 25 renal transplant patients and considered parameters such as albumin concentrations, estimated glomerular filtration rate, serum creatinine, serum IgG levels, and ischaemia/reperfusion time. Two groups of patients could be distinguished according to their increased or non-increased FcRn expression levels between days 2 and 6 (d2-d6) post-transplantation. Leukocyte FcRn expression at d2-d6 was correlated with albumin concentrations at d0-d2. These results suggest that albumin concentrations at d0-d2 influence FcRn expression at d2-d6, raising new questions about the mechanisms underlying these original observations.

Characterization of oviduct epithelial spheroids for the study of embryo-maternal communication in cattle.

Most in vitro models of oviduct epithelial cells (OEC) used thus far to gain insights into embryo-maternal communication induce cell dedifferentiation or are technically challenging. Moreover, although the presence of developing embryos has been shown to alter gene expression in OEC, the effect of embryos on OEC physiology remains largely unknown. Here, we propose a model based on bovine oviduct epithelial spheroids (OES) with specific shape and diameter (100-200 µm) criteria. The aims of this study were to i) determine the appropriate culture conditions of bovine OES cultured in suspension by evaluating their morphology, total cell number, viability, and activity of ciliated cells; ii) monitor gene expression in OES at the time of their formation (day 0) and over the 10 days of culture; and iii) test whether the vicinity of developing embryos affects OES quality criteria. On day 10, the proportions of vesicle-shaped OES (V-OES) were higher in M199/500 (500 µl of HEPES-buffered TCM-199) and synthetic oviduct fluid (SOF)/25 (25-µL droplet of SOF medium under mineral oil) than in M199/25 (25-µL droplet of M199 under mineral oil). The proportion of viable cells in V-OES was not affected by culture conditions and remained high (>80%) through day 10. The total number of cells per V-OES decreased over time except in SOF/25, while the proportions of ciliated cells increased over time in M199/500 but decreased in M199/25 and SOF/25. The movement amplitude of OES in suspension decreased over time under all culture conditions. Moreover, the gene expression of ANXA1, ESR1, HSPA8, and HSPA1A in OES remained stable during culture, while that of PGR and OVGP1 decreased from day 0 to day 10. Last, the co-culture of developing embryos with OES in SOF/25 increased the rates of blastocysts on days 7 and 8 compared to embryos cultured alone, and increased the proportion of V-OES compared to OES cultured alone. In conclusion, M199/500 and SOF/25 provided the optimal conditions for the long-time culture of OES. The supporting effect of OES on embryo development and of developing embryos on OES morphology was evidenced for the first time. Altogether, these results point OES as an easy-to-use, standardizable, and physiological model to study embryo-maternal interactions in cattle.

TCR-independent CD137 (4-1BB) signaling promotes CD8+-exhausted T cell proliferation and terminal differentiation.

CD137 (4-1BB)-activating receptor represents a promising cancer immunotherapeutic target. Yet, the cellular program driven by CD137 and its role in cancer immune surveillance remain unresolved. Using T cell-specific deletion and agonist antibodies, we found that CD137 modulates tumor infiltration of CD8+-exhausted T (Tex) cells expressing PD1, Lag-3, and Tim-3 inhibitory receptors. T cell-intrinsic, TCR-independent CD137 signaling stimulated the proliferation and the terminal differentiation of Tex precursor cells through a mechanism involving the RelA and cRel canonical NF-κB subunits and Tox-dependent chromatin remodeling. While Tex cell accumulation induced by prophylactic CD137 agonists favored tumor growth, anti-PD1 efficacy was improved with subsequent CD137 stimulation in pre-clinical mouse models. Better understanding of T cell exhaustion has crucial implications for the treatment of cancer and infectious diseases. Our results identify CD137 as a critical regulator of Tex cell expansion and differentiation that holds potential for broad therapeutic applications.

A superoxide-driven redox state promotes geroconversion and resistance to senolysis in replication-stress associated senescence.

Using S-phase synchronized RPE1-hTERT cells exposed to the DNA damaging agent, methyl methanesulfonate, we show the existence of a redox state associated with replication stress-induced senescence termed senescence-associated redox state (SA-redox state). SA-redox state is characterized by its reactivity with superoxide-sensing fluorescent probes such as dihydroethidine, lucigenin and mitosox and peroxynitrite or hydroxyl radical sensing probe hydroxyphenyl fluorescein (HPF) but not the hydrogen peroxide (H2O2) reactive fluorescent probe CM-H2DCFDA. Measurement of GSH and GSSH also reveals that SA-redox state mitigates the level of total GSH rather than oxidizes GSH to GSSG. Moreover, supporting the role of superoxide (O2.-) in the SA-redox state, we show that incubation of senescent RPE1-hTERT cells with the O2.- scavenger, Tiron, decreases the reactivity of SA-redox state with the oxidants' reactive probes lucigenin and HPF while the H2O2 antioxidant N-acetyl cysteine has no effect. SA-redox state does not participate in the loss of proliferative capacity, G2/M cell cycle arrest or the increase in SA-ß-Gal activity. However, SA-redox state is associated with the activation of NF-κB, dictates the profile of the Senescence Associated Secretory Phenotype, increases TFEB protein level, promotes geroconversion evidenced by increased phosphorylation of S6K and S6 proteins, and influences senescent cells response to senolysis. Furthermore, we provide evidence for crosstalk between SA redox state, p53 and p21. While p53 mitigates the establishment of SA-redox state, p21 is critical for the sustained reinforcement of the SA-redox state involved in geroconversion and resistance to senolysis.

Therapeutic Potential of a Senolytic Approach in a Murine Model of Chronic GVHD.

Graft-versus-host disease (GVHD) is a life-threatening systemic complication of allogeneic hematopoietic stem cell transplantation (HSCT) characterized by dysregulation of T and B cell activation and function, scleroderma-like features, and multi-organ pathology. The treatment of cGVHD is limited to the management of symptoms and long-term use of immunosuppressive therapy, which underscores the need for developing novel treatment approaches. Notably, there is a striking similarity between cytokines/chemokines responsible for multi-organ damage in cGVHD and pro-inflammatory factors, immune modulators, and growth factors secreted by senescent cells upon the acquisition of senescence-associated secretory phenotype (SASP). In this pilot study, we questioned the involvement of senescent cell-derived factors in the pathogenesis of cGVHD triggered upon allogeneic transplantation in an irradiated host. Using a murine model that recapitulates sclerodermatous cGVHD, we investigated the therapeutic efficacy of a senolytic combination of dasatinib and quercetin (DQ) administered after 10 days of allogeneic transplantation and given every 7 days for 35 days. Treatment with DQ resulted in a significant improvement in several physical and tissue-specific features, such as alopecia and earlobe thickness, associated with cGVHD pathogenesis in allograft recipients. DQ also mitigated cGVHD-associated changes in the peripheral T cell pool and serum levels of SASP-like cytokines, such as IL-4, IL-6 and IL-8Rα. Our results support the involvement of senescent cells in the pathogenesis of cGVHD and provide a rationale for the use of DQ, a clinically approved senolytic approach, as a potential therapeutic strategy.

A convolutional neural network model for EPID-based non-transit dosimetry.

PURPOSE: To develop an alternative computational approach for EPID-based non-transit dosimetry using a convolutional neural network model. METHOD: A U-net followed by a non-trainable layer named True Dose Modulation recovering the spatialized information was developed. The model was trained on 186 Intensity-Modulated Radiation Therapy Step & Shot beams from 36 treatment plans of different tumor locations to convert grayscale portal images into planar absolute dose distributions. Input data were acquired from an amorphous-Silicon Electronic Portal Image Device and a 6 MV X-ray beam. Ground truths were computed from a conventional kernel-based dose algorithm. The model was trained by a two-step learning process and validated through a five-fold cross-validation procedure with sets of training and validation of 80% and 20%, respectively. A study regarding the dependance of the amount of training data was conducted. The performance of the model was evaluated from a quantitative analysis based the ϒ-index, absolute and relative errors computed between the inferred dose distributions and ground truths for six square and 29 clinical beams from seven treatment plans. These results were also compared to those of an existing portal image-to-dose conversion algorithm. RESULTS: For the clinical beams, averages of ϒ-index and ϒ-passing rate (2%-2mm > 10% Dmax ) of 0.24 (±0.04) and 99.29 (±0.70)% were obtained. For the same metrics and criteria, averages of 0.31 (±0.16) and 98.83 (±2.40)% were obtained with the six square beams. Overall, the developed model performed better than the existing analytical method. The study also showed that sufficient model accuracy can be achieved with the amount of training samples used. CONCLUSION: A deep learning-based model was developed to convert portal images into absolute dose distributions. The accuracy obtained shows that this method has great potential for EPID-based non-transit dosimetry.

Bacteriocin Production Correlates with Epidemiological Prevalence of Phylotype I Sequevar 18 Ralstonia pseudosolanacearum in Madagascar.

Bacterial wilt caused by the Ralstonia solanacearum species complex (RSSC) is a major threat to vegetable crops in Madagascar. For more effective disease management, surveys were carried out in the main vegetable production areas of the country, leading to the collection of 401 new RSSC isolates. Phylogenetic assignment of the isolates revealed a high prevalence of phylotype I sequevar 18. This result contrasts sharply with the epidemiological pattern of RSSC in neighboring islands, including Reunion Island, Comoros, Mayotte, Mauritius, Rodrigues, and the Seychelles, where phylotype I sequevar 31 is widespread. Molecular typing characterization of the Malagasy isolates allowed the identification of 96 haplotypes. Some are found in various plots located in different provinces, which suggests that they were probably disseminated via infected plant material. To find out a potential explanation for the observed epidemiological pattern, we examined the capacity of the Malagasy strains to produce bacteriocin. Interestingly, the highly prevalent genetic lineages I-18 produce bacteriocins that are active against all the genetic lineages present in the country. This work sheds light on the potential impact of bacteriocins in the epidemiology of Malagasy RSSC. IMPORTANCE Knowledge of the epidemiology of a plant pathogen is essential to develop effective control strategies. This study focuses on the epidemiological pattern of Ralstonia pseudosolanacearum phylotype I populations responsible for bacterial wilt in Madagascar. We identified, with the newly collected isolates in three provinces, four genetic lineages probably propagated via infected plant material in Madagascar. We revealed that the epidemiological situation in Madagascar contrasts with that of neighboring Indian Ocean islands. Interestingly, our study on the bacteriocin-producing capacity of Malagasy isolates revealed a correlation between the inhibitory activity of the producing strains and the observed epidemiology. These results suggested that the epidemiology of plant pathogens may be impacted by bacteriocin production.

A 132 bp deletion affecting the KCNQ1OT1 gene associated with Silver-Russell syndrome clinical phenotype.

BACKGROUND: Imprinting centre 2 (IC2) in the chromosomal region 11p15.5 regulates the monoallelic expression of imprinted genes by differential methylation of paternal and maternal chromosomes. Copy number variants in IC2 are associated with Beckwith-Wiedemann syndrome and Silver-Russell syndrome (SRS). Clinical outcome of IC2 deletions seems to depend on the parental origin of the chromosome, deletion size and inclusion or exclusion of enhancer and promoter regions. RESULTS: A paternally inherited 132 bp deletion within the KCNQ1OT1 gene was found in a proband with an SRS clinical phenotype. The patient's father and paternal grandmother, who both carry the deletion on their maternal chromosome, are unaffected. Review of other IC2 deletions and their associated clinical presentation was useful in understanding the genetic-phenotypic correlation. CONCLUSION: Only six cases have been reported with deletions involving exclusively IC2, one being identical to our proband's 132 bp deletion. Our study, which is based on more extensive segregation data than the previous 132 bp deletion report, confirms the association of this deletion with growth restriction when paternally inherited. Remarkably, even though our patient has the same deletion, he has more pronounced phenotypic features; our findings thus suggest that some degree of clinical variability may be associated with this loss.

Fertility Outcomes after Surgical Management of Colorectal Endometriosis: A Single-center Retrospective Study.

STUDY OBJECTIVE: To assess the pregnancy rate after surgery for colorectal endometriosis. DESIGN: A retrospective, single-center study performed from January 2014 to December 2019. SETTING: A university tertiary referral center. PATIENTS: Patients with the intention to get pregnant younger than the age of 43 years, with or without a history of infertility and who were surgically managed for colorectal endometriosis. INTERVENTIONS: Complete excision of deeply infiltrating endometriosis. MEASUREMENTS AND MAIN RESULTS: The postoperative pregnancy rate was assessed. Seventy-seven patients had surgery; their mean age was 32.5 ± 4.4 years. Preoperative documented infertility was present in 77.9% of patients (n = 60). The mean length of history of infertility was 36.2 ± 24.9 months. The procedure was performed by laparoscopic surgery in 92.2% of patients (n = 71). Nonconservative, conservative, and mixed treatment were performed in 66.2% (n = 51), 29.9% (n = 23), and 3.9% of patients (n = 3), respectively. According to the Clavien-Dindo classification, the 3B complication rate was 6.5% (n = 5). The mean follow-up was 46.7 ± 20.6 months. Clinical pregnancies were defined by the presence of intrauterine pregnancy with an embryo with cardiac activity. The postoperative pregnancy rate was 62.3% (n = 48), and 54.2% (n = 26) were spontaneous. The mean number of pregnancies was 1.2 ± 0.4 per patient. In addition, 18.7% of patients (n = 9) got pregnant twice. The mean time from surgery to pregnancy was 13.8 ± 13.1 months. The live birth rate was 89.1% (n = 41). There were no significant differences concerning the prognostic criteria reported in the literature (antimüllerian hormone level, age, presence of adenomyosis). There were no predictive criteria for live births. CONCLUSION: According to this study, surgery for colorectal endometriosis results in a high postoperative pregnancy rate. Studies with a high level of evidence are needed to determine good candidates for this type of surgery.

The neonatal Fc receptor expression during macrophage differentiation is related to autophagy.

The neonatal Fc receptor (FcRn) plays a central role in recycling and biodistributing immunoglobulin G. FcRn is also involved in many physiological immune functions as well as pathological immune responses in cancer or autoimmune diseases. Low levels of FcRn in tumor cells and the microenvironment is associated with poor prognosis in non-small cell lung cancers. Among cells that are present in the tumor microenvironment, macrophages express high levels of FcRn. Macrophages are involved in these pathophysiological contexts by their dual differentiation states of pro- or anti-inflammatory macrophages. However, variations in FcRn protein expression have not been described in macrophage subtypes. In this work, we studied FcRn expression in an in vitro model of pro- and anti-inflammatory macrophage differentiation. We demonstrated an inverse relation between FcRn protein and mRNA expression in macrophage populations. Autophagy, which is involved in protein degradation and acquisition of phagocytic function in macrophages, participated in regulating FcRn levels. Intravenous immunoglobulin protected FcRn against autophagosome degradation in anti-inflammatory macrophages. Our data demonstrate that autophagy participates in regulating FcRn expression in pro- and anti-inflammatory macrophages. This finding raises new questions concerning the regulation of FcRn in immune functions.

Multimodal MRI-Based Whole-Brain Assessment in Patients In Anoxoischemic Coma by Using 3D Convolutional Neural Networks.

BACKGROUND: There is an unfulfilled need to find the best way to automatically capture, analyze, organize, and merge structural and functional brain magnetic resonance imaging (MRI) data to ultimately extract relevant signals that can assist the medical decision process at the bedside of patients in postanoxic coma. We aimed to develop and validate a deep learning model to leverage multimodal 3D MRI whole-brain times series for an early evaluation of brain damages related to anoxoischemic coma. METHODS: This proof-of-concept, prospective, cohort study was undertaken at the intensive care unit affiliated with the University Hospital (Toulouse, France), between March 2018 and May 2020. All patients were scanned in coma state at least 2 days (4 ± 2 days) after cardiac arrest. Over the same period, age-matched healthy volunteers were recruited and included. Brain MRI quantification encompassed both "functional data" from regions of interest (precuneus and posterior cingulate cortex) with whole-brain functional connectivity analysis and "structural data" (gray matter volume, T1-weighted, fractional anisotropy, and mean diffusivity). A specifically designed 3D convolutional neuronal network (CNN) was created to allow conscious state discrimination (coma vs. controls) by using raw MRI indices as the input. A voxel-wise visualization method based on the study of convolutional filters was applied to support CNN outcome. The Ethics Committee of the University Teaching Hospital of Toulouse, France (2018-A31) approved the study and informed consent was obtained from all participants. RESULTS: The final cohort consisted of 29 patients in postanoxic coma and 34 healthy volunteers. Coma patients were successfully discerned from controls by using 3D CNN in combination with different MR indices. The best accuracy was achieved by functional MRI data, in particular with resting-state functional MRI of the posterior cingulate cortex, with an accuracy of 0.96 (range 0.94-0.98) on the test set from 10-time repeated tenfold cross-validation. Even more satisfactory performances were achieved through the majority voting strategy, which was able to compensate for mistakes from single MR indices. Visualization maps allowed us to identify the most relevant regions for each MRI index, notably regions previously described as possibly being involved in consciousness emergence. Interestingly, a posteriori analysis of misclassified patients indicated that they may present some common functional MRI traits with controls, which suggests further favorable outcomes. CONCLUSIONS: A fully automated identification of clinically relevant signals from complex multimodal neuroimaging data is a major research topic that may bring a radical paradigm shift in the neuroprognostication of patients with severe brain injury. We report for the first time a successful discrimination between patients in postanoxic coma patients from people serving as controls by using 3D CNN whole-brain structural and functional MRI data. Clinical Trial Number http://ClinicalTrials.gov (No. NCT03482115).

Mechanisms of Self-Inflicted Injuries at an Urban City Hospital.

BACKGROUND: Suicide is a major public health issue with root causes including psychological, economical, and societal factors. METHODS: Retrospective review identified self-inflicted traumatic injuries (SITIs) at Grady Health System between 2009 and 2017. Patients were categorized by penetrating or blunt mechanism of injury (MOI). Outcomes included hospital length of stay (HLOS) and ventilator duration, mortality, and location of death. RESULTS: 678 patients in total were identified. Penetrating MOI was most prevalent (n = 474). Patients with a blunt MOI were significantly younger (32 Y vs. 37 Y; P < .0001). Psychiatric illness was equally common between MOI at more than 50%. Penetrating traumas required longer ventilator times (1 D vs. 0 D; P < .0001) but shorter overall HLOS (4 D vs. 6 D; P = .0013). Mortality was twice as high in the penetrating group (29.8% vs. 11.8%; P < .0001). CONCLUSION: Self-inflicted traumatic injuries occurred most often among younger adults and those with history of psychiatric illness. Penetrating traumas result in worse outcomes. Self-inflicted traumatic injuries carry high morbidity and mortality. Improved prevention strategies targeting high-risk groups are needed.

Toll-like receptor 4 selective inhibition in medullar microenvironment alters multiple myeloma cell growth.

Bone marrow (BM) mesenchymal stromal cells (MSCs) are abnormal in multiple myeloma (MM) and play a critical role by promoting growth, survival, and drug resistance of MM cells. We observed higher Toll-like receptor 4 (TLR4) gene expression in MM MSCs than in MSCs from healthy donors. At the clinical level, we highlighted that TLR4 expression in MM MSCs evolves in parallel with the disease stage. Thus, we reasoned that the TLR4 axis is pivotal in MM by increasing the protumor activity of MSCs. Challenging primary MSCs with TLR4 agonists increased the expression of CD54 and interleukin-6 (IL-6), 2 factors directly implicated in MM MSC-MM cell crosstalk. Then, we evaluated the therapeutic efficacy of a TLR4 antagonist combined or not with conventional treatment in vitro with MSC-MM cell coculture and in vivo with the Vk*MYC mouse model. Selective inhibition of TLR4 specifically reduced the MM MSC ability to support the growth of MM cells in an IL-6-dependent manner and delayed the development of MM in the Vk*MYC mouse model by altering the early disease phase in vivo. For the first time, we demonstrate that specific targeting of the pathological BM microenvironment via TLR4 signaling could be an innovative approach to alter MM pathology development.

The redox-senescence axis and its therapeutic targeting.

SIGNIFICANCE: Cellular growth arrest, associated with 'senescence', helps to safeguard against the accumulation of DNA damage which is often recognized as the underlying mechanism of a wide variety of age-related pathologies including cancer. Cellular senescence has also been described as a 'double-edged sword'. In cancer, for example, the creation of an immune-suppressive milieu by senescent tumor cells through the senescence-associated secretory phenotype contributes toward carcinogenesis and cancer progression. RECENT ADVANCES: The potential for cellular senescence to confer multi-faceted effects on tissue fate has led to a rejuvenated interest in its landscape and targeting. Interestingly, redox pathways have been described as both triggers and propagators of cellular senescence, leading to intricate cross-links between both pathways. CRITICAL ISSUES: In this review, we describe the mechanisms driving cellular senescence, the interface with cellular redox metabolism as well as the role that chemotherapy-induced senescence plays in secondary carcinogenesis. Notably, the role that anti-apoptotic proteins of the Bcl-2 family play in inducing drug resistance via mechanisms that involve senescence induction. FUTURE DIRECTIONS: Though the therapeutic targeting of senescent cells as cancer therapy remains in its infancy, we summarize the current development of senotherapeutics, including recognized senotherapies, as well as the repurposing of drugs as senomorphic/senolytic candidates.

Implementation and evaluation of eight virtual surgical electives for medical students during the COVID-19 pandemic.

BACKGROUND: Eight novel virtual surgery electives (VSEs) were developed and implemented in April-May 2020 for medical students forced to continue their education remotely due to COVID-19. METHODS: Each VSE was 1-2 weeks long, contained specialty-specific course objectives, and included a variety of teaching modalities. Students completed a post-course survey to assess changes in their interest and understanding of the specialty. Quantitative methods were employed to analyze the results. RESULTS: Eighty-three students participated in the electives and 67 (80.7%) completed the post-course survey. Forty-six (68.7%) respondents reported "increased" or "greatly increased" interest in the course specialty completed. Survey respondents' post-course understanding of each specialty increased by a statistically significant amount (p-value = <0.0001). CONCLUSION: This initial effort demonstrated that VSEs can be an effective tool for increasing medical students' interest in and understanding of surgical specialties. They should be studied further with more rigorous methods in a larger population.