Abstract Triple negative breast cancers (TNBC) present a poor prognosis primarily due to their resistance to chemotherapy. This resistance is known to be associated with elevated expression of ...certain anti-apoptotic members within the proteins of the BCL-2 family (namely BCL-xL, MCL-1 and BCL-2). These regulate cell death by inhibiting pro-apoptotic protein activation through binding and sequestration and they can be selectively antagonized by BH3 mimetics. Yet the individual influences of BCL-xL, MCL-1, and BCL-2 on the sensitivity of TNBC cells to chemotherapy, and their regulation by cancer-associated fibroblasts (CAFs), major components of the tumor stroma and key contributors to therapy resistance remain to be delineated. Using gene editing or BH3 mimetics to inhibit anti-apoptotic BCL-2 family proteins in TNBC line MDA-MB-231, we show that BCL-xL and MCL-1 promote cancer cell survival through compensatory mechanisms. This cell line shows limited sensitivity to chemotherapy, in line with the clinical resistance observed in TNBC patients. We elucidate that BCL-xL plays a pivotal role in therapy response, as its depletion or pharmacological inhibition heightened chemotherapy effectiveness. Moreover, BCL-xL expression is associated with chemotherapy resistance in patient-derived tumoroids where its pharmacological inhibition enhances ex vivo response to chemotherapy. In a co-culture model of cancer cells and CAFs, we observe that even in a context where BCL-xL reduced expression renders cancer cells more susceptible to chemotherapy, those in contact with CAFs display reduced sensitivity to chemotherapy. Thus CAFs exert a profound pro-survival effect in breast cancer cells, even in a setting highly favoring cell death through combined chemotherapy and absence of the main actor of chemoresistance, BCL-xL.
Cancer-associated fibroblasts (CAF) are a major cellular component of epithelial tumors. In breast cancers in particular these stromal cells have numerous tumorigenic effects in part due to their ...acquisition of a myofibroblastic phenotype. Breast CAFs (bCAFs) typically express MCL-1. We show here that pharmacological inhibition or knock down of this regulator of mitochondrial integrity in primary bCAFs directly derived from human samples mitigates myofibroblastic features. This decreases expression of genes involved in actomyosin organization and contractility (associated with a cytoplasmic retention of the transcriptional regulator, yes-associated protein-YAP) and decreases bCAFs ability to promote cancer cells invasion in 3D coculture assays. Our findings underscore the usefulness of targeting MCL-1 in breast cancer ecosystems, not only to favor death of cancer cells but also to counteract the tumorigenic activation of fibroblasts with which they co-evolve. Mechanistically, pharmacological inhibition of MCL-1 with a specific BH3 mimetic promotes mitochondrial fragmentation in bCAFs. Inhibition of the mitochondrial fission activity of DRP-1, which interacts with MCL-1 upon BH3 mimetic treatment, allows the maintenance of the myofibroblastic phenotype of bCAFs.
This study aimed to investigate the indications and outcomes of Home Sleep Testing (HST) for patients with suspected obstructive sleep apnea (OSA), aligning with guidelines set forth by the American ...Academy of Sleep Medicine and the European Sleep Research Society. Specifically, we aimed to audit whether validated type 3 polygraphy could effectively ensure patient care while optimizing resource utilization.PURPOSEThis study aimed to investigate the indications and outcomes of Home Sleep Testing (HST) for patients with suspected obstructive sleep apnea (OSA), aligning with guidelines set forth by the American Academy of Sleep Medicine and the European Sleep Research Society. Specifically, we aimed to audit whether validated type 3 polygraphy could effectively ensure patient care while optimizing resource utilization.A retrospective analysis was conducted on data from patients undergoing type 3 polygraphy for suspected OSA in a tertiary referral hospital between January 2022 and December 2022. Demographic, clinical, and management data were collected. The efficacy of HST in guiding management plans was evaluated, with outcomes categorized as effective or ineffective based on subsequent need for in-laboratory polysomnography.METHODSA retrospective analysis was conducted on data from patients undergoing type 3 polygraphy for suspected OSA in a tertiary referral hospital between January 2022 and December 2022. Demographic, clinical, and management data were collected. The efficacy of HST in guiding management plans was evaluated, with outcomes categorized as effective or ineffective based on subsequent need for in-laboratory polysomnography.While 85% of patients received a reliable diagnosis, 44.4% of them still required subsequent polysomnography, primarily due to adherence to funding regulations, rather than clinical need for further testing. Factors impacting the efficacy of HST included patient age, severity of apnea, and referral by a certified sleep specialist physician.RESULTSWhile 85% of patients received a reliable diagnosis, 44.4% of them still required subsequent polysomnography, primarily due to adherence to funding regulations, rather than clinical need for further testing. Factors impacting the efficacy of HST included patient age, severity of apnea, and referral by a certified sleep specialist physician.Our study highlighted the potential of type 3 polygraphy, as a valuable tool for diagnosing OSA in an outpatient setting. However, having the result interpreted by a certified sleep specialist doctor was not enough. To streamline the care pathway, the referral for polygraphy had also to be made by a trained specialist. Challenges related to funding regulations, patient demographics and physician training stress the need for optimized diagnostic pathways to improve patient care and resource utilization.CONCLUSIONOur study highlighted the potential of type 3 polygraphy, as a valuable tool for diagnosing OSA in an outpatient setting. However, having the result interpreted by a certified sleep specialist doctor was not enough. To streamline the care pathway, the referral for polygraphy had also to be made by a trained specialist. Challenges related to funding regulations, patient demographics and physician training stress the need for optimized diagnostic pathways to improve patient care and resource utilization.
Lipopolysaccharide‐responsive beige‐like anchor protein (LRBA) belongs to the enigmatic class of BEACH domain‐containing proteins, which have been attributed various cellular functions, typically ...involving intracellular protein and membrane transport processes. Here, we show that LRBA deficiency in mice leads to progressive sensorineural hearing loss. In LRBA knockout mice, inner and outer hair cell stereociliary bundles initially develop normally, but then partially degenerate during the second postnatal week. LRBA deficiency is associated with a reduced abundance of radixin and Nherf2, two adaptor proteins, which are important for the mechanical stability of the basal taper region of stereocilia. Our data suggest that due to the loss of structural integrity of the central parts of the hair bundle, the hair cell receptor potential is reduced, resulting in a loss of cochlear sensitivity and functional loss of the fraction of spiral ganglion neurons with low spontaneous firing rates. Clinical data obtained from two human patients with protein‐truncating nonsense or frameshift mutations suggest that LRBA deficiency may likewise cause syndromic sensorineural hearing impairment in humans, albeit less severe than in our mouse model.
Synopsis
Genetic deletion of LRBA in mouse cochlear hair cells impairs stereociliar targeting of the actin adaptors radixin and Nherf2. As a result, Lrba‐KO hair bundles degenerate during early postnatal development, leading to a progressive form of sensorineural hearing impairment.
LRBA deficiency leads to a progressive and complex form of hearing loss that is characterized by increased auditory brainstem response thresholds and strongly attenuated distortion product otoacoustic emissions.
After initially normal formation of inner and outer hair cell stereociliar arrays, hair bundles of Lrba‐KO mice degenerate during the second postnatal week, leading to impaired synaptic sound encoding and cochlear amplification.
The observed hair bundle phenotype arises from a specific reduction in the actin adaptor proteins radixin and Nherf2, which link the stereociliar plasma membrane to the cytoskeleton and hence may provide mechanical stability within the taper region.
Genetic deletion of LRBA in mouse cochlear hair cells impairs stereociliar targeting of the actin adaptors radixin and Nherf2. As a result, Lrba‐KO hair bundles degenerate during early postnatal development, leading to a progressive form of sensorineural hearing impairment.
Objective: Developing reliable and easy-to-use telemedicine tools is essential in primary care. We sought whether Sino-Nasal Outcome Test-22 could predict the need for surgery and localize pathology ...of rhinology patients and healthy volunteers solely based on the pattern of the baseline Sino-Nasal Outcome Test-22. Methods: Baseline Sino-Nasal Outcome Test-22 from 66 healthy volunteers and 383 rhinology patients was collected blindly prior to diagnosis. Participants were then categorized into 4 groups according to their diagnosis: control, no surgery (i.e. medical condition), functional nose surgery, and sinus surgery. The difference between groups was assessed by a multinomial logistic regression adjusted for age, gender, asthma, tobacco, history of nose surgery, and trauma. Results: The 22 items of Sino-Nasal Outcome Test differed significantly among the 4 groups (P < .05). Control subjects showed the lowest Sino-Nasal Outcome Test-22 scores for all items. Patients requiring sinus surgery and those listed for nose surgery exhibited a specific pattern of Sino-Nasal Outcome Test-22 score. Nasal and extranasal rhinology symptoms were more specific to the diagnosis than psychological or sleep dysfunction domains. Conclusion: Distinct Sino-Nasal Outcome Test-22 patterns were associated with subjects’ diagnosis. SNOT-22 was not only able to score severity but could also localize the disease, orientate the diagnosis, and predict the need for surgical treatment. The Sino-Nasal Outcome Test-22 may be the easy telemedicine tool the primary care needs for a better referral pattern.
Objective: To summarise treatment outcomes compared to surgical and patient variables for a multicentre recipient cohort using a fully implantable active middle ear implant for hearing impairment. To ...describe the authors' preferred surgical technique to determine microphone placement. Study Design: Multicentre retrospective, observational survey. Setting: Five tertiary referral centres. Patients: Carina recipients (66 ears, 62 subjects) using the current Cochlear® Carina® System or the legacy device, the Otologics® Fully Implantable Middle Ear, with a T2 transducer. Methods: Patient file review and routine clinical review. Patient outcomes assessed were satisfaction, daily use and feedback reports at the first fitting and ≥12 months after implantation. Descriptive and statistical analysis of correlations of variables and their influence on outcomes was performed. Independently reported preferred methods for microphone placement are collectively summarised. Results: The average implant experience was 3.5 years. Satisfaction increased significantly over time (p < 0.05). No correlation with covariates examined was observed. Feedback significantly decreased over time, showing a significant correlation with microphone location, primary motivation, gender, age at implantation, and contralateral hearing aid use (p < 0.05). Patient satisfaction was inversely correlated with reports of system feedback (p < 0.05). The implantable microphone was most commonly on the posterior inferior mastoid line, in 42/66 (65%) cases, correlating with less likelihood for feedback and consistent with author surgical preference. Conclusion: Carina recipients in this study present as satisfied consistent daily users with very few reports of persistent feedback. As microphone location is an influencing factor, a careful surgical consideration of microphone placement is required. The authors prefer a posterior inferior mastoid line position whenever possible.
Transcription factors of the SoxE family are critical players that underlie various embryological processes. However, little is known about their function during inner ear development. Here, we show ...that Sox10 is initially expressed throughout the otic vesicle epithelium and becomes later restricted to supporting cells as cell differentiation proceeds in the organ of Corti. Morphological analyses of Sox10 mutant mice reveal a significant shortening of the cochlear duct likely resulting from the progressive depletion of cochlear progenitors. While Sox10 appears dispensable for the differentiation and patterning of the inner ear prosensory progenitors, our data support a critical role for this transcription factor in the promotion of their survival. We provide genetic evidences that Sox10, in a concentration-dependant manner, could play a role in the regulation of Jagged1, a gene known to be important for inner ear prosensory development. Together, our results demonstrate that Sox10 regulates the biology of early cochlear progenitors during inner ear development, but, in contrast to neural crest-derived cells, this transcription factor is dispensable for their differentiation. Evidence also suggests that this effect occurs via the activation of the Jagged1 gene.
J. Neurochem. (2010) 114, 1827-1839. The cochleo-vestibular ganglion contains neural crest-derived glial cells and sensory neurons that are derived from the neurogenic otic placode. Little is known ...about the molecular mechanisms that regulate the tightly orchestrated development of this structure. Here, we report that Sox10, a high-mobility group DNA-binding domain transcription factor that is required for the proper development of neural crest cell derivatives, is specifically expressed in post-migratory neural crest cells in the cochleo-vestibular ganglion. Using Sox10-deficient mice, we demonstrate that this transcription factor is essential for the survival, but not the generation, of the post-migratory neural crest cells within the inner ear. In the absence of these neural crest-derived cells, we have investigated the survival of the otocyst-derived auditory neurons. Surprisingly, auditory neuron differentiation, sensory target innervation and survival are conserved despite the absence of glial cells. Moreover, brain-derived neurotrophic factor expression is increased in the hair cells of Sox10-deficient mice, a compensatory mechanism that may prevent spiral ganglion neuronal cell death. Taken together, these data suggest that in the absence of neural crest-derived glial cells, an increase trophic support from hair cells promotes the survival of spiral ganglion neurons in Sox10 mutant mice.
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