Role of ß3 subunit of the GABA type A receptor in triple negative breast cancer proliferation, migration, and cell cycle progression.

Triple negative breast cancer (TNBC) is known for its heterogeneous nature and aggressive onset. The unresponsiveness to hormone therapies and immunotherapy and the toxicity of chemotherapeutics account for the limited treatment options for TNBC. Ion channels have emerged as possible therapeutic candidates for cancer therapy, but little is known about how ligand gated ion channels, specifically, GABA type A ligand-gated ion channel receptors (GABAAR), affect cancer pathogenesis. Our results show that the GABAA ß3 subunit is expressed at higher levels in TNBC cell lines than non-tumorigenic cells, therefore contributing to the idea that limiting the GABAAR via knockdown of the GABAA ß3 subunit is a potential strategy for decreasing the proliferation and migration of TNBC cells. We employed pharmacological and genetic approaches to investigate the role of the GABAA ß3 subunit in TNBC proliferation, migration, and cell cycle progression. The results suggest that pharmacological antagonism or genetic knockdown of GABAA ß3 subunit decreases TNBC proliferation and migration. In addition, GABAA ß3 subunit knockdown causes cell cycle arrest in TNBC cell lines via decreased cyclin D1 and increased p21 expression. Our findings suggest that membrane bound GABAA receptors containing the ß3 subunit can be further developed as a potential novel target for the treatment of TNBC.

The buzz within: the role of the gut microbiome in honeybee social behavior.

Gut symbionts influence the physiology and behavior of their host, but the extent to which these effects scale to social behaviors is an emerging area of research. The use of the western honeybee (Apis mellifera) as a model enables researchers to investigate the gut microbiome and behavior at several levels of social organization. Insight into gut microbial effects at the societal level is critical for our understanding of how involved microbial symbionts are in host biology. In this Commentary, we discuss recent findings in honeybee gut microbiome research and synthesize these with knowledge of the physiology and behavior of other model organisms to hypothesize how host-microbe interactions at the individual level could shape societal dynamics and evolution.

Suppression of Richtmyer-Meshkov Instability via Special Pairs of Shocks and Phase Transitions.

The classical Richtmyer-Meshkov instability (RMI) is a hydrodynamic instability characterizing the evolution of an interface following shock loading. In contrast to other hydrodynamic instabilities such as Rayleigh-Taylor, it is known for being unconditionally unstable: regardless of the direction of shock passage, any deviations from a flat interface will be amplified. In this article, we show that for negative Atwood numbers, there exist special sequences of shocks which result in a nearly perfectly suppressed instability growth. We demonstrate this principle computationally and experimentally with stepped fliers and phase transition materials. A fascinating immediate corollary is that in specific instances, a phase-transitioning material may self-suppress RMI.

A combined exercise and cognitive training intervention induces fronto-cingulate cortical plasticity in first-episode psychosis patients.

OBJECTIVE: Schizophrenia (SZ) is characterized by neurobiological and associated cognitive and functional deficits, including pronounced cortical thinning, that lead to acute and long-term functional impairment. Research with older adults supports the role of non-pharmacological interventions, such as exercise (E) and cognitive training (CT), for cognitive impairments. This literature influenced the development of combined CT&E treatments for individuals with SZ. However, the impact of longer combined treatment duration (6 months) on neuroanatomy has yet to be explored in patients in the early course of the illness. The impact of adding exercise to cognitive training for key brain regions associated with higher-order cognition was examined here using magnetic resonance imaging (MRI) in first-episode psychosis (FEP) patients. METHODS: UCLA Aftercare Research Program patients with a recent first episode of schizophrenia were randomly assigned to either combined cognitive and exercise training (CT&E) (N = 20) or cognitive training alone (CT) (N = 17) intervention. Cortical thickness was measured longitudinally and analyzed for two regions of interest using FreeSurfer. RESULTS: Compared to patients in the CT group, those in the CT&E group demonstrated an increase in cortical thickness within the left anterior cingulate cortex over the six-month treatment period (ACC: F(1, 35) = 4.666, P < .04). Directional tendencies were similar in the left dorsolateral prefrontal cortex (DLPFC: F(1,35) = 4.132, P < .05). CONCLUSIONS: These findings suggest that exercise and cognitive training may synergistically increase fronto-cingulate cortical thickness to mitigate progressive neural atrophy in the early course of SZ. This combined intervention appears to be a valuable adjunct to standard pharmacologic treatment in FEP patients.

Shoshin beriberi and thiamine-responsive right heart failure: A case report in Mayotte Recognition and management of infant Shoshin beriberi.

Infant Shoshin beriberi is an acute life-threatening condition for which the diagnosis is frequently delayed. Therefore, rapid recognition of right heart failure with lactic acidemia is a crucial element in the diagnosis and therapeutic management. We present the case of a 2-month-old girl with bronchiolitis, right heart failure, and lactic acidosis, who quickly and favorably responded to thiamine supplementation. Thiamine deficiency was established through laboratory tests. We present a brief review of the literature with the different thiamine dosages proposed in emergencies and provide an emergency protocol in cases of clinical suspicion, since thiamine supplementation could help to speed up recovery in infants with Shoshin beriberi.

New Ameloblastoma Cell Lines Enable Preclinical Study of Targeted Therapies.

Ameloblastoma (AB) is an odontogenic tumor that arises from ameloblast-lineage cells. Although relatively uncommon and rarely metastatic, AB tumors are locally invasive and destructive to the jawbone and surrounding structures. Standard-of-care surgical resection often leads to disfigurement, and many tumors will locally recur, necessitating increasingly challenging surgeries. Recent genomic studies of AB have uncovered oncogenic driver mutations, including in the mitogen-activated protein kinase (MAPK) and Hedgehog signaling pathways. Medical therapies targeting those drivers would be a highly desirable alternative or addition to surgery; however, a paucity of existing AB cell lines has stymied clinical translation. To bridge this gap, here we report the establishment of 6 new AB cell lines-generated by "conditional reprogramming"-and their genomic characterization that reveals driver mutations in FGFR2, KRAS, NRAS, BRAF, PIK3CA, and SMO. Furthermore, in proof-of-principle studies, we use the new cell lines to investigate AB oncogene dependency and drug sensitivity. Among our findings, AB cells with KRAS or NRAS mutation (MAPK pathway) are exquisitely sensitive to MEK inhibition, which propels ameloblast differentiation. AB cells with activating SMO-L412F mutation (Hedgehog pathway) are insensitive to vismodegib; however, a distinct small-molecule SMO inhibitor, BMS-833923, significantly reduces both downstream Hedgehog signaling and tumor cell viability. The novel cell line resource enables preclinical studies and promises to speed the translation of new molecularly targeted therapies for the management of ameloblastoma and related odontogenic neoplasms.

Presentation, clinical course and complications in trauma patients with concomitant COVID-19 infection.

BACKGROUND: This study investigated the impact of COVID-19 infection on hospitalized trauma patients. METHODS: A retrospective review of hospitalized trauma patients at a level I trauma center was performed from March-December 2020. Data pertaining to patient demographics, presentation and hospital course was compared between COVID positive and negative trauma patients. RESULTS: There were 4,912 patients and 179 (3.64%) were COVID-19 positive. Demographics and clinical presentation did not differ significantly between those with and without concomitant COVID-19. However, COVID positive trauma patients had higher rates of acute kidney injury (p = 0.016), sepsis (p = 0.016), unplanned intubation (p = 0.002) and unplanned return to the ICU (p = 0.01). The COVID positive cohort also had longer hospital stays (p < 0.01) with no significant difference in mortality. CONCLUSIONS: In the setting of an ongoing pandemic, awareness of the complications COVID positive trauma patients are predisposed to is important for providers.

TRASS: a global approach to assess the severity of truncal acne.

INTRODUCTION: Only a small amount of published data regarding truncal acne is available, and no proper tool to assess its severity exists. AIM: The aim of the study was to provide dermatologists with an easy-to-use tool to assess truncal acne (TRASS, truncal acne severity scale) using a global approach. METHODS: A scoring tool that assesses the severity of acne (based on GEA and ECLA scales) on the trunk using a global approach was built, including three sub-scores: family history, clinical signs and quality of life (QoL). In order to test TRASS, the experts used photographs of 47 patients attending their clinics with truncal acne. The regression optimized (ROP) model was applied to assess the diagnosis performance of TRASS and to identify items contributing to the classification of the patients. Internal testing was made to demonstrate the robustness of the model. Correlation analyses between the different items were performed to evaluate the interaction between the different items and their impact on the severity grading of truncal acne. RESULTS: Patients with the most severe acne were identified by TRASS. The error level was 6.6% after internal validation and 10.4% when using the median value or the centile 75th (6.6% and 10.4%). Correlation was significant between systemic treatment and scars (P = 0.0025) and nodules (P = 0.01988) and between location and QoL (P = 0.0095). CONCLUSION: Truncal acne severity scale is the first global, patient-centred approach to evaluate truncal acne by scoring the importance of each factor independently from its clinical severity. TRASS may allow the practitioner to choose and validate the most suitable therapy together with the patient in order to treat his or her truncal acne successfully and to limit treatment failure.

Bisphenol-A analogs induce lower urinary tract dysfunction in male mice.

Bisphenol-A (BPA), an estrogenic endocrine disrupting chemical, significantly impacts numerous diseases and abnormalities in mammals. Estrogens are known to play an important role in the biology of the prostate; however, little is known about the role of bisphenols in the etiology of prostate pathologies, including benign prostate hyperplasia (BPH) and associated lower urinary tract dysfunction (LUTD). Bisphenol-F (BPF) and bisphenol-S (BPS) are analogs often used as substitutes for BPA; they are both reported to have in vitro and in vivo estrogenic effects similar to or more potent than BPA. The objective of this study was to assess the role of these bisphenols in the development of LUTD in adult male mice. In adult mice exposed to BPA, BPS or BPF, we examined urinary tract histopathology and physiological events associated with urinary dysfunction. Mice treated with bisphenols displayed increased bladder (p < 0.005) and prostate (p < 0.0001) mass, and there was an increased number of prostatic ducts in the prostatic urethra (p < 0.05) and decreased size of the urethra lumen (p < 0.05) compared to negative controls. After two months of bisphenol exposure, mice displayed notable differences in cystometric tracings compared to controls, consistent with LUTD. Treatment of male mice with all bisphenols also induced voiding dysfunction manifested by detrusor instability and histologic changes in the prostatic urethra of male rodents, consistent with LUTD. Our results implicate BPA and its replacements in the development and progression LUTD in mice and provide insights into the development and progression of BPH/LUTS in men.

Vestibular testing in children - The suppression head impulse (SHIMP) test.

INTRODUCTION: The incidence of vestibular disorders and vertigo during childhood is increasing and pediatric clinicians have become more sensitive to children's balance disorders; thus, there is a need for appropriate detection test procedures for peripheral vestibular hypofunction. In order to ensure a reliable diagnosis and minimize misdiagnosis, a standardized clinical procedure via careful history and clinical examination is recommended. However, children, especially, are often unable to verbalize "vertigo" in a concrete manner, which often necessitates a consultation with a pediatrician holding nonspecific symptoms. The so-called suppression of the head impulse test (SHIMPs) represents a modification of the video head impulse test (HIMP) and is used for a more sensitive assessment of residual vestibular functions. In adults, SHIMPs are already an established diagnostic method. Nevertheless, to date, nothing is known about the applicability and standard values in childhood. MATERIAL AND METHODS: In this monocentric, prospective study, we investigated whether SHIMPs enable a sensitive functional analysis of the vestibular system in healthy children of different ages. For this purpose, SHIMPs were performed in 40 children aged 3-18 years. RESULTS: In this study, we demonstrated that SHIMPs can be easily performed in children (3-18 years). It is vital that the test be appropriately explained for children to ensure sufficient test tolerance and compliance. CONCLUSION: SHIMPs are a helpful supplement to clinically established vestibular tests such as the HIMP in pediatric vestibular balance disorder diagnostics and can be integrated into the clinical routine, especially in children who have minimal verbal abilities or understanding of the instructions for HIMP. Similar to the HIMP, SHIMPs are characterized by a short test duration and a high tolerance.

Identifying microplastic litter with Laser Induced Breakdown Spectroscopy: A first approach.

The broad diversity of microplastic litter requires a selection of analytical techniques to reliably determine the particle's chemical composition. This study demonstrates that Laser Induced Breakdown Spectroscopy (LIBS) can identify microplastic particles based on their spectral fingerprints. By studying the spectral features of polymer reference spectra, microplastic litter can be distinguished from non-plastic materials. The results show that LIBS can be used as a fast in-situ technique for pre-characterization of the microparticle's material and is a possible tool for environmental studies on microplastics.

Impact of maternal decision-making autonomy and self-reliance in accessing health care on childhood diarrhea and acute respiratory tract infections in Nepal.

OBJECTIVE: This study aimed to examine the impact of maternal decision-making autonomy and self-reliance in accessing health care on childhood diarrhea and acute respiratory tract infection (ARI) in Nepal. STUDY DESIGN: This was a cross-sectional study. METHODS: This study used data from the Nepal Demographic and Health Survey 2016. Mothers aged 15-49 years provided information about the health of 5308 children included in this analysis. Composite measures of maternal decision-making autonomy and self-reliance in accessing health care were used as exposure variables. Childhood diarrhea and ARI in the 2 weeks preceding the survey were primary outcome variables. Descriptive statistics and multivariable survey-weighted logistic regression methods were used in the analyses. RESULTS: Maternal decision-making autonomy was high for approximately one-fourth (24.7%) of the children's mothers, and 81.7% of children's mothers reported self-reliance in accessing health care as a big problem. Diarrhea among children in the prior 2 weeks was reported among 8% (95% confidence interval [CI]: 6.9-8.4), whereas ARI was reported among 22% (95% CI: 21.1-23.5). The children of women who viewed a lack of self-reliance as a big problem had a 88% (adjusted odds ratio [aOR] = 1.88, 95% CI: 1.26-2.82, P < 0.01) higher odds of diarrhea and 59% (aOR = 1.59, 95% CI: 1.29-1.95, P < 0.001) higher odds of ARI compared with children of women who did not view self-reliance as a big problem. CONCLUSIONS: The study found a significant effect of maternal self-reliance in accessing health care on childhood diarrhea and ARI, independent of other sociodemographic factors. Improvement in maternal self-reliance in accessing health care of women is essential, particularly their autonomy with regard to healthcare seeking behavior and financial empowerment.

Repurposing CPAP machines as stripped-down ventilators.

The worldwide shortage of medical-grade ventilators is a well-known issue, that has become one of the central topics during the COVID-19 pandemic. Given that these machines are expensive and have long lead times, one approach is to vacate them for patients in critical conditions while patients with mild to moderate symptoms are treated with stripped-down ventilators. We propose a mass-producible solution that can create such ventilators with minimum effort. The central part is a module that can be attached to CPAP machines and repurpose them as low-pressure ventilators. Here, we describe the concept and first measurements which underline the potential of our solution. Our approach may serve as a starting point for open-access ventilator technologies.

Antidiuretic hormone inhibits osteogenic differentiation of dental follicle stem cells via V1a receptors and the PLC-IP3 pathway.

OBJECTIVE: The aim of this study was to elucidate the molecular mechanism by which antidiuretic hormone (ADH) inhibited osteogenesis in dental follicle stem cells. DESIGN: Rat dental follicle stem cells were cultured in osteogenic differentiation medium supplemented with ADH. Alkaline phosphatase enzyme activity, Alizarin Red S staining, MTT assay and RT-qPCR was used to examine ADH's impact on cell mineralization, viability, and osteogenic gene expression. Real-time calcium imaging analysis was performed to identify the ADH receptor and its mechanism of action. RESULTS: ADH supplementation to the osteogenic differentiation medium inhibited cell mineralization without compromising cell viability and downregulated the expression of key osteogenic genes: DCN (Decorin), RUNX2 (Runt-related transcription factor 2) and BSP (Bone sialoprotein). Real-time calcium imaging analysis revealed that ADH (1-1000 nM) increased intracellular calcium in a concentration-dependent manner. Pretreatment of cells with V2255, a V1a receptor blocker, inhibited the calcium signals, but not with the V1b (Nelivaptan) or V2 (Tolvaptan). V2255 also reversed the inhibitory effect of ADH on osteogenesis. Furthermore, U73122, a Phospholipase C (PLC) inhibitor, 2-APB, an Inositol Triphosphate (IP3) receptor blocker, and depletion of endoplasmic reticulum calcium stores abolished the calcium signals by ADH. CONCLUSIONS: Our results demonstrated that ADH activates V1a receptors and the PLC-IP3 pathway to stimulate intracellular calcium signals, which inhibits cell mineralization and osteogenic gene expression. These findings uncovered a novel function for ADH as a negative regulator of osteogenesis in dental follicle stem cells. The role of ADH in the pathogenesis of bone diseases remains to be determined.

Early versus late tube feeding initiation after PEG tube placement: Does time to feeding matter?

BACKGROUND: Variation exists in the timing of tube feed initiation after percutaneous endoscopic gastrostomy (PEG) tube placement. The aim of our study was to review outcomes of early tube feed (ETF) versus late tube feed (LTF) initiation after PEG tube placement. METHODS: We performed a retrospective review of all trauma patients who underwent PEG tube placement from 1/2014 to 12/2018. ETF was defined as initiation < 24 h and LTF > 24 h after placement. The primary outcome measure was feeding intolerance and secondary outcomes included post-operative complications. All statistical analyses were performed using standard statistical methods (e.g. Pearson's Chi-squared, Fisher's exact and Mann Whitney-U tests). RESULTS: There were 295 patients (164 ETF and 131 LTF) that received a PEG tube at our level 1 trauma center. There was no difference with feeding intolerance at 12 h (5% vs. 4%; p = 0.88), 24 h (1% vs. 2%; p = 1.00), and 48 h (4% vs. 4%; p = 1.00). There was no difference when comparing intolerance symptoms such as nausea and vomiting (1% vs. 2%; p = 0.79), abdominal tenderness (2% vs. 3%; p = 0.76), high gastric residuals (2% vs. 2%; p = 1.00) and aspiration (0% vs. 2%; p = 0.39). There was no difference when comparing post-operative complications (4% vs. 8%; p = 0.21). CONCLUSIONS: Early tube feeding after PEG placement is safe and equivalent to late tube feeding in the adult trauma population. Future prospective studies are warranted to establish the optimal timing for initiation of tube feeds after PEG tube placement.

Reconnaissance of tumor immune microenvironment spatial heterogeneity in metastatic renal cell carcinoma and correlation with immunotherapy response.

A clearer understanding of the tumor immune microenvironment (TIME) in metastatic clear cell renal cell carcinoma (ccRCC) may help to inform precision treatment strategies. We sought to identify clinically meaningful TIME signatures in ccRCC. We studied tumors from 39 patients with metastatic ccRCC using quantitative multiplexed immunofluorescence and relevant immune marker panels. Cell densities were analyzed in three regions of interest (ROIs): tumor core, tumor-stroma interface and stroma. Patients were stratified into low- and high-marker density groups using median values as thresholds. Log-rank and Cox regression analyses while controlling for clinical variables were used to compare survival outcomes to patterns of immune cell distributions. There were significant associations with increased macrophage (CD68+ CD163+ CD206+ ) density and poor outcomes across multiple ROIs in primary and metastatic tumors. In primary tumors, T-bet+ T helper type 1 (Th1) cell density was highest at the tumor-stromal interface (P = 0·0021), and increased co-expression of CD3 and T-bet was associated with improved overall survival (P = 0·015) and survival after immunotherapy (P = 0·014). In metastatic tumor samples, decreased forkhead box protein 3 (FoxP3)+ T regulatory cell density correlated with improved survival after immunotherapy (P = 0·016). Increased macrophage markers and decreased Th1 T cell markers within the TIME correlated with poor overall survival and treatment outcomes. Immune markers such as FoxP3 showed consistent levels across the TIME, whereas others, such as T-bet, demonstrated significant variance across the distinct ROIs. These findings suggest that TIME profiling outside the tumor core may identify clinically relevant associations for patients with metastatic ccRCC.

Creation and Characterization of Matter-Wave Breathers.

We report the creation of quasi-1D excited matter-wave solitons, "breathers," by quenching the strength of the interactions in a Bose-Einstein condensate with attractive interactions. We characterize the resulting breathing dynamics and quantify the effects of the aspect ratio of the confining potential, the strength of the quench, and the proximity of the 1D-3D crossover for the two-soliton breather. Furthermore, we demonstrate the complex dynamics of a three-soliton breather created by a stronger interaction quench. Our experimental results, which compare well with numerical simulations, provide a pathway for utilizing matter-wave breathers to explore quantum effects in large many-body systems.

Predictive value of FDG-PET imaging for relapse in metastatic melanoma patients treated with immunotherapy.

BACKGROUND: Anti-PD1 immunotherapy has shown a sustainable clinical activity in patients with metastatic melanoma. However, strong predictive factors of the long-term response or risk of relapse remain to be identified. OBJECTIVES: To determine whether FDG-PET imaging could be superior to CT scan in distinguishing residual tumours versus the absence of tumour in patients with a partial response (PR) or stable disease (SD) and whether a complete metabolic response (CMR) was associated with better outcomes. METHODS: Retrospective study conducted in all patients with metastatic melanoma treated with anti-PD1 immunotherapy between October 2014 and October 2017 considered to be in complete remission. The primary outcome was the occurrence of a relapse during the follow-up. CT scan and FDG-PET scan had to be performed within a maximum of 2 months of treatment discontinuation. For CT imaging, the Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 were used and included progressive disease (PD), SD, PR and complete response (CR). For FDG-PET imaging, the metabolic responses were classified as progressive metabolic disease, stable metabolic disease, residual FDG avidity (RFA) and CMR. RESULTS: Twenty-six patients were in complete remission after collegial decision. Two patients had a SD on CT scan and a CMR on FDG-PET scan, and none of them relapsed. Ten patients had a PR on CT scan and a CMR on FDG-PET scan, and none of them relapsed. The mean treatment duration to achieve a complete remission was 7 months (3-23). A univariate analysis showed that a RFA assessed on the FDG-PET scan was significantly associated with a relapse (P = 0.00231). CONCLUSIONS: Most patients with a PR on the CT scan and a CMR on the FDG-PET scan should be considered with a CR. Our study showed that FDG-PET imaging could play a crucial role in predicting the long-term outcome and help to decide whether treatment should be discontinued.