bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alterations in synapses and mitochondria induced by acute or chronic intermittent hypoxia in the pre-Bötzinger complex of rats: an ultrastructural triple-labeling study with immunocytochemistry and histochemistry
Authors: Kang Junjun , Lu Naining , Yang Shoujing , Guo Baolin , Zhu Yuanyuan , Wu Shengxi , Huang Xiaofeng , Wong-Riley Margaret T. T. , Liu Ying-Ying 
Published: June 2023

IntroductionThe pre-Bötzinger complex (pre-BötC), a kernel of inspiratory rhythmogenesis, is a heterogeneous network with excitatory glutamatergic and inhibitory GABAergic and glycinergic neurons. Inspiratory rhythm generation relies on synchronous activation of glutamatergic neuron, whilst inhibitory neurons play a critical role in shaping the breathing pattern, endowing the rhythm with flexibility in adapting to environmental, metabolic, and behavioral needs. Here we report ultrastructural alterations in excitatory, asymmetric synapses (AS) and inhibitory, symmetric synapses (SS), especially perforated synapses with discontinuous postsynaptic densities (PSDs) in the pre-BötC in rats exposed to daily acute intermittent hypoxia (dAIH) or chronic (C) IH.MethodsWe utilized for the first time a combination of somatostatin (SST) and neurokinin 1 receptor (NK1R) double immunocytochemistry with cytochrome oxidase histochemistry, to reveal synaptic characteristics and mitochondrial dynamic in the pre-BötC.ResultsWe found perforated synapses with synaptic vesicles accumulated in distinct pools in apposition to each discrete PSD segments. dAIH induced significant increases in the PSD size of macular AS, and the proportion of perforated synapses. AS were predominant in the dAIH group, whereas SS were in a high proportion in the CIH group. dAIH significantly increased SST and NK1R expressions, whereas CIH led to a decrease. Desmosome-like contacts (DLC) were characterized for the first time in the pre-BötC. They were distributed alongside of synapses, especially SS. Mitochondria appeared in more proximity to DLC than synapses, suggestive of a higher energy demand of the DLC. Findings of single spines with dual AS and SS innervation provide morphological evidence of excitation-inhibition interplay within a single spine in the pre-BötC. In particular, we characterized spine-shaft microdomains of concentrated synapses coupled with mitochondrial positioning that could serve as a structural basis for synchrony of spine-shaft communication. Mitochondria were found within spines and ultrastructural features of mitochondrial fusion and fission were depicted for the first time in the pre-BötC.ConclusionWe provide ultrastructural evidence of excitation-inhibition synapses in shafts and spines, and DLC in association with synapses that coincide with mitochondrial dynamic in their contribution to respiratory plasticity in the pre-BötC.
The volatile anesthetic isoflurane differentially inhibits voltage-gated sodium channel currents between pyramidal and parvalbumin neurons in the prefrontal cortex
Authors: Qiu Jingxuan , Yang Yaoxin , Liu Jin , Zhao Wenling , Li Qian , Zhu Tao , Liang Peng , Zhou Cheng 
Published: June 2023

BackgroundHow volatile anesthetics work remains poorly understood. Modulations of synaptic neurotransmission are the direct cellular mechanisms of volatile anesthetics in the central nervous system. Volatile anesthetics such as isoflurane may reduce neuronal interaction by differentially inhibiting neurotransmission between GABAergic and glutamatergic synapses. Presynaptic voltage-dependent sodium channels (Nav), which are strictly coupled with synaptic vesicle exocytosis, are inhibited by volatile anesthetics and may contribute to the selectivity of isoflurane between GABAergic and glutamatergic synapses. However, it is still unknown how isoflurane at clinical concentrations differentially modulates Nav currents between excitatory and inhibitory neurons at the tissue level.MethodsIn this study, an electrophysiological recording was applied in cortex slices to investigate the effects of isoflurane on Nav between parvalbumin (PV+) and pyramidal neurons in PV-cre-tdTomato and/or vglut2-cre-tdTomato mice.ResultsIsoflurane at clinically relevant concentrations produced a hyperpolarizing shift in the voltage-dependent inactivation and slowed the recovery time from the fast inactivation in both cellular subtypes. Since the voltage of half-maximal inactivation was significantly depolarized in PV+ neurons compared to that of pyramidal neurons, isoflurane inhibited the peak Nav currents in pyramidal neurons more potently than those of PV+ neurons (35.95 ± 13.32% vs. 19.24 ± 16.04%, P = 0.036 by the Mann-Whitney test).ConclusionsIsoflurane differentially inhibits Nav currents between pyramidal and PV+ neurons in the prefrontal cortex, which may contribute to the preferential suppression of glutamate release over GABA release, resulting in the net depression of excitatory-inhibitory circuits in the prefrontal cortex.
Time to achieve a patient acceptable symptom state in myasthenia gravis
Authors: Martinez-Harms Rodrigo , Barnett Carolina , Bril Vera 
Published: June 2023

IntroductionThe patient acceptable symptom state (PASS) is a reliable way to characterize a patient’s satisfaction with their disease state in a “Yes”/“No” dichotomous manner. There is limited data on the time required to reach an acceptable state in Myasthenia Gravis (MG). We aimed to determine the time to reach a first PASS “Yes” response in patients at MG diagnosis and a PASS “No” status, and also to determine the influence of various factors on this time.MethodsWe performed a retrospective study of patients diagnosed with myasthenia gravis who had an initial PASS “No” response and defined the time to reach a first PASS “Yes” by Kaplan–Meier analysis. Correlations were made between demographics, clinical characteristics, treatment and disease severity, using the Myasthenia Gravis Impairment Index (MGII) and Simple Single Question (SSQ).ResultsIn 86 patients meeting inclusion criteria, the median time to PASS “Yes” was 15  months (95% CI 11–18). Of 67 MG patients who achieved PASS “Yes,” 61 (91%), achieved it by 25  months after diagnosis. Patients who required only prednisone therapy achieved PASS “Yes” in a shorter time with a median of 5.5  months (p = 0.01). Very-late-onset MG patients reached PASS “Yes” status in a shorter time (HR = 1.99, 95% CI 0.26–2.63; p = 0.001).DiscussionMost patients reached PASS “Yes” by 25  months after diagnosis. MG patients who only required prednisone and those with very-late-onset MG reach PASS “Yes” in shorter intervals.
Changes in glycosylated proteins in colostrum and mature milk and their implication
Authors: Lu Jing , Zhang Wenyuan , Ma Changlu , Pang Xiaoyang , Dai Ying , Zhu Tong , Liu Jinqi , Xing Lina , Zhang Shuwen , Lv Jiaping 
Published: June 2023

IntroductionGlycosylation is one of the essential post-translational modifications that influences the function of milk proteins.MethodsIn the present study, 998 proteins and 764 glycosylated sites from 402 glycoproteins were identified in human milk by TMT labeling proteomics. Compared to human milk proteins, the glycoproteins were mainly enriched in cell adhesion, proteolysis, and defense/immune process.ResultsThe abundance of 353 glycosylated sites and their 179 parent proteins was quantified. After normalization to their parent protein’s abundance, 78 glycosylated sites in 56 glycoproteins and 10 glycosylated sites in 10 glycoproteins were significantly higher in colostrum and mature milk, respectively. These changed glycoproteins were mainly related to host defense. Intriguingly, one glycosylated site (Asp144) in IgA and two glycosylated sites (Asp38 and Asp1079) in tenascin are significantly upregulated even though their protein abundance was downregulated during lactation.DiscussionThis study helps us figure out the critical glycosylated sites in proteins that might influence their biological function in an unbiased way.
Are (poly)phenols contained in 100% fruit juices mediating their effects on cardiometabolic risk factors? A meta-regression analysis
Authors: Micek Agnieszka , Currenti Walter , Mignogna Cristiana , Rosi Alice , Barbagallo Ignazio , Alshatwi Ali A. , Del Rio Daniele , Mena Pedro , Godos Justyna 
Published: June 2023

BackgroundThe consumption of 100% fruit juices has not been associated with substantial detrimental outcomes in population studies and may even contribute to improving the cardiometabolic profile if included in a healthy balanced diet. The main contributors to such potential beneficial effects include vitamins, minerals, and likely the (poly)phenol content. This study aimed to investigate whether the (poly)phenols contained in 100% fruit juices may mediate their effects on cardiometabolic risk factors based on published randomized controlled trials (RCT).MethodsA systematic search in PubMed/MEDLINE and Embase, updated till the end of October 2022, was carried out to identify RCT providing quantitative data on (poly)phenol content in 100% fruit juices and used as an intervention to improve cardiometabolic parameters such as blood lipids, glucose, and blood pressure. Meta-regression analysis was performed to calculate the effect of the intervention [expressed as standardized mean difference and 95% confidence intervals (CI)] using the (poly)phenol content as moderator.ResultsA total of 39 articles on RCT investigating the effects of 100% fruit juices on cardiometabolic risk factors reporting data on total (poly)phenol and anthocyanin content were included in the analysis. Total (poly)phenol content was substantially unrelated to any outcome investigated. In contrast, each 100 mg per day increase in anthocyanins was related to 1.53 mg/dL decrease in total cholesterol (95% CI, −2.83, −0.22, p = 0.022) and 1.94 mg/dL decrease in LDL cholesterol (95% CI, −3.46, −0.42, p = 0.012). No other potential mediating effects of anthocyanins on blood triglycerides, glucose, systolic and diastolic pressure were found, while a lowering effect on HDL cholesterol after excluding one outlier study was observed.DiscussionIn conclusion, the present study showed that anthocyanins may mediate the potential beneficial effects of some 100% fruit juices on some blood lipids. Increasing the content of anthocyanins through specific fruit varieties or plant breeding could enhance the health benefits of 100% fruit juices.
Metformin is associated with improved clinical outcomes in patients with melanoma: a retrospective, multi-institutional study
Authors: Augustin Ryan C. , Huang Ziyu , Ding Fei , Zhai Shuyan , McArdle Jennifer , Santisi Anthony , Davis Michael , Sander Cindy , Davar Diwakar , Kirkwood John M. , Delgoffe Greg M. , Warner Allison Betof , Najjar Yana G. 
Published: June 2023

BackgroundPre-clinical studies have shown that metformin reduces intratumoral hypoxia, improves T-cell function, and increases sensitivity to PD-1 blockade, and metformin exposure has been associated with improved clinical outcomes in various types of cancer. However, the impact of this drug in diabetic melanoma patients has not yet been fully elucidated.MethodsWe reviewed 4,790 diabetic patients with stage I-IV cutaneous melanoma treated at the UPMC-Hillman Cancer Center and Memorial Sloan Kettering Cancer Center between 1996-2020. The primary endpoints included recurrence rates, progression free survival (PFS), and overall survival (OS) with and without metformin exposure. Tabulated variables included BRAF mutational status, immunotherapy (IMT) by type, and incidence of brain metastases.ResultsThe five-year incidence of recurrence in stage I/II patients was significantly reduced with metformin exposure (32.3% vs 47.7%, p=0.012). The five-year recurrence rate for stage III patients was also significantly reduced (58.3% vs 77.3%, p=0.013) in the metformin cohort. OS was numerically increased in nearly all stages exposed to metformin, though this did not reach statistical significance. The incidence of brain metastases was significantly lower in the metformin cohort (8.9% vs 14.6%, p=0.039).ConclusionThis is the first study to demonstrate significantly improved clinical outcomes in diabetic melanoma patients exposed to metformin. Overall, these results provide further rationale for ongoing clinical trials studying the potential augmentation of checkpoint blockade with metformin in advanced melanoma.
Provincial variation in colorectal cancer screening adherence in Canada; evidence from the Canadian Partnership for Tomorrow’s Health
Authors: Darvishian Maryam , Moustaqim-Barrette Amina , Awadalla Philip , Bhatti Parveen , Broet Philippe , McDonald Kelly , Murphy Rachel A. , Skead Kimberly , Urquhart Robin , Vena Jennifer , Dummer Trevor J. B. 
Published: June 2023

IntroductionAlthough colorectal cancer (CRC) screening program is proven to reduce CRC incidence and mortality, understanding patterns and predictors of suboptimal adherence in screening program requires further investigation in Canada.MethodsWe used self-reported data from five regional cohorts of the Canadian Partnership for Tomorrow’s Health (CanPath), namely the BC Generations Project (BCGP), Alberta’s Tomorrow Project (ATP), the Ontario Health Study (OHS), Quebec’s CARTaGENE, and the Atlantic Partnership for Tomorrow’s Health Study (Atlantic PATH). We stratified participants into the following four risk categories: 1) age 50-74 years, 2) family history in a first-degree relative, 3) personal history of chronic inflammatory bowel disease and/or polyps, and 4) co-existence of personal risk and family history. Multivariable logistic regression was used to identify predictors of adherence to the screening guidelines.ResultsAdherence to CRC screening varied considerably between regions, ranging from 16.6% in CARTaGENE to 47.7% in OHS. Compared to the largest cohort OHS, the likelihood of non-adherence to CRC screening was significantly higher in BCGP (OR 1.15, 95% CI 1.11-1.19), the Atlantic PATH (OR 1.90, 95% CI 1.82-1.99) and CARTaGENE (OR 5.10, 95% CI 4.85-5.36). Low physical activity, current smoking, presence of personal risk, family history of CRC significantly reduced the likelihood of adherence to screening recommendations.Discussion/conclusionCompared to the national target of ≥ 60% for participation in CRC screening, adherence to regular CRC screening was suboptimal in this cohort of Canadians and varied by region. Further efforts are needed to identify the specific barriers to screening adherence in different provinces and across risk categories.
Multicenter analysis of immunosuppressive medications on the risk of malignancy following adult solid organ transplantation
Authors: Shaw Reid , Haque Ali R. , Luu Tyler , O’Connor Timothy E. , Hamidi Adam , Fitzsimons Jack , Varda Bianca , Kwon Danny , Whitcomb Cody , Gregorowicz Alex , Roloff Gregory W. , Bemiss Bradford C. , Kallwitz Eric R. , Hagen Patrick A. , Berg Stephanie 
Published: June 2023

ObjectiveThis study aimed to assess the risk of maintenance immunosuppression on the post-transplant risk of malignancy across all solid organ transplant types.MethodsThis is a retrospective cohort study from a multicenter hospital system in the United States. The electronic health record was queried from 2000 to 2021 for cases of solid organ transplant, immunosuppressive medications, and post-transplant malignancy.ResultsA total of 5,591 patients, 6,142 transplanted organs, and 517 post-transplant malignancies were identified. Skin cancer was the most common type of malignancy at 52.8%, whereas liver cancer was the first malignancy to present at a median time of 351 days post-transplant. Heart and lung transplant recipients had the highest rate of malignancy, but this finding was not significant upon adjusting for immunosuppressive medications (heart HR 0.96, 95% CI 0.72 – 1.3, p = 0.88; lung HR 1.01, 95% CI 0.77 – 1.33, p = 0.94). Random forest variable importance calculations and time-dependent multivariate cox proportional hazard analysis identified an increased risk of cancer in patients receiving immunosuppressive therapy with sirolimus (HR 1.41, 95% CI 1.05 – 1.9, p = 0.04), azathioprine (HR 2.1, 95% CI 1.58 – 2.79, p &lt; 0.001), and cyclosporine (HR 1.59, 95% CI 1.17 – 2.17, p = 0.007), while tacrolimus (HR 0.59, 95% CI 0.44 – 0.81, p &lt; 0.001) was associated with low rates of post-transplant neoplasia.ConclusionOur results show varying risks of immunosuppressive medications associated with the development of post-transplant malignancy, demonstrating the importance of cancer detection and surveillance strategies in solid organ transplant recipients.
Impact of radiation on host immune system in patients treated with chemoradiotherapy and durvalumab consolidation for unresectable locally advanced non-small cell lung cancer
Authors: Pasquier Corentin , Chaltiel Léonor , Massabeau Carole , Rabeau Audrey , Lebas Louisiane , Lusque Amélie , Texier Jean-Sébastien , Moyal Elizabeth Cohen-Jonathan , Mazières Julien , Khalifa Jonathan 
Published: June 2023

BackgroundThe optimal modalities of radiotherapy when combining concurrent chemoradiation (CCRT) and immunotherapy (IO) for locally advanced non-small cell lung cancer (LA-NSCLC) remain to be determined. The aim of this study was to investigate the impact of radiation on different immune structures and immune cells in patients treated with CCRT followed by durvalumab.Material and methodsClinicopathologic data, pre- and post-treatment blood counts, and dosimetric data were collected in patients treated with CCRT and durvalumab consolidation for LA-NSCLC. Patients were divided into two groups according to the inclusion (NILN-R+) or not (NILN-R−) of at least one non-involved tumor-draining lymph node (NITDLN) in the clinical target volume (CTV). Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan–Meier method.ResultsFifty patients were included with a median follow-up of 23.2 months (95% CI 18.3–35.2). Two-year PFS and 2-year OS were 52.2% (95% CI 35.8–66.3) and 66.2% (95% CI 46.5–80.1), respectively. In univariable analysis, NILN-R+ (hazard ratio (HR) 2.60, p = 0.028), estimated dose of radiation to immune cells (EDRIC) &gt;6.3 Gy (HR 3.19, p = 0.049), and lymphopenia ≤ 500/mm3 at IO initiation (HR 2.69, p = 0.021) were correlated with poorer PFS; lymphopenia ≤ 500/mm3 was also associated with poorer OS (HR 3.46, p = 0.024). In multivariable analysis, NILN-R+ was the strongest factor associated with PFS (HR 3.15, p = 0.017).ConclusionThe inclusion of at least one NITDLN station within the CTV was an independent factor for poorer PFS in the context of CCRT and durvalumab for LA-NSCLC. The optimal sparing of immune structures might help in achieving better synergy between radiotherapy and immunotherapy in this indication.
Quantitative proteomics identifies tumour matrisome signatures in patients with non-small cell lung cancer
Authors: Titmarsh Helen F. , von Kriegsheim Alex , Wills Jimi C. , O’Connor Richard A. , Dhaliwal Kevin , Frame Margaret C. , Pattle Samuel B. , Dorward David A. , Byron Adam , Akram Ahsan R. 
Published: June 2023

IntroductionThe composition and remodelling of the extracellular matrix (ECM) are important factors in the development and progression of cancers, and the ECM is implicated in promoting tumour growth and restricting anti-tumour therapies through multiple mechanisms. The characterisation of differences in ECM composition between normal and diseased tissues may aid in identifying novel diagnostic markers, prognostic indicators and therapeutic targets for drug development.MethodsUsing tissue from non-small cell lung cancer (NSCLC) patients undergoing curative intent surgery, we characterised quantitative tumour-specific ECM proteome signatures by mass spectrometry.ResultsWe identified 161 matrisome proteins differentially regulated between tumour tissue and nearby non-malignant lung tissue, and we defined a collagen hydroxylation functional protein network that is enriched in the lung tumour microenvironment. We validated two novel putative extracellular markers of NSCLC, the collagen cross-linking enzyme peroxidasin and a disintegrin and metalloproteinase with thrombospondin motifs 16 (ADAMTS16), for discrimination of malignant and non-malignant lung tissue. These proteins were up-regulated in lung tumour samples, and high PXDN and ADAMTS16 gene expression was associated with shorter survival of lung adenocarcinoma and squamous cell carcinoma patients, respectively.DiscussionThese data chart extensive remodelling of the lung extracellular niche and reveal tumour matrisome signatures in human NSCLC.
Mendelian randomization analysis identified tumor necrosis factor as being associated with severe COVID-19
Authors: Song Hongfei , Lei Na , Zeng Ling , Li Xiuyan , Jiang Cen , Feng Quansheng , Su Yue , Liu Jibin , Mu Jie 
Published: June 2023

Background: Observational studies have shown that anti-tumor necrosis factor (TNF) therapy may be beneficial for patients with coronavirus disease 2019 (COVID-19). Nevertheless, because of the methodological restrictions of traditional observational studies, it is a challenge to make causal inferences. This study involved a two-sample Mendelian randomization analysis to investigate the causal link between nine TNFs and COVID-19 severity using publicly released genome-wide association study summary statistics.Methods: Summary statistics for nine TNFs (21,758 cases) were obtained from a large-scale genome-wide association study. Correlation data between single-nucleotide polymorphisms and severe COVID-19 (18,152 cases vs. 1,145,546 controls) were collected from the COVID-19 host genetics initiative. The causal estimate was calculated by inverse variance-weighted (IVW), MR–Egger, and weighted median methods. Sensitivity tests were conducted to assess the validity of the causal relationship.Results: Genetically predicted TNF receptor superfamily member 6 (FAS) positively correlated with the severity of COVID-19 (IVW, odds ratio = 1.10, 95% confidence interval = 1.01–1.19, p = 0.026), whereas TNF receptor superfamily member 5 (CD40) was protective against severe COVID-19 (IVW, odds ratio = 0.92, 95% confidence interval = 0.87–0.97, p = 0.002).Conclusion: Genetic evidence from this study supports that the increased expression of FAS is associated with the risk of severe COVID-19 and that CD40 may have a potential protective effect against COVID-19.