bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutational signatures reveal ternary relationships between homologous recombination repair, APOBEC, and mismatch repair in gynecological cancers
Authors: Farmanbar Amir , Firouzi Sanaz , Kneller Robert , Khiabanian Hossein 
Published: February 2022

Abstract
Background
Revealing the impacts of endogenous and exogenous mutagenesis processes is essential for understanding the etiology of somatic genomic alterations and designing precise prognostication and treatment strategies for cancer. DNA repair deficiency is one of the main sources of endogenous mutagenesis and is increasingly recognized as a target for cancer therapeutics. The role and prevalence of mechanisms that underly different forms of DNA repair deficiencies and their interactions remain to be elucidated in gynecological malignancies.

Methods
We analyzed 1231 exomes and 268 whole-genomes from three major gynecological malignancies including uterine corpus endometrial carcinoma (UCEC) as well as ovarian and cervical cancers. We also analyzed data from 134 related cell lines. We extracted and compared de novo and refitted mutational signature profiles using complementary and confirmatory approaches and performed interaction analysis to detect co-occurring and mutually exclusive signatures.

Results
We found an inverse relationship between homologous recombination deficiency (HRd) and mismatch repair deficiency (MMRd). Moreover, APOBEC co-occurred with HRd but was mutually exclusive with MMRd. UCEC tumors were dominated by MMRd, yet a subset of them manifested the HRd and APOBEC signatures. Conversely, ovarian tumors were dominated by HRd, while a subset represented MMRd and APOBEC. In contrast to both, cervical tumors were dominated by APOBEC with a small subsets showing the POLE, HRd, and MMRd signatures. Although the type, prevalence, and heterogeneity of mutational signatures varied across the tumor types, the patterns of co-occurrence and exclusivity were consistently observed in all. Notably, mutational signatures in gynecological tumor cell lines reflected those detected in primary tumors.

Conclusions
Taken together, these analyses indicate that application of mutation signature analysis not only advances our understanding of mutational processes and their interactions, but also it has the potential to stratify patients that could benefit from treatments available for tumors harboring distinct mutational signatures and to improve clinical decision-making for gynecological malignancies.
Radiomic analysis for predicting prognosis of colorectal cancer from preoperative 18F-FDG PET/CT
Authors: Lv Lilang , Xin Bowen , Hao Yichao , Yang Ziyi , Xu Junyan , Wang Lisheng , Wang Xiuying , Song Shaoli , Guo Xiaomao 
Published: February 2022

AbstractBackgroundTo develop and validate a survival model with clinico-biological features and18F- FDG PET/CT radiomic features via machine learning, and for predicting the prognosis from the primary tumor of colorectal cancer.MethodsA total of 196 pathologically confirmed patients with colorectal cancer (stage I to stage IV) were included. Preoperative clinical factors, serum tumor markers, and PET/CT radiomic features were included for the recurrence-free survival analysis. For the modeling and validation, patients were randomly divided into the training (n = 137) and validation (n = 59) set, while the 78 stage III patients [training (n = 55), and validation (n = 23)] was divided for the further experiment. After selecting features by the log-rank test and variable-hunting methods, random survival forest (RSF) models were built on the training set to analyze the prognostic value of selected features. The performance of models was measured by C-index and was tested on the validation set with bootstrapping. Feature importance and the Pearson correlation were also analyzed.ResultsRadiomics signature (containing four PET/CT features and four clinical factors) achieved the best result for prognostic prediction of 196 patients (C-index 0.780, 95% CI 0.634–0.877). Moreover, four features (including two clinical features and two radiomics features) were selected for prognostic prediction of the 78 stage III patients (C-index was 0.820, 95% CI 0.676–0.900). K–M curves of both models significantly stratified low-risk and high-risk groups (P < 0.0001). Pearson correlation analysis demonstrated that selected radiomics features were correlated with tumor metabolic factors, such as SUVmean, SUVmax.ConclusionThis study presents integrated clinico-biological-radiological models that can accurately predict the prognosis in colorectal cancer using the preoperative18F-FDG PET/CT radiomics in colorectal cancer. It is of potential value in assisting the management and decision making for precision treatment in colorectal cancer.Trial registrationThe retrospectively registered study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (No. 1909207-14-1910) and the data were analyzed anonymously.
Vagus nerve stimulation modulates hippocampal inflammation caused by continuous stress in rats
Authors: Namgung Uk , Kim Ki-Joong , Jo Byung-Gon , Park Jong-Min 
Published: February 2022

Abstract
Background
Previous studies have shown that vagus nerve stimulation (VNS) can attenuate inflammatory responses in peripheral tissues and also improve some neurological disorders and cognitive function in the brain. However, it is not clear how VNS is involved in neuropathological processes in brain tissues. Here, we investigated the regulatory effects of VNS on the production of proinflammatory cytokines in the hippocampus of an animal model of continuous stress (CS).

Methods
CS was induced by placing rats in cages immersed with water, and acute or chronic electrical stimulation was applied to the cervical vagus nerve of CS animals. Protein levels in the gastric and hippocampal tissues were measured by western blotting and protein signals analyzed by immunofluorescence staining. von Frey test and forced swimming test were performed to assess pain sensitivity and depressive-like behavior in rats, respectively.

Results
Levels of TNF-α, IL-1β, and IL-6 in the gastric and hippocampal tissues were significantly increased in CS animals compared to the untreated control and downregulated by acute VNS (aVNS). Iba-1-labeled microglial cells in the hippocampus of CS animals revealed morphological features of activated inflammatory cells and then changed to a normal shape by VNS. VNS elevated hippocampal expression of α7 nicotinic acetylcholine receptors (α7 nAChR) in CS animals, and pharmacological blockade of α7 nAChR increased the production of TNF-α, IL-1β, and IL-6, thus suppressing cholinergic anti-inflammatory activity that was mediated by VNS. Chronic VNS (cVNS) down-regulated the hippocampal production of active form of caspase 3 and 5-HT1A receptors and also decreased levels of TNF-α, IL-1β, and IL-6 in the gastric and hippocampal tissues of CS animals. Pain sensitivity and depressive-like behavior, which were increased by CS, were improved by cVNS.

Conclusions
Our data suggest that VNS may be involved in modulating pathophysiological processes caused by CS in the brain.
Maresin 1 promotes nerve regeneration and alleviates neuropathic pain after nerve injury
Authors: Wei Jinhuan , Su Wenfeng , Zhao Yayu , Wei Zhongya , Hua Yuchen , Xue Peng , Zhu Xiang , Chen Ying , Chen Gang 
Published: February 2022

Abstract
Background
Peripheral nerve injury (PNI) is a public health concern that results in sensory and motor disorders as well as neuropathic pain and secondary lesions. Currently, effective treatments for PNI are still limited. For example, while nerve growth factor (NGF) is widely used in the treatment of PNI to promote nerve regeneration, it also induces pain. Maresin 1 (MaR1) is an anti-inflammatory and proresolving mediator that has the potential to regenerate tissue. We determined whether MaR1 is able to promote nerve regeneration as well as alleviating neuropathic pain, and to be considered as a putative therapeutic agent for treating PNI.

Methods
PNI models were constructed with 8-week-old adult male ICR mice and treated with NGF, MaR1 or saline by local application, intrathecal injection or intraplantar injection. Behavioral analysis and muscle atrophy test were assessed after treatment. Immunofluorescence assay was performed to examine the expression of ATF-3, GFAP, IBA1, and NF200. The expression transcript levels of inflammatory factors IL1β, IL-6, and TNF-α were detected by quantitative real-time RT-PCR. AKT, ERK, mTOR, PI3K, phosphorylated AKT, phosphorylated ERK, phosphorylated mTOR, and phosphorylated PI3K levels were examined by western blot analysis. Whole-cell patch-clamp recordings were executed to detect transient receptor potential vanilloid 1 (TRPV1) currents.

Results
MaR1 demonstrated a more robust ability to promote sensory and motor function recovery in mice after sciatic nerve crush injury than NGF. Immunohistochemistry analyses showed that the administration of MaR1 to mice with nerve crush injury reduced the number of damaged DRG neurons, promoted injured nerve regeneration and inhibited gastrocnemius muscle atrophy. Western blot analysis of ND7/23 cells cultured with MaR1 or DRG neurons collected from MaR1 treated mice revealed that MaR1 regulated neurite outgrowth through the PI3K–AKT–mTOR signaling pathway. Moreover, MaR1 dose-dependently attenuated the mechanical allodynia and thermal hyperalgesia induced by nerve injury. Consistent with the analgesic effect, MaR1 inhibited capsaicin-elicited TRPV1 currents, repressed the nerve injury-induced activation of spinal microglia and astrocytes and reduced the production of proinflammatory cytokines in the spinal cord dorsal horn in PNI mice.

Conclusions
Application of MaR1 to PNI mice significantly promoted nerve regeneration and alleviated neuropathic pain, suggesting that MaR1 is a promising therapeutic agent for PNI.
TNFα-mediated necroptosis in brain endothelial cells as a potential mechanism of increased seizure susceptibility in mice following systemic inflammation
Authors: Huang Wan-Yu , Lai Yen-Ling , Liu Ko-Hung , Lin Shankung , Chen Hsuan-Ying , Liang Chih-Hung , Wu Hung-Ming , Hsu Kuei-Sen 
Published: February 2022

Abstract
Background
Systemic inflammation is a potent contributor to increased seizure susceptibility. However, information regarding the effects of systemic inflammation on cerebral vascular integrity that influence neuron excitability is scarce. Necroptosis is closely associated with inflammation in various neurological diseases. In this study, necroptosis was hypothesized to be involved in the mechanism underlying sepsis-associated neuronal excitability in the cerebrovascular components (e.g., endothelia cells).

Methods
Lipopolysaccharide (LPS) was used to induce systemic inflammation. Kainic acid intraperitoneal injection was used to measure the susceptibility of the mice to seizure. The pharmacological inhibitors C87 and GSK872 were used to block the signaling of TNFα receptors and necroptosis. In order to determine the features of the sepsis-associated response in the cerebral vasculature and CNS, brain tissues of mice were obtained for assays of the necroptosis-related protein expression, and for immunofluorescence staining to identify morphological changes in the endothelia and glia. In addition, microdialysis assay was used to assess the changes in extracellular potassium and glutamate levels in the brain.

Results
Some noteworthy findings, such as increased seizure susceptibility and brain endothelial necroptosis, Kir4.1 dysfunction, and microglia activation were observed in mice following LPS injection. C87 treatment, a TNFα receptor inhibitor, showed considerable attenuation of increased kainic acid-induced seizure susceptibility, endothelial cell necroptosis, microglia activation and restoration of Kir4.1 protein expression in LPS-treated mice. Treatment with GSK872, a RIP3 inhibitor, such as C87, showed similar effects on these changes following LPS injection.

Conclusions
The findings of this study showed that TNFα-mediated necroptosis induced cerebrovascular endothelial damage, neuroinflammation and astrocyte Kir4.1 dysregulation, which may coalesce to contribute to the increased seizure susceptibility in LPS-treated mice. Pharmacologic inhibition targeting this necroptosis pathway may provide a promising therapeutic approach to the reduction of sepsis-associated brain endothelia cell injury, astrocyte ion channel dysfunction, and subsequent neuronal excitability.
Universal Thermal Climate Index (UTCI) and adverse pregnancy outcomes in Ahvaz, Iran
Authors: Khodadadi Narges , Dastoorpoor Maryam , Khanjani Narges , Ghasemi Afsaneh 
Published: February 2022

AbstractBackgroundClimate change may jeopardize the health of mothers and their offspring. There are few studies on the association between increasing temperature and pregnancy outcomes. The aim of this study was to investigate the relation between Universal Thermal Climate Index (UTCI) and adverse pregnancy outcomes including stillbirth, low birth weight (LBW), preterm labor (PTL), spontaneous abortion (SA), preeclampsia and hypertension in Ahvaz, Iran.MethodsDistributed Lag Non-linear Models (DLNM) combined with quasi-Poisson regression were used to research the effect of UTCI on adverse pregnancy outcomes. The effect of time trend, air pollutants (NO2, SO2and PM10), and weekdays were adjusted.ResultsThe results showed that the low values of UTCI index (11.6 °C, in lags 0–6, 0–13) caused significant increase in the risk of preterm labor. However, hot thermal stress (high UTCI) significantly increased the risk of stillbirth in lag 0–13. We did not observe any significant relation between UTCI and other pregnancy outcomes in this study.ConclusionsIt seems like both hot and cold weathers can be associated with adverse pregnancy outcomes.
Factors associated with the uptake of long-acting reversible contraception among female sex workers in post-conflict Northern Uganda: a cross-sectional study
Authors: Ouma Simple , Tumwesigye Nazarius Mbona , Abbo Catherine , Ndejjo Rawlance 
Published: February 2022

Abstract
Background
Long-acting reversible contraception (LARC) is the most effective and reliable contraception option for female sex workers (FSWs) who desire future fertility. Unlike the other reversible contraceptive methods, LARC use requires only periodic users’ involvement at the time of application and re-application. However, only a few studies on LARC uptake among FSWs are available in Uganda. To fill this knowledge gap, we examined factors associated with the uptake of LARC among FSWs in post-conflict Northern Uganda.

Methods
We conducted a cross-sectional study among adult FSWs operating in the post-conflict Gulu district in Northern Uganda. We collected quantitative data among 280 FSWs of reproductive ages (18–49 years) who were neither pregnant nor using permanent contraception. We utilized a pretested semi-structured questionnaire to gather information from each participant through face-to-face interviews. We collected data on socio-demographic characteristics, sex work-related characteristics, obstetric history, HIV status, and LARC uptake. Data were then entered into EPI INFO 7, cleaned, and analyzed using multivariable Poisson regression in STATA 14.0 to obtained adjusted prevalence ratios (PR).

Results
Among the study participants: the mean age (SD, range) was 26.5 (5.9, 18–45) years, 48.6% reported at least one unintended pregnancy during sex work, and 37.4% had at least one induced abortion. Meanwhile, only less than two in three (58.6%) participants were using LARC. At multivariable level, factors that remained independently associated with LARC uptake included: longer duration of sex work (adjusted PR = 1.44, 95% CI: 1.03–2.02), higher parity (adjusted PR = 1.13, 95% CI: 1.02–1.26), history of unintended pregnancies during sex work (adjusted PR = 1.24 CI: 1.01–1.51), and being a brothel/lodge-based FSWs (adjusted PR = 1.28, 95% CI: 1.01–1.63).

Conclusions
The above findings revealed a gap in the uptake of LARC among FSWs in post-conflict Northern Uganda influenced by duration of sex work, parity, unintended pregnancies during sex work, and place of sex work. Interventions to improve LARC uptake should target the newly recruited FSWs with low parity and the non-brothel/lodge-based FSWs.
Surgical treatment of chronic Achilles tendon rupture results in improved gait biomechanics
Authors: Nordenholm Anna , Senorski Eric Hamrin , Westin Olof , Nilsson Helander Katarina , Möller Michael , Karlsson Jón , Zügner Roland 
Published: February 2022

Abstract
Background
Chronic Achilles tendon rupture is associated with persistent weakness at push-off with the affected foot and poor balance, resulting in significant alterations to normal gait. Surgical repair is the most common treatment for improving gait in patients with a Chronic Achilles tendon rupture, but, to date, the outcomes have not been quantified in the literature.

Methods
A total of 23 patients with a Chronic Achilles tendon rupture (mean age 61 ± 15 years) underwent three-dimensional gait analysis according to a standardized protocol using an optical tracking system. Data of spatiotemporal, kinematic and kinetic variables were collected preoperatively and one year postoperatively. In addition, the postoperative gait biomechanics were compared with the gait biomechanics of a control group consisting of 70 healthy individuals (mean age 49 ± 20 years). The prospectively collected data were analyzed by an independent t test.

Results
Postoperatively, increments were found in gait speed (mean difference − 0.12 m/s), stride length (− 0.12 m), peak ankle moment (− 0.64 Nm/kg), peak ankle power (− 1.38 W/kg), peak knee power (− 0.36 m) and reduced step width (0.01 m), compared with preoperative gait biomechanics (p < 0.014). Compared with the control group, patients with a Chronic Achilles tendon rupture exhibited slower postoperative gait speed (mean difference 0.24 m/s), wider step width (− 0.02 m), shorter stride length (0.16 m), longer relative stance phase (− 2.15%), lower peak knee flexion (17.03 degrees), greater peak knee extension (2.58 degrees), lower peak ankle moment (0.35 Nm/kg), peak ankle power (1.22 W/kg) and peak knee power (1.62 W/kg), (p < 0.010).

Conclusion
Surgical intervention and postoperative rehabilitation can be an effective treatment for alterations in gait after a Chronic rupture of the Achilles tendon. However, at one year postoperatively, patients still exhibit impairments in spatiotemporal variables and knee and ankle power compared with healthy controls.
The dual roles of autophagy and the GPCRs-mediating autophagy signaling pathway after cerebral ischemic stroke
Authors: Hou Weichen , Hao Yulei , Sun Li , Zhao Yang , Zheng Xiangyu , Song Lei 
Published: February 2022

AbstractIschemic stroke, caused by a lack of blood supply in brain tissues, is the third leading cause of human death and disability worldwide, and usually results in sensory and motor dysfunction, cognitive impairment, and in severe cases, even death. Autophagy is a highly conserved lysosome-dependent process in which eukaryotic cells removal misfolded proteins and damaged organelles in cytoplasm, which is critical for energy metabolism, organelle renewal, and maintenance of intracellular homeostasis. Increasing evidence suggests that autophagy plays important roles in pathophysiological mechanisms under ischemic conditions. However, there are still controversies about whether autophagy plays a neuroprotective or damaging role after ischemia. G-protein-coupled receptors (GPCRs), one of the largest protein receptor superfamilies in mammals, play crucial roles in various physiological and pathological processes. Statistics show that GPCRs are the targets of about one-fifth of drugs known in the world, predicting potential values as targets for drug research. Studies have demonstrated that nutritional deprivation can directly or indirectly activate GPCRs, mediating a series of downstream biological processes, including autophagy. It can be concluded that there are interactions between autophagy and GPCRs signaling pathway, which provides research evidence for regulating GPCRs-mediated autophagy. This review aims to systematically discuss the underlying mechanism and dual roles of autophagy in cerebral ischemia, and describe the GPCRs-mediated autophagy, hoping to probe promising therapeutic targets for ischemic stroke through in-depth exploration of the GPCRs-mediated autophagy signaling pathway.
Helmet noninvasive ventilation for COVID-19 patients (Helmet-COVID): statistical analysis plan for a randomized controlled trial
Authors: Arabi Yaseen , Aldekhyl Sara , Al Qahtani Saad , Al-Dorzi Hasan M. , Abdukahil Sheryl Ann , Jose Jesna , Al Harbi Mohammad Khulaif , Al Haji Husain , Al Mutairi Mohammed , Al Zumai Omar , Al Qasim Eman , Al Wehaibi Wedyan , Alshahrani Mohammed , Albrahim Talal , Mady Ahmed , Al Bshabshe Ali , Al Aseri Zohair , Al Duhailib Zainab , Kharaba Ayman , Alqahtani Rakan , Algethamy Haifa , Alfaris Omar , Alnafel Omar , Al-Fares Abdulrahman A. , Tlayjeh Haytham 
Published: February 2022

AbstractBackgroundNoninvasive respiratory support is frequently needed for patients with acute hypoxemic respiratory failure due to coronavirus disease 19 (COVID-19). Helmet noninvasive ventilation has multiple advantages over other oxygen support modalities but data about effectiveness are limited.MethodsIn this multicenter randomized trial of helmet noninvasive ventilation for COVID-19 patients, 320 adult ICU patients (aged ≥14 years or as per local standards) with suspected or confirmed COVID-19 and acute hypoxemic respiratory failure (ratio of arterial oxygen partial pressure to fraction of inspired oxygen < 200 despite supplemental oxygen with a partial/non-rebreathing mask at a flow rate of 10 L/min or higher) will be randomized to helmet noninvasive ventilation with usual care or usual care alone, which may include mask noninvasive ventilation, high-flow nasal oxygen, or standard oxygen therapy. The primary outcome is death from any cause within 28 days after randomization. The trial has 80% power to detect a 15% absolute risk reduction in 28-day mortality from 40 to 25%. The primary outcome will be compared between the helmet and usual care group in the intention-to-treat using the chi-square test. Results will be reported as relative risk and 95% confidence interval. The first patient was enrolled on February 8, 2021. As of August 1, 2021, 252 patients have been enrolled from 7 centers in Saudi Arabia and Kuwait.DiscussionWe developed a detailed statistical analysis plan to guide the analysis of the Helmet-COVID trial, which is expected to conclude enrollment in November 2021.Trial registrationClinicalTrials.govNCT04477668. Registered on July 20, 2020