bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of levothyroxine therapy on the pregnancy, neonatal and childhood outcomes of subclinical hypothyroidism during pregnancy: An updated systematic review, meta-analysis and trial sequential analysis
Authors: Jiao Xue-Feng , Zhang Miao , Chen Jingjing , Wei Qiang , Zeng Linan , Liu Dan , Zhang Chuan , Li Hailong , Zou Kun , Zhang Li , Zhang Lingli 
Published: August 2022

BackgroundSeveral systematic reviews and meta-analyses have investigated the effect of levothyroxine (LT4) therapy in pregnant women with subclinical hypothyroidism (SCH). However, all these studies have clinical or methodological problems (such as adopting the old 2011 American Thyroid Association [ATA] diagnostic criteria, directly combining randomized controlled trials [RCTs] and cohort studies for meta-analysis, and so on), and cannot provide accurate and satisfactory results. Thus, we performed this updated systematic review, meta-analysis and trial sequential analysis (TSA) to assess the effect of LT4 therapy in pregnant women with SCH, with the goal of providing more accurate and reliable evidence for clinical practice.MethodsWe searched nine databases from inception to February 2022. The search strategy targeted the RCTs and cohort studies on pregnancy, neonatal and childhood outcomes following LT4 treatment in pregnant women with SCH based on the new 2017 ATA diagnostic criteria. We performed meta-analyses of RCTs and cohort studies separately, and further performed meta-analyses by excluding studies with high risk of bias. TSA was performed to test whether the current evidence was sufficient, and the quality of evidence was evaluated using the GRADE method.ResultsA total of 9 RCTs and 13 cohort studies comprising 11273 pregnant women with SCH were included. There were no statistically significant differences between LT4 group and control group in all primary and secondary outcomes, such as preterm delivery (RR=0.46, 95%CI: 0.19-1.09, P=0.08, I2 = 65%), miscarriage (RR=0.36, 95%CI: 0.13-1.03, P=0.06, I2 = 38%), gestational hypertension (RR=0.91, 95%CI: 0.58-1.43, P=0.69, I2 = 0%), preeclampsia (RR=1.10, 95%CI: 0.61-1.97, P=0.76, I2 = 0%), gestational diabetes (RR=0.80, 95%CI: 0.51-1.25, P=0.32, I2 = 34%), and so on. TSA showed that the results for all outcomes were insufficient and inconclusive. According to GRADE, the evidences for four outcomes (miscarriage, gestational hypertension, gestational diabetes, and small for gestational age) were rated as moderate quality, while the evidences for the other outcomes were rated as low or very low quality.ConclusionUnlike previous systematic reviews and meta-analyses, our study found no evidence of benefit of LT4 therapy on pregnancy, neonatal and childhood outcomes in pregnant women with SCH.Systematic Review RegistrationPROSPERO, https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022321937, identifier CRD42022321937.
The prognostic value and clinical significance of mitophagy-related genes in hepatocellular carcinoma
Authors: Xu Wei , Zhao Dongxu , Huang Xiaowei , Zhang Man , Yin Minyue , Liu Lu , Wu Hongyu , Weng Zhen , Xu Chunfang 
Published: August 2022

Background: Mitophagy has been found to play a significant part in the cancer process in a growing number of studies in recent years. However, there is still a lack of study on mitophagy-related genes’ (MRGs) prognostic potential and clinical significance in hepatocellular carcinoma (HCC).Methods: We employed bioinformatics and statistical knowledge to examine the transcriptome data of HCC patients in the TCGA and GEO databases, with the goal of constructing a multigene predictive model. Then, we separated the patients into high- and low-risk groups based on the score. The model’s dependability was determined using principal components analysis (PCA), survival analysis, independent prognostic analysis, and receiver operating characteristic (ROC) analysis. Following that, we examined the clinical correlations, pharmacological treatment sensitivity, immune checkpoint expression, and immunological correlations between patients in high and low risk groups. Finally, we evaluated the variations in gene expression between high- and low-risk groups and further analyzed the network core genes using protein-protein interaction network analysis.Results: Prognostic models were built using eight genes (OPTN, ATG12, CSNK2A2, MFN1, PGAM5, SQSTM1, TOMM22, TOMM5). During validation, the prognostic model demonstrated high reliability, indicating that it could accurately predict the prognosis of HCC patients. Additionally, we discovered that typical HCC treatment medicines had varying impacts on patients classified as high or low risk, and that individuals classified as high risk are more likely to fail immunotherapy. Additionally, the high-risk group expressed more immunological checkpoints. The immunological status of patients in different risk categories varies as well, and patients with a high-risk score have a diminished ability to fight cancer. Finally, PPI analysis identified ten related genes with potential for research.Conclusion: Our prognostic model had good and reliable predictive ability, as well as clinical diagnosis and treatment guiding significance. Eight prognostic MRGs and ten network core genes merited further investigation.
Pan-cancer analyses confirmed the cuproptosis-related gene FDX1 as an immunotherapy predictor and prognostic biomarker
Authors: Zhang Chi , Zeng Yuanxiao , Guo Xiuchen , Shen Hangjing , Zhang Jianhao , Wang Kaikai , Ji Mengmeng , Huang Shengwei 
Published: August 2022

Background: The latest research identified cuproptosis as an entirely new mechanism of cell death. However, as a key regulator in copper-induced cell death, the prognostic and immunotherapeutic value of FDX1 in pan-cancer remains unclear.Methods: Data from the UCSC Xena, GEPIA, and CPTAC were analyzed to conduct an inquiry into the overall differential expression of FDX1 across multiple cancer types. The expression of FDX1 in GBM, LUAD and HCC cell lines as well as their control cell lines was verified by RT-QPCR. The survival prognosis, clinical features, and genetic changes of FDX1 were also evaluated. Finally, the relationship between FDX1 and immunotherapy response was further explored through Gene Set Enrichment Analysis enrichment analysis, tumor microenvironment, immune cell infiltration, immune gene co-expression and drug sensitivity analysis.Results: The transcription and protein expression of FDX1 were significantly reduced in most cancer types and had prognostic value for the survival of certain cancer patients such as ACC, KIRC, HNSC, THCA and LGG. In some cancer types, FDX1 expression was also markedly correlated with the clinical characteristics, TMB, MSI, and antitumor drug susceptibility or resistance of different tumors. Gene set enrichment analysis showed that FDX1 was significantly associated with immune-related pathways. Moreover, the expression level of FDX1 was confirmed to be strongly correlated with immune cell infiltration, immune checkpoint genes, and immune regulatory genes to a certain extent.Conclusion: This study comprehensively explored the potential value of FDX1 as a prognostic and immunotherapeutic marker for pan-cancer, providing new direction and evidence for cancer therapy.
Connective tissue growth factor-targeting DNA aptamer suppresses pannus formation as diagnostics and therapeutics for rheumatoid arthritis
Authors: Wu Gan , Liu Can , Cao Ben , Cao Zelin , Zhai Haige , Liu Bin , Jin Shengwei , Yang Xinyu , Lv Chen , Wang Jianguang 
Published: August 2022

Connective tissue growth factor (CTGF) has been recently acknowledged as an ideal biomarker in the early disease course, participating in the pathogenesis of pannus formation in rheumatoid arthritis (RA). However, existing approaches for the detection of or antagonist targeting CTGF are either lacking or unsatisfactory in the diagnosis and treatment of RA. To address this, we synthesized and screened high-affinity single-stranded DNA aptamers targeting CTGF through a protein-based SELEX procedure. The structurally optimized variant AptW2-1-39-PEG was characterized thoroughly for its high-affinity (KD 7.86 nM), sensitivity (minimum protein binding concentration, 2 ng), specificity (negative binding to other biomarkers of RA), and stability (viability-maintaining duration in human serum, 48 h) properties using various biochemical and biophysical assays. Importantly, we showed the antiproliferative and antiangiogenic activities of the aptamers obtained using functional experiments and further verified the therapeutic effect of the aptamers on joint injury and inflammatory response in collagen-induced arthritis (CIA) mice, thus advancing this study into actual therapeutic application. Furthermore, we revealed that the binding within AptW2-1-39-PEG/CTGF was mediated by the thrombospondin 1 (TSP1) domain of CTGF using robust bioinformatics tools together with immunofluorescence. In conclusion, our results revealed a novel aptamer that holds promise as an additive or alternative approach for CTGF-targeting diagnostics and therapeutics for RA.
Protein stability [determination] problems
Authors: Ahmad Faizan 
Published: August 2022

Human health depends on the correct folding of proteins, for misfolding and aggregation lead to diseases. An unfolded (denatured) protein can refold to its original folded state. How does this occur is known as the protein folding problem. One of several related questions to this problem is that how much more stable is the folded state than the unfolded state. There are several measures of protein stability. In this article, protein stability is given a thermodynamic definition and is measured by Gibbs free energy change (ΔGD0) associated with the equilibrium, native (N) conformation ↔ denatured (D) conformation under the physiological condition usually taken as dilute buffer (or water) at 25 °C. We show that this thermodynamic quantity (ΔGD0), where subscript D represents transition between N and D states, and superscript 0 (zero) represents the fact that the transition occurs in the absence of denaturant, can be neither measured nor predicted under physiological conditions. However, ΔGD can be measured in the presence of strong chemical denaturants such as guanidinium chloride and urea which are shown to destroy all noncovalent interactions responsible for maintaining the folded structure. A problem with this measurement is that the estimate of ΔGD0 comes from the analysis of the plot of ΔGDversus denaturant concentration, which requires a long extrapolation of values of ΔGD, and all the three methods of extrapolation give three different values of ΔGD0 for a protein. Thus, our confidence in the authentic value of ΔGD0 is eroded. Another problem with this in vitro measurement of ΔGD0 is that it is done on the pure protein sample in dilute buffer which is a very large extrapolation of the in vivo conditions, for the crowding effect on protein stability is ignored.
Characterizing the role of SLC3A2 in the molecular landscape and immune microenvironment across human tumors
Authors: He Jiajun , Liu Dong , Liu Mei , Tang Rong , Zhang Dongqing 
Published: August 2022

Background: Inducing ferroptosis in human tumors has become a potential strategy to improve the prognosis of patients, even in those with chemotherapeutic resistance. The xCT complex is a major target for ferroptosis induction, constituted by SLC7A11 and SLC3A2. The role of SLC7A11 in cancer has been widely studied in recent years. However, related research studies for its partner SLC3A2 are still rare.Methods: Bulk transcriptome, single-cell sequencing, and immunohistochemical staining were analyzed to explore the expression distribution of SLC3A2. Clinical outcomes were referred to uncover the relationship between SLC3A2 expression and patients’ prognosis. Immune cell infiltration was estimated by multiple deconvolution algorithms. The effect of SLC3A2 on the proliferation and drug resistance of cancer cell lines was evaluated by DEPMAP.Results: Upregulated SLC3A2 may have an adverse effect on the survival of multiple cancers such as lower-grade glioma and acute myeloid leukemia. SLC3A2 expression is indispensable for multiple cell lines’ proliferation, especially for ESO51 (a cell line for esophageal cancer). In addition, SLC3A2 expression level was related to the remodeling of the immune microenvironment in cancers and some immune checkpoints such as PD-1 and PD-L1, which were potential therapeutic targets in many distinct cancers.Conclusion: Our study systematically elucidated the role of SLC3A2 in the survival of cancer patients and the potential immunotherapeutic response. Few molecular mechanisms by which SLC3A2 regulates anti-tumor immunity have been clarified in the present study, which is the main limitation. Future research into the biological mechanism could further help with targeted treatment for cancer patients.
Case report: Meningitis and intracranial aneurysm caused by mixed infection of oral microflora dominated by anaerobes
Authors: Cheng Hongjiang , Xu Lina , Yang Fengbing , Jia Longbin , Zhao Doudou , Li Huimin , Liu Wei , Li Yujuan , Liu Xiaoli , Geng Xia , Guo Jiaying , Ling Chen , Zhang Jing 
Published: August 2022

IntroductionMeningitis caused by oral anaerobic bacteria is rare, especially when complicated with an infected intracranial aneurysm. This paper has described an extremely rare case of bacterial meningitis caused by a mixed infection of oral microflora dominated by anaerobes, which developed cerebral infarcts, brain abscess, intracranial aneurysm, and severe hydrocephalus during treatment.Case reportWe describe a 65-year-old male patient who was presented with fever and headache as the initial symptoms and then developed left ophthalmoplegia, right hemiplegia, and disturbance of consciousness. Brain imaging showed that intracranial lesions were increased progressively, and cerebral infarcts, brain abscesses, intracranial aneurysm, and severe hydrocephalus were appeared gradually. Eventually, we diagnosed it as anaerobic meningitis by making deoxyribonucleic acid sequencing from the brain abscess pus. After using an anti-microbial regimen that can sufficiently cover anaerobes, the patient's condition was effectively controlled.ConclusionAnaerobic meningitis can cause a series of intracranial complications. Among them, the intracranial aneurysm is extremely rare. When evidence shows that the infection originates from oral flora, physicians should consider the possibility of this type of encephalitis. An early diagnosis and timely treatment are crucial to improving the prognosis.
How do cardiovascular risk factors correlate with post-stroke cognitive function: Directly or indirectly through stroke severity?
Authors: Hua Jianian , Zhou Yixiu , Chen Licong , Tang Xiang , Diao Shanshan , Fang Qi 
Published: August 2022

ObjectivesCognitive impairment may affect one-third of stroke survivors. Cardiovascular risk factors and stroke severity were known to be associated with cognitive function after stroke. However, it is unclear whether cardiovascular risk factors directly affect cognition after stroke, indirectly affect cognition by changing stroke severity, or both. Moreover, the effect of a combination of hypertension and diabetes mellitus was conflicting. We aimed to investigate the multiple direct and indirect associations and inspire potential intervention strategies.Materials and methodsFrom February 2020 to January 2021, 350 individuals received cognitive tests within 7 days after incident stroke. Cognitive tests were performed using the Chinese version of the Mini-Mental State Examination (MMSE). A moderated mediation model was constructed to test the indirect associations between cardiovascular and demographic risk factors and cognition mediated through stroke severity, the direct associations between risk factors and cognition, and the moderating effects of hypertension and diabetes.ResultsAge (estimate, −0.112), atrial fibrillation (estimate, −4.092), and stroke severity (estimate, −1.994) were directly associated with lower cognitive function after stroke. Vascular disease (estimate, 1.951) and male sex (estimate, 2.502) were directly associated with better cognition after stroke. Higher education level was associated with better cognition directly (estimate, 1.341) and indirectly (estimate, 0.227) through stroke severity. The combination of hypertension decreased the magnitude of the negative association between atrial fibrillation and cognition (estimate, from −4.092 to −3.580).ConclusionThis is the first Chinese study exploring the moderated and mediating associations between cardiovascular risk factors, stroke severity, and cognitive function after stroke. Age, female sex, and atrial fibrillation were directly associated with lower cognition after stroke. The combination of hypertension might have a positive effect on cognition.
A Novel Therapeutic Approach With Sodium Pyruvate on Vital Signs, Acid–Base, and Metabolic Disturbances in Rats With a Combined Blast and Hemorrhagic Shock
Authors: Saha Biswajit , Sahu Geetaram , Sharma Pushpa 
Published: August 2022

BackgroundBlast injuries from improvised explosive devices (IEDs) are known to cause blast traumatic brain injuries (bTBIs), hemorrhagic shock (HS), organ damage, mitochondrial dysfunction, and subsequent free radical production. A pre-citric acid cycle reagent, pyruvate, is suggested to improve mitochondrial ATP production through the activation of the mitochondrial gatekeeper enzyme “pyruvate dehydrogenase complex (PDH).” Our study aimed to investigate the role of physiologic, metabolic, and mitochondrial effects of hypertonic sodium pyruvate resuscitation in rats with a combined blast and HS injury.MethodsA pre-clinical rat model of combined injury with repetitive 20 PSI blast exposure accompanied with HS and fluid resuscitation (sodium pyruvate as metabolic adjuvant or hypertonic saline as control), followed by transfusion of shed blood was used in this study. Control sham animals (instrumental and time-matched) received anesthesia and cannulation, but neither received any injury nor treatment. The mean arterial pressure and heart rate were recorded throughout the experiment by a computerized program. Blood collected at T0 (baseline), T60 (after HS), and T180 (end) was analyzed for blood chemistry and mitochondrial PDH enzyme activity.ResultsSodium pyruvate resuscitation significantly improved the mean arterial pressure (MAP), heart rate (HR), pulse pressure (PP), hemodynamic stability (Shock index), and autonomic response (Kerdo index) after the HS and/or blast injury. Compared with the baseline values, plasma lactate and lactate/pyruvate ratios were significantly increased. In contrast, base excess BE/(HCO3-) was low and the pH was also acidotic &lt;7.3, indicating the sign of metabolic acidosis after blast and HS in all animal groups. Sodium pyruvate infusion significantly corrected these parameters at the end of the experiment. The PDH activity also improved after the sodium pyruvate infusion.ConclusionIn our rat model of a combined blast and HS injury, hypertonic sodium pyruvate resuscitation was significantly effective in hemodynamic stabilization by correcting the acid–base status and mitochondrial mechanisms via its pyruvate dehydrogenase enzyme.
Association between serum calcium levels and first stroke: A community-based nested case-control study
Authors: Ding Congcong , Bi Chonglei , Lin Tengfei , Liu Lishun , Song Yun , Wang Binyan , Wang Ping , Fang Chongqian , Ma Hai , Huang Xiao , Xu Xiping , Zhang Hao , Hu Lihua , Huo Yong , Wang Xiaobin , Bao Huihui , Cheng Xiaoshu 
Published: August 2022

BackgroundEvidence from epidemiologic studies has been limited and inconsistent regarding the role of serum calcium in stroke incidence risk. We aimed to evaluate the association between serum albumin-corrected calcium and the risk of the first stroke in the Chinese community-dwelling population.MethodsThe study sample population was drawn from the “H-type Hypertension and Stroke Prevention and Control Project.” Using a nested case-control study, a total of 1,255 first-stroke cases and 1,255 controls matched for age, sex, and village were included in the final data analysis. We measured the serum calcium by inductively coupled plasma mass spectrometry and assessed the associations between serum albumin-corrected calcium and first stroke using conditional logistic regression.ResultsThe overall mean (SD) serum albumin-corrected calcium was 8.9 (0.6) mg/dl. Compared with the middle tertile (8.7–9.1 mg/dl), the multivariate-adjusted odds ratios (95% CIs) of first total stroke associated with the lowest tertile and the highest tertile of serum albumin-corrected calcium were 1.37 (1.10, 1.70) and 1.30 (1.04, 1.62), respectively. Similar trends were observed for the first ischemic stroke. Consistently, restricted cubic spline showed a U-shaped association between serum albumin-corrected calcium and risk of total stroke and ischemic stroke. However, serum albumin-corrected calcium had no significant effect on first hemorrhagic stroke. No significant effect modification was observed in the subgroup analysis.ConclusionsOur results suggested a U-shaped association between serum calcium and first stroke; both low and high serum calcium levels were associated with an increased risk of the first stroke in the Chinese population.
The Patient’s Perspective on Proton Radiotherapy of Skull Base Meningioma: A Retrospective Cross-Sectional Survey
Authors: Seidensaal Katharina , Sailer Jonas , Harrabi Semi Ben , von Gehlen Johannes , Seidensaal Irina , Weykamp Fabian , Bernhardt Denise , Debus Jürgen , Herfarth Klaus 
Published: August 2022

BackgroundRadiotherapy plays an important role in the management of skull base meningioma. The aim of the study was to investigate patient-reported outcomes.MethodsA questionnaire of 20 items was sent to 192 patients with meningioma of the skull base who have been treated with proton therapy at a single institution. The survey included dichotomous, scaling, and open questions about symptoms, social distancing, rehabilitation, work, reintegration, limitations in recreational activities, as well as daily life activities and correlating diagnoses. Additionally, symptoms were reported retrospectively by the patients at different time points. In total, 128 patients (66.7%) responded. The median age at the time of RT was 55 years (range: 28-91); the majority were female (79%). The median time between the treatment of meningioma and the survey was 38.5 months (range: 7-100).ResultsThe most common initial symptoms were visual impairment (N=54, 42.2%), dizziness (N=38, 29.7%), and double vision (N=32, 25%). The most limiting symptom in daily life at the time of the survey was fatigue (N=31, 24.2%); a significant proportion of patients reported depression as associated with diagnosis (31.3%). Only 53% of patients reported occupational activity before treatment, this number did not increase with time. Only N= 40 (31.3%) and N=35 (27.3%) patients reported no limitations in daily household chores or recreational activities by the disease and treatment. The course of cognitive function after treatment showed a temporary deterioration with subsequent improvement. Except for the improvement in emotional functioning, most domains showed a temporary deterioration during radiotherapy, still, the values reached after 6 months differed weekly or moderately from the initial values.ConclusionBesides neurological deficits, patients with skull base meningioma experience a variety of unspecific symptoms, which can be most limiting in daily life. Even successful treatment does not necessarily translate into the alleviation of those symptoms. A greater focus on the characterization of those symptom complexes is necessary. Greater focus on functional structures such as the hippocampus might improve the results. Due to the retrospective character, this study is hypothesis-generating.