Search

Abstract This study investigated the effects of heat shock protein 22 (HSP22) against doxorubicin (DOX)-induced kidney injury. Mice were randomly assigned to four groups: CON, ad-HSP22, DOX, and ad-HSP22 + DOX. Adeno-associated virus carrying the HSP22 gene (ad-HSP22) was administered via tail vein injection for four weeks, followed by intraperitoneal simulation with DOX (20 mg/kg) for another five days. Upon euthanasia, ELISA, histological staining (H&E, IHC, DHE, and TUNEL), and western blot analyses were employed to assess relevant markers. Serum biomarkers of kidney injury, SCr, and BUN, were upregulated after DOX administration but normalized with HSP22 overexpression. Pathological changes induced by DOX were also reversed by HSP22 overexpression in H&E, IHC, DHE, and TUNEL stains. DOX-induced upregulation of NOX-2 and NOX-4 and downregulation of SOD-1 and SOD-2 were reversed by HSP22 overexpression. Similarly, DOX-induced increases in Bax and decrease in Bcl-2 were attenuated by HSP22 overexpression. The study further demonstrated that the Nrf2/HO-1 signaling pathway was activated by HSP22 overexpression. In vitro experiments corroborated the findings from in vivo experiments. In conclusion, HSP22 alleviates DOX-induced kidney injury by suppressing oxidative stress and apoptosis, primarily through the activation of the Nrf2/HO-1 signaling pathway. These results suggest HSP22 as a potential therapeutic target for DOX-induced kidney injury.

Abstract Background Breast cancer is one of the most common malignant tumors in women. Cell division cycle associated 5 (CDCA5), a master regulator of sister chromatid cohesion, was reported to be upregulated in several types of cancer. Here, the function and regulation mechanism of CDCA5 in breast cancer were explored. Methods CDCA5 expression was identified through immunohistochemistry staining in breast cancer specimens. The correlation between CDCA5 expression with clinicopathological features and prognosis of breast cancer patients was analyzed using a tissue microarray. CDCA5 function in breast cancer was explored in CDCA5-overexpressed/knockdown cells and mice models. Co-IP, ChIP and dual-luciferase reporter assay assays were performed to clarify underlying molecular mechanisms. Results We found that CDCA5 was expressed at a higher level in breast cancer tissues and cell lines, and overexpression of CDCA5 was significantly associated with poor prognosis of patients with breast cancer. Moreover, CDCA5 knockdown significantly suppressed the proliferation and migration, while promoted apoptosis in vitro. Mechanistically, we revealed that CDCA5 played an important role in promoting the binding of E2F transcription factor 1 (E2F1) to the forkhead box M1 (FOXM1) promoter. Furthermore, the data of in vitro and in vivo revealed that depletion of FOXM1 alleviated the effect of CDCA5 overexpression on breast cancer. Additionally, we revealed that the Wnt/β-catenin signaling pathway was required for CDCA5 induced progression of breast cancer. Conclusions We suggested that CDCA5 promoted progression of breast cancer via CDCA5/FOXM1/Wnt axis, CDCA5 might serve as a novel therapeutic target for breast cancer treatment.

Immune checkpoint blockade (ICB) therapy, particularly PD1/PDL1 inhibition, has demonstrated success in bolstering durable responses in patients. However, the response rate remains below 30 %. In this study, we developed a polymeric bispecific antibody (BsAb) targeting PD1/PDL1 to enhance ICB therapy. Specifically, poly(L-glutamic acid) (PGLU) was conjugated with a double cyclic Fc binding peptide, Fc-III-4C, through condensation reactions between the -COOH group of PGLU and the -NH2 group of Fc-III-4C. This conjugate was then mixed with αPD1 and αPDL1 monoclonal antibodies (mAbs) in an aqueous solution. Mechanistically, the PD1/PDL1 BsAb (BsAbαPD1+αPDL1) acts as a bridge between tumor cells and CD8+ T cells, continuously activating CD8+ T cells to a greater extent. This leads to significantly suppressed tumor growth and prolonged survival in a mouse model of colon cancer compared to treatment with either a single mAb or a mixture of free mAbs. The tumor suppression rate achieved by the BsAbαPD1+αPDL1 was 90.1 %, with a corresponding survival rate of 83.3 % after 48 days. Thus, this study underscores the effectiveness of the BsAbαPD1+αPDL1 as a synchronizing T cell engager and dual ICBs, offering theoretical guidance for clinical ICB therapy.

Abstract Medullary Carcinoma of the Colon (MCC) is a rare histological subtype of colon cancer, and there is currently no recognized optimal treatment plan for it, with its prognosis remaining unclear. The aim of this study is to analyze the independent prognostic factors for MCC patients and develop and validate nomograms to predict overall survival (OS). A total of 760 patients newly diagnosed with MCC from 2004 to 2020 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. All patients were randomly allocated to a training group and a validation group in a 7:3 ratio. Univariate and multivariable Cox regression analyses were conducted to identify prognostic factors and construct nomograms. The nomogram prediction model was evaluated and validated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). The study found that elderly women are more susceptible to MCC, and the ascending colon and cecum are the most common sites of involvement. MCC is poorly differentiated, with stages II and III being the most common. Surgery is the primary treatment for MCC. The prognosis for patients with stage IV MCC is poor, with a median survival time of only 10 months. Independent prognostic factors for MCC include age, N stage, M stage, surgery, chemotherapy, and tumor size. Among them, age 7 cm (HR = 1.66, 95%CI 1.20–2.30) were risk factors for colon medullary carcinoma. The results of ROC, AUC, calibration curves, and DCA demonstrate that the nomogram prediction model exhibits good predictive performance. We have updated the demographic characteristics of colon medullary carcinoma and identified age, N staging, M staging, surgery, chemotherapy and tumor size as independent prognostic factors for colon medullary carcinoma. Additionally, we have established nomograms for prognostic prediction. These nomograms can provide personalized predictions and serve as valuable references for clinical decision-making.

Abstract Background Because the cases are quite scarce, we aimed to review cases of foreign body impaction penetrating the neck through the esophagus to analyze the characteristics of these cases. The open surgery skills of the surgeon, the treatment procedure and the surgeons’ experience in the rare diseases were analyzed. Methods We collected and analyzed all cases from 2015–2020 in our hospital. Surgical skills and procedures for fasting and anti-infection treatment were reviewed retrospectively. Follow-up was telephone communication. Results Our series included 15 cases. Tenderness in the pre-cervical site was a physical sign for screening. Thirteen cases underwent a lateral neck open surgery with the incision including the left side of neck and only two cases were incised from the right side of the neck. Pus was found 3 days after the impaction in one case, the shortest time observed in our series. The esophageal laceration was only sutured primarily in 5 cases (33.33%) among all fifteen cases. After sufficient drainage (average more than 9 days), antibiotic treatment and fasting (normally 2–3 weeks), patients gradually began to switch to solid foods from fluids after complete blood counts and confirmations from esophageal radiography result. No severe complications occurred, and all the patients have no swallowing dis-function and recovered well. Conclusion Surgery should be performed as soon as possible after impaction. Lateral neck approach surgery and the therapeutic procedure described in this article are safe and effective treatments.

Abstract Background Mechanical spinal cord injury (SCI) is a deteriorative neurological disorder, causing secondary neuroinflammation and neuropathy. ADAM8 is thought to be an extracellular metalloproteinase, which regulates proteolysis and cell adherence, but whether its intracellular region is involved in regulating neuroinflammation in microglia after SCI is unclear. Methods Using animal tissue RNA-Seq and clinical blood sample examinations, we found that a specific up-regulation of ADAM8 in microglia was associated with inflammation after SCI. In vitro, microglia stimulated by HMGB1, the tail region of ADAM8, promoted microglial inflammation, migration and proliferation by directly interacting with ERKs and Fra-1 to promote activation, then further activated Map3k4/JNKs/p38. Using SCI mice, we used BK-1361, a specific inhibitor of ADAM8, to treat these mice. Results The results showed that administration of BK-1361 attenuated the level of neuroinflammation and reduced microglial activation and recruitment by inhibiting the ADAM8/Fra-1 axis. Furthermore, treatment with BK-1361 alleviated glial scar formation, and also preserved myelin and axonal structures. The locomotor recovery of SCI mice treated with BK-1361 was therefore better than those without treatment. Conclusions Taken together, the results showed that ADAM8 was a critical molecule, which positively regulated neuroinflammatory development and secondary pathogenesis by promoting microglial activation and migration. Mechanically, ADAM8 formed a complex with ERK and Fra-1 to further activate the Map3k4/JNK/p38 axis in microglia. Inhibition of ADAM8 by treatment with BK-1361 decreased the levels of neuroinflammation, glial formation, and neurohistological loss, leading to favorable improvement in locomotor functional recovery in SCI mice. Graphical Abstract

Background Currently, several studies have explored the association between the modified creatinine index (mCI) and prognosis in patients on hemodialysis (HD). However, some of their results are contradictory. Therefore, this study was conducted to comprehensively assess the role of mCI in predicting prognosis in HD patients through meta-analysis.Methods We searched and screened literature from PubMed, Embase, Web of Science, and Cochrane databases from their establishment until March 2024. Relevant data were extracted. The statistical analysis was performed using Stata 15.0, RevMan 5.4, and Meta DiSc 1.4 software.Results The results showed a positive association between mCI and nutritional status in HD patients (BMI r = 0.19, 95% CI: 0.1–0.28, p = .000; albumin r = 0.36, 95% CI: 0.33–0.39, p = .000; normalized protein catabolic rate (nPCR) r = 0.25, 95% CI: 0.13–0.38, p = .000). In addition, mCI in deceased HD patients was significantly lower than that in HD survivors (SMD = −0.94, 95% CI: −1.46 to −0.42, p = .000). A low mCI was associated with an increased risk of all-cause death in HD patients (HR = 1.95, 95% CI: 1.57–2.42, p = .000). In addition, a low mCI was significantly associated with decreased overall survival (OS) in HD patients (HR = 3.01, 95% CI: 2.44–3.70, p = .000). mCI showed moderate diagnostic accuracy for sarcopenia in both male and female HD patients (male AUC = 0.7891; female AUC = 0.759).Conclusions The mCI can be used as a prognostic marker for HD patients, and monitoring mCI may help to optimize the management of HD and improve overall prognosis in patients.

Abstract Background Abnormal activation of FAK is associated with tumor development and metastasis. Through interactions with other intracellular signalling molecules, FAK influences cytoskeletal remodelling, modulation of adhesion signalling, and activation of transcription factors, promoting migration and invasion of tumor cells. However, the exact mechanism that regulates these processes remains unresolved. Herein, our findings indicate that the S-palmitoylation of FAK is crucial for both its membrane localization and activation. Methods The palmitoylation of FAK in U251 and T98G cells was assessed by an acyl-PEG exchange (APE) assay and a metabolic incorporation assay. Cellular palmitoylation was inhibited using 2-bromopalmitate, and the palmitoylation status and cellular localization of FAK were determined. A metabolic incorporation assay was used to identify the potential palmitoyl acyltransferase and the palmitoylation site of FAK. Cell Counting Kit-8 (CCK8) assays, colony formation assays, and Transwell assays were conducted to assess the impact of ZDHHC5 in GBM. Additionally, intracranial GBM xenografts were utilized to investigate the effects of genetically silencing ZDHHC5 on tumor growth. Results Inhibiting FAK palmitoylation leads to its redistribution from the membrane to the cytoplasm and a decrease in its phosphorylation. Moreover, ZDHHC5, a protein-acyl-transferase (PAT), catalyzes this key modification of FAK at C456. Knockdown of ZDHHC5 abrogates the S-palmitoylation and membrane distribution of FAK and impairs cell proliferation, invasion, and epithelial-mesenchymal transition (EMT). Taken together, our research reveals the crucial role of ZDHHC5 as a PAT responsible for FAK S-palmitoylation, membrane localization, and activation. Conclusions These results imply that targeting the ZDHHC5/FAK axis has the potential to be a promising strategy for therapeutic interventions for glioblastoma (GBM). Video Abstract

Check dams play a pivotal role in debris flow prevention and control engineering. However, their disaster prevention and mitigation capacity gradually decrease over service time due to repeated debris flow impacts. The study was carried out in 15 ditches and 55 check dams within Wudu District, Longnan City, Gansu Province. Seven key evaluation factors were selected for effectiveness and safety: reservoir siltation ratio, slope stability, drainage hole blockage, dam body damage, dam foundation damage, dam shoulder damage, and safety. The evaluation model of the serviceability of the indivusual dam and the comprehensive serviceability of the single trench of the barrage was established by using hierarchical analysis and fuzzy comprehensive evaluation method, and the serviceability was divided into four grades: excellent, good, medium and poor. The evaluation results show that the serviceability rating of individual dams is predominately "poor", accounting for 34.5%. Similarly, the collective serviceability rating of single trench dams for debris flow is predominately "poor", at 33.3%. The results of the evaluation are consistent with the fieldwork observations, providing a valuable reference for predicting the service performance and service life of barrage dams.

AbstractBackground The epidemiologic studies investigating the association of birthweight and genetic factors with gastrointestinal cancer remain scarce. The study aimed to prospectively assess the interactions and joint effects of birthweight and genetic risk levels on gastrointestinal cancer incidence in adulthood.Methods A total of 254,997 participants were included in the UK Biobank study. We used multivariate restricted cubic splines and Cox regression models to estimate the hazard ratios (HRs) and 95% confidential intervals (CI) for the association between birthweight and gastrointestinal cancer risk, then constructed a polygenic risk score (PRS) to assess its interaction and joint effect with birthweight on the development of gastrointestinal cancer.Results We documented 2512 incident cases during a median follow-up of 8.88 years. Compare with participants reporting a normal birthweight (2.5–4.5 kg), multivariable-adjusted HR of gastrointestinal cancer incidence for participants with high birthweight (≥4.5 kg) was 1.17 (95%CI: 1.01–1.36). Such association was remarkably observed in pancreatic cancer, with an HR of 1.82 (95%CI: 1.26–2.64). No statistically significant association was observed between low birth weight and gastrointestinal cancers. Participants with high birthweight and high PRS had the highest risk of gastrointestinal cancer (HR: 2.95, 95%CI: 2.19–3.96).Conclusion Our findings highlight that high birthweight is associated with a higher incidence of gastrointestinal cancer, especially for pancreatic cancer. Benefits would be obtained from birthweight control, particularly for individuals with a high genetic risk.KEY MESSAGESThe epidemiologic studies investigating the association of birthweight and genetic factors with gastrointestinal cancer remain scarce.This cohort study of 254,997 adults in the United Kingdom found an association of high birthweight with the incidence of gastrointestinal cancer, especially for pancreatic cancer, and also found that participants with high birthweight and high polygenic risk score had the highest risk of gastrointestinal cancer.Our data suggests a possible effect of in utero or early life exposures on adulthood gastrointestinal cancer, especially for those with a high genetic risk.

Riverine wetland is one of the important cityscapes along rivers, featuring powerful eco-hydrological regulations in safeguarding urban security and serving its quality. Over the past several decades, intensified climate change, together with the upgraded human activities, have deeply disturbed riverine wetland worldwide and caused variations in the amount and pattern, which might lead to negative effects on wetland ecosystem health (WEH), thus threaten the sustainability of the riverine urban agglomerations. To better understand the mechanism of the above effectiveness, the Riverine Urban Agglomerations along the Yellow River in China’s Ningxia Hui Autonomous Region (RUAN) was taken as an example in the present study. First, by establishing an object-oriented remote sensing image classification system based on Classification and Regression Tree (CART), riverine wetland distribution in years of 2000, 2009 and 2018 were determined for a two-Stage (ST-I: 2000–2009, ST-II: 2009–2018) comparative research. Second, the transition matrix and landscape index were used to measure the spatiotemporal dynamics of the riverine wetland in the two stages. Third, a Pressure-State-Response (P-S-R) model, together with its index system, was constructed to comprehensively assess the WEH in there. Results revealed that: (1) Wetlands in RUAN are dominated by the artificial ones, presenting an overall increase in area during the statistical period, varying with different trends in the two stages. Conversion between the wetlands and the non-wetlands were found frequent during the urbanization, leading to remarkable changes in wetland patterns in space. (2) Rivers are important and basic in forming riverine landscape in RUAN, the natural wetlands increased during the statistical period. In general, wetland patches and diversity increased, shapes of that became homogenized. Accordingly, the aggregation of wetlands decreased and the fragmentation of that worsened. (3) Riverine wetlands in most of RUAN experienced an increase of external pressure and a deterioration of state, showing an overall degradation. Meanwhile, the WEH was determined more by the fundamental state of itself, the external disturbance seemed function less. Above findings confirmed the vulnerability of riverine wetlands during urbanization in an arid circumstance. It is worthy of strengthening the protection of existing wetlands and minimizing or eliminating the conversion, to ensure the WEH and serve the sustainability of riverine urban agglomerations.

Abstract Background Synaptic degeneration occurs in the early stage of Alzheimer's disease (AD) before devastating symptoms, strongly correlated with cognitive decline. Circular RNAs (circRNAs) are abundantly enriched in neural tissues, and aberrant expression of circRNAs precedes AD symptoms, significantly correlated with clinical dementia severity. However, the direct relationship between circRNA dysregulation and synaptic impairment in the early stage of AD remains poorly understood. Methods Hippocampal whole-transcriptome sequencing was performed to identify dysregulated circRNAs and miRNAs in 4-month-old wild-type and APP/PS1 mice. RNA antisense purification and mass spectrometry were utilized to unveil interactions between circRIMS2 and methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3). The roles of circRIMS2/miR-3968 in synaptic targeting of UBE2K-mediated ubiquitination of GluN2B subunit of NMDA receptor were evaluated via numerous lentiviruses followed by morphological staining, co-immunoprecipitation and behavioral testing. Further, a membrane-permeable peptide was used to block the ubiquitination of K1082 on GluN2B in AD mice. Results circRIMS2 was significantly upregulated in 4-month-old APP/PS1 mice, which was mediated by METTL3-dependent N6-methyladenosine (m6A) modification. Overexpression of circRIMS2 led to synaptic and memory impairments in 4-month-old C57BL/6 mice. MiR-3968/UBE2K was validated as the downstream of circRIMS2. Elevated UBE2K induced synaptic dysfunction of AD through ubiquitinating K1082 on GluN2B. Silencing METTL3 or blocking the ubiquitination of K1082 on GluN2B with a short membrane-permeable peptide remarkably rescued synaptic dysfunction in AD mice. Conclusions In conclusion, our study demonstrated that m6A-modified circRIMS2 mediates the synaptic and memory impairments in AD by activating the UBE2K-dependent ubiquitination and degradation of GluN2B via sponging miR-3968, providing novel therapeutic strategies for AD.

Abstract The selenium-containing enzyme GPX4 moonlights as a central regulator of ferroptosis, an iron-dependent, nonapoptotic form of regulated cell death caused by lipid peroxidation. Yet, little is known about the mechanisms underlying the regulation of its post-transcriptional modifications. Here, we identify the tripartite motif-containing protein TRIM26 as an E3 ubiquitin ligase of GPX4. TRIM26 directly interacts with GPX4 through its Ring domain and catalyzes the ubiquitination of GPX4 at K107 and K117, which promotes the switch in polyubiquitination of GPX4 from K48 to K63, thus enhancing GPX4 protein stability. Moreover, PLK1-mediated S127 phosphorylation of TRIM26 enhances the interaction between TRIM26 and GPX4. Inhibition of TRIM26 phosphorylation causes a reduction in GPX4 K63-linked polyubiquitination and diminishes GPX4 protein levels in tumor cells. Further investigation revealed that TRIM26 is overexpressed in glioma cells. TRIM26 silencing dramatically impedes ferroptosis resistance and tumorigenesis in glioma in vivo and in vitro. Clinically, TRIM26 expression shows a direct correlation with GPX4 and PLK1 levels in glioma samples and is associated with poor outcome in patients with glioma. Collectively, these findings define the role of GPX4 K63-linked polyubiquitination in ferroptosis and suggest a potential strategy for glioma treatment.

Abstract Overcoming distant metastasis stands as a paramount challenge in enhancing the outcomes of breast cancer treatments. Thus, delving deeper into comprehending the intricate mechanisms underlying breast cancer metastasis becomes imperative, offering potential avenues for pioneering therapeutic approaches. PRMT6, an arginine N-methyltransferase, possesses the ability to methylate both histone and non-histone proteins. It has been reported that methylation of non-histone proteins impacts their cellular localization, stability, and activation, consequently influencing tumor progression. However, the extent to which PRMT6-mediated non-histone protein methylation influences cancer cell metastasis, particularly in the context of breast cancer, remains elusive. In this study, we established that PRMT6 exerted a positive regulatory influence on breast cancer metastasis through both in vivo and in vitro experiments. Mechanistically, we innovatively revealed that PRMT6 asymmetrically di-methylated STAT3 at arginine 729 (STAT3 R729me2a). This modification proved indispensable for STAT3’s membrane localization, its interaction with JAK2, STAT3 Y705 phosphorylation, and PRMT6-driven cancer cell metastasis. From a clinical perspective, we unearthed the promising potential of STAT3 R729me2a as a robust prognostic marker for predicting the overall survival time of breast cancer patients. In terms of therapeutic intervention, we demonstrated the significant capability of the PRMT6 inhibitor, EPZ020411, to curtail breast cancer metastasis both in vivo and in vitro. In sum, our study unveils the pivotal biological role of PRMT6-mediated STAT3 R729me2a in breast cancer metastasis and underscores the prospective utility of PRMT6 inhibitors as effective therapeutic strategies against STAT3-driven metastatic breast cancer.

Abstract Problem Artificial intelligence has been widely investigated for diagnosis and treatment strategy design, with some models proposed for detecting oral pharyngeal, nasopharyngeal, or laryngeal carcinoma. However, no comprehensive model has been established for these regions. Aim Our hypothesis was that a common pattern in the cancerous appearance of these regions could be recognized and integrated into a single model, thus improving the efficacy of deep learning models. Methods We utilized a point-wise spatial attention network model to perform semantic segmentation in these regions. Results Our study demonstrated an excellent outcome, with an average mIoU of 86.3%, and an average pixel accuracy of 96.3%. Conclusion The research confirmed that the mucosa of oral pharyngeal, nasopharyngeal, and laryngeal regions may share a common appearance, including the appearance of tumors, which can be recognized by a single artificial intelligence model. Therefore, a deep learning model could be constructed to effectively recognize these tumors.

Background: Colorectal Polyps are the main source of precancerous lesions in colorectal cancer. To increase the early diagnosis of tumors and improve their screening, we aimed to develop a simple and non-invasive diagnostic prediction model for colorectal polyps based on machine learning (ML) and using accessible health examination records. Methods: We conducted a single-center observational retrospective study in China. The derivation cohort, consisting of 5426 individuals who underwent colonoscopy screening from January 2021 to January 2024, was separated for training (cohort 1) and validation (cohort 2). The variables considered in this study included demographic data, vital signs, and laboratory results recorded by health examination records. With features selected by univariate analysis and Lasso regression analysis, nine machine learning methods were utilized to develop a colorectal polyp diagnostic model. Several evaluation indexes, including the area under the receiver-operating-characteristic curve (AUC), were used to compare the predictive performance. The SHapley additive explanation method (SHAP) was used to rank the feature importance and explain the final model. Results: 14 independent predictors were identified as the most valuable features to establish the models. The adaptive boosting machine (AdaBoost) model exhibited the best performance among the 9 ML models in cohort 1, with accuracy, sensitivity, specificity, positive predictive value, negative predictive value, F1 score, and AUC (95% CI) of 0.632 (0.618–0.646), 0.635 (0.550–0.721), 0.674 (0.591–0.758), 0.593 (0.576–0.611), 0.673 (0.654–0.691), 0.608 (0.560–0.655) and 0.687 (0.626–0.749), respectively. The final model gave an AUC of 0.675 in cohort 2. Additionally, the precision recall (PR) curve for the AdaBoost model reached the highest AUPR of 0.648, positioning it nearest to the upper right corner. SHAP analysis provided visualized explanations, reaffirming the critical factors associated with the risk of colorectal polyps in the asymptomatic population. Conclusions: This study integrated the clinical and laboratory indicators with machine learning techniques to establish the predictive model for colorectal polyps, providing non-invasive, cost-effective screening strategies for asymptomatic individuals and guiding decisions for further examination and treatment.

Background: Epidemiological studies have shown that fatty acids, especially polyunsaturated fatty acids (PUFAs), influence colorectal carcinogenesis. Colon polyps, particularly those identified as precancerous, are a frequently encountered phenomenon associated with PUFAs. However, the results are inconsistent. Therefore, we investigated the effect of PUFAs on colon polyps in individuals of European ancestry. Methods: Single nucleotide polymorphisms correlating with PUFAs and colon polyps were derived from extensive genome-wide association studies, encompassing a discovery cohort of 135,006 samples and a corresponding validation set with 114,999 samples. Causality was assessed by employing a range of techniques, such as inverse variance weighted (IVW), weighted median, MR-Egger, and simple and weighted modes. The analysis was complemented with sensitivity checks using leave-one-out and heterogeneity evaluation through MR-IVW and Cochran’s Q. Results: A thorough analysis was performed to examine the causal effects of PUFAs on the development of colon polyps. The findings indicated that levels of Omega-3 fatty acids (OR = 1.0014, 95% CI 1.0004–1.0024, p = 0.004), the ratio of Docosahexaenoic acid (DHA)/total fatty acids (FAs) (DHA/totalFA; OR = 1.0015, 95% CI 1.0002–1.0028, p = 0.023), and the ratio of Omega-3/totalFA (Omega-3/totalFA; OR = 1.0013, 95% CI 1.0003–1.0022, p = 0.010) were identified as biomarkers associated with an increased risk of colon polyps. Conversely, the ratio of Omega-6/Omega-3 (OR = 0.9986, 95% CI 0.9976–0.9995, p = 0.003) and the ratio of Linoleic acid (LA)/totalFA (LA/totalFA; OR = 0.9981, 95% CI 0.9962–0.9999, p = 0.044) were negatively associated with susceptibility to colon polyps. The MR-Egger and MR-IVW analysis revealed that pleiotropy and heterogeneity did not significantly impact the outcomes. Conclusion: This study has uncovered a possible adverse effect of PUFAs, notably Omega-3, on the formation of colon polyps. Elevated Omega-3 levels were correlated with a heightened risk of colon polyps.

Study region: Southern Gansu Plateau (SGP), located in the northeastern region of the Qinghai-Tibet Plateau, is a representative alpine-cold water source area for China’s large rivers, such as the Yellow River and Yangtze River. Study focus: Identifying the contributions of dominant factors to the regional soil erosion rate (A) is important for understanding the environmental processes and benefits of water and soil conservation, although related studies have seldom been conducted in alpine-cold regions such as the SGP. Accordingly, the main objectives of this study are (1) to determine the spatiotemporal dynamics of soil erosion and its driving factors in the SGP area; (2) to quantify the relationship between the main influential factors and soil erosion; and (3) to separate the contributions of the above factors to variations in regional soil erosion on the SGP. New hydrological insights for the region: The multiyear average regional A for the SGP region was calculated as 24.18 t·hm−2·a−1, corresponding to an overall low intensity of regional soil erosion. The contributions of various time-varying factors, such as rainfall, vegetation cover, and conservation practices, to the reduction in A were −20.01%, 81.07%, and 21.95%, respectively, indicating that the improvement in land surface vegetation ecology dominated the decrease in A under the background of climate warming. The findings are expected to contribute to soil and water conservation in alpine-cold river source regions.

AbstractBackground: Extramedullary disease (EMD) is an unusual event in patients with MM. This study aimed to assess the prognostic impact of EMD and develop an EMD-based risk model to estimate the survival of patients with newly diagnosed multiple myeloma (NDMM).Methods: A total of 518 patients were enrolled in this study, of which 121 presented with EMD at the initial diagnosis. Patients were divided into non-EMD, extramedullary-bone-related (EM-B) and extramedullary-extraosseous (EM-E) groups. Clinical characteristics were compared using the chi-squared test or Fisher’s exact test. Survival curves were plotted using the Kaplan-Meier method, and a nomogram was constructed based on the Cox proportional hazards model.Results: Compared to patients without EMDs, patients with EM-E were younger (p = 0.028), and those with EM-B had less renal damage (p

Accurate bird species recognition is crucial for ecological conservation, wildlife monitoring, and biological research, yet it poses significant challenges due to the high variability within species and the subtle similarities between different species. This paper introduces an automatic bird species recognition method from images that leverages feature enhancement and contrast learning to address these challenges. Our method incorporates a multi-scale feature fusion module to comprehensively capture information from bird images across diverse scales and perspectives. Additionally, an attention feature enhancement module is integrated to address noise and occlusion within images, thus enhancing the model’s robustness. Furthermore, employing a siamese network architecture allows effective learning of common features within instances of the same class and distinctions between different bird species. Evaluated on the CUB200-2011 dataset, our proposed method achieves state-of-the-art performance, surpassing existing methods with an accuracy of 91.3% and F1 score of 90.6%. Moreover, our approach showcases a notable advantage in scenarios with limited training data. When utilizing only 5% of the training data, our model still achieves a recognition accuracy of 65.2%, which is significantly higher than existing methods under similar data constraints. Notably, our model exhibits faster execution times compared to existing methods, rendering it suitable for real-time applications.

Abstract Objectives During clinical practice, we have detected a few cases of neck abscesses in patients diagnosed with esophageal foreign body impaction (EFB) but without the primary inflammatory disease. However, we do not know if neck abscesses caused by an inflammatory source are more like to be associated with a more severe progression or poorer prognosis. In this study, we aimed to identify differences between these two groups of patients by comparing progression and prognosis. Materials and methods We retrospectively reviewed all patients who underwent neck abscess incisions between January 2011 and March 2022 and divided these patients into two groups: an EFB group and an inflammation group. Data were described by percentages, means, and standard deviations (SDs). Fisher's precision probability test was used to compare differences between the EFB and inflammation groups. Categorical variables were analyzed by Pearson's Chi-squared test. In addition, three factors including hospital days, intensive care unit (ICU) stay, and drainage-tube removal time were used for multivariate analysis to identify independent correlations separately. Results We enrolled a total of 33 patients with neck abscesses who received surgical incisions; the EFB group included 14 (42%) cases, while the inflammatory group included 19 (58%) cases. No significant differences were identified between the two groups in terms of surgery type (with or without mediastinotomy) and postoperative management (negative pressure drainage or postoperative irrigation). There were no significant differences between the two groups in terms of hospital stay, the timing of drainage-tube removal, the risk of ICU admission, and the probability of receiving intubation and tracheotomy. The incidence rate of esophageal perforation differed significantly between the two groups (p

Abstract Although tyrosine kinase inhibitors (TKIs) improve the prognosis of chronic myeloid leukemia (CML) patients, resistance to TKIs and residual leukemia stem cells (LSCs) inevitably become the bottleneck of cure. Therefore, we need to explore novel treatment strategies based on conventional treatment strategies. Our previous study found that CML cell senescence may be one of the main factors to achieve clinical cure of CML. Studies have shown that lipid metabolism plays a key role in cellular senescence. Here, we found that long-chain acyl-CoA synthetase 1 (ACSL1) was significantly up-regulated in senescent CML cells. Furthermore, we demonstrated that overexpression of ACSL1 induces senescence and inhibits cell growth in K562 cells by altering cell cycle progression, and enhances the proliferation-inhibiting effect of imatinib. Overexpression of ACSL1 enhances imatinib-induced tumorigenic decline in K562 cells in vivo. Knockdown of ACSL1 reverses imatinib-induced senescence in K562 cells. Mechanistically, overexpression of ACSL1 induced senescence in K562 cells via the SIRT1/p53/p21 axis. Collectively, our study showed that ACSL1 promotes imatinib-induced K562 cells senescence and tumor growth by regulating SIRT1/p53/p21 pathway. The ACSL1/SIRT1/p53 signal axis is a novel mechanism of cell senescence in CML and a new potential target for eradication of CML LSCs.

BackgroundThe management guidelines of radioactive Iodine (RAI) therapy for distinct types of differentiated thyroid carcinoma (DTC) were the same in clinical practice. However, in distinct types DTC, differences in RAI avidity and response existed and the effect of RAI therapy could not be equated.MethodsDTC patients’ data in SEER database were extracted to perform retrospective analysis. The differences between case group and control group were compared by chi-square tests. We used Kaplan-Meier statistics and Cox regression analyses to investigate cancer-specific survival (CSS). Propensity score–matched was performed to make 1:1 case-control matching.Results105195 patients who receiving total thyroidectomy were identified in SEER database. Compared to papillary thyroid carcinoma (PTC) (52.3%), follicular thyroid carcinoma (FTC) (63.8%) and oncocytic carcinoma of thyroid (OCA) (64.4%) had higher rates of RAI therapy. In the multivariable Cox regression model, RAI therapy was independent prognosis factor in PTC but not in OCA and FTC. In subgroup analysis, RAI therapy could improve prognosis in PTC when gross extrathyroidal extension or lymph node metastases or early survival when distant metastases (DM) were presented. However, OCA and FTC patients with DM rather than regional lesions only could benefit from RAI therapy. High-risk patients receiving RAI therapy showed a better prognosis in PTC but not in OCA and FTC.ConclusionRAI therapy was an effective treatment for DTC and should be considered individually in PTC, OCA and FTC patients. Our results provided further guideline for treatment selection in DTC.

Familial non-medullary thyroid carcinoma (FNMTC) accounts for 3% to 9% of all thyroid cancer cases, yet its genetic mechanisms remain unknown. Our study aimed to screen and identify novel susceptibility genes for FNMTC. Whole-exome sequencing (WES) was conducted on a confirmed FNMTC pedigree, comprising four affected individuals across two generations. Variants were filtered and analyzed using ExAC and 1000 Genomes Project, with candidate gene pathogenicity predicted using SIFT, PolyPhen, and MutationTaster. Validation was performed through Sanger sequencing in affected pedigree members and sporadic patients (TCGA database) as well as general population data (gnomAD database). Ultimately, we identified the mutant PPP4R3A (NC_000014.8:g.91942196C>T, or NM_001366432.2(NP_001353361.1):p.(Asp409Asn), based on GRCH37) as an FNMTC susceptibility gene. Subsequently, a series of functional experiments were conducted to investigate the impact of PPP4R3A and its Asp409Asn missense variant in thyroid cancer. Our findings demonstrated that wild-type PPP4R3A exerted tumor-suppressive effects via the Akt-mTOR-P70 S6K/4E-BP1 axis. However, overexpression of the PPP4R3A Asp409Asn mutant resulted in loss of tumor-suppressive function, ineffective inhibition of cell invasion, and even promotion of cell proliferation and migration by activating the Akt/mTOR signaling pathway. These results indicated that the missense variant PPP4R3A Asp409Asn is a candidate susceptibility gene for FNMTC, providing new insights into the diagnosis and intervention of FNMTC.

Abstract Background Based on CDC estimates in the United States, the prevalence of obesity was 42.4% in 2017–2018, and the annual cost of obesity was $147 billion in 2008. Yet studies estimate that only 20–40% of adults with obesity received counseling from their primary care providers. Recent studies using shared medical appointments (SMA), where patients are seen by a multidisciplinary team, have shown promising results in obesity management. We developed an insurance‐based weight loss program incorporating SMA, called the Program for Reducing Obesity (PRO), and report our findings here. Methods Enrollment began in January 2019 at the UCLA Health Thousand Oaks clinic. Patients age ≥18 years with BMI ≥30 kg/m2 were eligible by referral to PRO, a program consisting of individual visits and SMAs with an obesity medicine board certified endocrinologist and registered dietitian. Primary outcomes were change in weight after 3, 6, and 12 months. Secondary outcomes included proportion that achieved ≥5% weight loss, change in percent body fat, HbA1c, HDL, triglycerides, and blood pressure. Results 102 patients (mean age 59.7 years, 72% women, mean weight 103.6 kg, mean BMI 36.6 kg/m2) have been analyzed, with 91 patients completing at least 12 months of the program. Patients achieved significant weight loss: 3.0%, 5.0%, and 7.8% of their baseline weight after 3, 6, and 12 months respectively. 52% of patients lost ≥5% of their baseline weight after 12 months. Patients had significant reductions in body fat: 2.1%, 7.4%, and 6.7% of their baseline (all p ≤ 0.01) after 3, 6, and 12 months respectively. Improvements were also seen in HbA1c (p ≤ 0.01), triglycerides (p ≤ 0.04), and systolic blood pressure (p ≤ 0.07) after 12 months although not all results achieved statistical significance. Conclusion Our institutional review of PRO, an insurance‐based obesity program utilizing SMA, demonstrates a successful approach to promoting weight loss in a community‐based setting.

Background Bicuspid aortic valve (BAV) is a congenital cardiac deformity, increasing the risk of developing calcific aortic valve disease (CAVD). The disturbance of hemodynamics can induce valvular calcification, but the mechanism has not been fully identified. Methods We constructed a finite element model (FEM) of the aortic valve based on the computed tomography angiography (CTA) data from BAV patients and tricuspid aortic valve (TAV) individuals. We analyzed the hemodynamic properties based on our model and investigated the characteristics of mechanical stimuli on BAV. Further, we detected the expression of Notch, NICD and Runx2 in valve samples and identified the association between mechanical stress and the Notch1 signaling pathway. Results Finite element analysis showed that at diastole phase, the equivalent stress on the root of BAV was significantly higher than that on the TAV leaflet. Correspondingly, the expression of Notch1 and NICH decreased and the expression of Runx2 elevated significantly on large BAV leaflet belly, which is associated with equivalent stress on leaflet. Our findings indicated that the root of BAV suffered higher mechanical stress due to the abnormal hemodynamic environment, and the disturbance of the Notch1/NICD/Runx2 signaling pathway caused by mechanical stimuli contributed to valvular calcification.

Abstract Exosomes serve as a crucial mode of communication between tumor-associated macrophages (TAMs) and cancer cells. This study attempted to explore the function of M1-derived exosomes and clarify their specific mechanism in head and neck squamous cell carcinoma (HNSCC). Moreover, the functional roles of M1-derived exosomes and their key molecule long noncoding RNA (lncRNA) HOXA transcript at the distal tip (HOTTIP) in HNSCC were investigated by conducting a series of in vitro and in vivo experiments. The dual-luciferase test was utilized to clarify the binding capacities between HOTTIP/mRNA and miRNAs. Accordingly, HOTTIP was found to be upregulated in M1-derived exosomes. Meanwhile, the in vitro experiments indicated that M1 exosomes suppressed proliferation, migration and invasion but induced apoptosis of cancer cells. This function was noted to be enhanced by HOTTIP-overexpressed M1 exosomes but was weakened by HOTTIP-knockdown ones, indicating that HOTTIP serves as a key molecule in M1 exosomes. Therefore, the function of HOTTIP in cancer cells was explored, for which overexpression of HOTTIP was found to inhibit proliferation, migration and invasion but induced apoptosis of cancer cells in vitro. A mechanism study further showed that M1 exosomes and HOTTIP activated the TLR5/NF-κB signaling pathway by competitively sponging miR-19a-3p and miR-19b-3p. Furthermore, cancer cells expressing HOTTIP were noted to induce the polarization of both local M1 and M2 macrophages; however, M1 exosomes were observed to reprogram local TAMs into M1 macrophages. More importantly, both cancer cells expressing HOTTIP and M1 exosomes reeducated circulating monocytes to express the M1 phenotype. The corresponding data demonstrated that the M1 exosomal lncRNA HOTTIP suppresses HNSCC progression by upregulating the TLR5/NF-κB signaling pathway through competitively sponging miR-19a-3p and miR-19b-3p. In particular, M1 exosomes and HOTTIP induce the polarization of M1 in circulating monocytes, thus providing novel insight into HNSCC immunotherapy.

IntroductionCirculating plasma cells (CPC) have been reported to be one of the indicators of high-risk multiple myeloma (MM), yet the prognostic significance of CPC in Chinese population and the genetic mechanisms underlying CPC formation have not been fully elucidated.MethodsPatients with newly diagnosed MM were included in this study. We used multi-parameter flow cytometry (MFC) for CPC quantification and next-generation sequencing (NGS) technology for mutational landscape mapping to identify the correlation of CPC level with clinical characteristics and the mutations.ResultsA total of 301 patients were enrolled in this investigation. We demonstrated that CPC quantification could effectively mirror the tumor load, and CPC ≥ 0.105% at diagnosis or detectable CPC after therapy indicates poor treatment response and adverse outcome, and the introduction of CPC into the R-ISS enables a more accurate risk stratification. Interestingly, we noticed an elevated percentage of light-chain MM in patients with higher CPC. Mutational landscape revealed that patients harboring mutations in TP53, BRAF, DNMT3A, TENT5C, and IL-6/JAK/STAT3 pathway-related genes tended to have higher CPC levels. Gene enrichment analysis demonstrated that pathways involving chromosome regulation and adhesion may be potential mechanisms accounting for CPC formation.DiscussionAccordingly, quantification of CPC may provide a less-invasive and reliable approach for identifying high-risk MM in Chinese population.

The Bailong river basin is a densely distributed area of geological disasters such as debris flow. In August 2020, due to the stimulation of heavy rainfall, a large-scale group debris flow disaster occurred in Wudu section of Bailong river basin, causing serious losses. This paper takes the Wudu section (Lianghekou Township, Dangchang County to Jugan Town, Wudu District) of Longnan City in Gansu Province as the research area. Through field investigation, we selected the area of drainage basin, shape coefficient of basin, average slope, density of gully, reference value of material source (HI), lithology, distance between basin center and active fault, one hour maximum rainfall and vegetation coverage as debris flow hazard assessment factors. Taking single gully and small watershed units of debris flow as evaluation units, the regional debris flow hazard assessment is carried out by using ArcGIS software based on the theory of disaster entropy. The results show that most of the debris flows in the study area belong to medium and high hazard debris flow gullies. Some of the most heavily weighted disaster-causing factors like the weight of lithology, source reference value (HI), distance from fault, vegetation coverage and average slope are consistent with the actual investigation results. Moreover, the evaluation results of small watershed units are more consistent with the development of debris flow in the study area.

Abstract Background Solid transplant patients are susceptible to Pneumocystis jirovecii pneumonia (PJP). While the vast majority of PJP cases occur within the first 6 months after transplantation, very few PJP cases are seen beyond 1 year post-transplantation (late-onset PJP). PJP and coronavirus disease 2019 (COVID-19, caused by infection with SARS-CoV-2) share quite a few common clinical manifestations and imaging findings, making the diagnosis of PJP often underappreciated during the current COVID-19 pandemic. To date, only 1 case of kidney transplantation who developed COVID-19 and late-onset PJP has been reported, but this patient also suffered from many other infections and died from respiratory failure and multiple organ dysfunction syndrome. A successful treatment of kidney patients with COVID-19 and late-onset PJP has not been reported. Case presentation We present a case of a 55-year-old male kidney transplant patient with COVID-19 who also developed late-onset PJP. He received a combined treatment strategy, including specific anti-pneumocystis therapy, symptomatic supportive therapy, adjusted immunosuppressive therapy, and use of antiviral drugs/antibiotics, ending with a favorable outcome. Conclusions This case highlights the importance of prompt and differential diagnosis of PJP in kidney transplant patients with SARS-CoV-2 infection. Further studies are required to clarify if kidney transplant patients with COVID-19 could be prone to develop late-onset PJP and how these patients should be treated.

Introduction: ACT001 is widely used for the treatment of glioblastomas, breast cancers, and leukemic and the mechanism underlying the effect is anti-inflammatory. However, whether ACT001 has any effects on acute respiratory distress syndrome (ARDS) is not clear. Objectives: To investigate whether ACT001 helps to reduce mortality and pneumonedema after ARDS, and explore whether the mechanism is related to balance autophagy and inflammatory response. Methods: In this study, a rat model based on CLP was used to explore the potency of ACT001 in ARDS. The expression of the autophagy-related protein, lung injuries, cytokines, and inflammatory-related protein was assessed. Results: Compared with CLP group, ACT001 improved the survival rate, and lung wet-to-dry weight ratio. ACT001 activates autophagy, which is involved in the pathophysiologic process of sepsis, balancing the cytokine excessive release and lung injury in ARDS. Conclusion: ACT001 reduces mortality through improved autophagy and attenuates inflammation after ARDS.

Abstract Background Breast cancer (BC) is one of the most common cancers and the leading cause of death in women. Previous studies have demonstrated that FAM49B is implicated in several tumor progression, however, the role and mechanism of FAM49B in BC remain to be explored. Therefore, in this study, we aimed to systematically study the role of FAM49B in the proliferation, metastasis, apoptosis, and chemoresistance of BC, as well as the corresponding molecular mechanisms and downstream target. Methods The ONCOMINE databases and Kaplan–Meier plotter databases were analyzed to find FAM49B and its prognostic values in BC. FAM49B expression in BC and adjacent non-tumor tissues was detected by western blot and IHC. Kaplan–Meier analysis was used to identify the prognosis of BC patients. After FAM49B knockdown in MCF-7 and MDA-MB-231 cells, a combination of co-immunoprecipitation, MTT, migration, and apoptosis assays, nude mouse xenograft tumor model, in addition to microarray detection and data analysis was used for further mechanistic studies. Results In BC, the results showed that the expression level of FAM49B was significantly higher than that in normal breast tissue, and highly expression of FAM49B was significantly positively correlated with tumor volume, histological grade, lymph node metastasis rate, and poor prognosis. Knockdown of FAM49B inhibited the proliferation and migration of BC cells in vitro and in vivo. Microarray analysis revealed that the Toll-like receptor signaling pathway was inhibited upon FAM49B knockdown. In addition, the gene interaction network and downstream protein validation of FAM49B revealed that FAM49B positively regulates BC cell proliferation and migration by promoting the Rab10/TLR4 pathway. Furthermore, endogenous FAM49B interacted with ELAVL1 and positively regulated Rab10 and TLR4 expression by stabilizing ELAVL1. Moreover, mechanistic studies indicated that the lack of FAM49B expression in BC cells conferred more sensitivity to anthracycline and increased cell apoptosis by downregulating the ELAVL1/Rab10/TLR4/NF-κB signaling pathway. Conclusion These results demonstrate that FAM49B functions as an oncogene in BC progression, and may provide a promising target for clinical diagnosis and therapy of BC.

ObjectiveThe association between sleep duration and cognition are inconclusive. Our study aimed to comprehensively investigate the effects of sleep duration on the risk of cognitive impairment in the middle-aged and older Chinese population.MethodsWe used the longitudinal cohort data from waves 1–4 (2011–2018) of the China Health and Retirement Longitudinal Study (CHARLS). Self-reported exposures included total sleep duration, nocturnal sleep duration, post-lunch napping, and changes in sleep duration over time according to face-to-face interviews. Cognitive function was assessed by a Chinese version of the Modified Mini-Mental State Examination (MMSE).ResultsA total of 7,342 eligible participants were included. The mean age was 61.5 ± 6.5 years, and 48.9% (3,588/7,342) were male. We identified a U-shaped association of total sleep duration as well as nocturnal sleep duration with the risk of cognitive impairment. People with 7–8 h of total sleep duration and 6–7 h of nocturnal sleep had the lowest risk of cognitive impairment. Further results showed that post-lunch napping within 2 h was beneficial to cognition and 60 min was optimal. Moreover, analyses of changes in sleep duration further supported that sleeping less or more was harmful to cognition. Notably, those “excessive-change” sleepers (from ≤6 to ≥9 h, or from ≥9 to ≤6 h) had more risks.ConclusionsKeeping 7–8 h per day was related to the lowest risk of cognitive impairment in midlife and late life, and an optimal post-lunch napping was 60 min for these stable sleepers. Especially, excessive changes in sleep duration over time led to poorer cognition. Our work highlights the importance of optimal sleep habits to cognitive function. The self-reported sleep measures limited our findings, and further studies are needed for verification.

Abstract Background Most well‐differentiated thyroid carcinomas display good therapeutic outcomes, but there are still some patients who are not sensitive to the general treatments lose their treatment opportunities. Thus, it is important to understand the molecular mechanisms that cause thyroid carcinoma, so as to find effective diagnostic and therapeutic targets. Aim of the study To explore the role of homeobox transcript antisense RNA (HOTAIR) in thyroid carcinoma through protein phosphatase methylesterase 1 (PPME1) by sponging microRNA 761 (miR‐761). Methods The regulation network amongst HOTAIR, miR‐761 and PPME1 was predicted by online sources. RT‐PCR was conducted to evaluate the expression of HOTAIR and miR‐761 in tumor tissues. Clinical data was collected and analyzed by Chi‐square test. Cell apoptosis and proliferation was evaluated using three types of cancer cells (HTh‐7, CAL‐62, BCPAP) after treated with si‐HOTAIR and miR‐761inhibitor. The binding site among HOTAIR, miR‐761 and PPME1 was verified by dual luciferase reporter assay. PPME1 expression was measured after HOTAIR and miR‐761 were suppressed by western blot. Survival time was measured in nude mice using log‐rank test. Results HOTAIR was expressed to a significantly greater extent than miR‐761 in thyroid tumor tissues (P

Abstract Background Thalassemia is a group of inherited hemoglobic disorders resulting from defects in the synthesis of one or more of the hemoglobin chains, which is one of the most prevalent inherited disorders in southern China. Only few studies reported the molecular characterization of α- and β-Thalassemia in Hubei Province in the central of China. Methods A total of 4889 clinically suspected cases of thalassemia were analyzed by Gap-PCR, PCR-based reverse dot blot (RDB). Results 1706 (33.8%) subjects harbored thalassemia mutations, including 539 (11.0%) subjects with α-thalassemia, 1140 (23.3%) subjects with β-thalassemia mutations, and 25 (0.51%) subjects with both α- and β-thalassemia mutations. Seven genotypes of α-thalassemia mutations and 29 genotypes of β-thalassemia mutations were characterized. --SEA/αα (66.05%), −α3.7/αα (24.12%), and -α4.2/αα (3.71%) accounted for 93.88% of the α-thalassemia mutations. βIVS-II-654/βN, βCD41–42/βN, βCD17/βN, βCD27–28/βN, βCD71–72/βN, β − 28/βN, β − 29/βN, βCD43/βN, βE/βN, accounting for 96.40% of all β-thalassemia genotypes. Furthermore, mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) were sensitive markers for both β-thalassemia and α-thalassemia with --SEA/αα, but not -α3.7/αα and -α4.2/αα. Conclusions: Our data indicated great heterogeneity and extensive spectrum of thalassemias in Hubei province of China.

Background. To explore clinical features and prognostic value of vascular endothelial growth factor (VEGF), interleukin (IL) 8, IL-10, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and receptor-interacting protein-2 (RIP2) in diffuse large B-cell lymphoma (DLBCL). Methods. A total of 68 DLBCL patients admitted to the Affiliated Hospital of Hebei Engineering University from January 2017 to June 2021 were included in this retrospective analysis. Serum VEGF was detected by enzyme-linked immunosorbent assay, serum IL-8 and IL-10 were detected by chemiluminescent enzyme immunoassay, and expression of PIK3CA and RIP2 in tumors was detected by immunohistochemistry. The correlation between clinical features of DLBCL and tumor-related index were analyzed. Cox regression was conducted to explore risk factors and hazard ratio. Results. The serum level or expressions of VEGF, IL-8, IL-10, and RIP2 were significantly elevated with the increase of Ann Arbor Stage, International Prognostic Index (IPI) scores, Eastern Cooperative Oncology Group (ECOG) scores, serum lactate dehydrogenase (LDH) level, and the number of extranodal sites (all P1), serum LDH level (≥245 U/L), IPI scores (3–5), ECOG scores (≥2), and bone marrow involvement were independent risk factors for the prognosis of DLBCL patients (all P

With the acquisition of sustainable development, pursuing the coordinated development of social economy and ecological environment has been a critical approach of Northeastern China. Since the reform and opening-up, marketization has profoundly affected the regional social economy. However, what role will marketization play in regional sustainable development? Can marketization improve sustainable development measured by the coupling coordination degree? This paper adopts the coupling coordination degree model (CCDM) to estimate the coupling coordination degree and further explore the impact of marketization on the coupling coordination degree in Northeastern China from 1994 to 2019. The results show that the average values of the static coupling degree (SCD), dynamic coupling degree (DCD), and coupling coordination degree (CCD) remained in a tiny coordinated state, which indicated that the level of sustainable development in Northeastern China is presented still primary from 1990 to 2019. Marketization has a significant negative impact on the coupling coordination degree, which indicates that marketization should be considered in the process of sustainable development in Northeastern China.

Background: Low vitamin D (VitD) status is becoming a global health issue. Previous heterogenous results are urging a meta-analysis to delineate a panorama of VitD conditions in the general population in Mainland of China. Methods: We performed a systematic review and meta-analysis by searching PubMed, Web of Science, EMBASE, China National Knowledge Infrastructure, WanFang, and VIP databases up to June 4, 2021. The inclusion criteria were as follows: (1) original articles or dissertations focused on VitD status of people in Mainland of China; and (2) studies were population-based, cross-sectional, or longitudinal cohort with baseline data. The outcomes were serum 25(OH)D concentration and the prevalence of low VitD status. Low VitD status included VitD deficiency (

The oncogenic fusion protein AML1-ETO has the ability of AML1 to interact with DNA but blocks AML1-dependent transcription. Here the authors report that histone lysine methyltransferase EZH1 interacts with AML1-ETO and methylates AML1-ETO at lysine 43, promoting AML1-ETO transcriptional repression in leukemia.

Abstract Background Deafness, autosomal recessive 77 (DFNB77) is a rare non-syndromic hearing loss (NSHL) worldwide, which is caused by deleterious variants within lipoxygenase homology domains 1 (LOXHD1). Here we identified that a novel missense variant of LOXHD1 was associated with NSHL in a Chinese family under consanguineous marriage. Case presentation A 28-year-old woman suffered a bilateral profound NSHL. Impedance audiometry, temporal bone computerized tomography (TBCT) scans and magnetic resonance imaging-inner ear hydrography (MRI-IEH) did not find any obvious abnormality of middle or inner ear. Routine genetic detection did not find pathogenic variants in common HL-associated genes. Therefore, we performed a whole-exome sequencing (WES) in this family. By trio-WES, co-segregation validation and bioinformatics analysis, we revealed that a novel homozygous variant in this patient, LOXHD1: c.5948C > T (p.S1983F), might be the pathogenic factor. Her parents (heterozygotes) and brother (wild-type) were asymptomatic. Conclusions We successfully identified a novel variant of LOXHD1 associated with a rare NSHL from a Chinese family. Our finds highlight the effectiveness of trio-WES for molecular diagnosis of rare NHSL, and expand the genotypic spectrum of DFNB77.

Snow is involved in and influences water–energy processes at multiple scales. Studies on land surface snow phenology are an important part of cryosphere science and are a hot spot in the hydrological community. In this study, we improved a statistical downscaling method by introducing a spatial probability distribution function to obtain regional snow depth data with higher spatial resolution. Based on this, the southern Gansu Plateau (SGP), an important water source region in the upper reaches of the Yellow River, was taken as a study area to quantify regional land surface snow phenology variation, together with a discussion of their responses to land surface terrain and local climate, during the period from 2003 to 2018. The results revealed that the improved downscaling method was satisfactory for snow depth data reprocessing according to comparisons with gauge-based data. The downscaled snow depth data were used to conduct spatial analysis and it was found that snow depth was on average larger and maintained longer in areas with higher altitudes, varying and decreasing with a shortened persistence time. Snow was also found more on steeper terrain, although it was indistinguishable among various aspects. The former is mostly located at high altitudes in the SGP, where lower temperatures and higher precipitation provide favorable conditions for snow accumulation. Climatically, factors such as precipitation, solar radiation, and air temperature had significantly singular effectiveness on land surface snow phenology. Precipitation was positively correlated with snow accumulation and maintenance, while solar radiation and air temperature functioned negatively. Comparatively, the quantity of snow was more sensitive to solar radiation, while its persistence was more sensitive to air temperature, especially extremely low temperatures. This study presents an example of data and methods to analyze regional land surface snow phenology dynamics, and the results may provide references for better understanding water formation, distribution, and evolution in alpine water source areas.

ObjectiveA hot genetic variant, rs641738 within the membrane-bound O-acyltransferase domain containing 7(MBOAT7) and transmembrane channel-like 4 (TMC4), was recently reported to be associated with several liver diseases. However, the results remain controversial. Therefore, this study aimed to explore the role of MBOAT7-TMC4 rs641738 in the risk of hepatocellular carcinoma (HCC) and persistent hepatitis B virus (HBV) infection.MethodsWe first conducted a case-control study that included 779 HCC cases and 1412 cancer-free controls. Controls consisted of 678 persistent HBV carriers and 734 spontaneously recovered subjects. The gene variant rs641738 was genotyped using the MassARRAY platform. The results were analyzed in five genetic models using multivariate logistic regression analyses. Next, we performed a systematic review and meta-analysis to further explore the role of this variant in HCC risk.ResultsThe results suggested no association between MBOAT7-TMC4 rs641738 and HCC risk in most genetic models (all P > 0.05). Although a marginally significant association was observed in TT vs. CC (P = 0.037) and the recessive models (P = 0.044). The meta-analysis of 2135 HCC cases and 4388 controls supported that this variant was not related to HCC risk, even in the TT vs. CC and recessive models. We also determined that this variant did not influence persistent HBV infection.ConclusionOur work highlights that MBOAT7-TMC4 rs641738 is not associated with the risk of HCC or persistent HBV infection. This study provides some clues to identify the “truth” of potential disease-related genetic factors in the post-genome era.

Berberine (BBR) has a neuroprotective effect against ischemic stroke, but its specific protective mechanism has not been clearly elaborated. This study explored the effect of BBR on the canopy FGF signaling regulator 2 (CNPY2) signaling pathway in the ischemic penumbra of rats. The model of cerebral ischemia-reperfusion injury (CIRI) was established by the thread embolization method, and BBR was gastrically perfused for 48 h or 24 h before operation and 6 h after operation. The rats were randomly divided into four groups: the Sham group, BBR group, CIRI group, and CIRI + BBR group. After 2 h of ischemia, followed by 24 h of reperfusion, we confirmed the neurologic dysfunction and apoptosis induced by CIRI in rats (p < 0.05). In the ischemic penumbra, the expression levels of CNPY2-regulated endoplasmic reticulum stress-induced apoptosis proteins (CNPY2, glucose-regulated protein 78 (GRP78), double-stranded RNA-activated protein kinase-like ER kinase (PERK), C/EBP homologous protein (CHOP), and Caspase-3) were significantly increased, but these levels were decreased after BBR treatment (p < 0.05). To further verify the inhibitory effect of BBR on CIRI-induced neuronal apoptosis, we added an endoplasmic reticulum-specific agonist and a PERK inhibitor to the treatment. BBR was shown to significantly inhibit the expression of apoptotic proteins induced by endoplasmic reticulum stress agonist, while the PERK inhibitor partially reversed the ability of BBR to inhibit apoptotic protein (p < 0.05). These results confirm that berberine may inhibit CIRI-induced neuronal apoptosis by downregulating the CNPY2 signaling pathway, thereby exerting a neuroprotective effect.

BackgroundThe prompt diagnosis of pulmonary tuberculosis (PTB) remains a challenge in clinical practice. The present study aimed to optimize an algorithm for rapid diagnosis of PTB in a real-world setting.Methods28,171 adult inpatients suspected of having PTB in China were retrospectively analyzed. Bronchoalveolar lavage fluid (BALF) and/or sputum were used for acid-fast bacilli (AFB) smear, Xpert MTB/RIF (Xpert), and culture. A positive mycobacterial culture was used as the reference standard. Peripheral blood mononuclear cells (PBMC) were used for T-SPOT.TB. We analyzed specimen types’ effect on these assays’ performance, determined the number of smears for diagnosing PTB, and evaluated the ability of these assays performed alone, or in combination, to diagnose PTB and nontuberculous mycobacteria (NTM) infections.ResultsSputum and BALF showed moderate to substantial consistency when they were used for AFB smear or Xpert, with a higher positive detection rate by BALF. 3-4 smears had a higher sensitivity than 1-2 smears. Moreover, simultaneous combination of AFB and Xpert correctly identified 44/51 of AFB+/Xpert+ and 6/7 of AFB+/Xpert- cases as PTB and NTM, respectively. Lastly, when combined with AFB/Xpert sequentially, T-SPOT showed limited roles in patients that were either AFB+ or Xpert+. However, T-SPOTMDC (manufacturer-defined cut-off) showed a high negative predicative value (99.1%) and suboptimal sensitivity (74.4%), and TBAg/PHA (ratio of Mycobacterium tuberculosis-specific antigens to phytohaemagglutinin spot-forming cells, which is a modified method calculating T-SPOT.TB assay results) ≥0.3 demonstrated a high specificity (95.7%) and a relatively low sensitivity (16.3%) in AFB-/Xpert- patients.ConclusionsConcurrently performing AFB smear (at least 3 smears) and Xpert on sputum and/or BALF could aid in rapid diagnosis of PTB and NTM infections in a real-world high-burden setting. If available, BALF is preferred for both AFB smear and Xpert. Expanding this algorithm, PBMC T-SPOTMDC and TBAg/PHA ratios have a supplementary role for PTB diagnosis in AFB-/Xpert- patients (moderately ruling out PTB and ruling in PTB, respectively). Our findings may also inform policy makers’ decisions regarding prevention and control of TB in a high burden setting.

Abstract Background It has been indicated that abnormal glucose metabolism mediated by hypoxia‐inducible factor 1α (HIF‐1α) played an essential role in the development of solid tumor. However, there were rare studies about the role of them in primary central nervous system lymphoma (PCNSL). Objective To investigate the protein levels of HIF‐1α, glucose transporter 1 (GLUT1), and hexokinase 2 (HK2) in PCNSL and whether their levels are associated with prognostic factors. Methods Expression of HIF‐1α, GLUT1, and HK2 in 39 tumor tissues was evaluated by immunohistochemical stainning. The correlation of the expression of HIF‐1α with the protein level of GLUT1 and HK2 was investigated. In addition, the association between these protein expression levels and clinical parameters and prognosis was analyzed. Results In the tumor specimens of PCNSL, positive stainings of HIF‐1α, GLUT1, and HK2 were in 23 patients (58.97%), 25 patients (64.1%), and 26 patients (66.67%), respectively, which were associated with the expression level of lactic dehydrogenase (LDH), but not with age, gender, number of lesion, ECOG score, or deep structure. The expression of HIF‐1α was positively correlated with the expression of GLUT1 (p

Background. Cochlear implant-based electrical stimulation may be an important reason to induce the residual hearing loss after cochlear implantation. In our previous study, we found that charge-balanced biphasic electrical stimulation inhibited the neurite growth of spiral ganglion neurons (SGNs) and decreased Schwann cell density in vitro. In this study, we want to know whether cochlear implant-based electrical stimulation can induce the change of electrical activity in cultured SGNs. Methods. Spiral ganglion neuron electrical stimulation in vitro model is established using the devices delivering cochlear implant-based electrical stimulation. After 48 h treatment by 50 μA or 100 μA electrical stimulation, the action potential (AP) and voltage depended calcium current (ICa) of SGNs are recorded using whole-cell electrophysiological method. Results. The results show that the ICa of SGNs is decreased significantly in 50 μA and 100 μA electrical stimulation groups. The reversal potential of ICa is nearly +80 mV in control SGN, but the reversal potential decreases to +50 mV in 50 μA and 100 μA electrical stimulation groups. Interestingly, the AP amplitude, the AP latency, and the AP duration of SGNs have no statistically significant differences in all three groups. Conclusion. Our study suggests cochlear implant-based electrical stimulation only significantly inhibit the ICa of cultured SGNs but has no effect on the firing of AP, and the relation of ICa inhibition and SGN damage induced by electrical stimulation and its mechanism needs to be further studied.

Pancreatic ductal adenocarcinoma is a lethal human cancer with a poor 5-year overall survival rate. Here the authors perform an exome-wide analysis in a cohort of PDAC patients to identify three novel missense variants in PKN1, DOK2, and APOB genes, that are associated with PDAC risk.

Abstract Background X-linked ichthyosis (XLI) is a recessive keratinization condition caused by deficient activity of steroid-sulfatase due to mutations in steroid sulfatase (STS) gene located on the X chromosome. In contrast, ichthyosis vulgaris (IV) is caused by filaggrin deficiency due to semi-dominant loss-of-function mutations of filaggrin (FLG) gene. Filaggrin defects could synergize with XLI to exacerbate its phenotype. Case presentation We report a Chinese family with patients presenting diverse phenotype of Keratosis pilaris. A next-generation sequencing panel interrogating 25 ichthyosis related genes with sequencing coverage of the coding regions and splice site junctions, was applied to screen genetic mutations. A gross deletion encompassing the STS gene ranging from exon 1–10 and the FLG c.3321delA mutation were identified in a 31-year old male proband, one of his sister, and his mother, and all the three patients showed obvious symptom. The deletion of STS gene was confirmed by real-time quantitative PCR. The proband’s another sister and his two nephews carried only FLG c.3321delA mutation. Patients carried both mutations presented more severe symptom, while those only carried FLG c.3321delA mutation showed slight or normal phenotype. Conclusions In conclusion, we found that the IV phenotype was exacerbated by co-inheritance of STS and FLG mutations in a Chinese family with ichthyosis. Other genomic regions no included in the study might be also involved in phenotypic modifications.