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Understanding the differences in ubiquitination-modified proteins between Duroc pigs and Tibetan fragrant pigs is crucial for comprehending the growth and development of their skeletal muscles. In this study, skeletal muscle samples from 30-day-old Duroc pigs and Tibetan fragrant pigs were collected. Using ubiquitination 4D-Label free quantitative proteomics, we analyzed and identified ubiquitination-modified peptides, screening out 109 differentially expressed ubiquitination-modified peptides. Further enrichment analysis was conducted on the proteins associated with these differential peptides. GO analysis results indicated that the differential genes were primarily enriched in processes such as regulation of protein transport, motor activity, myosin complex, and actin cytoskeleton. KEGG pathway analysis revealed significant enrichment in pathways such as Glycolysis/Gluconeogenesis and Hippo signaling pathway. The differentially expressed key ubiquitinated proteins, including MYL1, MYH3, TNNC2, TNNI1, MYLPF, MYH1, MYH7, TNNT2, TTN, and TNNC1, were further identified. Our analysis demonstrates that these genes play significant roles in skeletal muscle protein synthesis and degradation, providing new insights into the molecular mechanisms of muscle development in Duroc pigs and Tibetan fragrant pigs, and offering theoretical support for breeding improvements in the swine industry.

Background: Poly (ADP-ribose) polymerase (PARP) inhibitor and antiangiogenic agent monotherapy have shown to be effective as maintenance treatment in patients with ovarian cancer (OC). However, there is currently a lack of evidence-based study to directly compare the effects of combination therapy with these two drugs. Therefore, this study aimed to compare the efficacy and safety of combination therapy with PARP inhibitors and antiangiogenic agents in women with OC using a meta-analysis.Methods: An exhaustive search of literature was undertaken using multiple databases, including PubMed, Web of Science, Embase, and the Cochrane Library to identify pertinent randomized controlled trials (RCTs) published up until 17 December 2023. The data on progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were pooled. We computed the pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) for PFS and OS, along with the relative risks (RRs) and 95% CIs for AEs. Trial sequential analysis, heterogeneity test, sensitivity analysis, and publication bias assessment were performed. Stata 12.0 and Software R 4.3.1 were utilized for all analyses.Results: This meta-analysis included 7 RCTs with a total of 3,388 participants. The overall analysis revealed that combination therapy of PARP inhibitors and antiangiogenic agents significantly improved PFS (HR = 0.615, 95% CI = 0.517–0.731; 95% PI = 0.379–0.999), but also increased the risk of AEs, including urinary tract infection (RR = 1.500, 95% CI = 1.114–2.021; 95% PI = 0.218–10.346), fatigue (RR = 1.264, 95% CI = 1.141–1.400; 95% PI = 1.012–1.552), headache (RR = 1.868, 95% CI = 1.036–3.369; 95% PI = 0.154–22.642), anorexia (RR = 1.718, 95% CI = 1.320–2.235; 95% PI = 0.050–65.480), and hypertension (RR = 5.009, 95% CI = 1.103–22.744; 95% PI = 0.016–1580.021) compared with PARP inhibitor or antiangiogenic agent monotherapy. Our study has not yet confirmed the benefit of combination therapy on OS in OC patients (HR = 0.885, 95% CI = 0.737–1.063). Additionally, subgroup analyses further showed that combination therapy resulted in an increased risk of AEs, encompassing thrombocytopenia, vomiting, abdominal pain, proteinuria, fatigue, headache, anorexia, and hypertension (all p < 0.05).Conclusion: Our study demonstrated the PFS benefit of combination therapy with PARP inhibitors and antiangiogenic agents in patients with OC. The OS result need to be updated after the original trial data is mature. Clinicians should be vigilant of AEs when administering the combination therapy in clinical practice.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023494482.

Diseases pose a significant threat to the citrus industry, and the accurate detection of these diseases represent key factors for their early diagnosis and precise control. Existing diagnostic methods primarily rely on image models trained on vast datasets and limited their applicability due to singular backgrounds. To devise a more accurate, robust, and versatile model for citrus disease classification, this study focused on data diversity, knowledge assistance, and modal fusion. Leaves from healthy plants and plants infected with 10 prevalent diseases (citrus greening, citrus canker, anthracnose, scab, greasy spot, melanose, sooty mold, nitrogen deficiency, magnesium deficiency, and iron deficiency) were used as materials. Initially, three datasets with white, natural, and mixed backgrounds were constructed to analyze their effects on the training accuracy, test generalization ability, and classification balance. This diversification of data significantly improved the model’s adaptability to natural settings. Subsequently, by leveraging agricultural domain knowledge, a structured citrus disease features glossary was developed to enhance the efficiency of data preparation and the credibility of identification results. To address the underutilization of multimodal data in existing models, this study explored semantic embedding methods for disease images and structured descriptive texts. Convolutional networks with different depths (VGG16, ResNet50, MobileNetV2, and ShuffleNetV2) were used to extract the visual features of leaves. Concurrently, TextCNN and fastText were used to extract textual features and semantic relationships. By integrating the complementary nature of the image and text information, a joint learning model for citrus disease features was achieved. ShuffleNetV2 + TextCNN, the optimal multimodal model, achieved a classification accuracy of 98.33% on the mixed dataset, which represented improvements of 9.78% and 21.11% over the single-image and single-text models, respectively. This model also exhibited faster convergence, superior classification balance, and enhanced generalization capability, compared with the other methods. The image-text multimodal feature fusion network proposed in this study, which integrates text and image features with domain knowledge, can identify and classify citrus diseases in scenarios with limited samples and multiple background noise. The proposed model provides a more reliable decision-making basis for the precise application of biological and chemical control strategies for citrus production.

Introduction: Congenital heart disease (CHD) is a cardiovascular disorder caused by structural defects in the heart. Early screening holds significant importance for the effective treatment of this condition. Heart sound analysis is commonly employed to assist in the diagnosis of CHD. However, there is currently a lack of an efficient automated model for heart sound classification, which could potentially replace the manual process of auscultation.Methods: This study introduces an innovative and efficient screening and classification model, combining a locally concatenated fusion approach with a convolutional neural network based on coordinate attention (LCACNN). In this model, Mel-frequency spectral coefficients (MFSC) and envelope features are locally fused and employed as input to the LCACNN network. This model automatically analyzes feature map energy information, eliminating the need for denoising processes.Discussion: The proposed classification model in this study demonstrates a robust capability for identifying congenital heart disease, potentially substituting manual auscultation to facilitate the detection of patients in remote areas.Results: This study introduces an innovative and efficient screening and classification model, combining a locally concatenated fusion approach with a convolutional neural network based on coordinate attention (LCACNN). In this model, Mel-frequency spectral coefficients (MFSC) and envelope features are locally fused and employed as input to the LCACNN network. This model automatically analyzes feature map energy information, eliminating the need for denoising processes. To assess the performance of the classification model, comparative ablation experiments were conducted, achieving classification accuracies of 91.78% and 94.79% on the PhysioNet and HS databases, respectively. These results significantly outperformed alternative classification models.

BackgroundSpontaneous intracerebral hemorrhage (SICH) is associated with high mortality and disability. Accurately predicting adverse prognostic risks of SICH is helpful in developing risk stratification and precision medicine strategies for this phenomenon.MethodsWe analyzed 413 patients with SICH admitted to Hefei Second People's Hospital as a training cohort, considering 74 patients from the First Affiliated Hospital of Anhui Medical University for external validation. Univariate and multivariate logistic regression analyses were used to select risk factors for 90-day functional outcomes, and a nomogram was developed to predict their incidence in patients. Discrimination, fitting performance, and clinical utility of the resulting nomogram were evaluated through receiver operating characteristic (ROC) curves, accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), calibration plots, and decision curves analysis (DCA), respectively.ResultsOf the 413 patients, 180 had a poor prognosis. Univariate analysis showed significant variance of age, systolic pressure, intraventricular hemorrhage (IVH), Glasgow Coma Scale (GCS) scores, National Institute of Health Stroke Scale (NIHSS) scores, and hematoma volume between the groups (p < 0.05). Logistic multivariate regression analysis showed that age, IVH, NIHSS, and hematoma volume were associated with unfavorable outcomes. Based on the results, a nomogram model was developed with an area under the ROC curve of 0.91 (95% CI; 0.88–0.94) and 0.89 (95% CI; 0.80–0.95) in the training and validation sets, respectively. In the validation set, the accuracy, sensitivity, specificity, PPV, and NPV of the model were 0.851, 0.923, 0.812, 0.727, and 0.951, respectively. The calibration plot demonstrates the goodness of fit between the nomogram predictions and actual observations. Finally, DCA indicated significant clinical adaptability.ConclusionWe developed and validated a short-term prognostic nomogram model for patients with SICH including NIHSS scores, age, hematoma volume, and IVH. This model has valuable potential in predicting the prognosis of patients with SICH.

Heavy ion beam (HIB) is an effective physical mutagen that has been widely used in plant mutational breeding. Systemic knowledge of the effects caused by different HIB doses at developmental and genomic levels will facilitate efficient breeding for crops. Here we examined the effects of HIB systematically. Kitaake rice seeds were irradiated by ten doses of carbon ion beams (CIB, 25 – 300 Gy), which is the most widely used HIB. We initially examined the growth, development and photosynthetic parameters of the M1 population and found that doses exceeding 125 Gy caused significant physiological damages to rice. Subsequently, we analyzed the genomic variations in 179 M2 individuals from six treatments (25 – 150 Gy) via whole-genome sequencing (WGS). The mutation rate peaks at 100 Gy (2.66×10-7/bp). Importantly, we found that mutations shared among different panicles of the same M1 individual are at low ratios, validating the hypothesis that different panicles may be derived from different progenitor cells. Furthermore, we isolated 129 mutants with distinct phenotypic variations, including changes in agronomic traits, from 11,720 M2 plants, accounting for a 1.1% mutation rate. Among them, about 50% possess stable inheritance in M3. WGS data of 11 stable M4 mutants, including three lines with higher yields, reveal their genomic mutational profiles and candidate genes. Our results demonstrate that HIB is an effective tool that facilitates breeding, that the optimal dose range for rice is 67 – 90% median lethal dose (LD50), and that the mutants isolated here can be further used for functional genomic research, genetic analysis, and breeding.

The shikimate pathway is a general route for the biosynthesis of aromatic amino acids (AAAs) in many microorganisms. A 3-dehydroquinase, AroQ, controls the third step of the shikimate pathway that catalyzes the formation of 3-dehydroquinate from 3-dehydroshikimate via a trans-dehydration reaction. Ralstonia solanacearum harbors two 3-dehydroquinases, AroQ1 and AroQ2, sharing 52% similarity in amino acids. Here, we demonstrated that two 3-dehydroquinases, AroQ1 and AroQ2, are essential for the shikimate pathway in R. solanacearum. The growth of R. solanacearum was completely diminished in a nutriment-limited medium with the deletion of both aroQ1 and aroQ2, while substantially impaired in planta. The aroQ1/2 double mutant was able to replicate in planta but grew slowly, which was ~4 orders of magnitude less than the parent strain to proliferate to the maximum cell densities in tomato xylem vessels. Moreover, the aroQ1/2 double mutant failed to cause disease in tomato and tobacco plants, whereas the deletion of either aroQ1 or aroQ2 did not alter the growth of R. solanacearum or pathogenicity on host plants. Supplementary shikimic acid (SA), an important intermediate of the shikimate pathway, substantially restored the diminished or impaired growth of aroQ1/2 double mutant in a limited medium or inside host plants. The necessity of AroQ1 and AroQ2 on the pathogenicity of solanacearum toward host plants was partially due to insufficient SA inside host plants. Moreover, the deletion of both aroQ1 and aroQ2 significantly impaired the expression of genes for the type III secretion system (T3SS) both in vitro and in planta. Its involvement in the T3SS was mediated through the well-characterized PrhA signaling cascade and was independent of growth deficiency under nutrient-limited conditions. Taken together, R. solanacearum 3-dehydroquinases play important roles in bacterial growth, the expression of the T3SS, and pathogenicity in host plants. These results could extend our insights into the understanding of the biological function of AroQ and the sophisticated regulation of the T3SS in R. solanacearum.

White spot lesions (WSLs) have long been a noteworthy complication during orthodontic treatment. Recently, an increasing number of orthodontists have found that adolescents undergoing orthodontic treatment with clear aligners are at a higher risk of developing WSLs. The oral microbiota and metabolites are considered the etiologic and regulatory factors of WSLs, but the specific impact of clear aligners on the oral microbiota and metabolites is unknown. This study investigated the differences in the salivary microbiome and metabolome between adolescents with and without WSLs treated with clear aligners. Fifty-five adolescents (aged 11-18) with Invisalign appliances, 27 with and 28 without WSLs, were included. Saliva samples were analyzed using 16S rRNA gene sequencing and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS); the data were further integrated for Spearman correlation analysis. The relative abundances of 14 taxa, including Actinobacteria, Actinomycetales, Rothia, Micrococcaceae, Subdoligranulum, Capnocytophaga, Azospira, Olsenella, Lachnoanaerobaculum, and Abiotrophia, were significantly higher in the WSL group than in the control group. Metabolomic analysis identified 27 potential biomarkers, and most were amino acids, including proline and glycine. The metabolites were implicated in 6 metabolic pathways, including alanine, aspartate and glutamate metabolism; glycine, serine and threonine metabolism; and aminoacyl-tRNA biosynthesis. There was a correlation between the salivary microbial and metabolomic datasets, reflecting the impact of clear aligners on the metabolic activity of the oral flora. A concordant increase in the levels of Lachnoanaerobaculum, Rothia, Subdoligranulum and some amino acids had predictive value for WSL development. In summary, when adolescents undergo long-term clear aligner therapy with poor oral hygiene habits, clear aligners can disrupt the balance of the oral microecosystem and lead to oral microbiota dysbiosis, thereby increasing the risk of developing WSLs. Our findings might contribute to the understanding of the pathogenesis of WSLs and provide candidate biomarkers for the diagnosis and treatment of WSLs associated with clear aligners.

BackgroundThis study aimed to develop an autoimmune thyroid disease (AITD) risk prediction model for patients with vitiligo based on readily available characteristics.MethodsA retrospective analysis was conducted on the clinical characteristics, demographics, skin lesions, and laboratory test results of patients with vitiligo. To develop a model to predict the risk of AITD, the Least Absolute Shrinkage and Selection Operator (LASSO) method was used to optimize feature selection, and logistic regression analysis was used to select further features. The C-index, Hosmer–Lemeshow test, and decision curve analysis were used to evaluate the calibration, discrimination ability and clinical utility of the model. Internally, the model was verified using bootstrapping; externally, two independent cohorts were used to confirm model accuracy.ResultsSex, vitiligo type, family history of AITD, family history of other autoimmune disease, thyroid nodules or tumors, negative emotions, skin involvement exceeding 5% of body surface area, and positive immune serology (IgA, IgG, IgM, C3, and C4) were predictors of AITD in the prediction nomogram. The model showed good calibration and discrimination (C-index: 0.746; 95% confidence interval: 0.701–0.792). The accuracy of this predictive model was 74.6%.In both internal validation (a C-index of 1000 times) and external validation, the C-index outperformed (0.732, 0.869, and 0.777). The decision curve showed that the AITD nomogram had a good guiding role in clinical practice.ConclusionThe novel AITD nomogram effectively evaluated the risk of AITD in patients with vitiligo.

Neurogenic pain rises because of nervous system damage or dysfunction and is the most difficult to treat among other pathological pains. Acupuncture has been reported as a great treatment option for neurogenic pain owing to its unlimited advantages. However, previous studies on the analgesic effects of acupuncture for NP were scattered and did not form a whole. In this study, we first comprehensively review the relevant basic articles on acupuncture for NP published in the last 5 years and summarize the analgesic mechanisms of acupuncture in terms of nerve signaling, neuro-immune crosstalk, and metabolic and oxidative stress regulation. Acupuncture inhibits the upstream excitatory system and suppresses neuronal transmission efficiency by downregulating glutamate, NMDA receptors, P2XR, SP, CGRP, and other neurotransmitters and receptors in the spinal cord, as well as plasma channels such as TRPV1, HCN. It can also activate the downstream pain inhibitory pathway by upregulating opioid peptide (β-endorphin), MOR receptors, GABA and GABA receptors, bi-directional regulating 5-hydroxytryptamine (5-HT) and its receptors (upregulate 5-HT 1A and downregulate 5-HT7R) and stimulating hypothalamic appetite-modifying neurons. Moreover, neuroinflammation in pain can be inhibited by acupuncture through inhibiting JAK2/STAT3, PI3K/mTOR pathways, down regulating chemokine receptor CX3CR1 on microglia and up regulating adenosine receptor A1Rs on astrocytes, inhibiting the activation of glia and reducing TNF-α and other inflammatory substances. Acupuncture also inhibits neuronal glucose metabolism by downregulating mPFC's GLUT-3 and promotes metabolic alterations of the brain, thus exerting an analgesic effect. In conclusion, the regulation of nerve signal transduction and neuroimmune crosstalk at the peripheral and central levels mediates the analgesic effects of acupuncture for neuropathic pain in an integrated manner. These findings provide a reliable basis for better clinical application of acupuncture in the management of neuropathic pain.

ObjectiveStudies have shown that carbon dioxide (CO2) insufflation during endoscopic thyroidectomy is associated with many risks. Recently, we have designed a simple lifting tool using Kirschner wire. We aimed to use this tool for flap-lifting in modified areola approach endoscopic thyroidectomy and compare it with conventional CO2 insufflation.MethodsIn a prospective study, patients who underwent endoscopic thyroidectomy via modified areola approach were randomly assigned into gasless (n = 20) or CO2 groups (n = 22). Pre-operative variables included age, gender, tumor diameter, and clinical diagnosis. Intra-operative hemodynamic monitoring included mean arterial pressure, heart rate, pulse oximetry, end-tidal carbon dioxide (ET-CO2) and arterial pH. Other intra-operative details included total operative time, operative blood loss, conversion from endoscopic surgery to open surgery, intra-operative events, and endoscope video score. Postoperatively, the hospital stay, drainage volume, and complications were recoded.ResultsPatient characteristics were not different between the two groups. During the operation, ET-CO2 levels were significantly higher in the CO2 group (P < 0.05), whereas arterial pH levels were significantly lower (P < 0.05). The CO2 group had longer operation time and higher endoscope clarity VAS score than gasless group. Hospital stay, drainage volume, and postoperative complications did not differ significantly between the two groups (P > 0.05).ConclusionsThe gasless endoscopic thyroidectomy we performed via our Kirschner wire hook was safe, feasible, and yielded good results.

Breast cancer stem cells are responsible for cancer initiation, progression, and drug resistance. However, effective targeting strategies against the cell subpopulation are still limited. Here, we unveil two splice variants of very-low-density lipoprotein receptor, VLDLR-I and -II, which are highly expressed in breast cancer stem cells. In breast cancer cells, VLDLR silencing suppresses sphere formation abilities in vitro and tumor growth in vivo. We find that VLDLR knockdown induces transition from self-renewal to quiescence. Surprisingly, ligand-binding activity is not involved in the cancer-promoting functions of VLDLR-I and -II. Proteomic analysis reveals that citrate cycle and ribosome biogenesis-related proteins are upregulated in VLDLR-I and -II overexpressed cells, suggesting that VLDLR dysregulation is associated with metabolic and anabolic regulation. Moreover, high expression of VLDLR in breast cancer tissues correlates with poor prognosis of patients. Collectively, these findings indicate that VLDLR may be an important therapeutic target for breast cancer treatment.

BackgroundGestational trophoblastic neoplasia is an uncommon disease, whose clinical manifestations are similar to ectopic pregnancy, thus some rare pelvic lesion can be misdiagnosed as ectopic pregnancy.AimsThis study was presented to investigate the characteristics of gestational trophoblastic neoplasia misdiagnosed as ectopic pregnancy and reduce the misdiagnosis.MethodsThe clinicopathological data for 14 cases of gestational trophoblastic neoplasia misdiagnosed as ectopic pregnancy at West China Second Hospital Sichuan University from January 2006 to December 2020 were retrospectively analyzed.ResultsThe main clinical manifestations were amenorrhea, abnormal vaginal bleeding, and abdominal pain. At initial diagnosis, the serum hCG level was >10,000 mIU/mL in 5 patients and 13 points (very high risk). From 14 patients, only 3 had molar pregnancy previously. Only 3 patients had no metastasis at GTN diagnosis (from these 3, only one after molar pregnancy). After chemotherapy alone or in combination with surgery, all patients survived, with a median follow-up of 84 months (23–102 months).ConclusionIf we have positive hCG, without a sonographic topic gestation confirmation, associated with metastatic lesions, the GTN diagnosis should be considered instead of ectopic pregnancy, if the patient have had a pregnancy once during her life.

BackgroundTo systematically summarize the evidence for the efficacy of acupuncture in tinnitus treatment, we assessed the methodological quality, reporting quality, and evidence quality of systematic reviews/meta-analyses (SRs/MAs) of acupuncture in the treatment of tinnitus.MethodsFrom inception to March 2022, we conducted a detailed and comprehensive search of eight electronic databases in Chinese and English. The Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR-2), the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) were used to assess methodological quality, reporting quality and evidence quality for inclusion in SRs/MAs, respectively.ResultsFourteen published SRs/MAs met the inclusion criteria and were included in the study. Eleven studies reported that acupuncture was effective in treating tinnitus, and three studies reported that no firm conclusions could be drawn about the effectiveness of acupuncture in treating tinnitus. The results of the AMSTAR-2 assessment showed that the methodological quality of the included studies was relatively low in general, with one being moderate quality and the rest being very low quality. The PRISMA checklist evaluation results showed that no studies fully report checklists, with protocol registration and search strategies being the main reporting weaknesses. The GRADE assessment showed that no results were high-quality evidence, 17 results were moderate-quality evidence, 25 results were low-quality evidence, and 12 results were very low-quality evidence.ConclusionAcupuncture seems to be a positive and effective treatment for tinnitus. However, the methodological quality and quality of evidence for SRs/MAs in the included studies were generally low, and this result must be viewed with caution. Therefore, more high-quality, large-scale, multi-center randomized controlled trials are needed in the future to verify the effectiveness of acupuncture in the treatment of tinnitus.

In recent years, STROBY (50% Kresoxim-methyl) has been widely used to control tobacco brown spot in Guizhou Province, China. As a broad-spectrum fungicide, STROBY targets not only phytopathogens, but also affects many other microorganisms including those pathogenic, beneficial, or neutral to the plant hosts. To understand the effects of STROBY on the phyllosphere microbial communities of tobacco leaves during the development of tobacco brown spot, the fungal and bacterial communities of symptomatic and asymptomatic leaves at four time points, before spraying (August 29) and after spraying (September 3, 8, and 13), were investigated using the Illumina high-throughput sequencing. The results showed that STROBY had significant effects on the phyllosphere microbial communities of tobacco leaves. Microbial communities in asymptomatic leaves were more greatly affected than their counterparts in symptomatic leaves, and fungal communities were more sensitive than bacterial communities. Throughout the experiment, the most common genera in symptomatic leaves were Alternaria, Pseudomonas, Pantoea, and Sphingomonas, and in asymptomatic leaves, these were Golubevia and Pantoea. After spraying, the alpha diversity of fungal communities increased in symptomatic leaves and decreased in asymptomatic leaves, while the alpha diversity of bacteria increased in both types of leaves. Beta diversity showed that in asymptomatic leaves, the fungal communities in the first stage was significantly different from the remaining three stages. In contrast, the fungal communities in symptomatic leaves and the bacterial communities in all leaves did not fluctuate significantly during the four stages. Before spraying (August 29), the dominant functions of the fungal community were animal pathogen, endophyte, plant pathogen, and wood saprotroph. Whereas after spraying (September 3, 8, and 13), the proportion of the above fungal functions decreased and the unassigned functions increased, especially in asymptomatic leaves. This study describes the effects of STROBY application and tobacco brown spot presence in shaping the leaf phyllosphere microbial communities, and provides insights into the microbial community effects on tobacco leaves of a strobilurin fungicide.

Prostate cancer (PCa) is a common malignancy that poses a major threat to the health of men. Prostate-specific antigen (PSA) and its derivatives, as FDA-approved detection assays, are insufficient to serve as optimal markers for patient prognosis and clinical decision-making. It is widely acknowledged that aberrant glycolytic metabolism in PCa is related to tumor progression and acidifies the tumor microenvironment (TME). Considering the non-negligible impacts of glycolysis and immune functions on PCa, we developed a combined classifier in prostate cancer. The Glycolysis Score containing 19 genes and TME Score including three immune cells were created, using the univariate and multivariate Cox proportional hazards model, log-rank test, least absolute shrinkage and selection operator (LASSO) regression analysis and the bootstrap approach. Combining the glycolysis and immunological landscape, the Glycolysis-TME Classifier was then constructed. It was observed that the classifier was more accurate in predicting the prognosis of patients than the current biomarkers. Notably, there were significant differences in metabolic activity, signaling pathways, mutational landscape, immunotherapeutic response, and drug sensitivity among the Glycolysishigh/TMElow, Mixed group and Glycolysislow/TMEhigh identified by this classifier. Overall, due to the significant prognostic value and potential therapeutic guidance of the Glycolysis-TME Classifier, we anticipate that this classifier will be clinically beneficial in the management of patients with PCa.

As a new way of programmed cell death, pyroptosis plays a vital role in many diseases. In recent years, the relationship between pyroptosis and type 2 diabetes (T2D) has received increasing attention. Although the current treatment options for T2D are abundant, the occurrence and development of T2D appear to continue, and the poor prognosis and high mortality of patients with T2D remain a considerable burden in the global health system. Numerous studies have shown that pyroptosis mediated by the NLRP3 inflammasome can affect the progression of T2D and its complications; targeting the NLRP3 inflammasome has potential therapeutic effects. In this review, we described the molecular mechanism of pyroptosis more comprehensively, discussed the most updated progress of pyroptosis mediated by NLRP3 inflammasome in T2D and its complications, and listed some drugs and agents with potential anti-pyroptosis effects. Based on the available evidence, exploring more mechanisms of the NLRP3 inflammasome pathway may bring more options and benefits for preventing and treating T2D and drug development.

ObjectiveThe objective of this study is to introduce a novel technique of robotic-assisted laparoscopic pyeloplasty (RALP) for ureteropelvic junction obstruction (UPJO) with long proximal ureteral stricture in children.Materials and methodsClinical information on patients who underwent a modified RALP between July 2018 and May 2019 in our center was collected retrospectively. Our surgical modifications mainly include “double-flap” tailoring of the renal pelvis and anastomosis of spatulate ureter with the double-flap. Demographic, perioperative, postoperative, and follow-up information was recorded in detail.ResultsA total of 13 patients were included in the study. All the patients underwent a modified RALP without conversion to open surgery. They were followed up with a median time of 36 months. The anteroposterior diameter of the renal pelvis was 1.19 ± 0.21 at 6 months after the surgery, which was significantly lower than that on admission (3.93 ± 0.79). The split renal function of the children was also significantly improved from 0.37 ± 0.05) to 0.46 ± 0.02 at 6 months after surgery (p < 0.05). The diuretic renography revealed that all the patients have a T1/2 time less than 20 min postoperatively. The children were in good condition during the follow-up period.ConclusionsModified RALP is an effective surgical treatment for children with UPJO with long proximal ureteral stricture. The success rate of this modification has been preliminarily confirmed.

This study aims to explore the protective effects of 17 β-estradiol on the human uterosacral ligament fibroblasts (hUSLFs) under static or stretched conditions. The experiments were performed on hUSLFs derived from pelvic organ prolapse (POP) and non-POP patients. Fibroblasts were cultured after collagenase digestion and identified by morphological observation and immunocytochemical methods. 17 β-estradiol (10−10 M and 10−9 M) and mechanical stress induced by the FX-5000 T-cell stress loading system under a loading strain of 1/2 sin waveform uniaxial cyclic stress with a tensile strain of 20% and a frequency of 0.5 Hz were either or both applied on hUSLFs. Cell proliferation was measured by CCK8, and cell apoptosis and death were detected using Annexin V/7-AAD staining and flow cytometric analysis. We found that the fibroblasts growth rate of POP patients was significantly lower than controls. The cell apoptosis and death rate increased as the mechanical load intensifying. After 20% mechanical stretching for 24 h, the dead cell rate was higher in POP than control. Notably, 17 β-estradiol treatment reversed mechanical stress induced hUSLFs apoptosis and death in both POP and Control cells. The protein and mRNA levels of anti-apoptotic PARP1 (poly-ADP-ribose polymerase) and Bcl-2 were increased by estrogen treatment. Meanwhile, expression of estrogen receptor α, a target of Poly-ADP-Ribosylation of PARP1, was also enhanced by 17 β-estradiol under the mechanical load. In conclusion, estrogen application ameliorates the mechanical strain induced cell apoptosis and death in hUSLFs from POP patients. PARP1 might be involved in this protective process, providing novel insights into the mechanical biology of and possible therapies for POP.

BackgroundThe long-term outcomes of ablation index (AI)-guided radiofrequency catheter ablation (RFCA) on atrial fibrillation (AF) and different subtypes of heart failure (HF) remain unknown. The aim of the study was to evaluate the long-term prognosis of AI-guided RFCA procedures in patients with AF and concomitant HF.MethodsWe retrospectively included consecutive patients with AF and HF who underwent the initial RFCA procedure with AI guidance from March 2018 to June 2021 in our institution. The patients were categorized into two groups: HF with preserved ejection fraction (HFpEF) group and HF with mid-range ejection fraction (HFmrEF) +HF with reduced ejection fraction (HFrEF) group.ResultsA total of 101 patients were included. HFpEF and HFmrEF + HFrEF groups consisted of 71 (70.3%) and 30 patients (29.7%), respectively. During a median follow-up of 32.0 (18.2, 37.6) months, no significant difference was detected in AF recurrence between groups (21.1 vs. 33.3%) after multiple procedures, whereas the incidence of the composite endpoint of all-cause death, thromboembolic events, and HF hospitalization was significantly lower in HFpEF group (9.9 vs. 25.0%, Log-rank p = 0.018). In multivariable analysis, a history of hypertension [hazard ratio (HR) 4.667, 95% confidence interval (CI) 1.433–15.203, p = 0.011], left ventricular ejection fraction (LVEF) < 50% (HR 5.390, 95% CI 1.911–15.203, p = 0.001) and recurrent AF after multiple procedures (HR 7.542, 95% CI 2.355–24.148, p = 0.001) were independently associated with the incidence of the composite endpoint.ConclusionLong-term success could be achieved in 75% of patients with AF and concomitant HF after AI-guided RFCA procedures, irrespective of different HF subtypes. Preserved LVEF was associated with a reduction in the composite endpoint compared with impaired LVEF. Patients with recurrent AF tend to have a poorer prognosis.

ABI4 is considered an important transcription factor with multiple regulatory functions involved in many biological events. However, its role in abiotic stresses, especially low-temperature-induced stress, is poorly understood. In this study, the MtABI4 gene was derived from M. truncatula, a widely used forage grass. Analysis of subcellular localization indicated that ABI4 was localized in the nucleus. Identification of expression characteristics showed that ABI4 was involved in the regulatory mechanisms of multiple hormones and could be induced by the low temperature. IP-MS assay revealed that MtABI4 protein could interact with xanthoxin dehydrogenase protein (ABA2). The two-hybrid yeast assay and the biomolecular fluorescence complementarity assay further supported this finding. Expression analysis demonstrated that overexpression of MtABI4 induced an increase in ABA2 gene expression both in M. truncatula and Arabidopsis, which in turn increased the ABA level in transgenic plants. In addition, the transgenic lines with the overexpression of MtABI4 exhibited enhanced tolerance to low temperature, including lower malondialdehyde content, electrical conductivity, and cell membrane permeability, compared with the wide-type lines after being cultivated for 5 days in 4°C. Gene expression and enzyme activities of the antioxidant system assay revealed the increased activities of SOD, CAT, MDHAR, and GR, and higher ASA/DHA ratio and GSH/GSSG ratio in transgenic lines. Additionally, overexpression of ABI4 also induced the expression of members of the Inducer of CBF expression genes (ICEs)-C-repeat binding transcription factor genes(CBFs)-Cold regulated genes (CORs) low-temperature response module. In summary, under low-temperature conditions, overexpression of ABI4 could enhance the content of endogenous ABA in plants through interactions with ABA2, which in turn reduced low-temperature damage in plants. This provides a new perspective for further understanding the molecular regulatory mechanism of plant response to low temperature and the improvement of plant cold tolerance.

Talaromyces marneffei is a thermally dimorphic fungus that affects multiple organs and frequently invades immunocompromised individuals. However, only a few studies have reported the presence of intestinal infection associated with T. marneffei. Herein, we reported a case of intestinal T. marneffei infection in a man who complained of a 1-month history of intermittent fever, abdominal pain, and diarrhea. The result of the human immunodeficiency virus antibody test was positive. Periodic acid-Schiff and Gomorrah’s methylamine silver staining of the intestinal biopsy tissue revealed T. marneffei infection. Fortunately, the patient’s symptoms rapidly resolved with prompt antifungal treatment. In addition, we summarized and described the clinical characteristics, management, and outcomes of patients with intestinal T. marneffei infection. A total of 29 patients were identified, the majority of whom (65.52%) were comorbid with acquired immunodeficiency syndrome. The main clinical features included anemia, fever, abdominal pain, diarrhea, weight loss, and lymphadenopathy. The transverse and descending colon, ileocecum, and ascending colon were the most common sites of lesions. A considerable number of patients (31.03%) developed intestinal obstruction, intestinal perforation, and gastrointestinal bleeding. Of the 29 patients, six underwent surgery, 23 survived successfully with antifungal treatment, five died of T. marneffei infection, and one died of unknown causes. T. marneffei intestinal infection should be considered when immunodeficient patients in endemic areas present with non-specific symptoms, such as fever, abdominal pain, and diarrhea. Appropriate and timely endoscopy avoids delays in diagnosis. Early aggressive antifungal therapy improves the clinical outcomes of patients.

Objective: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer (PC) that may arise de novo or in patients previously treated with hormonal therapies for prostate adenocarcinoma as a mechanism of resistance. In our investigation, there appeared to be a strong correlation between neuroendocrine differentiation prostate cancer (NEDPC) and NEPC. The objectives of this study included exploring whether NEDPC is an intermediate stage in the progression of high-risk prostate cancer (HRPC) to NEPC and identifying risk factors and new targets associated with survival in the treatment of NEPC.Methods: The selected prostate cancer patients were progressed to high-risk and characterized by neuroendocrine. We collected the clinical data and characteristics of patients with three types of cancer: the incidence of metastasis, site and time of metastasis, recurrence rate, related treatment methods, etc. The similarity and differences of the three groups were compared through experiment and database.Results: By analyzing the clinical data and immunohistochemical results, we found that there seems to be a clinical feature of neuroendocrine differentiation (NED) status in between when patients progress from PC to NEPC. Finding novel treatment targets would therefore be beneficial by taking into account NEDPC as the stage of PC progression prior to NEPC. The metastasis-free survival curve and the immunohistochemical results are informing us that NEDPC can be a pre-state for diagnosing NEPC.Conclusion: NEPC is a late PC symptom that is frequently disregarded and has a bad prognosis. Finding novel treatment targets would therefore be beneficial by taking into account NEDPC as the stage of PC progression prior to NEPC.

BackgroundDistinguishing Crohn's disease (CD) and intestinal Behçet's disease (BD) is difficult in clinical practice.AimTo evaluate the ability of CT enterography (CTE) to enhance the diagnostic value of endoscopy in differentiating CD from intestinal BD and to establish differential diagnosis models.MethodsA total of 113 patients with CD and 70 patients with intestinal BD from seven tertiary inflammatory bowel disease centers were enrolled. The univariate and multivariate analyses were used by SAS software version 9.2. Three differential scoring models based on the multivariate analysis of endoscopic features alone (model 1), endoscopic features combined with clinical symptoms (model 2), and endoscopic features combined with clinical symptoms and CTE (model 3) were established.ResultsThe results showed that model 2 increased the efficacy of model 1 in differential diagnosis and model 3 had the highest accuracy of 84.15% at a cutoff value of two points. The scoring of model 3 was as follows: genital ulcer (−3 points), skin lesions (−3 points), oval ulcer (-2 points), longitudinal ulcer (1 point), number of ulcers > 5 (3 points), inflammatory polyps (2 points), mucosal severe enhancement (2 points), and fibrofatty proliferation (1 point).ConclusionClinical symptoms and CTE increased the ability of endoscopy to differentiate CD from intestinal BD.

To evaluate the application potential of high-density SNPs in rice distinctness, uniformity, and stability (DUS) testing, we screened 37,929 SNP loci distributed on 12 rice chromosomes based on whole-genome resequencing of 122 rice accessions. These SNP loci were used to analyze the DUS testing of rice varieties based on the correlation between the molecular and phenotypic distances of varieties according to UPOV option 2. The results showed that statistical algorithms and the number of phenotypic traits and SNP loci all affected the correlation between the molecular and phenotypic distances of rice varieties. Relative to the other nine algorithms, the Jaccard similarity algorithm had the highest correlation of 0.6587. Both the number of SNPs and the number of phenotypes had a ceiling effect on the correlation between the molecular and phenotypic distances of varieties, and the ceiling effect of the number of SNP loci was more obvious. To overcome the correlation bottleneck, we used the genome-wide prediction method to predict 30 phenotypic traits and found that the prediction accuracy of some traits, such as the basal sheath anthocyanin color, glume length, and intensity of the green color of the leaf blade, was very low. In combination with group comparison analysis, we found that the key to overcoming the ceiling effect of correlation was to improve the resolution of traits with low predictive values. In addition, we also performed distinctness testing on rice varieties by using the molecular distance and phenotypic distance, and we found that there were large differences between the two methods, indicating that UPOV option 2 alone cannot replace the traditional phenotypic DUS testing. However, genotype and phenotype analysis together can increase the efficiency of DUS testing.

BackgroundDifferential diagnosis of Crohn’s disease (CD) and ulcerative primary intestinal lymphoma (UPIL) is a tough problem in clinical practice.AimsOur study identified key differences between CD and UPIL patients and aimed to further establish a scoring model for differential diagnosis.MethodsA total of 91 CD and 50 UPIL patients from 9 tertiary inflammatory bowel disease centers were included. Univariate and multivariate analyses were used to determine significant markers for differentiating CD and UPIL. A differential scoring model was established by logistic regression analysis.ResultsThe differential model was based on clinical symptoms, endoscopic and imaging features that were assigned different scores: intestinal bleeding (−2 points), extraintestinal manifestation (2 points), segmental lesions (1 point), cobblestone sign (2 points), homogeneous enhancement (−1 point), mild enhancement (−1 point), engorged vasa recta (1 point). A total score of ≥1 point indicates CD, otherwise UPIL was indicated. This model produced an accuracy of 83.66% and an area under the ROC curve of 0.947. The area under the ROC curve for validation using the 10-fold validation method was 0.901.ConclusionThis study provided a convenient and useful model to differentiate CD from UPIL.

Myeloid sarcoma is a rare extramedullary tumor of immature myeloid cells. Certain known acute myeloid leukemia cytogenetic abnormalities, in particular t(8,21), has been associated with a higher incidence. Myeloid sarcoma, which rarely happens in acute promyelocytic leukemias, is more common in recurrent patients after the advent of all-trans retinoic acid (ATRA) and are rare in untreated acute promyelocytic leukemia. We described a case of, to our knowledge, de novo myeloid sarcoma of the spine confirmed as acute promyelocytic leukemia. Myeloid sarcoma is diagnosed by spinal tumor biopsy, and microscopic examination of a bone marrow smear and cytogenetic analysis led to a confirmed diagnosis of acute promyelocytic leukemia.

Clustered regularly interspaced short palindromic repeats (CRISPR)-associated systems have revolutionized traditional gene-editing tools and are a significant tool for ameliorating gene defects. Characterized by high target specificity, extraordinary efficiency, and cost-effectiveness, CRISPR/Cas systems have displayed tremendous potential for genetic manipulation in almost any organism and cell type. Despite their numerous advantages, however, CRISPR/Cas systems have some inherent limitations, such as off-target effects, unsatisfactory efficiency of delivery, and unwanted adverse effects, thereby resulting in a desire to explore approaches to address these issues. Strategies for improving the efficiency of CRISPR/Cas-induced mutations, such as reducing off-target effects, improving the design and modification of sgRNA, optimizing the editing time and the temperature, choice of delivery system, and enrichment of sgRNA, are comprehensively described in this review. Additionally, several newly emerging approaches, including the use of Cas variants, anti-CRISPR proteins, and mutant enrichment, are discussed in detail. Furthermore, the authors provide a deep analysis of the current challenges in the utilization of CRISPR/Cas systems and the future applications of CRISPR/Cas systems in various scenarios. This review not only serves as a reference for improving the maturity of CRISPR/Cas systems but also supplies practical guidance for expanding the applicability of this technology.

SOX3 is critical for the development of the pituitary, brain, and face, and SOX3 mutations may lead to hypopituitarism, intellectual disability, and craniofacial abnormalities. Common SOX3 mutations are duplications and deletions of the whole or part of SOX3, yet only a few cases with point mutations were reported by far. We present a case with growth retardation, small penis, and learning difficulty. Further assessment confirmed growth hormone deficiency, hypogonadotropic hypogonadism (HH), and borderline intellectual disability. He also responded well to gonadotropin-releasing hormone stimulation test, which suggests defects in the hypothalamus, contrary to previous studies that reported defects in the pituitary. A pathogenic frame-shift mutation of SOX3 was found. A heterogeneous missense mutation in SEMA3A was identified in this patient as well, which may also contribute to the development of HH. As far as we know, this is the first report that a frame-shift mutation of SOX3 constitutes rare genetic causes of HH and growth hormone deficiency. Whether mutations in these two genes act synergistically in the pathogenesis of the patient’s phenotype remains to be further investigated. We believe that our case extends the phenotypic spectrum and genetic variability of SOX3 mutation.

Background: Stem cell-derived exosomes have great potential in the treatment of myocardial ischemia–reperfusion injury (IRI). Extracorporeal cardiac shock waves (ECSW) as effective therapy, in part, could activate the function of exosomes. In this study, we explored the effect of ECSW-induced exosome derived from endothelial colony-forming cells on cardiomyocyte hypoxia/reoxygenation (H/R) injury and its underlying mechanisms.Methods: The exosomes were extracted and purified from the supernatant of endothelial colony-forming cells (ECFCs-exo). ECFCs-exo treated with shock wave (SW-exo) or without shock wave (CON-exo) were performed with high-throughput sequencing of the miRNA. H9c2 cells were incubated with SW-exo or CON-exo after H/R injury. The cell viability, cell apoptosis, oxidative stress level, and inflammatory factor were assessed. qRT-PCR was used to detect the expression levels of miRNA and mRNA in cells and exosomes. The PTEN/PI3K/AKT pathway-related proteins were detected by Western blotting, respectively.Results: Exosomes secreted by ECFCs could be taken up by H9c2 cells. Administration of SW-exo to H9c2 cells after H/R injury could significantly improve cell viability, inhibit cell apoptosis, and downregulate oxidative stress level (p

Pleomorphic adenomas (PAs) are the most common benign salivary neoplasms. PAs are generally slow-growing but may sometimes become aggressive and grow rapidly within a short period of time. Here, we report the case of an 83-year-old Chinese woman with an anterior neck mass that had been growing over the past 30 years. She felt uncomfortable because the mass had grown quite rapidly in the past year. The final diagnosis of a PA of the left submandibular gland was confirmed by histopathological and immunohistochemical examinations after surgical resection. Our patient recalled a history of an excision of a neck mass 40 years prior to presentation at another hospital. Based on our imaging findings and surgical findings, we speculate that the neck mass 40 years prior may also have been a PA. Our case reminds us the rare recurrence possibility of PAs, and early and thorough resection may have a good prognosis. In addition, to the best of our knowledge, this is the largest PA of the submandibular gland reported to date.

Abnormal expression of the transcription factor Y-box-binding protein-1 (YBX1) is associated with the proliferation, migration, aggressiveness, and stem-like properties of various cancers. These characteristics contribute to the tumorigenesis and metastasis of cancer. We found that the expression levels of Mucin-1 (MUC1) and YBX1 were positively correlated in lung adenocarcinoma cells and lung adenocarcinoma tissue. Our retrospective cohort study of 176 lung adenocarcinoma patients after surgery showed that low expression of both YBX1 and MUC1 was an independent predictor of the prognosis and recurrence of lung adenocarcinoma. In lung adenocarcinoma cells, the silencing/overexpression of YBX1 caused a simultaneous change in MUC1, and MUC1 overexpression partially reversed the decreased tumor cell migration, aggressiveness, and stemness caused by YBX1 silencing. Moreover, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays proved that MUC1 was the downstream target of YBX1 and that YBX1 bound to the -1480~-1476 position in the promoter region of MUC1 to regulate its transcription. Furthermore, in mouse xenograft models and a lung cancer metastasis model, MUC1, which is downstream of YBX1, partially reversed the decreased number and size of tumors caused by YBX1 silencing. In conclusion, our findings indicated a novel mechanism by which YBX1 promotes the stemness and metastasis of lung adenocarcinoma by targeting MUC1 and provided a combination approach for diagnosis different from traditional single tumor biomarkers to predict patient prognosis and provide clinical treatment targets.

Radiation mutation breeding has been used for nearly 100 years and has successfully improved crops by increasing genetic variation. Global food production is facing a series of challenges, such as rapid population growth, environmental pollution and climate change. How to feed the world's enormous human population poses great challenges to breeders. Although advanced technologies, such as gene editing, have provided effective ways to breed varieties, by editing a single or multiple specific target genes, enhancing germplasm diversity through mutation is still indispensable in modern and classical radiation breeding because it is more likely to produce random mutations in the whole genome. In this short review, the current status of classical radiation, accelerated particle and space radiation mutation breeding is discussed, and the molecular mechanisms of radiation-induced mutation are demonstrated. This review also looks into the future development of radiation mutation breeding, hoping to deepen our understanding and provide new vitality for the further development of radiation mutation breeding.

The purpose of the study was to assess the artificial saliva (AS) pH on ruminal fermentation and rumen bacteria community in the rumen simulation technique (RUSITEC) system. The experiment was performed in two treatments (low AS pH vs. high AS pH) with four replicates. The low AS pH was sustained by altering the composition of the AS (NaHCO3 from 9.8 to 1.96 g/L, Na2HPO4 from 9.3 to 1.86 g/L) according to McDougall's method. The diets were supplemented with 16 g basic diets with forage to the concentrate ratio of 50:50. The experiments were conducted over 13-day incubation periods, with 9 days adaption and 4 days sample collection. The results showed low AS pH decreased dry matter (DM) degradability (64.37 vs. 58.67%), organic matter (OM) degradability (64.38 vs. 59.32%), neutral detergent fiber (NDF) degradability (46.87 vs. 39.94%), acid detergent fiber (ADF) degradability (38.16 vs. 31.13%), and crude protein (CP) degradability (70.33 vs. 62.99%), respectively. Compared with the high AS pH, the low AS pH increased the proportion of butyrate (P = 0.008) and decreased the proportion of propionate (P < 0.001). At the bacteria community, the low AS pH increased the abundances of Spirochaetes (P = 0.001) and Synergistetes (P = 0.004) and decreased the Verrucomicrobia abundance (P = 0.004) in solid-associated bacteria. At the genus level, the low AS pH increased the abundance of Lactobacillus (P = 0.050) and decreased the abundance of Schwartzia (P = 0.002) in solid-associated bacteria. The abundances of Prevotellaceae_YAB2003_group (P = 0.040), Schwartzia (P = 0.002), and Ruminobacter (P = 0.043) were lower in the low AS pH group compared with the high AS pH group in liquid-associated bacteria. Low AS pH decreased the number of Ruminococcus albus, Ruminococcus flavefaciens, Fibrobacter succinogenes (P < 0.001) both in the solid- and liquid-associated bacteria, respectively. The results of the present study included three groups of bacteria communities according to the different sensitives to rumen pH: the abundances of Lactobacillus, Succinivibrio, and Prevotella_7 are increased with decreasing AS pH; the amounts of R. albus, R. flavefaciens, F. succinogenes as well as the abundances of Schwartzia and Ruminobacter decreased with the reducing AS pH; the abundances of Selenomonas_1, Rikenellaceae_RC9_gut_group, and Succiniclasticum were not affected by the AS pH in RUSTITEC.

Background: To determine the respiratory outcomes in patients following COVID-19-related hospitalization.Methods: Systematic review and meta-analysis of the literature.Results: Forced vital capacity (FVC, % of predicted): 0–3 months post discharge: 96.1, 95% CI [82.1–110.0]; 3–6 months post discharge: 99.9, 95% CI [84.8, 115.0]; >6 months post discharge: 97.4, 95% CI [76.8–118.0]. Diffusing capacity of the lungs for carbon monoxide (DLCO, % of predicted): 0–3 months post discharge: 83.9, 95% CI [68.9–98.9]; 3–6 months post discharge: 91.2, 95% CI [74.8–107.7]; >6 months post discharge: 97.3, 95% CI [76.7–117.9]. Percentage of patients with FVC less than 80% of predicted: 0–3 months post discharge: 10%, 95% CI [6–14%]; 3–6 months post discharge: 10%, 95% CI [2–18%]; >6 months post discharge: 13%, 95% CI [8–18%]. Percentage of patients with DLCO less than 80% of predicted: 0–3 months post discharge: 48%, 95% CI [41–56%]; 3–6 months post discharge: 33%, 95% CI [23–44%]; >6 months post discharge: 43%, 95% CI [22–65%].Conclusion: The meta-analysis confirms a high prevalence of persistent lung diffusion impairment in patients following COVID-19-related hospitalization. Routine respiratory follow-up is thus strongly recommended.

Background: It is common for patients with gastric cancer to develop distant metastases in the liver, lung, bone, and brain. Although the thyroid also has an abundant blood supply, gastric cancer metastasis to the thyroid is uncommon. Due to the rarity of such metastasis, its clinical features are not well understood. Here, we present the case of a patient with gastric cancer metastasis to the thyroid treated at our hospital.Case Summary: We report the case of a 63-year-old female with a mass in the anterior neck and mild hoarseness for 6 months. The patient underwent proximal subtotal gastrectomy for Siewert III oesophagogastric junction cancer 6 years ago. Subsequently, she received 8 cycles of adjuvant chemotherapy. Her condition was stable until mild hoarseness developed for no apparent reason 6 months prior to presenting at our clinic. Both ultrasonography and computed tomography confirmed a heterogeneous mass in the right lobe of the thyroid gland. Blood thyroid function tests and tumor marker expression levels were normal. Thyroid malignancy was suspected, and the patient underwent a right thyroidectomy. During the surgery, a tumor was found that had invaded the right recurrent laryngeal nerve and trachea. H&E staining and immunohistochemistry results suggested that the cancer cells originated from gastric cancer. The patient was diagnosed with thyroid metastasis of gastric cancer. She refused further treatment and died within 6 months.Conclusion: Metastasis of gastric cancer to the thyroid is rare and is associated with a poor prognosis. Immunohistochemical diagnosis is essential for a conclusive diagnosis. For patients with a history of malignant tumors, the possibility of metastatic thyroid nodules should be ruled out when diagnosing thyroid nodules.

Background: Extracorporeal cardiac shock waves (ECSW) have great potential in the treatment of coronary heart disease. Endothelial progenitor cells (EPCs) are a class of pluripotent progenitor cells derived from bone marrow or peripheral blood, which have the capacity to migrate to ischemic myocardium and differentiate into mature endothelial cells and play an important role in neovascularization and endothelial repair. In this study, we investigated whether ECSW therapy can improve EPCs dysfunction and apoptosis induced by hypoxia and explored the underlying mechanisms.Methods: EPCs were separated from ApoE gene knockout rat bone marrow and identified using flow cytometry and fluorescence staining. EPCs were used to produce in vitro hypoxia-injury models which were then divided into six groups: Control, Hypoxia, Hypoxia + ECSW, Hypoxia + LY294002 + ECSW, Hypoxia + MK-2206 + ECSW, and Hypoxia + L-NAME + ECSW. EPCs from the Control, Hypoxia, and Hypoxia + ECSW groups were used in mRNA sequencing reactions. mRNA and protein expression levels were analyzed using qRT-PCR and western blot analysis, respectively. Proliferation, apoptosis, adhesion, migration, and angiogenesis were measured using CCK-8, flow cytometry, gelatin, transwell, and tube formation, respectively. Nitric oxide (NO) levels were measured using an NO assay kit.Results: Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis showed that differentially expressed genes were enriched in cancer signaling, PI3K-Akt signaling, and Rap1 signaling pathways. We selected differentially expressed genes in the PI3K-Akt signaling pathway and verified them using a series of experiments. The results showed that ECSW therapy (500 shots at 0.09 mJ/mm2) significantly improved proliferation, adhesion, migration, and tube formation abilities of EPCs following hypoxic injury, accompanied by upregulation of p-PI3K, p-Akt, p-eNOS, Bcl-2 protein and NO, PI3K, and Akt mRNA expression, and downregulation of Bax and Caspase3 protein expression. All these effects of ECSW were eliminated using inhibitors specific to PI3K (LY294002), Akt (MK-2206), and eNOS (L-NAME).Conclusion: ECSW exerted a strong repaired effect on EPCs suffering inhibited hypoxia injury by inhibiting cell apoptosis and promoting angiogenesis, mainly through activating the PI3K/Akt/eNOS signaling pathway, which provide new evidence for ECSW therapy in CHD.

Shiyiwei Shenqi Tablet (SSTs) has been widely used for treatment of different types of cancer including breast cancer. SST has drawn more and more interest due to the low rate of side effects. The aim of this study was to investigate the metabolites in serums of breast cancer patients who received base-line chemotherapy only or combination treatment with SST. An untargeted metabolomics method was developed to investigate the alteration of metabolism in patients’ serums using ultra-high-performance liquid chromatography/Q-exactive Orbitrap mass spectrometry. The patients were separated based on the metabolomics data, and further analyses showed that SST treatment can affect the metabolism of glucose, fatty acid, bile acid and amino acid. In particular, SST treatment significantly reduced some short peptides which are potential tumor neoantigens. This study may provide novel insights into the mechanism underlying interaction between SST and base-line chemotherapy in terms of affecting metabolic pathways and thereby changing metabolic products, which might shed new light for clinical medication.

The cholinergic system is critical in Parkinson’s disease (PD) pathology, which accounts for various clinical symptoms in PD patients. The substantia innominata (SI) provides the main source of cortical cholinergic innervation. Previous studies revealed cholinergic-related dysfunction in PD pathology at early stage. Since PD is a progressive disorder, alterations of cholinergic system function along with the PD progression have yet to be elucidated. Seventy-nine PD patients, including thirty-five early-stage PD patients (PD-E) and forty-four middle-to-late stage PD patients (PD-M), and sixty-four healthy controls (HC) underwent brain magnetic resonance imaging and clinical assessments. We employed seed-based resting-state functional connectivity analysis to explore the cholinergic-related functional alterations. Correlation analysis was used to investigate the relationship between altered functional connectivity and the severity of motor symptoms in PD patients. Results showed that both PD-E and PD-M groups exhibited decreased functional connectivity between left SI and left frontal inferior opercularis areas and increased functional connectivity between left SI and left cingulum middle area as well as right primary motor and sensory areas when comparing with HC. At advanced stages of PD, functional connectivity in the right primary motor and sensory areas was further increased. These altered functional connectivity were also significantly correlated with the Unified Parkinson’s Disease Rating Scale motor scores. In conclusion, this study illustrated that altered cholinergic function plays an important role in the motor disruptions in PD patients both in early stage as well as during the progression of the disease.

BackgroundColorectal cancer (CRC) is a common malignant tumor with high metastatic and recurrent rates. This study probes the effect and mechanism of long non-coding RNA MIR31HG on the progression of CRC cells.Materials and MethodsQuantitative real-time PCR (qRT-PCR) was used to analyze the expression of MIR31HG and miR-361-3p in CRC tissues and normal tissues. Gain- or loss-of-function assays were conducted to examine the roles of MIR31HG, miR-361-3p and YY1 transcription factor (YY1) in the CRC progression. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and colony formation experiment were conducted to test CRC cell proliferation. CRC cell invasion was determined by Transwell assay. The glucose detection kit and lactic acid detection kit were utilized to monitor the levels of glucose and lactate in CRC cells. The glycolysis level in CRC cells was examined by the glycolytic stress experiment. Western blot was performed to compare the expression of glycolysis-related proteins (PKM2, GLUT1 and HK2) and angiogenesis-related proteins (including VEGFA, ANGPT1, HIF1A and TIMP1) in HUVECs. The binding relationships between MIR31HG and miR-361-3p, miR-361-3p and YY1 were evaluated by the dual-luciferase reporter assay and RNA immunoprecipitation (RIP).ResultsMIR31HG was up-regulated in CRC tissues and was associated with poorer prognosis of CRC patients. The in-vitro and in-vivo experiments confirmed that overexpressing MIR31HG heightened the proliferation, growth, invasion, glycolysis and lung metastasis of CRC cells as well as the angiogenesis of HUVECs. In addition, MIR3HG overexpression promoted YY1 mRNA and protein level, and forced overexpression of YY1 enhanced MIR31HG level. Overexpressing YY1 reversed the tumor-suppressive effect mediated by MIR31HG knockdown. miR-361-3p, which was inhibited by MIR31HG overexpression, repressed the malignant behaviors of CRC cells. miR-361-3p-mediated anti-tumor effects were mostly reversed by upregulating MIR31HG. Further mechanism studies illustrated that miR-361-3p targeted and negatively regulated the expression of YY1.ConclusionThis study reveals that MIR31HG functions as an oncogenic gene in CRC via forming a positive feedback loop of MIR31HG-miR-361-3p-YY1.

BackgroundAlthough the RNA modification N6-methyladenosine ZC3H13 has been found to play vital regulatory roles in many types of cancers, its role in predicting the tumor immune microenvironment (TME) and response to immune checkpoint blockade (ICB) in kidney renal clear cell carcinoma (KIRC) remains unclear.MethodsWe comprehensively analyzed the expression, prognostic significance and immunological role of ZC3H13 in pan-cancers and systematically correlated ZC3H13 with TME cell-infiltration, ICB response and targeted therapy in KIRC. The data were collected from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Genotype-Tissue Expression (GTEx), Broad Institute Cancer Cell Line Encyclopedia (CCLE) and DrugBank database. Also, we performed RNA sequencing (RNA-seq) of 46 renal cell carcinoma tissues and 11 adjacent normal tissues to validate our result. All analyses were implemented using R software, version 3.6.3.ResultsZC3H13 was significantly differentially expressed in most tumors. However, its expression profiles and prognostic significance were consistent only in KIRC, regardless of overall survival, progression-free survival and cancer-specific survival. Additionally, ZC3H13 expression was correlated with clinicopathological factors in KIRC. Furthermore, we found that ZC3H13 might shape a noninflamed phenotype and could predict a lower response to ICB in KIRC. These results could be validated in our own RNA-seq data. Tumor mutation burden (TMB) was significantly higher in the low ZC3H13 group. Finally, we found that ZC3H13 could predict the sensitivity of targeted therapy for KIRC.ConclusionsZC3H13 might shape a noninflamed phenotype in KIRC. Moreover, ZC3H13 could predict the prognosis and clinical response of ICB and the sensitivity to targeted therapies in KIRC.

Bovine Viral Diarrhea Virus (BVDV) is the main pathogen of bovine viral diarrhea disease (BVD), which leads to enormous economic losses in the cattle industry. A sensitive and specific detection for BVDV is advantageous to the control of BVDV. Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas systems have been used for detecting virus RNA. In this study, the expression and purification of LwCas13a protein was optimized and the RNase activity of LwCas13a in vitro was verified. CRISPR-LwCas13a system could detect BVDV virus and BVDV RNA with high specificity and simplicity. The detection limit of the LwCas13a system was 103 pM, and there were no cross-reactions with HEK293T and MDBK. In summary, a sensitive, specific, and simple nucleic acid detection method based on CRISPR-Cas13a was developed for BVDV. This method provides a new detection strategy for early diagnosis of BVDV.

Background: A comprehensive and thorough understanding of functional acetabular component orientation is essential for optimizing the clinical outcome after total hip arthroplasty (THA). This study aimed to quantify the functional acetabular anteversion and inclination of unilateral THA patients during walking and static standing and to determine whether the functional acetabular orientation falls within the Lewinnek safe zone.Methods: Seventeen patients with unilateral THA received a CT scan and dual fluoroscopic imaging during level walking and static standing to evaluate in vivo hip kinematics. The pelvic functional coordinate system of the 3D CT-based computer model was defined by the line of gravity and anterior pelvic plane (APP) to measure functional acetabular anteversion and inclination in different postures. The Lewinnek safe zone was used to determine the acetabular malposition during functional activities.Results: The THA side demonstrated an average of 10.1° (± 9.6°, range –7.5° to 29.9°) larger functional anteversion and 16.0° (± 9.2°, range –7.2° to 29.9°) smaller inclination than native hips during level walking. Functional acetabular anteversion in the THA side during level walking and static standing was significantly larger than anatomical measurements (p < 0.05). Acetabular orientation of most well-placed THA components anatomically in the Lewinnek safe zone fell outside the safe zone during more than half of the gait cycle and static standing.Conclusion: The current study revealed that an anatomically well-placed acetabular cup does not guarantee a well-functional orientation during daily activities. The in vivo mechanical performance and loading conditions of the THA component during other weight-bearing activities should be investigated in further studies.

Objection: Cumulative studies have identified the effectiveness of cardiac shock wave therapy (CSWT) in treating heart failure after acute myocardial infarction (AMI), but little have been discussed with regard to the beneficial effects of CSWT on anti-fibrosis along with the underlying mechanism. In this study, we investigated whether CSWT could reduce post-AMI fibrosis and further explored the molecular mechanism.Methods: Rat heart failure (HF) models induced by ligating the left anterior descending coronary artery were established and validated by echocardiography. Eligible animals were randomly categorized into five groups: the sham group, the HF group, the HF + CSWT group, the HF + LY294002 group, and the HF + CSWT + LY294002 group. The cardiac weight, serum level of BNP, NT-pro BNP and echocardiography parameters were measured to assess cardiac function in different groups. Masson's trichrome staining was used to assess the proportions of the fibrotic area. The expression level of CD34, αSMA was measured by RT-PCR, Immunohistochemistry and Immunofluorescent analyses and the level of PI3K/Akt was quantified by Immunohistochemistry and Western blotting.Results: The application of CSWT significantly improved cardiac function and reduced myocardial fibrosis and level of CD34 and αSMA, compared to the HF group. CSWT led to significant elevations of p-PI3K and p-Akt expression levels compared to that of the HF group and the inhibition of the PI3K/Akt pathway abolished the observed beneficial effects of CSWT.Conclusion: CSWT can facilitate the alleviation of cardiac fibrosis induced by AMI through the activation of PI3K/Akt signaling pathway.

Numerous studies have shown that the expression of circular RNA (circRNA) is closely related to the malignant progression of cancer. However, the role of circ-MFN2 in colorectal cancer (CRC) is unclear. Our study aims to explore the role and mechanism of circ-MFN2 in CRC progression. The relative expression levels of circ-MFN2, microRNA (miR)-574-3p and insulin-like growth factor 1 receptor (IGF1R) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability was determined using 3-(4, 5-dimethyl-2 thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay. The colony number and radioresistance of cells were assessed using colony formation assay. Moreover, the migration and invasion of cells were measured using transwell assay. Tumor xenograft model was constructed to evaluate the effect of circ-MFN2 knockdown on CRC tumor growth. Furthermore, dual-luciferase reporter assay was used to verify the interaction between miR-574-3p and circ-MFN2 or IGF1R. In addition, the protein level of IGF1R was evaluated by western blot (WB) analysis. Circ-MFN2 expression was elevated in CRC tissues and cells. Knockdown of circ-MFN2 restrained the proliferation, migration, invasion, and radioresistance of CRC cells in vitro. Furthermore, silenced circ-MFN2 also reduced the tumor volume and weight of CRC in vivo. MiR-574-3p could be sponged by circ-MFN2, and its inhibitor reversed the suppression effect of circ-MFN2 silencing on CRC progression. Moreover, IGF1R was a target of miR-574-3p, and its overexpression reversed the inhibition effect of miR-574-3p mimic on CRC progression. In addition, circ-MFN2 could positively regulate IGF1R expression by sponging miR-574-3p. Our results revealed that circ-MFN2 promoted the proliferation, metastasis and radioresistance of CRC through regulating the miR-574-3p/IGF1R axis, suggesting that circ-MFN2 might be a novel therapeutic biomarker for CRC.

MYC/BCL2/BCL6 triple-hit lymphoma (THL) is an uncommon subset of high-grade B-cell lymphoma with aggressive clinical behavior and poor prognosis. TP53 mutation is an independently poor progonistic indicator in patients with THL, hence novel therapeutic strategies are needed for these patients. CD19-directed chimeric antigen receptor(CAR19)-T cell therapy has shown promising efficacy for relapsed/refractory diffuse large B cell lymphoma (RR DLBCL), but the majority of CAR19-T cell products to date have been manufactured using viral vectors. PiggyBac transposon system, with an inclination to memory T cells, offers a more convenient and economical alternative for transgene delivery. We herein report the first case of triple-hit RR DLBCL with TP53 mutation who was treated with piggyBac-generated CAR19-T cells and accompanied by grade 2 cytokine release syndrome. The patient obtained a complete remission (CR) in the 2nd month post-infusion and demanded maintenance therapy. Whether maintenance therapy is favorable and how to administrate it after CAR-T cell infusion remain controversial. Preclinical studies demonstrated that lenalidomide could enhance antitumor activity of CAR19-T cells. Therefore, we pioneered oral lenalidomide after CAR19-T therapy in the patient from the 4th month, and he discontinued after one cycle due to side effects. The patient has still kept sustained CR for over 24 months. Our case have firstly demonstrated the feasibility, preliminary safety and efficacy of piggyBac-produced CAR19-T cell therapy in triple-hit lymphoma. The innovative combination with lenalidomide warrants further investigation. Our findings shed new light on the possible solutions to improve short-term relapse after CAR19-T cell therapy in RR DLBCL. ChiCTR, number ChiCTR1800018111.

Objective: To present our primary experience of robotic-assisted laparoscopic pyeloplasty (RALP) for severe ureteropelvis junction obstruction (UPJO) infants under 3 months.Methods: We performed a retrospective study of 9 infants under 3 months who underwent RALP for severe UPJO between April 2017 and March 2019 in our center. The severe UPJO was defined as infants with severe hydronephrosis (Society of Fetal Urology grades III or IV, anteroposterior diameter >3 cm or split renal function 20 min) involving bilateral, solitary kidney, or contralateral renal hypoplasia UPJO at the same time. All clinical, perioperative, and postoperative information was collected.Results: There were four bilateral UPJO cases, two solitary kidney UPJO cases and three unilateral UPJO with contralateral renal hypoplasia cases included. One single surgeon performed RALP on all of the infants. The mean age of the infants was 1.62 ± 0.54 months. The mean operative time was 109.55 ± 10.47 min. The mean estimated blood loss was 19.29 ± 3.19 ml, and the mean length of hospital stay was 5.57 ± 0.73 days. According to the ultrasonography results, all patients had a significant recovery of renal function at 12 months after the operation.Conclusions: To maximize the protection of renal function, early RALP is a safe and feasible option for the treatment of severe UPJO in infants under 3 months.

RNA modification of N6-methyladenosine (m6A) plays critical roles in various biological processes, such as cancer development, inflammation, and the anticancer immune response. However, the role played by a comprehensive m6A modification pattern in regulating anticancer immunity in kidney renal clear cell carcinoma (KIRC) has not been fully elucidated. In this study, we identified two independent m6A modification patterns with distinct biological functions, immunological characteristics, and prognoses in KIRC. Next, we developed an m6A score algorithm to quantify an individual's m6A modification pattern, which was independently validated in external cohorts. The m6A cluster 1 and low m6A score groups were characterized by a hot tumor microenvironment with an increased infiltration level of cytotoxic immune cells, higher tumor mutation burden, higher immune checkpoint expression, and decreased stroma-associated signature enrichment. In general, the m6A cluster 1 and low m6A score groups reflected an inflammatory phenotype, which may be more sensitive to anticancer immunotherapy. The m6A cluster 2 and high m6A score groups indicated a non-inflammatory phenotype, which may not be sensitive to immunotherapy but rather to targeted therapy. In this study, we first identified m6A clusters and m6A scores to elucidate immune phenotypes and to predict the prognosis and immunotherapy response in KIRC, which can guide urologists for making more precise clinical decisions.

BackgroundThe corpus callosum (CC) is an important feature of Parkinson’s disease (PD) not only in motor but also in non-motor functions. However, CC is not a homogeneous component, and the damage of specific subsection may contribute to corresponding clinical deficit.ObjectiveThe objective of the study is to investigate the structural alterations of different callosal subsections cross-sectionally and longitudinally in PD and evaluate their relationships to clinical performance.MethodsThirty-nine PD patients who had been longitudinally reexamined and 82 normal controls (NC) were employed. According to their specific callosal–cortical connectivity, 3D CC was divided into five subsections (including prefrontal, premotor, motor, somatosensory, and temporal–parietal–occipital subsection). The fractional anisotropy (FA), mean diffusivity (MD), and volume of whole CC and its subsections were computed and compared between groups. Regression model was constructed to explore the relationships between callosal structure and clinical performance.ResultsAt baseline, PD did not show any significant macro/microstructural difference compared with NC. During disease course, there was a decreased FA and increased MD of whole CC as well as its subsections (except temporal–parietal–occipital subsection), and the volume of motor subsection was decreased. Moreover, the FA of temporal–parietal–occipital subsection and volume of motor subsection were correlated with the mood domain at baseline, and the MD of somatosensory subsection was associated with the motor domain at follow-up.ConclusionThe structure of CC and its connectivity-specific subsections remain preserved at a relatively early stage in PD and are progressively disrupted during disease course. Besides, different callosal subsections possess specific associations with clinical performance in PD.