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Research into mRNA vaccines is advancing rapidly, with proven efficacy against coronavirus disease 2019 and promising therapeutic potential against a variety of solid tumors. Adjuvants, critical components of mRNA vaccines, significantly enhance vaccine effectiveness and are integral to numerous mRNA vaccine formulations. However, the development and selection of adjuvant platforms are still in their nascent stages, and the mechanisms of many adjuvants remain poorly understood. Additionally, the immunostimulatory capabilities of certain novel drug delivery systems (DDS) challenge the traditional definition of adjuvants, suggesting that a revision of this concept is necessary. This review offers a comprehensive exploration of the mechanisms and applications of adjuvants and self-adjuvant DDS. It thoroughly addresses existing issues mentioned above and details three main challenges of immune-related adverse event, unclear mechanisms, and unsatisfactory outcomes in old age group in the design and practical application of cancer mRNA vaccine adjuvants. Ultimately, this review proposes three optimization strategies which consists of exploring the mechanisms of adjuvant, optimizing DDS, and improving route of administration to improve effectiveness and application of adjuvants and self-adjuvant DDS. [ABSTRACT FROM AUTHOR]

Background: Ubiquitination is a critical post-translational modification which can be reversed with an enzyme family known as deubiquitinating enzymes (DUBs). It has been reported that dysregulation of deubiquitination leads to carcinogenesis. As a member of the DUBs family, proteasome 26 S subunit non-ATPase 7 (PSMD7) serves as an underlying tumour-promoting factor in multiple cancers. However, the clinical significance and biological functions of PSMD7 in pancreatic cancer (PC) remain unclear. Results: In this study, we first reported frequent overexpression of PSMD7 in PC tissues, and high levels of PSMD7 were markedly linked to shorter survival and a malignant phenotype in PC patients. An array of in vitro and in vivo gain/loss-of-function tests revealed that PSMD7 facilitates the progression of PC cells. Additionally, we found that PSMD7 promotes PC cell progression by activating the Notch homolog 1 (Notch1) signalling. Interestingly, in PC cells, the inhibitory effect of PSMD7 knockdown on cellular processes was comparable to that observed upon Notch1 knockdown. Mechanistically, PSMD7 deubiquitinated and stabilised sex determining region Y (SRY)-box 2 (SOX2), a key mediator of Notch1 signalling. The stabilisation of SOX2, mediated by PSMD7, dramatically increased SOX2 protein levels, subsequently activating the Notch1 pathway. Finally, restoration of SOX2 expression abrogated the PSMD7-silenced antitumour effect. Conclusions: Taken together, our work identifies and validates PSMD7 as a promoter of PC progression through augmentation of the Notch1 signalling pathway mediated by SOX2. This finding suggests that PSMD7 holds promise as a potential therapeutic target for the management of this refractory disease. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown an association between gut microbiota and cardiovascular diseases (CVDs). However, the underlying causal relationship remains unclear. This study aims to elucidate the causal relationship between gut microbiota and CVDs and to explore the pathogenic role of gut microbiota in CVDs. Methods: In this two-sample Mendelian randomization study, we used genetic instruments from publicly available genome-wide association studies, including single-nucleotide polymorphisms (SNPs) associated with gut microbiota (n = 14,306) and CVDs (n = 2,207,591). We employed multiple statistical analysis methods, including inverse variance weighting, MR Egger, weighted median, MR pleiotropic residuals and outliers, and the leave-one-out method, to estimate the causal relationship between gut microbiota and CVDs. Additionally, we conducted multiple analyses to assess horizontal pleiotropy and heterogeneity. Results: GWAS summary data were available from a pooled sample of 2,221,897 adult and adolescent participants. Our findings indicated that specific gut microbiota had either protective or detrimental effects on CVDs. Notably, Howardella (OR = 0.955, 95% CI: 0.913–0.999, P =.05), Intestinibacter (OR = 0.908, 95% CI:0.831–0.993, P =.03), Lachnospiraceae (NK4A136 group) (OR = 0.904, 95% CI:0.841–0.973, P =.007), Turicibacter (OR = 0.904, 95% CI: 0.838–0.976, P =.01), Holdemania (OR, 0.898; 95% CI: 0.810–0.995, P =.04) and Odoribacter (OR, 0.835; 95% CI: 0.710–0.993, P =.04) exhibited a protective causal effect on atrial fibrillation, while other microbiota had adverse causal effects. Similar effects were observed with respect to coronary artery disease, myocardial infarction, ischemic stroke, and hypertension. Furthermore, reversed Mendelian randomization analyses revealed that atrial fibrillation and ischemic stroke had causal effects on certain gut microbiotas. Conclusion: Our study underscored the importance of gut microbiota in the context of CVDs and lent support to the hypothesis that increasing the abundance of probiotics or decreasing the abundance of harmful bacterial populations may offer protection against specific CVDs. Nevertheless, further research is essential to translate these findings into clinical practice. [ABSTRACT FROM AUTHOR]

Background: Allergic rhinitis is a common health concern that affects quality of life. This study aims to examine the online search trends of allergic rhinitis in China before and after the COVID-19 epidemic and to explore the association between the daily air quality and online search volumes of allergic rhinitis in Beijing. Methods: We extracted the online search data of allergic rhinitis-related keywords from the Baidu index database from January 23, 2017 to June 23, 2022. We analyzed and compared the temporal distribution of online search behaviors across different themes of allergic rhinitis before and after the COVID-19 pandemic in mainland China, using the Baidu search index (BSI). We also obtained the air quality index (AQI) data in Beijing and assessed its correlation with daily BSIs of allergic rhinitis. Results: The online search for allergic rhinitis in China showed significant seasonal variations, with two peaks each year in spring from March to May and autumn from August and October. The BSI of total allergic rhinitis-related searches increased gradually from 2017 to 2019, reaching a peak in April 2019, and declined after the COVID-19 pandemic, especially in the first half of 2020. The BSI for all allergic rhinitis themes was significantly lower after the COVID-19 pandemic than before (all p values < 0.05). The results also revealed that, in Beijing, there was a significant negative association between daily BSI and AQI for each allergic rhinitis theme during the original variant strain epidemic period and a significant positive correlation during the Omicron variant period. Conclusion: Both air quality and the interventions used for COVID-19 pandemic, including national and local quarantines and mask wearing behaviors, may have affected the incidence and public concern about allergic rhinitis in China. The online search trends can serve as a valuable tool for tracking real-time public concerns about allergic rhinitis. By complementing traditional disease monitoring systems of health departments, these search trends can also offer insights into the patterns of disease outbreaks. Additionally, they can provide references and suggestions regarding the public's knowledge demands related to allergic rhinitis, which can further be instrumental in developing targeted strategies to enhance population-based disease education on allergic diseases. [ABSTRACT FROM AUTHOR]

Background: Established associated factors for DDH include female sex, breech presentation, family history, congenital malformations, oligohydramnios, and maternal hyperthyroidism. However, evidence for environmental factors that may contribute to DDH is limited and inconsistent. Methods: A systematic review of medical literature was conducted to collect data on environmental factors, including latitude, longitude, average yearly precipitation, average yearly temperature, minimum monthly temperature, and maximum monthly temperature, from all institutions that published articles on DDH. Univariate linear regression analysis was used to examine the correlation between environmental factors and DDH incidence, while multiple regression analysis was conducted to identify significant associated factors for DDH incidence. Results: Data from a total of 93 unique manuscripts were analyzed, revealing a significant negative correlation between DDH incidence and temperature, including average yearly temperature (r = -0.27, p = 0.008), minimum monthly temperature (r = -0.28, p = 0.006), and maximum monthly temperature (r = -0.23, p = 0.029). Additionally, there was a significant positive correlation between DDH incidence and latitude (r = 0.27, p = 0.009), and a significant negative correlation between DDH incidence and average yearly precipitation (r = -0.29, p = 0.004). In the final multiple regression analysis, temperature, including average yearly temperature, minimum monthly temperature, and maximum monthly temperature, were identified as significant associated factors for DDH incidence. Conclusion: The findings of this study suggest an association between cold weather and DDH incidence. Further research should explore the link between cold weather and DDH incidence, offering insights into potential interventions for cold climates. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have revolutionized cancer management and have been widely applied; however, they still have some limitations in terms of efficacy and toxicity. There are multiple treatment regimens in Traditional Chinese Medicine (TCM) that play active roles in combination with Western medicine in the field of oncology treatment. TCM with ICIs works by regulating the tumor microenvironment and modulating gut microbiota. Through multiple targets and multiple means, TCM enhances the efficacy of ICIs, reverses resistance, and effectively prevents and treats ICI-related adverse events based on basic and clinical studies. However, there have been few conclusions on this topic. This review summarizes the development of TCM in cancer treatment, the mechanisms underlying the combination of TCM and ICIs, existing studies, ongoing trials, and prospects for future development. [ABSTRACT FROM AUTHOR]

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) exploit the concept of synthetic lethality and offer great promise in the treatment of tumors with deficiencies in homologous recombination (HR) repair. PARPi exert antitumor activity by blocking Poly(ADP-ribosyl)ation (PARylation) and trapping PARP1 on damaged DNA. To date, the U.S. Food and Drug Administration (FDA) has approved four PARPi for the treatment of several cancer types including ovarian, breast, pancreatic and prostate cancer. Although patients with HR-deficient tumors benefit from PARPi, majority of tumors ultimately develop acquired resistance to PARPi. Furthermore, even though BRCA1/2 mutations are commonly used as markers of PARPi sensitivity in current clinical practice, not all patients with BRCA1/2 mutations have PARPi-sensitive disease. Thus, there is an urgent need to elucidate the molecular mechanisms of PARPi resistance to support the development of rational effective treatment strategies aimed at overcoming resistance to PARPi, as well as reliable biomarkers to accurately identify patients who will most likely benefit from treatment with PARPi, either as monotherapy or in combination with other agents, so called marker-guided effective therapy (Mget). In this review, we summarize the molecular mechanisms driving the efficacy of and resistance to PARPi as well as emerging therapeutic strategies to overcome PARPi resistance. We also highlight the identification of potential markers to predict PARPi resistance and guide promising PARPi-based combination strategies. [ABSTRACT FROM AUTHOR]

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) exploit the concept of synthetic lethality and offer great promise in the treatment of tumors with deficiencies in homologous recombination (HR) repair. PARPi exert antitumor activity by blocking Poly(ADP-ribosyl)ation (PARylation) and trapping PARP1 on damaged DNA. To date, the U.S. Food and Drug Administration (FDA) has approved four PARPi for the treatment of several cancer types including ovarian, breast, pancreatic and prostate cancer. Although patients with HR-deficient tumors benefit from PARPi, majority of tumors ultimately develop acquired resistance to PARPi. Furthermore, even though BRCA1/2 mutations are commonly used as markers of PARPi sensitivity in current clinical practice, not all patients with BRCA1/2 mutations have PARPi-sensitive disease. Thus, there is an urgent need to elucidate the molecular mechanisms of PARPi resistance to support the development of rational effective treatment strategies aimed at overcoming resistance to PARPi, as well as reliable biomarkers to accurately identify patients who will most likely benefit from treatment with PARPi, either as monotherapy or in combination with other agents, so called marker-guided effective therapy (Mget). In this review, we summarize the molecular mechanisms driving the efficacy of and resistance to PARPi as well as emerging therapeutic strategies to overcome PARPi resistance. We also highlight the identification of potential markers to predict PARPi resistance and guide promising PARPi-based combination strategies. [ABSTRACT FROM AUTHOR]

Background: Pichia pastoris (Komagataella phaffii) is a model organism widely used for the recombinant expression of eukaryotic proteins, and it can metabolize methanol as its sole carbon and energy source. Methanol is oxidized to formaldehyde by alcohol oxidase (AOX). In the dissimilation pathway, formaldehyde is oxidized to CO2 by formaldehyde dehydrogenase (FLD), S-hydroxymethyl glutathione hydrolase (FGH) and formate dehydrogenase (FDH). Results: The transcriptome and metabolome of P. pastoris were determined under methanol cultivation when its dissimilation pathway cut off. Firstly, Δfld and Δfgh were significantly different compared to the wild type (GS115), with a 60.98% and 23.66% reduction in biomass, respectively. The differential metabolites between GS115 and Δfld were mainly enriched in ABC transporters, amino acid biosynthesis, and protein digestion and absorption. Secondly, comparative transcriptome between knockout and wild type strains showed that oxidative phosphorylation, glycolysis and the TCA cycle were downregulated, while alcohol metabolism, proteasomes, autophagy and peroxisomes were upregulated. Interestingly, the down-regulation of the oxidative phosphorylation pathway was positively correlated with the gene order of dissimilation pathway knockdown. In addition, there were significant differences in amino acid metabolism and glutathione redox cycling that raised our concerns about formaldehyde sorption in cells. Conclusions: This is the first time that integrity of dissimilation pathway analysis based on transcriptomics and metabolomics was carried out in Pichia pastoris. The blockage of dissimilation pathway significantly down-regulates the level of oxidative phosphorylation and weakens the methanol assimilation pathway to the point where deficiencies in energy supply and carbon fixation result in inefficient biomass accumulation and genetic replication. In addition, transcriptional upregulation of the proteasome and autophagy may be a stress response to resolve formaldehyde-induced DNA–protein crosslinking. [ABSTRACT FROM AUTHOR]

Background: Although the incidence, types, and radiological outcomes of simultaneous ipsilateral pelvic ring and acetabular fractures have been reported, there have been no reports on factors that may affect the quality of acetabular fracture reduction. Here, we evaluate the radiological outcomes of patients treated for simultaneous ipsilateral pelvic and acetabular fractures and analyze the factors that affect the quality of acetabular fracture reduction.Methods: We conducted a retrospective review of patients treated for simultaneous ipsilateral pelvic ring and acetabular fractures between 2016 and 2020. Factors that may predict inadequate reduction of the acetabular fracture were analyzed.Results: Data from 27 hips of 26 patients were collected. AO B2.2 and anterior columnar fractures were the most common types of pelvic ring and acetabular fractures, respectively. Univariate analysis revealed that Matta's criteria for pelvic ring fracture may be useful for predicting fair to poor quality of acetabular fracture reduction on X-rays. Furthermore, associated fractures identified by Letournel's classification system on computed tomography may be predictive of greater step-offs.Conclusions: Associated fractures identified via Letournel's classification may contribute to inadequate reduction of acetabular fractures. Matta's criteria for pelvic ring fractures may also be useful for predicting the risk of inadequate reduction of the acetabulum on X-ray scans. These findings may be assessed intraoperatively by fluoroscopy before beginning osteosynthesis for acetabular fractures. [ABSTRACT FROM AUTHOR]

Background: Changshun green-shell laying hens are unique to Guizhou Province, China, and have high egg quality. Improving egg production performance has become an important breeding task, and in recent years, the development of high-throughput sequencing technology provides a fast and exact method for genetic selection. Therefore, we aimed to use this technology to analyze the differences between the ovarian mRNA transcriptome of low and high-yield Changshun green-shell layer hens, identify critical pathways and candidate genes involved in controlling the egg production rate, and provide basic data for layer breeding. Results: The egg production rates of the low egg production group (LP) and the high egg production group (HP) were 68.00 ± 5.56 % and 93.67 ± 7.09 %, with significant differences between the groups (p < 0.01). Moreover, the egg weight, shell thickness, strength and layer weight of the LP were significantly greater than those of the HP (p < 0.05). More than 41 million clean reads per sample were obtained, and more than 90 % of the clean reads were mapped to the Gallus gallus genome. Further analysis identified 142 differentially expressed genes (DEGs), and among them, 55 were upregulated and 87 were downregulated in the ovaries. KEGG pathway enrichment analysis identified 9 significantly enriched pathways, with the neuroactive ligand-receptor interaction pathway being the most enriched. GO enrichment analysis indicated that the GO term transmembrane receptor protein tyrosine kinase activity, and the DEGs identified in this GO term, including PRLR, NRP1, IL15, BANK1, NTRK1, CCK, and HGF may be associated with crucial roles in the regulation of egg production. Conclusions: The above-mentioned DEGs may be relevant for the molecular breeding of Changshun green-shell laying hens. Moreover, enrichment analysis indicated that the neuroactive ligand-receptor interaction pathway and receptor protein tyrosine kinases may play crucial roles in the regulation of ovarian function and egg production. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSCs) exhibit active abilities to suppress or modulate deleterious immune responses by various molecular mechanisms. These cells are the subject of major translational efforts as cellular therapies for immune-related diseases and transplantations. Plenty of preclinical studies and clinical trials employing MSCs have shown promising safety and efficacy outcomes and also shed light on the modifications in the frequency and function of regulatory T cells (T regs). Nevertheless, the mechanisms underlying these observations are not well known. Direct cell contact, soluble factor production, and turning antigen-presenting cells into tolerogenic phenotypes, have been proposed to be among possible mechanisms by which MSCs produce an immunomodulatory environment for T reg expansion and activity. We and others demonstrated that adult bone marrow (BM)-MSCs suppress adaptive immune responses directly by inhibiting the proliferation of CD4+ helper and CD8+ cytotoxic T cells but also indirectly through the induction of T regs. In parallel, we demonstrated that fetal liver (FL)-MSCs demonstrates much longer-lasting immunomodulatory properties compared to BM-MSCs, by inhibiting directly the proliferation and activation of CD4+ and CD8+ T cells. Therefore, we investigated if FL-MSCs exert their strong immunosuppressive effect also indirectly through induction of T regs. Methods: MSCs were obtained from FL and adult BM and characterized according to their surface antigen expression, their multilineage differentiation, and their proliferation potential. Using different in vitro combinations, we performed co-cultures of FL- or BM-MSCs and murine CD3+CD25−T cells to investigate immunosuppressive effects of MSCs on T cells and to quantify their capacity to induce functional T regs. Results: We demonstrated that although both types of MSC display similar cell surface phenotypic profile and differentiation capacity, FL-MSCs have significantly higher proliferative capacity and ability to suppress both CD4+ and CD8+ murine T cell proliferation and to modulate them towards less active phenotypes than adult BM-MSCs. Moreover, their substantial suppressive effect was associated with an outstanding increase of functional CD4+CD25+Foxp3+ T regs compared to BM-MSCs. Conclusions: These results highlight the immunosuppressive activity of FL-MSCs on T cells and show for the first time that one of the main immunoregulatory mechanisms of FL-MSCs passes through active and functional T reg induction. [ABSTRACT FROM AUTHOR]

Background: Although the benefits of sodium–glucose cotransporter 2 inhibitors (SGLT2i) on cardiovascular events have been reported in patients with type 2 diabetes mellitus (T2DM) with or without heart failure (HF), the impact of SGLT2i on cardiac remodelling remains to be established. Methods: We searched the PubMed, Embase, Cochrane Library and Web of Science databases up to November 16th, 2020, for randomized controlled trials reporting the effects of SGLT2i on parameters of cardiac structure, cardiac function, plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) level or the Kansas City Cardiomyopathy Questionnaire (KCCQ) score in T2DM patients with or without chronic HF. The effect size was expressed as the mean difference (MD) or standardized mean difference (SMD) and its 95% confidence interval (CI). Subgroup analyses were performed based on the stage A–B or stage C HF population and HF types. Results: Compared to placebo or other antidiabetic drugs, SGLT2i showed no significant effects on left ventricular mass index, left ventricular end diastolic volume index, left ventricular end systolic volume index, or left atrial volume index. SGLT2i improved left ventricular ejection fraction only in the subgroup of HF patients with reduced ejection fraction (MD 3.16%, 95% CI 0.11 to 6.22, p = 0.04; I2 = 0%), and did not affect the global longitudinal strain in the overall analysis including stage A–B HF patients. SGLT2i showed benefits in the E/e' ratio (MD − 0.45, 95% CI − 0.88 to − 0.03, p = 0.04; I2 = 0%), plasma NT-proBNP level (SMD − 0.09, 95% CI − 0.16 to − 0.03, p = 0.004; I2 = 0%), and the KCCQ score (SMD 3.12, 95% CI 0.76 to 5.47, p = 0.01; I2 = 0%) in the overall population. Conclusion: The use of SGLT2i was associated with significant improvements in cardiac diastolic function, plasma NT-proBNP level, and the KCCQ score in T2DM patients with or without chronic HF, but did not significantly affect cardiac structural parameters indexed by body surface area. The LVEF level was improved only in HF patients with reduced ejection fraction. [ABSTRACT FROM AUTHOR]

Background: To compare the outcomes after surgical intervention, including external fixation (EF) with the optional addition of K-pins or open reduction and internal fixation (ORIF) with a volar locking plate (VLP), in patients with distal radius fracture aged > 80 years.Methods: We reviewed 69 patients with a distal radius fracture aged > 80 years who treated under surgical intervention from 2011 to 2017 retrospectively. Their demographic data and complications were recorded. Preoperative, postoperative, and last follow-up plain films were analyzed. The functional outcomes of wrist range of motion were also evaluated.Results: 41 patients were treated with EF with the optional addition of K-pins, while 28 patients were treated with ORIF with a VLP. The radiological parameters, including ulnar variance and radial inclination, at the last follow-up were significantly more acceptable in the VLP group (p = 0.01, p = 0.03, respectively). The forearm supination was significantly better in patients treated with VLP (p = 0.002). The overall incidence of complications was lower in the VLP group (p = 0.003).Conclusion: VLP provides better radiological outcomes, wrist supination and lower complication rates than EF. Therefore, although EF is still widely used because of its acceptable results and easy application, we recommend VLP as a suitable treatment option for distal radius fracture in the geriatric population aged > 80 years. [ABSTRACT FROM AUTHOR]

Background: Primary angiosarcomas of the right atrium are extremely rare, often resulted in missed diagnosis or misdiagnosis with routine examination tools. These malignant cardiac tumors are highly aggressive with generally poor prognosis. Surgical excision is the mainstay of treatment as it is essentially not responsive to current regimens of chemoradiotherapy.Case Presentation: Herein, we describe a patient who initially presented with paroxysmal atrial fibrillation and was subsequently treated with radiofrequency catheter ablation (RFCA). Prior to RFCA, an initial transesophageal echocardiography revealed a local thickening of the intratrial septum. Three months later, she was hospitalized with progressive dyspnea and massive pericardial effusion. A large immobile, non-pedunculated mass, occupying almost half of the right atrium was detected by transthoracic and transesophageal echocardiogram. Multimodality cardiac imaging was useful in further characterizing this mass, which was ultimately diagnosed as an angiosarcoma based upon biopsy results. The growth rate was extremely rapid following RFCA, and patient underwent surgical excision. After discharge, the angiosarcoma recurred and patient survived for 7 months from the first episode of tamponade.Conclusions: Primary cardiac angiosarcoma of the right atrium can easily be mistaken for structural anomalies in its early stages, losing the opportunity for initiating earlier treatments to improve potential patient outcomes. The correct diagnosis of this rare case relied on the comprehensive utilization of multimodal imaging techniques including biopsy. [ABSTRACT FROM AUTHOR]

Background: Disease-disease similarities can be investigated from multiple perspectives. Identifying similar diseases based on the underlying biomolecular interactions can be especially useful, because it may shed light on the common causes of the diseases and therefore may provide clues for possible treatments. Here we introduce DeCoaD, a web-based program that uses a novel method to assign pair-wise similarity scores, called correlations, to genetic diseases. Findings: DeCoaD uses a random walk to model the low of information in a network within which nodes are either diseases or proteins and links signify either protein-protein interactions or disease-protein associations. For each protein node, the total number of visits by the random walker is called the weight of that node. Using a disease as both the starting and the terminating points of the random walks, a corresponding vector, whose elements are the weights associated with the proteins, can be constructed. The similarity between two diseases is deined as the cosine of the angle between their associated vectors. For a user-specified disease, DeCoaD outputs a list of similar diseases (with their corresponding correlations), and a graphical representation of the disease families that they belong to. Based on a probabilistic clustering algorithm, DeCoaD also outputs the clusters that the disease of interest is a member of, and the corresponding probabilities. The program also provides an interface to run enrichment analysis for the given disease or for any of the clusters that contains it. Conclusions: DeCoaD uses a novel algorithm to suggest non-trivial similarities between diseases with known gene associations, and also clusters the diseases based on their similarity scores. DeCoaD is available at http://www.ncbi. nlm.nih.gov/CBBresearch/Yu/mn/DeCoaD/. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung cancer patients with mutated EGFR. However, the efficacy of EGFR-TKIs in wild-type EGFR tumors has been shown to be marginal. Methods that can sensitize EGFR-TKIs to EGFR wild-type NSCLC remain rare. Hence, we determined whether combination treatment can maximize the therapeutic efficacy of EGFR-TKIs. Methods: We established a focused drug screening system to investigate candidates for overcoming the intrinsic resistance of wild-type EGFR NSCLC to EGFR-TKIs. Molecular docking assays and western blotting were used to identify the binding mode and blocking effect of the candidate compounds. Proliferation assays, analyses of drug interactions, colony formation assays, flow cytometry and nude mice xenograft models were used to determine the effects and investigate the molecular mechanism of the combination treatment. Results: Betulinic acid (BA) is effective at targeting EGFR and synergizes with EGFR-TKIs (gefitinib and osimertinib) preferentially against wild-type EGFR. BA showed inhibitory activity due to its interaction with the ATP-binding pocket of EGFR and dramatically enhanced the suppressive effects of EGFR-TKIs by blocking EGFR and modulating the EGFR-ATK-mTOR axis. Mechanistic studies revealed that the combination strategy activated EGFR-induced autophagic cell death and that the EGFR-AKT-mTOR signaling pathway was essential for completing autophagy and cell cycle arrest. Activation of the mTOR pathway or blockade of autophagy by specific chemical agents markedly attenuated the effect of cell cycle arrest. In vivo administration of the combination treatment caused marked tumor regression in the A549 xenografts. Conclusions: BA is a potential wild-type EGFR inhibitor that plays a critical role in sensitizing EGFR-TKI activity. BA combined with an EGFR-TKI effectively suppressed the proliferation and survival of intrinsically resistant lung cancer cells via the inhibition of EGFR as well as the induction of autophagy-related cell death, indicating that BA combined with an EGFR-TKI may be a potential therapeutic strategy for overcoming the primary resistance of wild-type EGFR-positive lung cancers. Highlights: 1. BA is a potent wild-type EGFR inhibitor. 2. BA enhances the anticancer efficacy of erlotinib/gefitinib in NSCLC patients with wild-type EGFR. 3. The combination of BA and gefitinib/osimertinib synergistically blocks EGFR and inhibits the PI3K-AKT-mTOR signaling pathway, leading to autophagic cell death and cell cycle arrest. 4. This combination strategy targets wild-type EGFR in NSCLC and induces autophagy and tumor suppression in vivo. BA, an EGFR inhibitor, sensitizes EGFR-TKIs' activity, indicating that BA plus EGFR-TKIs may be a potential therapeutic strategy to overcome the primary resistance of wild-type EGFR NSCLC. [ABSTRACT FROM AUTHOR]

Background: To compare the surgical effects of coronary intervention through the transradial intervention (TRI) versus distal transradial intervention (dTRI) approach.Methods: From September 2020 to April 2021, 302 patients undergoing coronary artery angiography (CAG) or percutaneous coronary intervention in our hospital were retrospectively included. Patients were divided into the TRI group and dTRI group with 151 cases in each group. The technique features, lesion features, and cannulation process were compared between the two groups.Results: The number of patients who underwent CAG in the dTRI group (35.1%) was significantly greater compared with the TRI group (12.6%) (P < 0.01). The rates of triple vessel lesions, calcification lesions and chronic total occlusion lesions were increased in the TRI group compared with the dTRI group (P < 0.05). The average radial artery diameter (RAD) in the TRI group (2.550 ± 0.417 mm) was greater than that in the dTRI group (2.070 ± 0.360 mm) (P < 0.05). The hemostasis time of the dTRI group (173.272 ± 41.807 min) was lower than that of the TRI group (273.417 ± 42.098 min) (P < 0.05). The radial artery occlusion (RAO) rates in the dTRI group (2.6%) were lower than those in the TRI group (8.6%) (P < 0.05). The dTRI group had a higher satisfaction score than the TRI group (P > 0.05). RAD at the puncture site was a predictor of the overall cannulation success rate with an AUC of 0.747 (95% CI 0.663-0.860; P < 0.05).Conclusions: Despite a steep learning curve, the dTRI approach had a shorter hemostasis time, reduced RAO rates, and notable preliminary safety results compared with the TRI approach. The dTRI approach can be used as a supplemental method to the TRI approach. [ABSTRACT FROM AUTHOR]

Background: Osteosynthesis for sacroiliac joint (SIJ) diastasis using an iliosacral screw (ISS) and a trans-iliac-trans-sacral screw (TITSS) can be performed using a closed or an open method. However, no clear indication for open reduction has been established. Methods: Data on patients with unilateral traumatic SIJ diastasis who underwent ISS and TITSS fixation were retrospectively collected and separated into groups according to the reduction method: closed reduction group (C group) and open reduction group (O group). Demographic data and perioperative image assessments were compared between the groups. The critical distance of the SIJ was identified to elucidate the indication for open reduction of the diastatic SIJ. Results: Fifty-six patients met the inclusion criteria over a 3-year period. There was no significant difference in the reduction quality of pelvic ring injuries between the groups, according to Matta’s and Lefaivre’s criteria. The improvement in the SIJ distance was significantly greater in the O group than in the C group in the axial plane on multiplanar computed tomography (p = 0.021). This model predicted that a difference of > 3.71 mm between the injured and healthy SIJ was a recommended indication for open reduction, with an area under the curve of 0.791 (95% confidence interval 0.627–0.955, p = 0.004). Conclusions: Open reduction for SIJ diastasis might achieve better reduction quality than does closed reduction in the axial plane in selected cases. When the difference between the injured and healthy SIJ was wider than 3.71 mm, open reduction was recommended for satisfactory radiological outcomes. [ABSTRACT FROM AUTHOR]

Background: Osteosynthesis for geriatric femoral pertrochanteric fractures using the linear compression integrated screw intramedullary nail system (INTERTAN™) has become popular. Nonetheless, cases of perioperative peri-implant fractures have been reported following this surgical technique. The factors responsible for this complication remain unclear. Therefore, we investigated perioperative peri-implant fracture risk factors and incidence, as well as overall outcomes, using the INTERTAN™ system for geriatric femoral pertrochanteric fractures. Methods: We retrospectively reviewed 98 consecutive patients with geriatric femoral pertrochanteric fractures after INTERTAN™ fixation, with at least a 12-month follow-up period between May 2020 and April 2022 at a single medical institute. The patients’ demographic characteristics, fracture pattern, quality of reduction, quality of fixation, nail length, morphology of the femur, and perioperative complications were recorded and analyzed. Results: Among the 98 patients, 92 achieved union during follow-up. Twelve perioperative peri-implant fractures (12.2%) were recorded, all of which occurred during or within 1 month of osteosynthesis. Except for one patient who underwent re-osteosynthesis, the others underwent nonoperative treatment, and all achieved union. Multiple regression analysis revealed morphology of the femur with low-lesser trochanter width (odds ratio (OR) 0.532, 95% confidence interval (CI) 0.33–0.86, p = 0.01) to be the only factor contributing to perioperative peri-implant fractures. When the Youden index was used, the optimal cut-off value was 20.2 mm of low-lesser trochanter width. Low-lesser trochanter width < 20.2 mm was found to be a potential factor causing perioperative peri-implant fractures (OR 17.81, 95% CI 1.67–19.76, p = 0.017). Conclusions: Morphology of the femur with a low-lesser trochanter width smaller than 20.2 mm was found to be the only potential contributor to perioperative peri-implant fractures when using INTERTAN™ for geriatric femoral pertrochanteric fractures. Care should be taken during osteosynthesis, focusing not only on the fracture site but also on the femoral cortex around the implant. Although perioperative peri-implant fractures were observed within one month following osteosynthesis, the majority of these cases were effectively treated without surgical intervention. [ABSTRACT FROM AUTHOR]

Background: Studies have shown that HSP20 (heat-shock protein 20) genes play important roles in regulating plant growth, development, and stress response. However, the grape HSP20 gene family has not been well studied. Results: A total of 48 VvHSP20 genes were identified from the grape genome, which were divided into 11 subfamilies (CI, CII, CIII, CV, CVI, CVII, MI, MII, ER, CP and PX/Po) based on a phylogenetic analysis and subcellular localization. Further structural analysis showed that most of the VvHSP20 genes (93.8%) had no intron or only one intron, while genes that clustered together based on a phylogenetic tree had similar motifs and evolutionarily conserved structures. The HSP20s share a conservedα-crystalline domain (ACD) and the different components of the ACD domain suggest the functional diversity of VvHSP20s. In addition, the 48 VvHSP20 genes were distributed on 12 grape chromosomes and the majority of VvHSP20 genes were located at the proximal or distal ends of chromosomes. Chromosome mapping indicated that four groups of VvHSP20 genes were identified as tandem duplication genes. Phytohormone responsive, abiotic and biotic stress-responsive, and plant development-related cis-elements were identified from the cis-regulatory elements analysis of VvHSP20s. The expression profiles of VvHSP20s genes (VvHSP20–1, 11, 14, 17, 18, 19, 20, 24, 25, 28, 31, 39, 42, and 43) were largely similar between RNA-Seq and qRT-PCR analysis after hydrogen peroxide (H2O2) treatment. The results showed that most VvHSP20s were down-regulated by H2O2 treatment during fruit development. VvHSP20s genes were indeed found to be involved in the grape berry development and differences in their transcriptional levels may be the result of functional differentiation during evolution. Conclusions: Our results provide valuable information on the evolutionary relationship of genes in the VvHSP20 family, which is useful for future studies on the functional characteristics of VvHSP20 genes in grape. [ABSTRACT FROM AUTHOR]

Background: The tumour microenvironment conferred by mesenchymal stem cells (MSCs) plays a key role in tumour development and progression. We previously determined that platelet-activating factor receptor (PAFR) was overexpressed in ovarian cancer cells (OCCs) and that PAF can promote ovarian cancer progression via PAF/PAFR-mediated inflammatory signalling pathways. Evidence suggests that MSCs can secrete high concentrations of PAF. Here, we investigated the role of PAF/PAFR signalling in the microenvironment mediated by MSCs and OCCs and its effect on cancer progression.Methods: The PAF concentrations in the culture media of MSCs, OCCs and co-cultured MSCs and OCCs were determined by ELISA. The effects of MSCs on OCCs in vitro were assessed on cells treated with conditioned medium (CM). The expression and phosphorylation of key proteins in the PAF/PAFR signalling pathway were evaluated. In vivo, MSCs/RFP and SKOV3 cells were co-administered at different proportions to nude mice by interscapular injection. Mice in the WEB2086 group were intraperitoneally injected with the PAFR antagonist WEB2086 at a dose of 1 mg/kg.d for the duration of the animal experiments. Tumour progression was observed, and the weight and survival time of mice were measured. The PAF concentration in peripheral and tumour site blood was determined by ELISA.Results: High concentrations of PAF were detected in CM from MSCs and MSCs co-cultured with OCCs. Both types of medium promoted non-mucinous OCC proliferation and migration but had no effect on mucinous-type OCCs. These effects could be blocked by PAFR inhibitors. The expression and phosphorylation of key proteins in the PAF/PAFR pathway significantly increased upon treatment with PAF and MSC-CM. In vivo, the tumour volume was larger following co-injection of SKOV3 cells and MSCs/RFP than following injection of SKOV3 cells alone. The tumour-promoting effect of MSCs/RFP was blocked by the PAFR antagonist WEB2086. Serum PAF concentrations significantly increased in co-injected mice.Conclusion: Our results suggest that the tumour-promoting effect of MSCs on OCCs via their cross-talk in the tumour microenvironment was, at least in part, mediated by the PAF/PAFR pathway, suggesting a new target for the treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, frequently accompanied by metastasis and aerobic glycolysis. Cancer cells adjust their metabolism by modulating the PKM alternative splicing and facilitating PKM2 isoform expression. Therefore, identifying factors and mechanisms that control PKM alternative splicing is significant for overcoming the current challenges in ATC treatment. Results: In this study, the expression of RBX1 was largely enhanced in the ATC tissues. Our clinical tests suggested that high RBX1 expression was significantly related to poor survival. The functional analysis indicated that RBX1 facilitated the metastasis of ATC cells by enhancing the Warburg effect, and PKM2 played a key role in RBX1-mediated aerobic glycolysis. Furthermore, we confirmed that RBX1 regulates PKM alternative splicing and promotes the PKM2-mediated Warburg effect in ATC cells. Moreover, ATC cell migration and aerobic glycolysis induced by RBX1-mediated PKM alternative splicing are dependent on the destruction of the SMAR1/HDAC6 complex. RBX1, as an E3 ubiquitin ligase, degrades SMAR1 in ATC through the ubiquitin–proteasome pathway. Conclusion: Overall, our study identified the mechanism underlying the regulation of PKM alternative splicing in ATC cells for the first time and provides evidence about the effect of RBX1 on cellular adaptation to metabolic stress. [ABSTRACT FROM AUTHOR]

Objective: This retrospective study aimed to explore whether puncturing and aspirating asynchronized large follicles during long GnRH-a protocol COH impacted IVF-ET outcomes. Methods: A total of 180 patients with asynchronized follicles during long GnRH-a protocol COH were retrospectively analyzed. They were divided into a puncture group, Group 1 (n = 81), and a non-puncture group, Group 2 (n = 99), according to whether puncture and aspiration were performed on the prematurely developing large follicles. The data of the selected patients were statistically analyzed to assess the effect of large follicle puncture and aspiration during ovulation induction on the final pregnancy results. In addition, we tentatively divided these 180 patients into either Group A (DF ≤ 14 mm) or Group B (DF > 14 mm) according to whether the diameter of the dominant large follicles (DF) exceeded 14 mm at the time of appearance. These two groups were then further divided into four subgroups: Subgroup A1 (DF ≤ 14 mm, patients underwent large follicle puncture), Subgroup A2 (DF ≤ 14 mm, patients did not undergo large follicle puncture), Subgroup B1 (DF > 14 mm, patients underwent large follicle puncture), and Subgroup B2 (DF > 14 mm, patients did not undergo large follicle puncture) based on whether large follicle puncture and aspiration were performed or not, aiming to compare the effects of large follicle puncture and aspiration on the clinical outcomes of patients with dominant large follicles at different time points. Results: Group 1 exhibited significantly higher oocyte maturation rate (92.3% vs. 88.9%, P = 0.009) and high-quality embryo rate (75.2% vs. 65.7%, P = 0.007) compared with Group 2. No differences were observed in the number of oocytes retrieved, 2PN fertilization rate, clinical pregnancy rate, abortion rate, and live birth rate between the two groups (P > 0.05). When the dominant large follicles' diameter was ≤ 14 mm, the final oocyte maturation rate (92.7% vs. 88.1%, P = 0.023), high-quality embryo rate (72.9% vs. 61.8%, P = 0.047) and live birth rate (54.5% vs. 31.9%, P = 0.043) of Subgroup A1 were significantly higher than those of Subgroup A2. In contrast, when the dominant large follicles' diameter was > 14 mm, no statistical difference was observed in all data. Conclusions: Large follicle puncture and aspiration in long GnRH-a protocol COH could improve the oocyte maturation rate and high-quality embryo rate in patients with asynchronized follicles. However, clinical pregnancy and live birth rates were not significantly improved. In addition, when the dominant follicles' diameter did not exceed 14 mm, large follicles puncture and aspiration significantly improved the patient's oocyte maturation rate, high-quality embryo rate and live birth rate. [ABSTRACT FROM AUTHOR]

Background: Microglia mediate amyloid-beta peptide (Aβ)-induced neuroinflammation, which is one of the key events in the pathogenesis of Alzheimer's disease (AD). Decoy receptor 3 (DcR3)/TNFRSF6B is a pleiotropic immunomodulator that promotes macrophage differentiation toward the M2 anti-inflammatory phenotype. Based on its role as an immunosupressor, we examined whether DcR3 could alleviate neuroinflammation and AD-like deficits in the central nervous system. Method: We crossed human APP transgenic mice (line J20) with human DcR3 transgenic mice to generate wild-type, APP, DcR3, and APP/DcR3 mice for pathological analysis. The Morris water maze, fear conditioning test, open-field, and elevated-plus maze were used to access their cognitive behavioral changes. Furthermore, the pathological and immune profiles were examined by immunostaining, ELISA, Q-PCR, and IP. In vitro assays were designed to examine DcR3-mediated innate cytokine profile alteration and the potential protective mechanism. Results: We reported that DcR3 ameliorates hippocampus-dependent memory deficits and reduces amyloid plaque deposition in APP transgenic mouse. The protective mechanism of DcR3 mediates through interacting with heparan sulfate proteoglycans and activating IL-4+ YM1+ M2a-like microglia that reduces Aβ-induced proinflammatory cytokines and promotes phagocytosis ability of microglia. Conclusion: The neuroprotective effect of DcR3 is mediated via modulating microglia activation into anti-inflammatory M2a phenotype, and upregulating DcR3 expression in the brain may be a potential therapeutic approach for AD. [ABSTRACT FROM AUTHOR]

Background: Adult sporadic Burkitt lymphoma (BL) is a rare but highly aggressive subtype of lymphoma which lacks its own unique prognostic model. Systemic inflammatory biomarkers have been confirmed as prognostic markers in several types of malignancy. Our objective was to explore the predictive value of pretreatment inflammatory biomarkers and establish a novel, clinically applicable prognostic index for adult patients with sporadic BL. Methods: We surveyed retrospectively 336 adult patients with newly diagnosed sporadic BL at 8 Chinese medical centers and divided into training cohort (n = 229) and validation cohort (n = 107). The pretreatment inflammatory biomarkers were calculated for optimal cut-off value. The association between serum biomarkers and overall survival (OS) was analyzed by Kaplan–Meier curves and Cox proportional models. The risk stratification was defined based on normal LDH level, Ann Arbor stage of I and completely resected abdominal lesion or single extra-abdominal mass < 10 cm. Results and conclusions: Univariate and multivariate analyses revealed that platelets< 254 × 109/L, albumin< 40 g/L, lactate dehydrogenase≥334 U/L independently predicted unfavorable OS. We used these data as the basis for the prognostic index, in which patients were stratified into Group 1 (no or one risk factor), Group 2 (two risk factors), or Group 3 (three risk factors), which were associated with 5-year OS rates of 88.1, 72.4, and 45%, respectively. In the subgroup analysis for high-risk patients, our prognostic model results showed that high-risk patients with no more than one adverse factor presented a 5-year survival rate of 85.9%, but patients with three adverse factors had a 5-year survival rate of 43.0%. Harrell's concordance index (C-index) of the risk group score was 0.768. Therefore, the new prognostic model could be used to develop risk-adapted treatment approaches for adult sporadic BL. [ABSTRACT FROM AUTHOR]

Background: Enteral nutrition is a major pathway of nutrition for patients requiring critical care. However, it remains unclear whether intermittent or continuous feeding is the better approach, especially after nasogastric enteral nutrition via a gastric tube. Therefore, this randomized controlled clinical study was designed to observe the effects of different methods on critically ill patients.Methods: Different Feeding Methods on Gastrointestinal Function of Critical patients (DFM-GFC) is a randomized clinical study that will be performed to assess the effects of three feeding methods on critically ill patients. A total of 90 critically ill patients will be equally randomized into three groups: continuous feeding, cyclic feeding, and intermittent feeding. The patients will be administered a gastrointestinal nutrition preparation over 24 h via a gastric tube or over 16 h via an intermittent pump. The primary outcome is the mean duration (days) to reach the caloric goal in each group. Secondary outcomes include the rate of onset of gastric residual, abdominal pressure, the rate of onset pneumonia, and the proportion of individuals achieving the caloric goal. Additionally, the length of intensive care unit (ICU) stay and mortality rate at 28 days post-enrolment will be evaluated.Discussion: This study will observe the effects of different feeding methods on various parameters, such as the energy target and gastrointestinal motility, in critically ill patients to improve quality of life and reduce the case fatality rate. The purpose of this study is to explore whether there is a more effective, safer and cost-efficient feeding method for the clinical treatment of critically ill patients.Trial Registration: ID: NCT04224883, ClinicalTrials.gov , registered January 9, 2020. [ABSTRACT FROM AUTHOR]

Background: To date, no study has compared the surgical outcomes between posterior wall acetabular fractures with and without associated femoral head fractures. Therefore, we evaluated whether an associated femoral head fracture increases the incidence of fracture sequelae, including post-traumatic osteoarthritis (PTOA) and osteonecrosis of the femoral head (ONFH), following osteosynthesis for posterior wall acetabular fractures.Methods: This retrospective clinical study enrolled 183 patients who underwent osteosynthesis for posterior wall acetabular fractures between 2009 and 2019 at a level-1 trauma center. The incidence of PTOA, ONFH, and conversion to total hip arthroplasty (THA) was reviewed.Results: The incidence of PTOA, ONFH, and conversion to THA following osteosynthesis were 20.2%, 15.9%, and 17.5%, respectively. The average time for conversion to THA was 18.76 ± 20.15 months (range, 1-82). The results for the comparison of patients with associated femoral head fractures and isolated posterior wall acetabular fractures were insignificant (PTOA: 27.3% vs. 15.7%, p = 0.13; ONFH: 18.2% vs. 14.3%, p = 0.58; conversion to THA: 20.4% vs. 15.7%, p = 0.52). Upon evaluating other variables, only marginal impaction negatively affected ONFH incidence (odds ratio: 2.90).Conclusions: Our methods failed to demonstrate a significant difference in the rate of PTOA, ONFH, or conversion to THA in posterior wall acetabular fractures with and without an associated femoral head fracture. Beyond femoral head fractures, the marginal impaction of the acetabulum could have led to early sequelae.Level Of Evidence: Level III. [ABSTRACT FROM AUTHOR]

Background: Adult sporadic Burkitt lymphoma (BL) is a rare but highly aggressive subtype of lymphoma which lacks its own unique prognostic model. Systemic inflammatory biomarkers have been confirmed as prognostic markers in several types of malignancy. Our objective was to explore the predictive value of pretreatment inflammatory biomarkers and establish a novel, clinically applicable prognostic index for adult patients with sporadic BL.Methods: We surveyed retrospectively 336 adult patients with newly diagnosed sporadic BL at 8 Chinese medical centers and divided into training cohort (n = 229) and validation cohort (n = 107). The pretreatment inflammatory biomarkers were calculated for optimal cut-off value. The association between serum biomarkers and overall survival (OS) was analyzed by Kaplan-Meier curves and Cox proportional models. The risk stratification was defined based on normal LDH level, Ann Arbor stage of I and completely resected abdominal lesion or single extra-abdominal mass < 10 cm.Results and Conclusions: Univariate and multivariate analyses revealed that platelets< 254 × 109/L, albumin< 40 g/L, lactate dehydrogenase≥334 U/L independently predicted unfavorable OS. We used these data as the basis for the prognostic index, in which patients were stratified into Group 1 (no or one risk factor), Group 2 (two risk factors), or Group 3 (three risk factors), which were associated with 5-year OS rates of 88.1, 72.4, and 45%, respectively. In the subgroup analysis for high-risk patients, our prognostic model results showed that high-risk patients with no more than one adverse factor presented a 5-year survival rate of 85.9%, but patients with three adverse factors had a 5-year survival rate of 43.0%. Harrell's concordance index (C-index) of the risk group score was 0.768. Therefore, the new prognostic model could be used to develop risk-adapted treatment approaches for adult sporadic BL. [ABSTRACT FROM AUTHOR]

Background: Gonadotropin-releasing hormone antagonist(GnRH-ant) has been shown to have a negative effect on endometrial receptivity. Therefore, the use of lower doses of GnRH-ant during controlled ovarian stimulation (COS) may improve endometrial receptivity and clinical pregnancy rate. However, the GnRH-ant dose is relatively flexible and there is no fixed requirement for guidance. In this retrospective study, we determined the effects of half-dose and full-dose GnRH-ant on IVF-ET outcomes.Methods: Of the 316 cycles in the 314 patients analyzed in this study, 149 received GnRH-ant half-dose (Group1), while 167 received GnRH-ant full-dose (Group2). The groups were further classified based on age and BMI. Age subgroups, were divided as age ≤ 35(subgroup A) and age > 35(subgroup B): 180 cycles in subgroup A (107 cycles in subgroup A1,73 cycles in subgroup A2), 136 cycles in subgroup B (42 cycles in subgroup B1,94 cycles in subgroupB2). The subgroups based on BMI were divided as BMI < 25 (subgroup C)and BMI ≥ 25 (subgroup D):208 cycles in subgroup C (94 cycles in subgroup C1,114 cycles in subgroup C2), 108 cycles in subgroup D (55 cycles in subgroup D1,53 cycles in subgroup D2).Results: The number of fertilized oocytes, superior-quality embryos, clinical pregnancy rate, and live birth rate differed significantly between the two groups. However, the number of retrieved oocytes and available embryos were significantly higher in Group 1 than Group 2 (8.17 ± 4.10 vs. 7.07 ± 4.05, 2.96 ± 2.03 vs. 2.52 ± 1.62, respectively,p<0.05). Differences between the age subgroups were not statistically significant. However, in the subgroups based on BMI, the fertilized oocytes, available embryos, the number of superior-quality embryos, and the live birth rate differed significantly between the four subgroups. The number of retrieved oocytes was higher in subgroup C1 than in subgroup C2 (8.24 ± 4.04 vs. 6.83 ± 3.92,p < 0.05), In addition, the clinical pregnancy rate was slightly higher in subgroup D1 than in subgroup D2(45.45 vs. 24.53%, P < 0.05).Conclusions: The results showed that half-dose GnRH-ant was as effective as full-dose GnRH-ant for most patients. Moreover, half-dose GnRH-ant may be more suitable in patients with BMI greater than or equal to 25. The findings of this study need to be validated in a large sample RCT.Trial Registration: Retrospectively registered. [ABSTRACT FROM AUTHOR]

Background: Our previous study showed a close relationship between computed tomography (CT)-derived bidimensional measurement of primary tumor and retropharyngeal nodes (BDMprn) and gross tumor volume of primary tumor and retropharyngeal nodes (GTVprn) in nasopharyngeal carcinoma (NPC) and better prognosis for NPC patients with smaller BDMprn. In this study, we report the results on of a study to validate the use of BDM in a separate cohort of NPC patients. Methods: We retrospectively reviewed 103 newly diagnosed NPC cases who were treated with radiotherapy/ concurrent chemoradiotherapy (CCRT) or CCRT with adjuvant chemotherapy from 2002 to 2009. We used magnetic resonance imaging (MRI) to measure BDMprn. We calculated overall survival, recurrence-free and distant metastasisfree survival curves and set a BDMprn cut off point to categorize patients into a high- or low-risk group. We then used Cox proportional hazard model to evaluate the prognostic influence of BDMprn after correcting age, gender and chemotherapy status. Results: After adjusting for age, gender, and chemotherapy status, BDMprn remained an independent prognostic factor for distant metastasis [Hazard ratio (HR) = 1.046; P = 0.042] and overall survival (HR = 1.012; P = 0.012). Patients with BDMprn < 15 cm2 had a greater 3-year overall survival rate than those with BDMprn ≧ 15 cm2 (92.3% vs. 73.7%; P = 0.009). They also had a greater 3-year distant metastasis-free survival (94% vs.75%; P = 0.034). Conclusion: The predictive ability of BDMprn was validated in a separate NPC cohort. A BDMprn of 15 cm2 can be used to separate NPC patients into high- and low-risk groups and predict survival rates and metastasis potential. It can, therefore, be used as a reference to design clinical trials, predict prognosis, and make treatment decisions. [ABSTRACT FROM AUTHOR]

Background: Micro/nano-textured hierarchical titanium topography is more bioactive and biomimetic than smooth, micro-textured or nano-textured titanium topographies. Bone marrow mesenchymal stem cells (BMSCs) and exosomes derived from BMSCs play important roles in the osseointegration of titanium implants, but the effects and mechanisms of titanium topography on BMSCs-derived exosome secretion are still unclear. This study determined whether the secretion behavior of exosomes derived from BMSCs is differently affected by different titanium topographies both in vitro and in vivo. Results: We found that both micro/nanonet-textured hierarchical titanium topography and micro/nanotube-textured hierarchical titanium topography showed favorable roughness and hydrophilicity. These two micro/nano-textured hierarchical titanium topographies enhanced the spreading areas of BMSCs on the titanium surface with stronger promotion of BMSCs proliferation in vitro. Compared to micro-textured titanium topography, micro/nano-textured hierarchical titanium topography significantly enhanced osseointegration in vivo and promoted BMSCs to synthesize and transport exosomes and then release these exosomes into the extracellular environment both in vitro and in vivo. Moreover, micro/nanonet-textured hierarchical titanium topography promoted exosome secretion by upregulating RAB27B and SMPD3 gene expression and micro/nanotube-textured hierarchical titanium topography promoted exosome secretion due to the strongest enhancement in cell proliferation. Conclusions: These findings provide evidence that micro/nano-textured hierarchical titanium topography promotes exosome biogenesis and extracellular secretion for enhanced osseointegration. Our findings also highlight that the optimized titanium topography can increase exosome secretion from BMSCs, which may promote osseointegration of titanium implants. [ABSTRACT FROM AUTHOR]

Background: In most institutions, arterial embolization (AE) remains a standard procedure to achieve hemostasis during the resuscitation of patients with pelvic fractures. However, the actual benefits of AE are controversial. In this study, we aimed to explore AE-related outcomes following resuscitation at our center and to assess the predictive value of contrast extravasation (CE) during computed tomography (CT) for patients with hemodynamically unstable closed pelvic fractures.Methods: We retrospectively reviewed data from patients who were treated for closed pelvic fractures at a single center between 2014 and 2017. Data regarding the AE and clinical parameters were analyzed to determine whether poor outcomes could be predicted.Results: During the study period, 545 patients were treated for closed pelvic fractures, including 131 patients who underwent angiography and 129 patients who underwent AE. Nonselective bilateral internal iliac artery embolization (nBIIAE) was the major AE strategy (74%). Relative to the non-AE group, the AE group had higher values for injury severity score, shock at hospital arrival, and unstable fracture patterns. The AE group was also more likely to require osteosynthesis and develop surgical site infections (SSIs). Fourteen patients (10.9%) experienced late complications following the AE intervention, including 3 men who had impotence at the 12-month follow-up visit and 11 patients who developed SSIs after undergoing AE and osteosynthesis (incidence of SSI: 11/75 patients, 14.7%). Nine of the 11 patients who developed SSI after AE had undergone nBIIAE. The positive predictive value of CE during CT was 29.6%, with a negative predictive value of 91.3%. Relative to patients with identifiable CE, patients without identifiable CE during CT had a higher mortality rate (30.0% vs. 11.0%, p = 0.03).Conclusion: Performing AE for pelvic fracture-related hemorrhage may not be best practice for patients with no CE detected during CT or for unstable patients who do not respond to resuscitation after exclusion of other sources of hemorrhage. Given the high incidence of SSI following nBIIAE, this procedure should be selected with care. Given their high mortality rate, patients without CE during imaging might be considered for other hemostasis procedures, such as preperitoneal pelvic packing. [ABSTRACT FROM AUTHOR]

Background: 5-Azacytidine (5-azaC) promotes the development of 'Kyoho' grape berry but the associated changes in gene expression have not been reported. In this study, we performed transcriptome analysis of grape berry at five developmental stages after 5-azaC treatment to elucidate the gene expression networks controlling berry ripening. Results: The expression patterns of most genes across the time series were similar between the 5-azaC treatment and control groups. The number of differentially expressed genes (DEGs) at a given developmental stage ranged from 9 (A3_C3) to 690 (A5_C5). The results indicated that 5-azaC treatment had not very great influences on the expressions of most genes. Functional annotation of the DEGs revealed that they were mainly related to fruit softening, photosynthesis, protein phosphorylation, and heat stress. Eight modules showed high correlation with specific developmental stages and hub genes such as PEROXIDASE 4, CAFFEIC ACID 3-O-METHYLTRANSFERASE 1, and HISTONE-LYSINE N-METHYLTRANSFERASE EZA1 were identified by weighted gene correlation network analysis. Conclusions: 5-AzaC treatment alters the transcriptional profile of grape berry at different stages of development, which may involve changes in DNA methylation. [ABSTRACT FROM AUTHOR]

Background: 'Fengzao' is an early-ripening bud mutant of 'Kyoho', which matures nearly 30 days earlier than 'Kyoho'. To gain a better understanding of the regulatory role of miRNAs in early-ripening of grape berry, high-throughput sequencing approach and quantitative RT-PCR validation were employed to identify miRNAs at the genome-wide level and profile the expression patterns of the miRNAs during berry development in 'Kyho' and 'Fengzao', respectively. Results: Nine independent small RNA libraries were constructed and sequenced in two varieties from key berry development stages. A total of 108 known miRNAs and 61 novel miRNAs were identified. Among that, 159 miRNAs identified in 'Fengzao' all completely expressed in 'Kyoho' and there were 10 miRNAs specifically expressed in 'Kyoho'. The expression profiles of known and novel miRNAs were quite similar between two varieties. As the major differentially expressed miRNAs, novel_144, vvi-miR3626-3p and vvi-miR3626-5p only expressed in 'Kyoho', vvi-miR399b and vvi-miR399e were down-regulated in 'Fengzao', while vvi-miR477b-3p up-regulated in 'Fengzao'. According to the expression analysis and previous reports, miR169-NF-Y subunit, miR398-CSD, miR3626-RNA helicase, miR399- phosphate transporter and miR477-GRAS transcription factor were selected as the candidates for further investigations of miRNA regulation role in the early-ripening of grape. The qRT-PCR analyses validated the contrasting expression patterns for these miRNAs and their target genes. Conclusions: The miRNAome of the grape berry development of 'Kyoho', and its early-ripening bud mutant, 'Fengzao' were compared by high-throughput sequencing. The expression pattern of several key miRNAs and their target genes during grape berry development and ripening stages was examined. Our results provide valuable basis towards understanding the regulatory mechanisms of early-ripening of grape berry. [ABSTRACT FROM AUTHOR]

Background: Gustilo type III tibial fractures commonly involve extensive soft tissue and bony defects, requiring complex reconstructive operations. Although several methods have been proposed, no research has elucidated the efficacies and differences between vascular bone graft (VBG) and the Masquelet technique (MT) to date. We aimed to evaluate and compare the clinical effectiveness of VBG and the MT for the reconstruction of Gustilo type III tibial fractures.Methods: This retrospective cohort study enrolled patients who underwent reconstruction for Gustilo type III tibial fractures using VBG or the MT in a single center from January 2000 to December 2020. The patients' demographics, injury characteristics, and surgical interventions were documented for analysis. The clinical outcomes including union status, time to union, postoperative infections, and the causes of union failure were compared between the two groups.Results: We enrolled 44 patients: 27 patients underwent VBG, and 17 underwent MT. The average union time was 20.5 ± 15.4 and 15.1 ± 9.0 months in the VBG and MT groups, respectively (p = 0.232). The postoperative deep infection rates were 70.4% and 47.1% in the VBG and MT groups (p = 0.122), respectively. Though not statistically significant, the VBG group had a shorter union time than did the MT group when the bone defect length was > 60 mm (21.0 ± 17.0 versus 23.8 ± 9.4 months, p = 0.729), while the MT group had a shorter union time than did the VBG group when the bone defect was length < 60 mm (17.2 ± 5.6 versus 10.7 ± 4.7 months, p = 0.067).Conclusions: VBG and MT are both promising reconstruction methods for Gustilo type III tibial fractures. VBG appears to have more potential in reconstructing larger bone defects, while MT may play an important role in smaller bone defects, severe surgical site infections, and osteomyelitis. Therefore, flexible treatment strategies are required for good outcomes in Gustilo type III open tibial fractures. [ABSTRACT FROM AUTHOR]

Background: Sphingosine-1 receptor 1 (S1P1) plays a major role in regulating lymphocyte egress from peripheral lymph tissue. Lymphocyte trafficking is potentially a critical response to tumors and to tumor vaccines. Also, the receptor has been shown to influence metastasis. However, there is little information on its expression in the aged ovary or ovarian tumors. As a basis for further studies in the laying hen model of spontaneous ovarian cancer, the objective of this study was to determine if S1P1 is expressed in hens, and if the morphological distribution of S1P1 is similar in hen and human ovary and ovarian tumors. Methods: S1P1 mRNA was ascertained in hen tissue by RT-PCR using hen specific primers. S1P1 protein expression and localization was evaluated in hen and human tissue with a human S1P1 antibody by Western blot and immunohistochemistry. Results: S1P1 mRNA was expressed in all hen tissues examined. Protein was detected in human and hen ovary and ovarian tumors at 47, 72 and 108 kDa in Western blots. S1P1 was similarly expressed on endothelial cells, lymphocytes and surface epithelial cells in normal ovaries and tumor-containing ovaries of the hen. In addition, S1P1 distribution was heterogeneous in both hen and human ovarian tumors by immunohistochemistry. Conclusion: The results show that S1P1 is expressed in the hen and human ovary as well as in ovarian tumors. These findings support the use of the hen in further studies of the role of S1P1 in metastasis and immune cell trafficking in ovarian tumor development. [ABSTRACT FROM AUTHOR]

Background: In a previous study, the early ripening of Kyoho grape following H2O2 treatment was explored at the physiological level, but the mechanism by which H2O2 promotes ripening at the molecular level is unclear. To reveal the molecular mechanism, RNA-sequencing analysis was conducted on the different developmental stages of Kyoho berry treated with H2O2. Results: In the comparison of treatment and control groups, 406 genes were up-regulated and 683 were down-regulated. Time course sequencing (TCseq) analysis showed that the expression patterns of most of the genes were similar between the treatment and control, except for some genes related to chlorophyll binding and photosynthesis. Differential expression analysis and the weighted gene co-expression network were used to screen significantly differentially expressed genes and hub genes associated with oxidative stress (heat shock protein, HSP), cell wall deacetylation (GDSL esterase/lipase, GDSL), cell wall degradation (xyloglucan endotransglucosylase/ hydrolase, XTH), and photosynthesis (chlorophyll a-b binding protein, CAB1). Gene expression was verified with RT-qPCR, and the results were largely consistent with those of RNA sequencing. Conclusions: The RNA-sequencing analysis indicated that H2O2 treatment promoted the early ripening of Kyoho berry by affecting the expression levels of HSP, GDSL, XTH, and CAB1 and- photosynthesis- pathways. [ABSTRACT FROM AUTHOR]

Background: Multidrug resistance is a growing global public health threat with far more serious consequences than generally anticipated. In this study, we investigated the antibiotic resistance and genomic traits of a clinical strain of Escherichia coli LCT-EC001. Results: LCT-EC001 was resistant to 16 kinds of widely used antibiotics, including fourth-generation cephalosporins and carbapenems. In total, up to 68 determinants associated with antibiotic resistance were identified, including 8 beta-lactamase genes (notably producing ESBLs and KPCs), 31 multidrug efflux system genes, 6 outer membrane transport system genes, 4 aminoglycoside-modifying enzyme genes, 10 two-component regulatory system genes, and 9 other enzyme or transcriptional regulator genes, covering nearly all known drug-resistance mechanisms in E. coli. More than half of the resistance genes were located close to mobile genetic elements, such as plasmids, transposons, genomics islands, and insertion sequences. Phylogenetic analysis revealed that this strain may have evolved from E. coli K-12 but is a completely new MLST type. Conclusions: Antibiotic resistance was extremely severe in E. coli LCT-EC001, mainly due to mobile genetic elements that allowed the gain of a large quantity of resistance genes. The antibiotic resistance genes of E. coli LCT-EC001 can probably be transferred to other bacteria. To the best of our knowledge, this is the first report of a strain of E. coli which has such a large amount of antibiotic resistance genes. Apart from providing an E. coli reference genome with an extremely high multidrug-resistant background for future analyses, this work also offers a strategy for investigating the complement and characteristics of genes contributing to drug resistance at the whole-genome level. [ABSTRACT FROM AUTHOR]

Background: Atrophic nonunion of femoral shaft fracture after intramedullary (IM) nailing is uncommon. The treatment for femoral shaft aseptic atrophic non-union remained controversial. The aim of this study was to compare the surgical results between exchanging reamed nailing (ERN) and augmentative antirotational plating (AAP) for femoral shaft aseptic atrophic nonunion.Methods: We retrospectively reviewed the patients with femoral shaft nonunion between the year of 2014 and 2015. The patients with nonunion after plate osteosynthesis, septic nonunion, hypertrophic nonunion, additional surgery during revision surgery were excluded. All the patients were followed up at least 12 months.Results: Overall, the union rate after revision surgery was 70.8%. The union rate was significantly higher in the AAP group than in the ERN group. Operating time was also significantly shorter in the AAP group. Regarding the location of nonunion, the union rate was comparable between groups for isthmic nonunions. However, for non-isthmic nonunions, the union rate was significantly higher and operating time was significantly shorter in the AAP group.Conclusion: AAP showed an overall higher union rate for management of femoral shaft aseptic atrophic nonunion compared with ERN. Especially for non-isthmic femoral shaft atrophic nonunions, AAP provided a significantly higher union rate and significantly shorter operating time. [ABSTRACT FROM AUTHOR]

Background: Meta-analysis is a useful tool for combining evidence from multiple studies to estimate a pooled treatment effect. An extension of meta-analysis, network meta-analysis, is becoming more commonly used as a way to simultaneously compare multiple treatments in a single analysis. Despite the variety of approaches available for presenting fitted models, ascertaining an intuitive understanding of these models is often difficult. This is especially challenging in large networks with many different treatments. Here we propose two visualisation methods, so that network meta-analysis models can be more easily interpreted.Methods: Our methods can be used irrespective of the statistical model or the estimation method used and are grounded in network analysis. We define three types of distance measures between the treatments that contribute to the network. These three distance measures are based on 1) the estimated treatment effects, 2) their standard errors and 3) the corresponding p-values. Then, by using a suitable threshold, we categorise some treatment pairs as being "close" (short distances). Treatments that are close are regarded as "connected" in the network analysis theory. Finally, we group the treatments into communities using standard methods for network analysis. We are then able to identify which parts of the network are estimated to have similar (or different) treatment efficacy and which parts of the network are better identified. We also propose a second method using parametric bootstrapping, where a heat map is used in the visualisation. We use the software R and provide the code used.Results: We illustrate our new methods using a challenging dataset containing 22 treatments, and a previously fitted model for this data. Two communities of treatments that appear to have similar efficacy are identified. Furthermore using our methods we can identify parts of the network that are better (and less well) identified.Conclusions: Our new visualisation approaches may be used by network meta-analysts to gain an intuitive understanding of the implications of their fitted models. Our visualisation methods may be used informally, to identify the most salient features of the fitted models that can then be reported, or more formally by presenting the new visualisation devices within published reports. [ABSTRACT FROM AUTHOR]

Background: The long noncoding RNA (lncRNA) OTUD6B antisense RNA 1 (OTUD6B-AS1) is oriented in an antisense direction to the protein-coding gene OTUD6B on the opposite DNA strand. TCGA database data show that the expression of the lncRNA OTUD6B-AS1 is downregulated and that OTUD6B-AS1 acts as an antioncogene in a variety of tumors. However, the expression and biological functions of the lncRNA OTUD6B-AS1 are still unknown in tumors, including clear cell renal cell carcinoma (ccRCC). Methods: The expression level of OTUD6B-AS1 was measured in 75 paired human ccRCC tissue and corresponding adjacent normal renal tissue samples. The correlations between the OTUD6B-AS1 expression level and clinicopathological features were evaluated using the chi-square test. The effects of OTUD6B-AS1 on ccRCC cells were determined via MTT assay, clone formation assay, transwell assay, and flow cytometry. Furthermore, the impact of OTUD6B-AS1 overexpression on the activation of the Wnt/β-catenin signaling pathway was investigated. Finally, ACHN cells with OTUD6B-AS1 overexpression were subcutaneously injected into nude mice to evaluate the influence of OTUD6B-AS1 on tumor growth in vivo. Results: In this study, we found that the expression of the lncRNA OTUD6B-AS1 was downregulated in ccRCC tissue samples and that patients with low OTUD6B-AS1 expression had shorter overall survival than patients with high OTUD6B-AS1 expression, which showed that the different expression level of OTUD6B-AS1 indirectly correlated with survival of patients. Lentivirus-mediated OTUD6B-AS1 overexpression significantly decreased the proliferation of ccRCC cells and promoted the apoptosis of the cells. Furthermore, OTUD6B-AS1 overexpression partly inhibited cell migration and invasion. The overexpression of OTUD6B-AS1 decreased the activity of the Wnt/β-catenin pathway and suppressed the expression of epithelial-to-mesenchymal transition (EMT)-related proteins (E-cadherin, N-cadherin and Snail) in ccRCC cells. In addition, compared with the parental ACHN cells, OTUD6B-AS1-overexpressing ACHN cells injected into nude mice exhibited decreased tumor growth in vivo. Conclusions: Taken together, our findings present a road map for targeting the newly identified lncRNA OTUD6B-AS1 to suppress ccRCC progression in cell lines, and these results elucidate a novel potential therapeutic target for ccRCC treatment. [ABSTRACT FROM AUTHOR]

Objective: RAId is a software package that has been actively developed for the past 10 years for computationally and visually analyzing MS/MS data. Founded on rigorous statistical methods, RAId’s core program computes accurate E-values for peptides and proteins identified during database searches. Making this robust tool readily accessible for the proteomics community by developing a graphical user interface (GUI) is our main goal here. Results: We have constructed a graphical user interface to facilitate the use of RAId on users’ local machines. Written in Java, RAId_GUI not only makes easy executions of RAId but also provides tools for data/spectra visualization, MS-product analysis, molecular isotopic distribution analysis, and graphing the retrieval versus the proportion of false discoveries. The results viewer displays and allows the users to download the analyses results. Both the knowledge-integrated organismal databases and the code package (containing source code, the graphical user interface, and a user manual) are available for download at https://www.ncbi.nlm.nih.gov/CBBresearch/Yu/downloads/raid.html. [ABSTRACT FROM AUTHOR]

Background: In schizophrenia, executive dysfunction is the most critical cognitive impairment, and is associated with abnormal neural activities, especially in the frontal lobes. Complexity estimation using electroencephalogram (EEG) recording based on nonlinear dynamics and task performance tests have been widely used to estimate executive dysfunction in schizophrenia.Methods: The present study estimated the cool executive function based on fractal dimension (FD) values of EEG data recorded from first-episode schizophrenia patients and healthy controls during the performance of three cool executive function tasks, namely, the Trail Making Test-A (TMT-A), Trail Making Test-B (TMT-B), and Tower of Hanoi tasks.Results: The results show that the complexity of the frontal EEG signals that were measured using FD was different in first-episode schizophrenia patients during the manipulation of executive function. However, no differences between patients and controls were found in the FD values of the EEG data that was recorded during the performance of the Tower of Hanoi task.Conclusions: These results suggest that cool executive function exhibits little impairment in first-episode schizophrenia patients. [ABSTRACT FROM AUTHOR]