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While the microbiome has an established role in asthma development, less is known about its contribution to morbidity in children with asthma.In this ancillary study of the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we analyzed the gut microbiome and metabolome of wheeze frequency in children with asthma.Bacterial 16S ribosomal RNA microbiome and untargeted metabolomic profiling were performed on fecal samples collected from 3-year-old children with parent-reported physician-diagnosed asthma. We analyzed wheeze frequency by calculating the proportion of quarterly questionnaires administered between ages 3 and 5 years in which parents reported the child had wheezed (wheeze proportion). Taxa and metabolites associated with wheeze were analyzed by identifying log fold changes with respect to wheeze frequency and correlation/linear regression analyses, respectively. Microbe-metabolite and microbe-microbe correlation networks were compared between subjects with high and low wheeze proportion.Specific taxa, including the genus Veillonella and histidine pathway metabolites, were enriched in subjects with high wheeze proportion. Among wheeze-associated taxa, Veillonella and Oscillospiraceae UCG-005, which was inversely associated with wheeze, were correlated with the greatest number of fecal metabolites. Microbial networks were similar between subjects with low versus high wheeze frequency.Gut microbiome features are associated with wheeze frequency in children with asthma, suggesting an impact of the gut microbiome on morbidity in childhood asthma.

Background: Despite emerging research on new treatment strategies, chemotherapy remains one of the most important therapeutic modalities for cancers. Imidazopyridines are important targets in organic chemistry and, given their numerous applications, they are worthy of attention. Objective: The objective of this study was to design and synthesize a novel series of imidazo[1,2-a]pyridine-derived compounds and investigate their antitumor effects and the underlying mechanisms. Methods: Imidazo[1,2-a]pyridine-derived compounds were synthesized with new strategies and conventional methods. The antitumor activities of the new compounds were evaluated by MTT assay. Flow cytometry and immunofluorescence were performed to examine the effects of the most effective antiproliferative compound on cell apoptosis. Western blot analysis was used to assess the expression of apoptotic proteins. Results: Fifty-two new imidazo[1,2-a]pyridine compounds were designed and successfully synthesized. The compound, 1-(imidazo[1,2-a]pyridin-3-yl)-2-(naphthalen-2-yl)ethane-1,2-dione, named La23, showed high potential for suppressing the viability of HeLa cells (IC50 15.32 μM). La23 inhibited cell proliferation by inducing cell apoptosis, and it reduced the mitochondrial membrane potential of HeLa cells. Moreover, treatment with La23 appeared to increase the expression of apoptotic-related protein P53, Bax, cleaved caspase-3, and cytochrome c at a low concentration range. Conclusion: The novel imidazo[1,2-a]pyridine compound, La23, was synthesized and it suppressed cell growth by inducing cell apoptosis via the p53/Bax mitochondrial apoptotic pathway.

Purpose This study aimed to assess pathogen distributions and antimicrobial sensitivity characteristics in patients with non-small cell lung cancer (NSCLC) with severe radiation pneumonitis (SRP) and secondary infections. Methods and Materials Data from 1746 patients with NSCLC and SRP after thoracic radiation therapy from January 2009 to December 2020 were retrospectively analyzed. Pneumonia incidence, causative pathogens, and antibiotic resistance characteristics in patients with secondary lung infections were analyzed. Risk factors associated with mortality were identified through univariate and multivariate analyses. Antifungal drug efficacy and duration-related effects were assessed with Forest plots and receiver operating characteristic curves. Results Overall, 44.5% of patients with NSCLC and SRP (777 of 1746 patients) were diagnosed with secondary lung infections. In total, 899 bacterial strains were isolated from these patients, with Acinetobacter baumannii (n = 206; 27%), Klebsiella pneumonia (n = 200; 26.2%), and Pseudomonas aeruginosa (n = 104; 13.6%) being the most common. Carbapenems and cefoperazone-sulbactam resistance rates of 52.7% and 32.2%, 28.8% and 26.4%, and 23.7% and 20.2% were observed for these isolates, respectively. Infection-related deaths occurred in 22.4% of patients with SRP. Independent risk factors for infection-related death included poor performance status scores, inappropriate empirical antimicrobial treatment, bacteria/fungal coinfection, and lack of empirical antifungal treatment. Receiver operating characteristic curves showed that the cutoff value of empirical antifungal treatment duration was 9 (area under the curve: 0.819). Conclusions For patients with SRP and secondary lung infections, appropriate empirical antimicrobial treatment could decrease infection-related mortality, and cefoperazone-sulbactam may be an appropriate antibacterial drug. Empirical antifungal treatment for a minimum of 9 days might contribute to better outcomes. Although this represents a promising treatment approach for patients with SRP and secondary lung infections before antibacterial susceptibility testing, further prospective validation is essential.

OBJECTIVE To find and explore the relationship among the length of the embryo's main anchoring villus and the week of gestation, embryonic crown-rump length (CRL), and maternal blood human chorionic gonadotropin (hCG) during early pregnancy using ultrasound. METHODS A total of 108 women with singleton pregnancies underwent ultrasound examination of the fetus during the early months of their pregnancy (5+5 -13+6 weeks of pregnancy). The main anchoring villus was detected using HD-Flow and SlowflowHD mode ultrasound. The detection rate and length of the main anchoring villus were recorded. The correlations among main anchoring villus with gestational weeks, CRL, and blood hCG were obtained. RESULTS The main anchoring villus was detected in all women (108/108). It could be found throughout the early gestational weeks from as early as 4+6 weeks. The length of the main anchoring villus increased with gestational age, and was positively correlated with CRL and the logarithm of hCG (P

Patients with persistent ulcerative colitis (UC) are at a higher risk of developing colitis-associated cancer (CAC). Previous studies have reported that intestinal microbiota disturbance plays an important role in the process of CAC development in patients with UC, indicating that targeted intervention of intestinal microbiota and its metabolites may be a potential therapeutic strategy. Gut microbiota in the process of colorectal cancer development in UC patients was analyzed using the gutMEGA database and verified in fecal samples. The abundance of Bacteroides fragilis reduced significantly in the process of colitis associated cancer development. Broad-spectrum antibiotics (BSAB) intervene with the intestinal microbiota of mice and accelerate the process of colon cancer development. However, gavage transplantation with B. fragilis can effectively reverse the effects of BSAB. In the intestinal tract, B. fragilis promotes the secretion of short-chain fatty acids (SCFAs). Subsequently, SCFAs, especially butyrate, negatively regulate the inflammatory signaling pathway mediated by NLRP3 to inhibit the activation of macrophages and the secretion of proinflammatory mediators such as IL-18 and IL-1β, reducing the level of intestinal inflammation and restricting CAC development. In conclusion, colonization with B. fragilis has been shown to be effective in ameliorating intestinal epithelial damage caused by chronic inflammation and preventing the development of colonic tumors. Thus, it can be a therapeutic intervention strategy with good clinical application prospects.

Objectives: Allergic rhinitis (AR) is associated with increased risk of major depression in the general population, however, no previous study has evaluated its role among pregnant women. We aimed to investigate the potential impact of AR during pregnancy on the development of postpartum depression (PPD). Methods: This is a population-based case-control study. Data were retrieved from the National Health Insurance Research Database (NHIRD). Medical records of a total of 199 470 deliveries during 2000 and 2010 were identified. Among which, 1416 women with PPD within 12 months after delivery were classified as the case group, while 198 054 women without PPD after delivery formed the control group. Univariate and multivariate regression analyses were conducted to determine the associations between AR during pregnancies and other study variables with PPD. Results: AR during pregnancy was found in 9.53% women who developed PPD and 5.44% in women without PPD. After adjusting for age at delivery, income level, various pregnancy and delivery-related conditions, asthma, atopic dermatitis and other medical comorbidities in the multivariate analysis, AR was significantly associated with increased odds of PPD (aOR: 1.498, 95% CI: 1.222-1.836). Conclusion: AR during pregnancy was independently and significantly associated with an approximately 50% increased risk of PPD among women giving birth. Closely monitoring of AR is warranted in the future in order to optimize mother and child outcomes after delivery.

The polarization of macrophages plays a critical role in the pathophysiology of rheumatoid arthritis. The macrophages can have pro-inflammatory M1 polarization and various types of alternative anti-inflammatory M2 polarization. Our preliminary results showed that the CDKN2B-AS1/MIR497/TXNIP axis might regulate macrophages of rheumatoid arthritis patients. Therefore, we hypothesized that this axis regulated the polarization of rheumatoid macrophages. Flow cytometry was used to determine the surface polarization markers in M1 or M2 macrophages from healthy donors and rheumatoid arthritis patients. The QPCR and Western Blotting were used to compare the expression of the CDKN2B-AS1/MIR497/TXNIP axis in these macrophages. We Knocked down and overexpressed the axis in the macrophage cell line MD to test its roles in macrophage polarization. Compared to cells from healthy donors, cells from rheumatoid arthritis patients expressed higher levels of CD40 and CD80 and lower levels of CD16, CD163, CD206, and CD200R after polarization, they also expressed higher CDKN2B-AS1, lower MIR497, and higher TXNIP. In macrophages from healthy donors, there was no correlation among CDKN2B-AS1, MIR497, and TXNIP. But in macrophages from patients, there were significant correlations. The CDKN2B-AS1 knockdown, MIR497 mimics suppressed the M1 polarization but promoted the M2 polarization in MD cells, while the MIR497 knockdown and the TXNIP overexpression did the opposite. This study demonstrated that elevated CDKN2B-AS1 in macrophages promotes the M1 polarization and inhibited the M2 polarization of macrophages by the CDKN2B-AS1/ MIR497/TXNIP axis.

The human microbiome has a role in the development of multiple diseases. Individual microbiome profiles are highly personalized, though many species are shared. Understanding the relationship between the human microbiome and disease may inform future individualized treatments. We hypothesize the blood microbiome signature may be a surrogate for some lung microbial characteristics. We sought associations between the blood microbiome signature and lung-relevant host factors. Based on reads not mapped to the human genome, we detected microbial nucleic acids through secondary use of peripheral blood RNA-sequencing from 2,590 current and former smokers with and without chronic obstructive pulmonary disease (COPD) from the COPDGene study. We used the Genome Analysis Toolkit (GATK) microbial pipeline PathSeq to infer microbial profiles. We tested associations between the inferred profiles and lung disease relevant phenotypes and examined links to host gene expression pathways. We replicated our analyses using a second independent set of blood RNA-seq data from 1,065 COPDGene study subjects and performed a meta-analysis across the two studies. The four phyla with highest abundance across all subjects were Proteobacteria, Actinobacteria, Firmicutes and Bacteroidetes. In our meta-analysis, we observed associations (q-value Acinetobacter, Serratia, Streptococcus and Bacillus inferred abundances and Modified Medical Research Council (mMRC) dyspnea score. Current smoking status was associated (q Acinetobacter, Serratia and Cutibacterium abundance. All 12 taxa investigated were associated with at least one white blood cell distribution variable. Abundance for nine of the 12 taxa was associated with sex, and seven of the 12 taxa were associated with race. Host-microbiome interaction analysis revealed clustering of genera associated with mMRC dyspnea score and smoking status, through shared links to several host pathways. This study is the first to identify a bacterial microbiome signature in the peripheral blood of current and former smokers. Understanding the relationships between systemic microbial signatures and lung-related phenotypes may inform novel interventions and aid understanding of the systemic effects of smoking.

Steroid receptor coactivators (SRCs) possess specific and distinct oncogenic roles in the initiation of cancer and in its progression to a more aggressive disease. These coactivators interact with nuclear receptors and other transcription factors to boost transcription of multiple genes, which potentiate cancer cell proliferation, migration, invasion, tumor angiogenesis and epithelial–mesenchymal transition (EMT). Targeting SRCs using small molecule inhibitors (SMIs) is a promising approach to control cancer progression and metastasis. By high-throughput screening analysis, we recently identified SI-2 as a potent SRC SMI. To develop therapeutic agents, SI-10 and SI-12, the SI-2 analogs are synthesized that incorporate the addition of F atoms to the SI-2 chemical structure. As a result, these analogs exhibit a significantly prolonged plasma half-life, minimal toxicity and improved hERG activity. Biological functional analysis showed that SI-10 and SI-12 treatment (5–50 nM) can significantly inhibit viability, migration and invasion of breast cancer cells in vitro and repress the growth of breast cancer PDX organoids. Treatment of mice with 10 mg/kg/day of either SI-10 or SI-12 was sufficient to repress the growth of xenograft tumors derived from MDA-MB-231 and LM2 cells. Furthermore, in spontaneous and experimental metastasis mouse models developed from MDA-MB-231 and LM2 cells, respectively, SI-10 and SI-12 effectively inhibited the progression of breast cancer lung metastasis. These results demonstrate that SI-10 and SI-12 are promising therapeutic agents and are specifically effective in blocking tumor metastasis, a key point in tumor progression to a more lethal state that results in patient mortality in the majority of cases.

Relationships among autonomic nervous system, diabetes and metabolic syndrome.

Impaired type I interferons (IFNs) may cause immune deficiency in tumours. Current supplementary IFN therapy partially restores anticancer immunity but simultaneously induces immune evasion by upregulating multiple immune checkpoints. Here we create a T lymphocyte membrane-decorated epigenetic nanoinducer that is engineered with programmed cell death protein 1 (PD1), which we call OPEN, for the delivery of the IFN inducer ORY-1001. OPEN increases IFNs and blocks IFN-induced immune checkpoint upregulation. OPEN also targets tumours that express programmed cell death ligand 1 (PDL1) through PDL1/PD1 recognition and subsequently triggers the internalization of OPEN and immune checkpoint proteins. OPEN, which is loaded with ORY-1001, upregulates intratumoural IFNs and downstream major histocompatibility complex I and PDL1. The replenished PDL1 enables further ligation of OPEN, which in turn blocks PDL1. These sequential processes result in an eight- and 29-fold increase of the intratumoural densities of total and active cytotoxic T lymphocytes, respectively, and a strong inhibition of xenograft tumour growth. This T lymphocyte membrane-decorated epigenetic nanoinducer presents a generalizable platform to boost antitumour immunity.

BackgroundInfertility is a widespread global challenge. Currently, the most effective treatment strategy for infertility is in vitro fertilization (IVF), which is an assisted reproductive technique (ART). The use of IVF for assisted pregnancy dates back to the last 41 years when the first IVF baby was born. During IVF, many oocytes are obtained in an IVF cycle, and more than one embryo is formed. Subsequently, frozen-thawed embryo transfer (FET) is increasingly being used in IVF cycles for women in whom a fresh embryo transfer fails to result in a pregnancy, or in those who return for a second baby. However, the pregnancy success rates following FET treatment cycles are reportedly lower than in fresh embryo transfers. Therefore, recent related studies are increasing determining mechanisms of improving the sustained pregnancy rate of FET and reducing the rate of early abortion.The Gushen’antai pill (GSATP), which contains a mixture of 10 herbs, has been widely used in traditional Chinese medicine (TCM) as a pharmacological option to prevent miscarriage. However, randomized controlled trials (RCT) have never been conducted to provide high-level clinical evidence on the clinical efficacy of GSATP. The objective of this study is to investigate the effect of GSATP of hormone therapy (HT) FET cycles on pregnancy rate.MethodsA total of 300 subjects aged between 18 and 40 years which prepared for HT cycle FET will be enrolled in the study. The patients were from five different hospitals, with 60 patients from each hospital. Patients were randomly divided into two groups, and medication was started on the day of endometrial transformation. After FET 28 days, B-ultrasound was done to determine whether to continue the medication. Baseline assessments were carried out before the trial and outcomes were collected 4, 6, 8, 10, and 12 weeks of each gestational cycle.DiscussionDifferences in ongoing pregnancy rate, clinical pregnancy rate, implantation rate, and threatened abortion rate between the two groups will be statistically analyzed. We can finally have an objective evaluation of the efficacy of the traditional Chinese medicine Gushen’antai pills.Trial registrationChiCTR1900026737. Registered October 20, 2019.

A biological research framework to define Alzheimer’ disease with dichotomized biomarker measurement was proposed by National Institute on Aging–Alzheimer’s Association (NIA–AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic 18F-AV-1451 tau PET staging scheme with longitudinal clinical validation. Seven hundred and thirty-four participants with baseline 18F-AV-1451 tau PET (baseline age 73.9 ± 7.7 years, 375 female) were stratified into five stages by a topographic PET staging scheme. Cognitive trajectories and clinical progression were compared across stages with or without further dichotomy of amyloid status, using linear mixed-effect models and Cox proportional hazard models. Significant cognitive decline was first observed in stage 1 when tau levels only increased in transentorhinal regions. Rates of cognitive decline and clinical progression accelerated from stage 2 to stage 3 and stage 4. Higher stages were also associated with greater CSF phosphorylated tau and total tau concentrations from stage 1. Abnormal tau accumulation did not appear with normal β-amyloid in neocortical regions but prompt cognitive decline by interacting with β-amyloid in temporal regions. Highly accumulated tau in temporal regions independently led to cognitive deterioration. Topographic PET staging scheme have potentials in early diagnosis, predicting disease progression, and studying disease mechanism. Characteristic tau spreading pattern in Alzheimer’s disease could be illustrated with biomarker measurement under NIA–AA framework. Clinical–neuroimaging–neuropathological studies in other cohorts are needed to validate these findings.

Oral squamous cell carcinoma (OSCC) is known for its high incidence, death rate, and relatively low 5-year survival. Long non-coding RNAs (lncRNAs) have been shown to play a significant role in cancerization and cancer progression. However, research on the association of polymorphisms in these lncRNAs with the prognosis of OSCC is lacking. Fifteen functional single-nucleotide polymorphisms (SNPs) in seven lncRNAs were selected to explore the relationship between these lncRNA SNPs and the prognosis among 209 OSCC patients. Kaplan-Meier analysis and Cox proportional hazards regression models were used to examine the associations. Further functional exploration of significant SNPs was done by eQTL analysis. Using multivariate Cox hazards regression analysis, a predictive role of NEAT1 rs3741384 GG and UCA1 rs7255437 TC+TT in a worse prognosis of OSCC was identified. In addition, a marked increased risk of death was observed with an increasing number of unfavourable genotypes (NUG). The NUG was then incorporated with clinical variables in the receiver operating characteristic curve, and the results indicated a potential role of the NUG in predicting OSCC patient risk of death (area under the curve increase from 0.616 to 0.703). In conclusion, the study findings indicate that genetic variants rs3741384 in NEAT and rs7255437 in UCA1 may influence the survival of OSCC patients.

Intracerebral haemorrhage (ICH) can be a catastrophic event; even if the initial stages of the pathology were well-managed, a number of patients experience varied residual neurological deficits following the insult. Ferroptosis is a recently identified type of cell demise which is tightly linked to the neurological impairment associated with ICH. In the current work, the prophylactic impact of scalp acupuncture (SA) therapy on autologous blood injection murine models of ICH was investigated in order to establish whether SA could mitigate the secondary damage arising following ICH by moderating ferroptosis. The pathophysiological mechanisms associated with this process were also explored. Ludmila Belayev tests were utilised for the characterisation of neurological damage. Haematoxylin–eosin staining was employed in order to determine the cerebral impact of the induced ICH. Malondialdehyde (MDA) and iron titres in peri-haemorrhagic cerebral tissues were appraised using purchased assay kits. Transmission electron microscopy delineated mitochondrial appearances within nerve cell bodies from the area of haemorrhage. Western blotting techniques were utilised to assay the degree of protein expression of NeuN, sequestosome 1 (p62), nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1). The frequencies of Nrf2, GPX4 and FTH1 positive cells, respectively, were documented with immunohistochemical staining. The results demonstrated that therapy with SA after ICH mitigated MDA and iron sequestration, diminished the appearance of contracted mitochondria with increased outer mitochondrial membrane diameter within the nerve cell bodies, and suppressed neuronal ferroptosis. The pathways responsible for these effects may encompass amplified p62, Nrf2, GPX4 and FTH1 expression, together with decreased Keap1 expression. Application of SA reduced identified neurobehavioural abnormalities after ICH; no disparities were observed between the consequences of SA therapy and deferoxamine delivery. It can be surmised that intervention with SA enhanced recovery after ICH by triggering the antioxidant pathway, p62/Keap1/Nrf2, and causing FTH1 and GPX4 upregulation, factors that participate in diminishing excess iron and thus in mitigating lipid peroxidation insults arising from ferroptosis following ICH. Supplementary Information The online version contains supplementary material available at 10.1007/s12031-021-01890-y.

Background and aims Nonalcoholic fatty liver disease, especially nonalcoholic steatohepatitis (NASH), has become a major cause of liver transplantation and liver-associated death. NASH is the hepatic manifestation of metabolic syndrome and is characterized by hepatic steatosis, inflammation, hepatocellular injury, and different degrees of fibrosis. However, there is no US Food and Drug Administration-approved medication to treat this devastating disease. Therapeutic activators of the AMP-activated protein kinase (AMPK) have been proposed as a potential treatment for metabolic diseases such as NASH. Cordycepin, a natural product isolated from the traditional Chinese medicine Cordyceps militaris, has recently emerged as a promising drug candidate for metabolic diseases. Approach and results We evaluated the effects of cordycepin on lipid storage in hepatocytes, inflammation, and fibrosis development in mice with NASH. Cordycepin attenuated lipid accumulation, inflammation, and lipotoxicity in hepatocytes subjected to metabolic stress. In addition, cordycepin treatment significantly and dose-dependently decreased the elevated levels of serum aminotransferases in mice with diet-induced NASH. Furthermore, cordycepin treatment significantly reduced hepatic triglyceride accumulation, inflammatory cell infiltration, and hepatic fibrosis in mice. In vitro and in vivo mechanistic studies revealed that a key mechanism linking the protective effects of cordycepin were AMPK phosphorylation-dependent, as indicated by the finding that treatment with the AMPK inhibitor Compound C abrogated cordycepin-induced hepatoprotection in hepatocytes and mice with NASH. Conclusion Cordycepin exerts significant protective effects against hepatic steatosis, inflammation, liver injury, and fibrosis in mice under metabolic stress through activation of the AMPK signaling pathway. Cordycepin might be an AMPK activator that can be used for the treatment of NASH.

Immune checkpoint molecules, also known as cosignaling molecules, are pivotal cell-surface molecules that control immune cell responses by either promoting (costimulatory molecules) or inhibiting (coinhibitory molecules) a signal. These molecules have been studied for many years. The application of immune checkpoint drugs in the clinic provides hope for cancer patients. Recently, the poliovirus receptor (PVR)-like protein cosignaling network, which involves several immune checkpoint receptors, i.e., DNAM-1 (DNAX accessory molecule-1, CD226), TIGIT (T-cell immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif (ITIM)), CD96 (T cell activation, increased late expression (TACLILE)), and CD112R (PVRIG), which interact with their ligands CD155 (PVR/Necl-5), CD112 (PVRL2/nectin-2), CD111 (PVRL1/nectin-1), CD113 (PVRL3/nectin-3), and Nectin4, was discovered. As important components of the immune system, natural killer (NK) and T cells play a vital role in eliminating and killing foreign pathogens and abnormal cells in the body. Recently, increasing evidence has suggested that this novel cosignaling network axis costimulates and coinhibits NK and T cell activation to eliminate cancer cells after engaging with ligands, and this activity may be effectively targeted for cancer immunotherapy. In this article, we review recent advances in research on this novel cosignaling network. We also briefly outline the structure of this cosignaling network, the signaling cascades and mechanisms involved after receptors engage with ligands, and how this novel cosignaling network costimulates and coinhibits NK cell and T cell activation for cancer immunotherapy. Additionally, this review comprehensively summarizes the application of this new network in preclinical trials and clinical trials. This review provides a new immunotherapeutic strategy for cancer treatment.

Introduction: Autoimmune hemolytic anemia is a potentially lethal disease characterized by autoimmune hemolysis. Although human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been reported as a promising therapy, there is limited evidence regarding warm autoimmune hemolytic anemia (wAIHA) patients. This study aimed to investigate the potential therapeutic effects of hUC-MSCs via immune regulation in wAIHA patients. Methods: Peripheral blood mononuclear cells (PBMCs) from 10 wAIHA patients and 8 healthy controls were isolated from peripheral blood and cultured for 3 days with or without the presence of hUC-MSCs; PBMCs were co-cultured with hUC-MSCs using Transwell assays. The supernatant cytokine levels were measured after culture through AimPlex Multiple Immunoassays for Flow, including IL-2, IL-4, IL-10, IFN-γ, TNF-α, and IL-17A. The percentages of regulatory T cells, regulatory B cells, and Th1/Th2 in PBMCs were also assessed before and after culturing. Results: In the wAIHA group, hUC-MSCs could upregulate the Treg and Breg proportions after culturing for 3 days, and the Treg and Breg percentages increased after co-culturing with hUC-MSCs in the wAIHA group compared with PBMC cultured alone for 3 days (8.29 ± 8.59 vs. 6.82 ± 1.32, 3.82 ± 1.87 vs. 1.75 ± 1.20, respectively). Compared with the PBMC wAIHA group, the levels of TNF-α (2.13 ± 2.07 vs. 16.20 ± 21.13 pg/mL, p = 0.019) and IL-10 (10.51 ± 18.42 vs. 37.78 ± 44.20 pg/mL, p = 0.012) were significantly elevated in the PBMC + hUC-MSCs wAIHA group. Conclusion: The hUC-MSCs contributed to the increasing proportion of regulatory cell populations in PBMCs of wAIHA patients, thereby potentially regulating autoimmune response; thus, hUC-MSCs may be a promising approach for wAIHA treatment.

Comprehensive investigations on the incidence and prognosis of pituitary tumors are still lacking. The present study aims to summarize the incidence, demographics, and survival outcome of pituitary adenoma on a population-based level. This study includes all pituitary adenomas reported in the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2016 in the United States. Extensive clinical and demographic characteristics were extracted and submitted to group comparisons. The standardized incidence rate was calculated and stratified by year at diagnosis, age/sex and age/treatment groups. The Kaplan–Meier analysis and multivariable regressions were performed to identify the factors associated with overall survival. A total of 47,180 pituitary tumors were identified, including 47,030 typical adenomas, 111 uncertain behavior pituitary adenomas, and 39 pituitary carcinomas. The overall standardized incidence rate was 4.8 cases per 100,000 person-years and the annual incidence rate continually trended upwards, with a peak seen in 2015. We noticed a bimodal age-related distribution in females and a unimodal distribution in males. In the multivariate regression analysis, the factors associated with prolonged survival included typical adenoma, younger age, and smaller tumor size. Whereas, black and male patients had worse overall survival. Our study provides a reliable estimate on the incidence of pituitary adenoma and confirms that the annual standardized incidence rate is increasing. Pituitary adenomas have a satisfactory long-term prognosis and age, tumor size, and tumor subtypes are related to overall survival. Though statistically significant, our inferential findings should be constrained within the limitations of SEER database.

Purpose To investigate the relationship between obstructive sleep apnea (OSA) severity and high-sensitivity C-reactive protein (Hs-CRP), and their respective impact on the clinical outcomes in patients undergoing off-pump cardiac artery bypass grafting (OPCABG). Methods We enrolled consecutive eligible patients listed for elective OPCABG who underwent cardiorespiratory polygraphy before surgery between January 2019 and December 2019 in this prospective observational single-center study. Baseline, intraoperative, and postoperative clinical data were compared between absent-mild and moderate-severe OSA groups. Regression analysis investigated the relationship between Hs-CRP level and severity of OSA, and further assessed the factors influencing postoperative atrial fibrillation, duration of hospitalization, and hospital cost. Results Patients with moderate-severe OSA accounted for 42.3% (52/123) of the cohort. Partial pressure of carbon dioxide (PCO2), Hs-CRP, apnea hypopnea index (AHI), mean apnea time, maximum apnea time, and oxygen desaturation index ODI ≥ 3% were significantly higher in the moderate-severe OSA group than in the absent-mild OSA group. Left ventricle ejection fraction (LVEF), lowest arterial oxygen saturation (SaO2), and mean SaO2 were significantly lower in the moderate-severe OSA group. Moderate-severe OSA was associated with elevated Hs-CRP level (OR = 2.356, 95% CI 1.101–5.041, P = 0.027). Hs-CRP was an independent risk factor for post-CABG atrial fibrillation (POAF) (OR = 1.212, P = 0.01). Hs-CRP level independently correlated with duration of hospitalization (B = 0.456, P = 0.001) and hospital cost (B = 1.111, P = 0.044). Conclusion Hs-CRP level was closely related to OSA severity and have potential utility in predicting POAF, duration of hospitalization, and hospital costs in patients undergoing OPCABG.

Background Nucleic acid amplification testing (NAT) for blood screening has been previously performed in some countries to determine NAT yields. The current study sought to explore the non-discriminating reactive NAT yields using individual-NAT (ID-NAT) and characteristics of HBV NAT yields through a 10-year retrospective analysis in Zhejiang, China. Methods Blood donations were analyzed using individual-NAT mode by the transcription-mediated amplification (TMA) method. Supplementary HBV serological tests were performed using chemiluminescent immunoassay, and HBV viral load assay was performed by real-time polymerase chain reaction. Follow-up studies were performed in partial donors with low HBV viral loads. Results Non-discriminating reactive NAT yields and HBV NAT yields varied in different years. The yields ranged from 853.73 per million to 2018.68 per million and 624.60 per million to 1669.50 per million, respectively. In the 476 NAT yields, 19 were probable window periods (WP), 33 probable occult hepatitis B virus infections (OBIs), 409 were confirmed OBIs and 15 were chronic HBV infections. ID-NAT results were categorized in four groups, and the findings showed that the levels of HBV DNA viral loads were different in the four different groups (χ2 = 275.02, p 2 = 49.429, p Conclusion NAT screening of blood donations can reduce the risk of transfusion-transmitted HBV infections. Positive proportions of anti-HBs and anti-HBc are correlated with the HBV viral load level. However, low level of viral load donors pose risks in HBV NAT assays, and show fluctuating state for HBV viral load and leads to non-repeated NAT results during follow up studies.

IL-6 is reported to be the main upstream activator, instead of the downstream target of JAK2/STAT3. This study is intended to explore the correlation of IL-6 and JAK2/STAT3 signaling pathway with clinicopathological features and prognosis in nasopharyngeal carcinoma (NPC). First, NPC tissues and normal nasopharyngeal epithelial tissues were obtained from 117 NPC patients. Next, we detected expression levels of IL-6 in serum and those of STAT3, p-STAT3, JAK2, p-JAK2 and CyclinD1 in tissues. A follow-up was conducted in all the patients and the survival was analyzed. To verify the correlation of IL-6 and JAK2/STAT3 pathway, CNE-1 and SUNE1 NPC cells were interpreted with IL-6 and JAK2/STAT3 signaling pathway inhibitor AG490 to detect cell viability, migration and invasion. We observed thatIL-6 increased in serum of NPC patients. The expressions of IL-6, STAT3, p-STAT3, JAK2, p-JAK2 and CyclinD1 in NPC tissues were higher and correlated with TNM stage and lymph node metastasis (LNM). Survival rates were reduced in patients with positive expressions of IL-6, STAT3, p-STAT3, JAK2, p-JAK2 and CyclinD1. LNM and positive expressions of IL-6 and p-STAT3 were risk factors for poor prognosis of NPC. Besides, recombinant human IL-6 promoted cell proliferation, invasion and migration while AG490 inhibited cell proliferation, invasion and migration in CNE-1 and SUNE1 NPC cells. The results demonstrated that increased IL-6 expression and the activated JAK2/STAT3 signaling pathway had effects on prognosis and reduced the survival time in NPC patients, which provide a potential target for the treatment of NPC.

Cystic renal masses are often encountered during abdominal imaging. Although most of them are benign simple cysts, some cystic masses have malignant characteristics. The Bosniak classification system provides a useful way to classify cystic masses. The Bosniak classification is based on the results of a well-established computed tomography protocol. Over the past 30 years, the classification system has been refined and improved. This paper reviews the literature on this topic and compares the advantages and disadvantages of different screening and classification methods. Patients will benefit from multimodal diagnosis for lesions that are difficult to classify after a single examination.

Background:. Andersson lesions (ALs) are not uncommon in ankylosing spondylitis (AS). Plain radiography (PR) is widely used for the diagnosis of ALs. However, in our practice, there were some ALs in AS patients that could not be detected on plain radiographs. This study aimed to propose the concept of occult ALs and evaluate the prevalence and radiographic characteristics of the occult ALs in AS patients. Methods:. A total of 496 consecutive AS patients were admitted in the Affiliated Drum Tower Hospital, Medical School of Nanjing University between April 2003 and November 2019 and they were retrospectively reviewed. The AS patients with ALs who met the following criteria were included for the investigation of occult ALs: (1) with pre-operative plain radiographs of the whole-spine and (2) availability of pre-operative computed tomography (CT) and/or magnetic resonance imaging (MRI) of the whole-spine. The occult ALs were defined as the ALs which were undetectable on plain radiographs but could be detected by CT and/or MRI. The extensive ALs involved the whole discovertebral junction or manifested as destructive lesions throughout the vertebral body. Independent-samples t test was used to compare the age between the patients with only occult ALs and those with only detectable ALs. Chi-square or Fisher exact test was applied to compare the types, distribution, and radiographic characteristics between detectable and occult ALs as appropriate. Results:. Ninety-two AS patients with a mean age of 44.4 ± 10.1 years were included for the investigation of occult ALs. Twenty-three patients had occult ALs and the incidence was 25% (23/92). Fifteen extensive ALs were occult, and the proportion of extensive ALs was significantly higher in detectable ALs (97% vs. 44%, χ2 = 43.66, P

Human pluripotent stem cell (hPSC)-derived pancreatic β cells are an attractive cell source for treating diabetes. However, current derivation methods remain inefficient, heterogeneous, and cell line dependent. To address these issues, we first devised a strategy to efficiently cluster hPSC-derived pancreatic progenitors into 3D structures. Through a systematic study, we discovered 10 chemicals that not only retain the pancreatic progenitors in 3D clusters but also enhance their potentiality towards NKX6.1+/INS+ β cells. We further systematically screened signaling pathway modulators in the three steps from pancreatic progenitors toward β cells. The implementation of all these strategies and chemical combinations resulted in generating β cells from different sources of hPSCs with high efficiency. The derived β cells are functional and can reverse hyperglycemia in mice within two weeks. Our protocol provides a robust platform for studying human β cells and developing hPSC-derived β cells for cell replacement therapy., Human pluripotent stem cell (hPSC) derived pancreatic beta cells are a promising and potentially limitless source for cell replacement therapy. Here the authors perform stage-wise chemical screening to develop an improved protocol for hPSC differentiation to functional pancreatic beta cells at high efficiency.

The role of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer with peritoneal metastasis (GCPM) is still controversial, mainly due to the limited survival benefit and uncertain patient selection. This study aims to construct a selecting strategy in GCPM for CRS + HIPEC.From a prospective established database, 125 patients were enrolled. All these patients were pathologically confirmed as GCPM and treated with CRS + HIPEC with or without preoperative or postoperative chemotherapy. The clinical documents and follow-up results were collected and analyzed with the primary endpoint of overall survival (OS) and the secondary endpoint of perioperative serious adverse events (SAEs).The median OS of 125 GCPM patients treated with CRS + HIPEC was 10.7 months, with 1-, 2-, 3-, and 5-year survival rates of 43.8%, 24.7%, 18.6%, and 15.7%, respectively. The multivariate analysis identified completeness of cytoreduction (CC), SAEs, HIPEC drugs, and adjuvant chemotherapy as independent prognostic factors on OS. The median OS was 30.0 (95%CI: 16.8-43.3) months in CC-0 group, significantly better than 7.3 (95%CI: 5.8-8.8) months in CC1-3 group (P 0.001). The median OS showed no significant difference among CC-1 (8.5, 95%CI: 6.7-10.2, months), CC-2 (5.6, 95%CI: 3.0-8.2, months) and CC-3 (6.5, 95%CI: 5.2-7.7, months) groups (P 0.05 for all pairwise comparations). The nomogram based on peritoneal metastasis timing, preoperative tumor marker (TM), and peritoneal cancer index (PCI), with AUC of 0.985, showed a good accuracy and consistency between actual observation and prediction of the probability of complete CRS. The cutoffs of PCI were 16 for synchronous GCPM with normal TM, 12 for synchronous GCPM with abnormal TM, 10 for metachronous GCPM with normal TM, and 5 for metachronous GCPM with abnormal TM, setting the probability to achieve complete CRS as 50%.Only complete CRS + HIPEC (CC-0) could improve survival for high selected GCPM patients with acceptable safety. An incomplete CRS (CC1-3) should be avoided for GCPM patients. Synchronous GCPM with PCI ≤16 and normal TM, synchronous GCPM with PCI ≤12 and abnormal TM, metachronous GCPM with PCI ≤10 and normal TM, or metachronous GCPM with PCI ≤5 and abnormal TM maybe potential indications for complete CRS + HIPEC treatment.

The hippocampus plays a crucial role in learning and memory, and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases. Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing. Here, we reported a variety of new aging-associated phenotypic changes of the primate hippocampus. These include, in particular, increased DNA damage and heterochromatin erosion with time, alongside loss of proteostasis and elevated inflammation. To understand their cellular and molecular causes, we established the first single-nucleus transcriptomic atlas of primate hippocampal aging. Among the 12 identified cell types, neural transiently amplifying progenitor cell (TAPC) and microglia were most affected by aging. In-depth dissection of gene-expression dynamics revealed impaired TAPC division and compromised neuronal function along the neurogenesis trajectory; additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte, as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis. This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases. Supplementary Information The online version contains supplementary material available at 10.1007/s13238-021-00852-9.

Background The paucity of accurate quantitative standards for determining the quantity of red blood cells (RBCs) needed for perioperative patients and the predominant application of the "preoperative hemoglobin + surgery type" empirical decision-making model have led to widespread RBC application problems. Objective The mathematical model of preoperative variables constructed by machine learning (ML) methods can help doctors decide preoperative RBC applications. Methods We retrospectively analysed 130 996 records of patients who received surgery in our hospital from January 2011 to June 2017. Through the analysis of multiple preoperative parameters that may affect the RBC transfusion volume, we used ML algorithms to build up the artificial intelligence (AI) model to predict the accurate RBC demand quantity and compared each result with those predicted by clinicians. Results Among the seven ML algorithms, the light gradient boosting machine (Lightgbm) algorithm was the best. The AI model predicted whether the patients needed RBC transfusion, and the area under curve (AUC) was 0.908 (95% CI 0.907-0.913). The AI model was more accurate than doctors in predicting RBC of 0, 2, and 4 units (85% data), with RMSEs of 1.61 vs. 2.15, 1.06 vs. 1.21, and 1.46 vs. 1.68, respectively. However, the AI model was not better than doctors in 1, 3, 5-6, 7-8, and 9-10 units (15% data), with RMSEs of 0.92 vs. 0.89, 0.92 vs. 0.89, 2.73 vs. 1.94, 4.53 vs. 3.92, and 6.26 vs. 5.08, respectively. Conclusion Through the comparison of seven ML methods, the Lightgbm algorithm-based model is more accurate than clinician experience-based in predicting preoperative RBC transfusion, which reduces the risk of untimely blood supply caused by insufficient preoperative blood preparation, and reduces the unnecessary cost of blood compatibility testing caused by excessive preoperative blood preparation.

BACKGROUND: Loss of control (LOC) eating is associated with poor weight loss outcomes following bariatric surgery. It is not clear whether eating patterns (e.g., total number of daily meals/snacks, eating after suppertime, eating when not hungry) and unhealthy weight control behaviors (e.g., smoking, using laxatives) are associated with or predictive of LOC eating. OBJECTIVE: To examine whether eating patterns and unhealthy weight control behaviors are associated with LOC eating, and, if so, whether they predict LOC eating in bariatric patients. SETTING: Multicenter study, United States. METHODS: This is a secondary analysis of the Longitudinal Assessment of Bariatric Surgery-2 study. Assessments were conducted at pre-surgery, and 12, 24, 36, 48, 60, and 84 months after surgery. Logistic mixed models were used to examine the longitudinal associations between eating patterns, unhealthy weight control behaviors, and LOC eating. Time-lag techniques were applied to examine whether the associated patterns and behaviors predict LOC eating. RESULTS: Participants (N=1,477) were mostly women (80%), white (86.9%), and married (62.5%). At the time of surgery, the mean age was 45.4±11.0 years, and mean body mass index was 47.8±7.5 kg/m(2). Total number of daily meals/snacks, food intake after suppertime, eating when not hungry, eating when feeling full, and use of any unhealthy weight control behaviors were positively associated with LOC eating (p

This study sought to design and validate a nomogram capable of predicting outcomes in extensive-stage small-cell lung cancer (ES-SCLC) patients with superior vena cava syndrome (SVCS) based upon the timing of their radiotherapy treatment. We retrospectively analyzed data from 175 ES-SCLC patients with SCVS, comparing outcomes between those that underwent upfront thoracic radiotherapy (initial radiotherapy with simultaneous chemotherapy) and those that underwent consolidative thoracic radiotherapy (following 4–6 cycles of chemotherapy). Significant predictors of patient outcomes were identified using a Cox proportional hazard model and were used to construct our nomogram. This model was subsequently validated using receiver operating characteristic (ROC) curves, concordance index (C-index) values, and a risk classification system in order to evaluate its discriminative and predictive accuracy. The overall survival (OS) of ES-SCLC patients with SVCS that underwent chemotherapy (CT), consolidative thoracic radiotherapy (cc-TRT), and upfront thoracic radiotherapy (cu-TRT) was 8.2, 11.7, and 14.9 months, respectively (p

The ability to detect antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently under investigation with various performance characteristics and indications for use. In this article, we analyzed the ability of the Abbott SARS-CoV-2 immunoglobulin class G (IgG), EuroImmun SARS-CoV-2 enzyme-linked immunosorbent assay (ELISA) IgG, and EuroImmun SARS-CoV-2 ELISA immunoglobulin class A (IgA) kits to detect evidence of previous infection with SARS-CoV-2. We tested 49 known coronavirus disease-19 (COVID-19) patients and 111 prepandemic stored serology specimens. This resulted in a sensitivity of 95.9%, 100.0%, and 91.3% and a specificity of 98.2%, 98.2%, and 90.8% respectively, using manufacturer recommended cutoffs after inconclusive results (one for EuroImmun IgG and five for EuroImmun IgA) being excluded in the final statistical analyses. Cross-reactivity of hepatitis C virus seropositive specimens was observed resulting in false positives (p < 0.05). If a two-tiered algorithmic approach was applied, that is, testing with Abbott SARS-CoV-2 assay followed by EuroImmun SARS-CoV-2 IgG, 100% specificity and sensitivity could be obtained after six inconclusive results were excluded from data set before statistical analyses. Performance characteristics presented demonstrate the superior performance of IgG class antibodies for investigating previous infections. In addition, utilizing a second antibody test for supplementary testing may significantly enhance performance, particularly in lower prevalence settings.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide. However, the mechanisms underlying the acquisition of the metastatic potential in PDAC has not been well understood. In this study, we identified a total of 154 genes upregulated in primary tissues of PDAC with liver metastasis using the Genome Cancer Atlas (TCGA) and GSE151580 cohorts. The epithelial-mesenchymal transition and glycolysis were enriched by the liver metastasis-related genes, indicating that the liver metastasis-related genes might be functionally relevant to liver metastasis in PDAC. Moreover, we also found that the liver metastasis-related genes were primarily regulated at epigenetic level. Particularly, SFN, a cell cycle checkpoint protein, and KRT19, a marker gene for ductal cells, were predicted to be regulated by multiple methylation sites at the promoter. Clinically, we for the first time defined a liver metastasis score (LMS), which was derived from liver metastasis-related genes, and closely associated with clinical characteristics such as disease type and tumor grade, in PDAC. Furthermore, we also divided the samples into high and low LMS groups using three cohorts with long-term follow-up (TCGA, GSE71729, and E-MTAB-6134), which exhibited significantly different prognostic outcomes across three PDAC cohorts, suggesting that the LMS might be a good indicator for risk stratification in PDAC. Furthermore, we also found that the liver metastasis-related genes were primarily expressed in malignant ductal cells by integrative analysis of the bulk and single-cell gene expression data. Moreover, the malignant ductal cells and M0 macrophages were highly correlated with LMS, indicating that the two cell types might function as tumor-promoting cells in PDAC. In summary, the systematic analysis for the first time defined an LMS score to evaluate the risk of liver metastasis in PDAC and revealed that malignant ductal cells might promote PDAC liver metastasis, which greatly improves our understanding of the liver metastasis-related genes, their underlying mechanisms, and association with prognosis in PDAC.

Background Co-trimoxazole, a sulfonamide antibiotic, is used to treat a variety of infections worldwide, and it remains a common first-line medicine for prophylaxis against Pneumocystis jiroveci pneumonia. However, it can cause severe cutaneous adverse reaction (SCAR), including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. The pathomechanism of co-trimoxazole–induced SCAR remains unclear. Objective We aimed to investigate the genetic predisposition of co-trimoxazole–induced SCAR. Methods We conducted a multicountry case-control association study that included 151 patients with of co-trimoxazole–induced SCAR and 4631 population controls from Taiwan, Thailand, and Malaysia, as well as 138 tolerant controls from Taiwan. Whole-genome sequencing was performed for the patients and population controls from Taiwan; it further validated the results from Thailand and Malaysia. Results The whole-genome sequencing study (43 case patients vs 507 controls) discovered that the single-nucleotide polymorphism rs41554616, which is located between the HLA-B and MICA loci, had the strongest association with co-trimoxazole–induced SCAR (P = 8.2 × 10−9; odds ratio [OR] = 7.7). There were weak associations of variants in co-trimoxazole–related metabolizing enzymes (CYP2D6, GSTP1, GCLC, N-acetyltransferase [NAT2], and CYP2C8). A replication study using HLA genotyping revealed that HLA-B∗13:01 was strongly associated with co-trimoxazole–induced SCAR (the combined sample comprised 91 case patients vs 2545 controls [P = 7.2 × 10−21; OR = 8.7]). A strong HLA association was also observed in the case patients from Thailand (P = 3.2 × 10−5; OR = 3.6) and Malaysia (P = .002; OR = 12.8), respectively. A meta-analysis and phenotype stratification study further indicated a strong association between HLA-B∗13:01 and co-trimoxazole–induced drug reaction with eosinophilia and systemic symptoms (P = 4.2 × 10−23; OR = 40.1). Conclusion This study identified HLA-B∗13:01 as an important genetic factor associated with co-trimoxazole–induced SCAR in Asians.

Background/Purpose Hemophagocytic lymphohistiocytosis (HLH), a rarely occurring syndrome with various triggers, is associated with early mortality. Owing to a lack of sufficient corresponding data in Taiwan, this study aimed to identify the outcome and potential factors associated with 180-day mortality in pediatric HLH. Methods This retrospective study analyzed clinical and laboratory data on pediatric patients diagnosed with HLH at our institute (1995–2019). Logistic regression analysis was conducted to determine the associations between various factors and 180-day mortality. Results Overall, 48 patients had HLH; their median age at diagnosis was 5 years (interquartile range: 2–11 years). Clinical presentations and laboratory parameters required for diagnosis included fever (98%), splenomegaly (79%), hyperferritinemia (98%), hemophagocytosis (94%), thrombocytopenia (90%), anemia (63%), hypertriglyceridemia (68%), and neutropenia (57%). The 5-year overall survival (OS) rate was 49%. Of 22 patients who had died at the last follow-up, 15 (68%) died within 180 days after diagnosis. In the multivariate analysis, hemoglobin (odds ratio [OR]: 0.564, p = 0.024) and triglyceride (OR: 1.004, p = 0.049) were significantly associated with 180-day mortality. Higher triglyceride levels at diagnosis were related to significantly lower 180-day OS rates (52.9% vs. 86.1%, p = 0.018). Conclusion The overall outcome in our cohort was similar to that reported in some of the largest international cohorts. Hypertriglyceridemia and anemia may be indicative of poor prognoses in pediatric HLH patients independently and may be used to guide treatment strategy formulations for better outcomes.

Background It is reported that appropriately 50% of early breast cancer patients with 1–2 positive sentinel lymph node (SLN) micro-metastases could not benefit from axillary lymph node dissection (ALND) or breast-conserving surgery with whole breast irradiation. However, whether patients with 1–2 positive SLN macro-metastases could benefit from ALND remains unknown. The aim of our study was to develop and validate nomograms for assessing axillary non-SLN metastases in patients with 1–2 positive SLN macro-metastases, using their pathological features alone or in combination with STMs. Methods We retrospectively reviewed pathological features and STMs of 1150 early breast cancer patients from two independent cohorts. Best subset regression was used for feature selection and signature building. The risk score of axillary non-SLN metastases was calculated for each patient as a linear combination of selected predictors that were weighted by their respective coefficients. Results The pathology-based nomogram possessed a strong discrimination ability for axillary non-SLN metastases, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.727 (95% CI: 0.682–0.771) in the primary cohort and 0.722 (95% CI: 0.653–0.792) in the validation cohort. The addition of CA 15–3 and CEA can significantly improve the performance of pathology-based nomogram in the primary cohort (AUC: 0.773 (0.732–0.815) vs. 0.727 (0.682–0.771), P P Conclusion The nomograms based on pathological features can be used to identify axillary non-SLN metastases in breast cancer patients with 1–2 positive SLN. In addition, the combination of STMs and pathological features can identify patients with patients with axillary non-SLN metastases more accurately than pathological characteristics alone.

Background and objectives Cancer morbidity and mortality rates remain high, and thus, at present, considerable efforts are focused on finding drugs with higher sensitivity against tumor cells and fewer side effects. Disulfiram (DSF), as an anti-alcoholic drug, kills the cancer cells by inducing apoptosis. Several preclinical and clinical studies have examined the potential of repurposing DSF as an anticancer treatment. This systematic review aimed to assess evidence regarding the antineoplastic activity of DSF in in vitro and in vivo models, as well as in humans. Methods Two authors independently conducted this systematic review of English and Chinese articles from the PubMed, Embase, and the Cochrane Library databases up to July 2019. Eligible in vitro studies needed to include assessments of the apoptosis rate by flow cytometry using annexin V/propidium iodide, and studies in animal models and clinical trials needed to examine tumor inhibition rates, and progression-free survival (PFS) and overall survival (OS), respectively. Data were analyzed using descriptive statistics. Results Overall, 35 studies, i.e., 21 performed in vitro, 11 based on animal models, and three clinical trials, were finally included. In vitro and animal studies indicated that DSF was associated with enhanced apoptosis and tumor inhibition rates, separately. Human studies showed that DSF prolongs PFS and OS. The greatest anti-tumor activity was observed when DSF was used as combination therapy or as a nanoparticle-encapsulated molecule. There was no noticeable body weight loss after DSF treatment, which indicated that there was no major toxicity of DSF. Conclusions This systematic review provides evidence regarding the anti-tumor activity of DSF in vitro, in animals, and in humans and indicates the optimal forms of treatment to be evaluated in future research.

The surgical management of large or giant prostate still has challenges to urologists, especially if combined with bladder stones, and the traditional techniques by open prostatectomy and cystolithotomy have significant morbidity rates. The endoscopic procedure might not be feasible to treat both conditions in a single procedure, despite advances in surgical techniques and instrumentation, we present a one-session procedure by a combined endoscopic and open approach for treating benign prostatic hyperplasia (BPH) larger than 100 g combined with bladder stones in the elderly patient with other comorbidities. Between May 2017 and January 2020, bipolar transurethral plasma kinetic enucleation of the prostate (TUEP) followed by open cystolithotomy was performed to six patients at our institution, three of them combined with a big bladder stone(s). All the patients have other chronic chest and heart diseases; we retrospectively collected the data. All the patients diagnosed as BPH of big size or giant prostate over 100 g, with bladder stone, and all the patients treated with the same procedure. We founded that the combination methods showed a significant effect in terms of surgery time, patient outcomes and recovery, hospital discharge. The mean age of patients was 78.16 ± 4.2 (73–84) years, and the mean prostate-specific antigen (PSA) value was 16.27 ± 10.01 (8.32–32.17) ng/mL. The mean size of the prostate measured by MRI/US was 266.16 ± 89.1 (169–405) mL. The mean total operation time was 70.5 ± 10.9 (60–90) min, while the mean enucleation time was 28.38 ± 6.61 (23–40) min. The mean intraoperative blood loss was 193.33 ± 19.66 (170–220) mL. The mean resected prostate weight was 217.166 ± 94.67 (117–365) g. The mean post-operative hospital stay was 2.6 ± 0.81 (2–4) days. One patient was readmitted 2 months later due to urinary tract infection, and one patient complains of urine incontinence who spontaneously subsided in 4 months after surgery, other that no severe postoperative complications observed, a significant reduction of serum PSA and IPSS recorded at 3 months, postoperatively. Although simple open prostatectomy remains the reference standard for the treatment. Of excessively large or giant prostatic hyperplasia, the combination procedure not only facilitates the management of selected cases of hyperplasia but further imparts significant benefits to patients and surgeons alike. This treatment plan is safe, time-consuming, and could revolutionize future treatment approaches to giant prostate.

Background Neuromyelitis optica spectrum disorders (NMOSD) are associated with recurrent episodes of optic neuritis and transverse myelitis, often resulting in high attack-related disability. Therapeutic apheresis has been recommended as a second-line treatment for steroid-refractory NMOSD. To assess the efficacy and safety of two apheresis techniques, lymphoplasmapheresis (LPE) and therapeutic plasma exchange (TPE), in refractory NMOSD and to provide a new treatment option for patients with refractory NMOSD. Methods This retrospective study examined NMOSD patients who had undergone either LPE or TPE treatment between January 2015 and January 2018. The patients were monitored for improvements in disabilities, incidences of adverse reactions, and safety of the procedure over a one-year follow-up period. The primary outcome measures included changes in the visual outcome scale (VOS) score, the expanded disability status scale (EDSS), and the annualized relapse rate (ARR). Results Neurological function and objective response rates were significantly improved in 76.5% of patients treated with LPE and 83.3% of patients treated with TPE. There were no significant differences in the two treatment groups (P=0.392). Similarly, there were no differences in the reduction in the relative relapse rate between the two groups (P=0.494). Adverse reactions, mostly of mild or moderate intensity, were recorded in 9.3% of procedures in 38% of patients. The most commonly observed adverse events (AEs) were similar between the two treatment cohorts. Conclusions Patients treated with LPE showed improved neurological function comparable to that reported with TPE treatment. No superiority was shown for either of the apheresis techniques.

Rationale and Objectives The purpose of this study was to investigate the role of computed tomography (CT) radiomics for the prediction of the human epidermal growth factor 2 (HER2) status in patients with gastric cancer. Methods One hundred and thirty two consecutive patients with advanced gastric cancer undergoing radical gastrectomy were retrospectively reviewed. All patients received preoperative contrast CT examination, and immunohistochemistry results of their HER2 status were available. All the subjects were randomly divided into a training cohort (n = 90) and a test cohort (n = 42). Arterial phase (AP) and portal phase (PP) contrast CT images were retrieved for tumor segmentation and feature extraction. Receiver operating characteristics (ROC) curves and area under the curve (AUC) were used to evaluate the performance of the radiomics classifiers. Results Among the 132 patients, a total of 99 patients were HER2 negative, and the remaining 33 patients were border line or positive. The AP radiomics model could distinguish HER2-negative cases with an AUC of 0.756 (95% confidence interval [CI]: 0.656–0.840) in the training cohort, which was confirmed in the test cohort with AUC of 0.830 (95% CI: 0.678–0.930). The PP radiomics model showed AUCs of 0.715 (95% CI: 0.612–0.804) and 0.718 (95% CI: 0.554–0.849) in the training and test cohort for distinction of negative HER2 cases, respectively. Conclusion Radiomics models based on standard-of-care CT images hold promise for distinguishing HER2-negative gastric cancer.

Interleukin-22 (IL-22), secreted by tumor infiltrated lymphocytes, is identified as a tumor-promoting factor in certain cancers, which was secreted by tumor infiltrated lymphocytes. However, the role of IL-22 in breast cancer remains conflicting. In this study, we assessed the expression of IL-22, IL-22 receptor 1 (IL-22R1), CD4, CD8, FOXP3, and CD68 in breast cancer by immunohistochemistry. IL-22 expression was exhibited in 105 (69.1%) cases in tumor cells (tIL-22), whereas only 24 (15.8%) samples displayed IL-22 expression in stromal cells. Multivariate analysis showed that tIL-22 expression was a poor prognostic factor for overall survival (OS) (

The model provided by the International Classification of Functioning, Disability and Health (ICF) is used to describe, classify and measure function in both health care practice and research. ICF for Children and Youth (ICF-CY) has not been applied to the rehabilitation of patients with visual impairment. The purpose of this case report is to describe the process of evaluation and treatment of low vision patients based on ICF-CY models. The patient was a 9-year-old girl. The diagnosis included retinopathy of prematurity (ROP) (OU), secondary glaucoma after iridectomy (OD), keratoleukoma (OD), retinal detachment (OS), strabismus postoperation (OU), nystagmus. The patient complained of being unable to see clearly, of fear of falling down stairs and of being unable to study normally. The ICF-CY framework is used to assess the overall function and disability of this girl. We provided visual devices and instruction to improve the body structure and function, mobility restriction and environmental factors associated with the cognitive function of patients. The results showed that with the help of devices and the guidance of her parents, friends and health professionals, the patient's cognitive function, learning ability and social ability were significantly improved and her psychological conditions had also been improved. As a result, using the ICF-CY model to evaluate and intervene in patients is helpful for accurately dealing with different functional problems and their correlations.

Current clinical treatment targeting osteosarcoma (OS) are limited for OS patients with pulmonary metastasis or relapse, which led to high mortality (70%-85%) for advanced osteosarcoma patients. Although ongoing efforts have been made to illustrate the mechanisms of tumorigenesis and progression in OS; however, it was far for us to learn a comprehensive molecular mechanism implies in OS development. In our study, we implicated a circRNA hsa_circ_0002137, which was higher expressed in osteosarcoma tumours compared with paracancerous tissue. The dysregulated expression pattern was also found in osteosarcoma cell lines. The role of circ_0002137 was explored via down- or up-regulated experiments. It was proved that down-regulation of circ_0002137 suppressed the progress of OS, including cell invasion, cell cycle and cell apoptosis. Furthermore, the correlation between circ_0002137 and miR-433-3p was predicted using bioinformatic tools and verified utilizing RNA pull-down assay and luciferase reporter assay. Interestingly, we found that the inhibitory effect of circ_0002137 on OS was dependent of insulin-like growth factor-1 receptor (IGF1R). In conclusion, it was demonstrated that circ_0002137 could restrain the progression of OS through regulating miR-433-3p/IGF1R axis, providing a comprehensive landscape of circ_0002137 in the generation and development of OS.

To evaluate the contributory value of positron emission tomography (PET)-intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) in the prediction of lymphovascular space invasion (LVSI) in patients with cervical cancer without lymphatic metastasis. A total of 90 patients with cervical cancer without signs of lymph node metastasis on PET/MRI were enrolled in this study. The tumours were classified into LVSI-positive (n = 25) and LVSI-negative (n = 65) groups according to postoperative pathology. The PET-derived parameters (SUVmax, SUVmean, metabolic tumour volume (MTV) and total lesion glycolysis (TLG)) and IVIM-derived parameters (ADCmean, ADCmin, Dmean, Dmin, f, D* and gross tumour volume (GTV)) between the two groups were evaluated using a Student’s t test (Mann-Whitney U test for variables with a nonnormal distribution) and receiver operating characteristic (ROC) curves. The optimal combination of PET/MR parameters for predicting LVSI was investigated using univariate and multivariate logistic regression models and evaluated by ROC curves. The optimal cutoff threshold values corresponded to the maximal values of the Youden index. A control model was established using 1000 bootstrapped samples, for which the performance was validated using calibration curves and ROC curves. PET-derived parameters (SUVmax, SUVmean, MTV, TLG) and IVIM MRI-derived parameters (Dmin, ADCmin, GTV) were significantly different between patients with and without LVSI (P < 0.05). Logistic analyses showed that a combination of TLG and Dmin had the strongest predictive value for LVSI diagnosis (area under the curve (AUC), 0.861; sensitivity, 80.00; specificity, 86.15; P < 0.001). The optimal cutoff threshold values for Dmin and TLG were 0.58 × 10−3 mm2/s and 66.68 g/cm3, respectively. The verification model showed the combination of TLG and Dmin had the strongest predictive value, and its ROC curve and calibration curve showed good accuracy (AUC, 0.878) and consistency. The combination of TLG and Dmin may be the best indicator for predicting LVSI in cervical cancer without lymphatic metastasis.

Objective To investigate the therapeutic efficacy of titanium elastic intramedullary nail (TEN) and open reduction and internal fixation with plate (ORIF) in the treatment of humeral fracture in children. Methods A retrospective study was carried out in a total of 69 patients who were admitted to the hospital from January 2013 to December 2018. These patients, including 41 males and 28 females, were aged from 6 to 12 years old with a median of 8 years. These patients were diagnosed with humeral fracture and underwent the surgery of ORIF (n = 22) or TEN (n = 47). The intraoperative bleeding, operation time, length of stay (LOS), and fracture healing time were compared between the two groups. The therapeutic effect was assessed by the shoulder range of motion, the elbow range of motion, the UCLA shoulder function score, and the Mayo elbow performance score (MEPS) 6 months after the surgery. Results The intraoperative bleeding (97.20 ± 27.83 mL vs 185.60 ± 37.50 mL, P, Compared with the open reduction and internal fixation with plate, titanium elastic intramedullary nail can be a good technique for the treatment of humeral fracture in children, with the advantages of less intraoperative bleeding, shorter operative time, quicker healing, and better recovery of shoulder mobility and range of motion.

Peritoneal mesothelioma (PM) is a rare and aggressive primary peritoneal malignancy characterized by widespread multiple metastatic tumour nodules originating from the peritoneum. The conventional classification distinguishes diffuse malignant peritoneal mesothelioma (DMPM) and border-line forms: multicystic peritoneal mesothelioma (MCPM) and well-differentiated papillary peritoneal mesothelioma (WDPPM). Despite the novel achievements in the management of PM, there is difficulty in conducting randomized trials due to its rarity and aggressive biology in many cases. As there is, a necessity to standardize diagnosis and management of PM, the Peritoneal Surface Oncology Group International (PSOGI) commissioned a steering committee to elaborate clinical guidelines.

This was a national survey that determined the prevalence of depressive symptoms (depression thereafter) and its relationship with quality of life (QOL) in frontline clinicians working in psychiatric hospitals in China during the COVID-19 pandemic. Depression and QOL were assessed using the Patient Health Questionnaire nine items (PHQ-9) and the World Health Organization Quality of Life Questionnaire-brief version (WHOQOL-BREF), respectively. Multivariable logistic regression analyses and analysis of covariance were used. A total of 10,516 frontline clinicians participated in this study, of which, 28.52% (n=2,999) met screening criteria for depression. Compared to those without depression, clinicians with depression had a lower quality of life (F (1, 10515) =2874.66, P

Genome‐wide 5hmC profiling in cell‐free DNA acquired from CRC patients, adenoma patients, and healthy individuals revealed that the differential 5hmC‐modified regions were gathered into four clusters with no overlap, although there are a few overlapped genes shared between the different clusters. CRC patients with adenoma history showed exclusive 5hmC‐gain characteristics, which was consistent with the ‘parallel’ evolution hypothesis in adenoma., Approximately 85% colorectal cancers (CRCs) are thought to evolve through the adenoma‐to‐carcinoma sequence associated with specific molecular alterations, including the 5‐hydroxymethylcytosine (5hmC) signature in circulating cell‐free DNA (cfDNA). To explore colorectal disease progression and evaluate the use of cfDNA as a potential diagnostic factor for CRC screening, here, we performed genome‐wide 5hmC profiling in plasma cfDNA and tissue genomic DNA (gDNA) acquired from 101 samples (63 plasma and 38 tissues), collected from 21 early‐stage CRC patients, 21 AD patients, and 21 healthy controls (HC). The gDNA and cfDNA 5hmC signatures identified in gene bodies and promoter regions in CRC and AD groups were compared with those in HC group. All the differential 5hmC‐modified regions (DhMRs) were gathered into four clusters: Disease‐enriched, AD‐enriched, Disease‐lost, and AD‐lost, with no overlap. AD‐related clusters, AD‐enriched and AD‐lost, displayed the unique 5hmC signals in AD patients. Disease‐enriched and Disease‐lost clusters indicated the general 5hmC changes when colorectal lesions occurred. Cancer patients with a confirmable adenoma history segmentally gathered in AD‐enriched clusters. KEGG functional enrichment and GO analyses determined distinct differential 5hmC‐modified profiles in cfDNA of HC individuals, AD, and CRC patients. All patients had comprehensive 5hmC signatures where Disease‐enriched and Disease‐lost DhMR clusters demonstrated similar epigenetic modifications, while AD‐enriched and AD‐lost DhMR clusters indicated complicated subpopulations in adenoma. Analysis of CRC patients with adenoma history showed exclusive 5hmC‐gain characteristics, consistent with the ‘parallel’ evolution hypothesis in adenoma, either developed through the adenoma‐to‐carcinoma sequence or not. These findings deepen our understanding of colorectal disease and suggest that the 5hmC modifications of different pathological subtypes (cancer patients with or without adenoma history) could be used to screen early‐stage CRC and assess adenoma malignancy with large‐scale follow‐up studies in the future.

Therapeutic angiogenesis is one promising strategy for the treatment of ischemic heart disease, which is the leading cause of death globally. In recent years, extracellular vesicles (EVs) have quickly gained much attention as a cell-free approach to stimulate angiogenesis. However, clinical applications of EVs are limited by their insufficient targeting capability. Herein, we introduce a method to enhance therapeutic angiogenesis based on platelet membrane-engineered EVs. Methods Platelet-mimetic EVs (P-EVs) were fabricated by fusing the membranes of EVs with platelet membranes by extrusion. A mouse model of myocardial ischemia reperfusion (MI/R) was established and injected with PBS, EVs, and P-EVs to evaluate their targeting ability and therapeutic angiogenesis efficacy. Results P-EVs inherited the adhesive proteins and natural targeting ability to injured vasculature of platelets and retained the pro-angiogenic potential of EVs. In the MI/R model, P-EVs preferentially accumulated in the injured endothelium of the ischemic hearts and enhanced the angiogenesis potency of EVs. Conclusions This engineering strategy to modify pre-isolated EVs with platelet membranes by membrane fusion bestows EVs with the targeting ability of platelets and offers an exciting opportunity to design other targeted EVs fused with cell membranes from different sources for therapeutic angiogenesis.

Objective Riedel's thyroiditis (RT) is a very rare chronic fibrosing thyroiditis that is often associated with multifocal fibrosclerosis. Although the relationship of RT and IgG4-related disease (IgG4-RD) has been suggested, the expression of IgG and IgG4 in thyroid tissues of patients with RT has seldom been studied. Design A case series and literature review. Patients and measurements We searched our hospital's pathology database and identified five cases of RT between 2000 and 2019. The expression levels of IgG4 and IgG in thyroid tissues were detected by immunohistochemistry. We also performed a literature search of the electronic databases PubMed/MEDLINE, Web of Science and China National Knowledge Internet (CNKI). Eight papers were included in this study. Results According to immunohistochemistry, the numbers of IgG4+ plasma cells per high-power field (HPF) of the five RT patients at our hospital were 80, 8, 50, 10 and 22, and the respective IgG4+/IgG+ ratios were 76%, 80%, 43%, 19% and 28%. In the literature, 15 RT patients with confirmed IgG4 and IgG immunohistochemical findings were identified. Only seven of them fulfilled the IgG4-RD diagnostic criteria in terms of immunohistochemistry (IgG4+ > 10/HPF, IgG4+/IgG+ > 40%). In order to ensure that most RT cases can meet the IgG4 immunohistochemical criteria, an organ-specific cut-off value (≥10 IgG4+ plasma cells/HPF and ≥ an IgG4+/IgG ratio of 20%) was finally selected in our study. Conclusion Our findings of IgG4 expression in patients with RT suggest that a cut-off of 10 IgG4+ plasma cells/HPF and an IgG4+/IgG ratio of 20% are more suitable diagnostic criteria for RT in IgG4-RD.

Background Suicidality is common in patients with migraine. Here, we performed a systematic review and estimated the prevalence of suicidal ideation (SI) and suicide attempt (SA) in patients with migraine. Methods We searched Pubmed, Embase, Web of Science, Cochrane database library, CINAHL, and PsycINFO for relevant publications. A random-effects model was used to pool the estimates of the prevalence of SI and SA, which were also stratified by the geographical location of the research institutions from the studies included in this meta-analysis. Results Fifteen studies involving 2,247,648 participants with migraine were selected. Pooled prevalence estimates of SI and SA were 15.5% [95% confidence interval (CI) 10.4–21.3%] and 3.9% (95% CI 0.9–8.8%), respectively, and the prevalence of SI was higher in Asian countries (21.5%, 95%CI 16.8–26.6%) compared with non-Asian countries (11.0%, 95%CI 6.1–17.2%). Measures of heterogeneity between studies were high for all outcomes (I2 = 89–100%), indicating that the substantial between-study heterogeneity in estimated proportions was not attributed to sampling error. The leave-one-out analysis showed that no single study significantly affected the final pooled results. Conclusions This meta-analysis indicated a high prevalence of SI and SA in migraine patients. Thus, it is necessary to design targeted preventive measures for the management of migraine-related suicide.