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Colorectal cancer (CRC) is the most common digestive tract malignancy, attributing to approximately 9.4% of global cancer-related deaths. However, the pathogenesis of CRC is poorly understood. The testis-expressed 11 (TEX11) gene is located on the X chromosome and is required for spermatogenesis, and is reported might serve as a biomarker for early onset CRC according to database analysis. However, the role played by TEX11 in cancer progression remains to be investigated. In this study, we show that TEX11 expression is significantly downregulated in CRC cell lines and clinical CRC tissue samples, and TEX11 expression correlates with poor prognosis in CRC patients. We further demonstrate that TEX11 can significantly inhibit the proliferative capacity of CRC cells in vitro and in vivo. Mechanistically, we demonstrate that TEX11 promotes transcription of COP1 by upregulating FOXO3a expression. This enhanced COP1 expression subsequently accelerates the degradation of the negative transcriptional regulator c-Jun, which, in turn, enhances p21 transcription inhibiting CRC cell cycle progression and proliferation. Overall, our findings suggest that TEX11 may be a valuable therapeutic target for the treatment of CRC.

Background Although the diagnostic value of plasma heat-shock protein 90α (HSP90α) in hepatocellular carcinoma (HCC) has been previously reported, the causal effect of the plasma HSP90α levels on HCC prognosis remains largely unclear. To this extent, we sought to assess whether the plasma HSP90α acts as a prognostic factor for HCC patients. Methods A total of 2150 HCC patients were included in this retrospective study between August 2016 and July 2021. Plasma HSP90α levels were tested within a week before treatment and their association with prognosis was assessed. Results An optimal cutoff value of 143.5 for the HSP90α based on the overall survival (OS) was determined using the X-tile software. HCC patients with HSP90α p p Conclusions Our study confirmed that the plasma HSP90α level can be used as a prognostic biomarker for HCC.

Background Cryptococcosis and pneumocystosis are opportunistic infections which are more common in immunosuppressed individuals. Herein, we report a rare case of coinfection of pulmonary cryptococcosis (PC) and Pneumocystis jirovecii pneumonia (PJP) in a patient without a previous predisposing illness. Case presentation A 76-year-old man was admitted to our hospital with complaints of cough, expectoration, shortness of breath, and fever. A chest computed tomography (CT) showed multiple nodules with diffuse ground-glass opacities (GGOs) in both lungs. The patient was diagnosed as extrinsic allergic alveolitis (Pigeon breeder’s lung). After treatment with corticosteroids, the patient improved with significant absorption of GGOs on chest CT. However, pulmonary nodules gradually enlarged and such lesions could not be explained by EAA. Based on the positivity of serum cryptococcal antigen and pathological examination of lung nodule which confirmed the presence of Cryptococcus spores, PC was diagnosed later and fluconazole was administered. However, repeated chest CT performed about 2 months after antifungal treatment showed significantly increased GGOs in both lungs. The pathological examination of new lung lesions revealed the presence of P. jirovecii. The patient was finally diagnosed having coinfection of PC and PJP and sulfamethoxazole was further prescribed. Thereafter, the patient improved again with significant absorption of GGOs as noted on chest CT. Conclusions Concomitant PC and PJP is very rare, especially in a patient without a previous predisposing illness. Additionally, when pulmonary lesions cannot be completely explained by one kind of infectious disease, the possibility of mixed infection should be considered.

Glioblastoma (GBM) is a deadly and common primary brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity. Sex differences may play a role in patient outcome. Previous studies showed that ER-α36, a variant of the estrogen receptor (ER), mediated non-genomic estrogen signaling and is highly expressed in many ER-negative malignant tumors. ER-α36 also associates with epidermal growth factor receptor (EGFR). The primary purpose of this study is to investigate the cross talk between ER-α36 and EGFR in estrogen-mediated GBM cell proliferation. Here, we showed that ER-α36 was highly expressed and confirmed that ER-α36 co-labels with EGFR in human GBM samples using immunohistochemical techniques. We also investigated the mechanisms of estrogen-induced proliferation in ER-α-negative cell lines. We found that GBM cells showed varying responsive to mitogenic estrogen signaling which correlated with ER-α36 expression, and knockdown of ER-α36 diminished the response. Exposure to estrogen also caused upregulation of cyclin protein expression in vitro. We also found that low concentration of estrogen promoted SRC-Y-416 and inhibited SRC-Y-527 phosphorylation, corresponding with activated SRC signaling. Inhibiting SRC or EGFR abolished estrogen-induced mitogenic signaling, including cyclin expression and MAPK phosphorylation. Cumulatively, our results demonstrate that ER-α36 promotes non-genomic estrogen signaling via the EGFR/SRC/MAPK pathway in GBM. This may be important for the treatment of ER-α-negative GBMs that retain high level of ER-α36, since estrogen may be a viable therapeutic target for these patients.

X-box binding protein 1 (XBP1) is a transcription factor that recognizes the CRE-like element in enhancers of human T-cell leukemia virus and MHC class II gene and induces their transcription. This study was performed to characterize the function of XBP1, which was identified to be a differentially expressed gene via GEO database, in chronic rhinosinusitis (CRS) without nasal polyps (CRSsNP). XBP1 expression was significantly elevated in both CRSsNP patients and mice who were accompanied with mucosal thickening, goblet cell hyperplasia and chemosis, glandular hyperplasia, and dense infiltration of inflammatory cells. Silencing of XBP1 suppressed the development of CRSsNP in mice. Mechanistically, knockdown of XBP1 downregulated the expression of hypoxia-inducible factor 1-alpha (HIF-1a), and overexpression of XBP1 led to the opposite result. Silencing of HIF-1a inhibited β-catenin expression and impaired the Wnt/β-catenin pathway. Further overexpression of HIF-1a in XBP1-silenced CRSsNP mice exacerbated pathological changes in mouse nasal mucosal tissues, promoted inflammation, and activated the Wnt/β-catenin pathway. Taken together, overexpression of XBP1 may be associated with increased expression of HIF-1a and possibly contribute to the Wnt/β-catenin pathway activation and the development of CRSsNP.

Metals are essential components in life processes and participate in many important biological processes. Dysregulation of metal homeostasis is correlated with many diseases. Metals are also frequently incorporated into diagnosis and therapeutics. Understanding of metal homeostasis under (patho)physiological conditions and the molecular mechanisms of action of metallodrugs in biological systems has positive impacts on human health. As an emerging interdisciplinary area of research, metalloproteomics involves investigating metal-protein interactions in biological systems at a proteome-wide scale, has received growing attention, and has been implemented into metal-related research. In this review, we summarize the recent advances in metalloproteomics methodologies and applications. We also highlight emerging single-cell metalloproteomics, including time-resolved inductively coupled plasma mass spectrometry, mass cytometry, and secondary ion mass spectrometry. Finally, we discuss future perspectives in metalloproteomics, aiming to attract more original research to develop more advanced methodologies, which could be utilized rapidly by biochemists or biologists to expand our knowledge of how metal functions in biology and medicine.

STUDY QUESTION Are mutations in MOS (MOS proto-oncogene, serine/threonine kinase) involved in early embryonic arrest in infertile women? SUMMARY ANSWER We identified mutations in MOS that may cause human female infertility characterized by preimplantation embryonic arrest (PREMBA), and the effects of the mutations in human embryonic kidney 293T (HEK293T cells) and mouse oocytes provided evidence for a causal relation between MOS and female infertility. WHAT IS KNOWN ALREADY MOS, an activator of mitogen-activated protein kinase, mediates germinal vesicle breakdown and metaphase II arrest. Female MOS knockout mice are viable but sterile. Thus, MOS seems to be an important part of the mammalian cell cycle mechanism that regulates female meiosis. STUDY DESIGN, SIZE, DURATION Whole-exome sequencing, bioinformatics filtering analysis and genetic analysis were performed to identify two different biallelic mutations in MOS in two independent families. The infertile patients presenting with early embryonic arrest were recruited from October 2018 to June 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS The female patients diagnosed with primary infertility were recruited from the reproduction centres of local hospitals. Genomic DNA from the affected individuals, their family members and healthy controls was extracted from peripheral blood. We performed whole-exome sequencing in patients diagnosed with PREMBA. Functional effects of the mutations were investigated in HEK293T cells by western blotting and in mouse oocytes by microinjection and immunofluorescence. MAIN RESULTS AND THE ROLE OF CHANCE We identified the homozygous missense mutation c.285C>A (p.(Asn95Lys)) and the compound heterozygous mutations c.467delG (p.(Gly156Alafs*18)) and c.956G>A (p.(Arg319His)) in MOS in two independent patients. The mutations c.285C>A (p.(Asn95Lys)) and c.467delG (p.(Gly156Alafs*18)) reduced the protein level of MOS, and all mutations reduced the ability of MOS to phosphorylate its downstream target, extracellular signal-regulated kinase1/2. In addition, the identified mutations reduced the capacity of exogenous human MOS to rescue the metaphase II exit phenotype, and the F-actin cytoskeleton of mouse oocytes was affected by the patient-derived mutations. LIMITATIONS, REASONS FOR CAUTION Owing to the lack of in vivo data from patient oocytes, the exact molecular mechanism affected by MOS mutations and leading to PREMBA is still unknown and should be further investigated using knock-out or knock-in mice. WIDER IMPLICATIONS OF THE FINDINGS We identified recessive mutations in MOS in two independent patients with the PREMBA phenotype. Our findings reveal the important role of MOS during human oocyte meiosis and embryonic development and suggest that mutations in MOS may be precise diagnostic markers for clinical genetic counselling. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Natural Science Foundation of China (81725006, 81822019, 81771581, 81971450, 81971382,82001538 and 82071642), the project supported by the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), the Project of the Shanghai Municipal Science and Technology Commission (19JC1411001), the Natural Science Foundation of Shanghai (19ZR1444500 and 21ZR1404800), the Shuguang Program of the Shanghai Education Development Foundation and the Shanghai Municipal Education Commission (18SG03), the Foundation of the Shanghai Health and Family Planning Commission (20154Y0162), the Capacity Building Planning Program for Shanghai Women and Children’s Health Service and the collaborative innovation centre project construction for Shanghai Women and Children’s Health. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A.

Cancer biomarker discovery is critically dependent on the integrity of biofluid and tissue samples acquired from study participants. Multi-omic profiling of candidate protein, lipid, and metabolite biomarkers is confounded by timing and fasting status of sample collection, participant demographics and treatment exposures of the study population. Contamination by hemoglobin, whether caused by hemolysis during sample preparation or underlying red cell fragility, contributes 0–10 g/L of extraneous protein to plasma, serum, and Buffy coat samples and may interfere with biomarker detection and validation. We analyzed 617 plasma, 701 serum, and 657 buffy coat samples from a 7-year longitudinal multi-omic biomarker discovery program evaluating 400+ participants with or at risk for pancreatic cancer, known as Project Survival. Hemolysis was undetectable in 93.1% of plasma and 95.0% of serum samples, whereas only 37.1% of buffy coat samples were free of contamination by hemoglobin. Regression analysis of multi-omic data demonstrated a statistically significant correlation between hemoglobin concentration and the resulting pattern of analyte detection and concentration. Although hemolysis had the greatest impact on identification and quantitation of the proteome, distinct differentials in metabolomics and lipidomics were also observed and correlated with severity. We conclude that quality control is vital to accurate detection of informative molecular differentials using OMIC technologies and that caution must be exercised to minimize the impact of hemolysis as a factor driving false discovery in large cancer biomarker studies.

The emerging COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has claimed over six million lives globally to date. Despite the availability of vaccines, the pandemic still cannot be fully controlled owing to rapid mutation of the virus that renders enhanced transmissibility and antibody evasion. This is thus an unmet need to develop safe and effective therapeutic options for COVID-19, in particular, remedies that can be used at home. Considering the great success of multi-targeted cocktail therapy for the treatment of viral infections, metal-based drugs might represent a unique and new source of antivirals that resemble a cocktail therapy in terms of their mode of actions. In this review, we first summarize the role that metal ions played in SARS-CoV-2 viral replication and pathogenesis, then highlight the chemistry of metal-based strategies in the fight against SARS-CoV-2 infection, including both metal displacement and chelation based approaches. Finally, we outline a perspective and direction on how to design and develop metal-based antivirals for the fight against the current or future coronavirus pandemic.

ObjectivesMusculoskeletal pain (MSP) is a major reason for consultation in primary care and is becoming increasingly prevalent among medical students. There is little research on the current situation of MSP among Chinese medical and dental students. Data on the analysis of risk factors related to MSP are also limited. The objectives of this study were to investigate the prevalence and characteristics of MSP among Chinese medical and dental students and to explore the risk factors for MSP and students' intent to seek medical treatment.MethodsAn anonymous, internet-based, cross-sectional, open survey was distributed to medical and dental students at Fujian Medical University, Fuzhou, China. Data on the demographic information and characteristics of MSP were collected and analyzed. In addition to descriptive statistics, logistic regression was used to analyze significant risk factors contributing to MSP.ResultsA total of 1,178 students responded to the survey (response rate = 79.6%), including 722 medical students and 456 dental students. The age ranged from 16 to 24. There were 553 male students and 625 female students. A total of 523 students reported neck pain (NP, 44.4%), 361 students reported low back pain (LBP, 30.6%), and 182 students reported joint pain (JP, 15.4%). Sixty-six students (5.6%) simultaneously suffered from NP, LBP, and JP. The prevalence of NP (49.1 vs. 41.4%, P = 0.01), LBP (34.6 vs. 28.1%, P = 0.02), and JP (20.2 vs. 12.5%, P < 0.001) was significantly higher in dental students than in medical students. The prevalence of MSP was significantly different among the academic years for NP and LBP (P = 0.02 and P < 0.001, respectively). Univariate and multivariate regression analyses demonstrated that female sex, PSS-10 score, and major of stomatology were risk factors for MSP. Medical and dental students' intention to seek treatment for MSP was low and was significantly associated with the severity of pain.ConclusionsThe prevalence of MSP in Chinese medical and dental students is high, especially for NP and LBP, and is significantly higher in dental students than in medical students. The prevalence of NP and LBP were significantly different among academic grades. Female sex, PSS-10 score, and major of stomatology were risk factors for MSP. Students' intent to seek treatment for MSP was very low and was determined by the severity of pain.

CD248, also known as endosialin or tumor endothelial marker 1, is a type I single transmembrane glycoprotein. CD248 has been demonstrated to be upregulated in cancers, tumors and many fibrotic diseases in human and mice, such as liver damage, pulmonary fibrosis, renal fibrosis, arthritis and tumor neovascularization. However, no definite CD248 orthologs in fish have been documented so far. In this study, we report the identification of cd248a and cd248b in the zebrafish. Both the phylogenetic analysis and the conserved synteny strongly suggested that zebrafish cd248a and cd248b are orthologs of the human CD248. Both cd248a and cd248b exhibited similar and dynamic expression pattern in early development, both genes had weak maternal expression, the zygotic transcripts were first seen in anterior somites and head mesenchyme, then shifted to eyes and head mesenchyme, later expanded to branchial arches, and gradually declined with development. The expression profiles of cd248a and cd248b were upregulated upon LPS (Lipopolysaccharide) challenge. Both Cd248a protein and Cd248b protein were localized on the cell membrane and cytoplasm, and overexpression of cd248a and cd248b induced the expression of pro-inflammatory cytokines, in vitro and in vivo. Moreover, deficiency of cd248a or cd248b both downregulated the expression of pro-inflammatory cytokines and upregulated anti-inflammatory cytokine. Additionally, loss of cd248a or cd248b both downregulated the expression of pro-inflammatory cytokines after LPS treatment. Taken together, these results indicated that cd248a and cd248b in zebrafish were involved in immune response and would provide further information to understand functions of Cd248 protein in innate immunity of fish.

Coronavirus disease 2019 (COVID-19) is a novel acute respiratory infectious disease that can lead to multiple-organ dysfunction in patients with severe disease. However, there is a lack of effective antiviral drugs for COVID-19. Herein, we investigated the efficacy and safety of convalescent plasma (CP) therapy for treating severe COVID-19 in an attempt to explore new therapeutic methods. The clinical data of 3 imported patients with severe COVID-19 who underwent treatment with CP and who were quarantined and treated in a designated COVID-19 hospital from March 2020 to April 2020 were collected and analyzed. The 3 patients, including a 57-year-old male, 65-year-old female, and 59-year-old female, were clinically classified as having severe COVID-19. The main underlying diseases included hypertension, diabetes, sequelae of cerebral infarction, and postoperative thyroid adenoma. The common symptoms included cough, fever, and shortness of breath. All patients received antiviral drugs and other supportive treatments. Additionally, CP treatment was administered. At 48 to 72 hours after the CP transfusion, all 3 of the patients exhibited an improvement and alleviation of symptoms, an elevated arterial oxygen saturation, and decreased C-reactive protein and interleukin-6 levels. The counts of the total lymphocytes and T lymphocytes (CD3+) and their subsets (CD4 + and CD8+) were also obviously increased. Repeated chest computed tomography also revealed obvious absorption of the lesions in the bilateral lungs. Only 1 patient had a mild allergic reaction during the CP infusion, but no severe adverse reactions were observed. The early treatment with CP in patients with severe COVID-19 can rapidly improve the condition of the patients, and CP therapy is generally effective and safe.

Wound is highly susceptible to bacterial infection, which can cause chronic wound and serial complications. However, timely treatment is hampered by the lack of real-time monitoring of wound status and effective therapeutic systems. Herein, in situ biosynthesis of functional conjugated polymer in artificial hydrogel was developed via the utilization of biological microenvironment to realize monitoring in real time of wound infection and inhibition of bacteria for the first time. Specially, an easily polymerizable aniline dimer derivative (N-(3-sulfopropyl) p-aminodiphenylamine, SPA) was artfully in situ polymerized into polySPA (PSPA) in calcium alginate hydrogel, which was initiated via the catalysis of hydrogen peroxide (H

Background Since the release of the LACC trial results in 2018, the safety of laparoscopic radical hysterectomy (LRH) for cervical cancer has received huge attention and heated discussion. We developed modified laparoscopic radical hysterectomy (MLRH) incorporating a series of measures to prevent tumor spillage, which has been performed in our center since 2015. Objective Present study retrospectively analyzed relevant indicators of MLRH and evaluated disease-free survival (DFS) primarily in the treatment of early cervical cancer compared with open surgery. Methods Patients with 2014 International Federation of Gynecology and Obstetrics clinical stages 1B1 and 2A1 cervical cancer who underwent radical hysterectomy in the gynecological department of our hospital from October 2015 to June 2018 were enrolled retrospectively in this study. Patients were divided into two groups based on the surgical procedure: open radical hysterectomy (ORH) group (n = 336) and MLRH group (n = 302). Clinical characteristics, surgical indices, and survival prognosis were analyzed, including 2.5-year overall survival (OS) rate, 2.5-year DFS rate, recurrence rate, and recurrence pattern. Results Compared to the ORH group, the MLRH group exhibited a longer operative time, longer normal bladder function recovery time, less intraoperative blood loss volume, and more harvested pelvic lymph nodes (P < 0.05). No significant differences were observed in postoperative complications, the 2.5-year OS, 2.5-year DFS, and recurrence rate between the two groups (P > 0.05); however, the recurrence pattern was significantly different (P < 0.05). The MLRH group mainly exhibited local single metastasis (7/11), whereas the ORH group mainly exhibited distant multiple metastases (14/16). Stratified analysis revealed that overall survival rate was higher in the MLRH group than in the ORH group in patients with stage 1B1 and middle invasion (P < 0.05). Conclusion MLRH does not show a survival disadvantage in the treatment of early-stage cervical cancer when compared with open surgery. In addition, MLRH shows a survival advantage in patients with stage 1B1 and middle 1/3 invasion. Considering this is a retrospective study, further prospective study is necessary for more sufficient data support. Trial registration Present research is a retrospective study. The study had retrospectively registered on Chinese Clinical Trial Registry (http://www.chictr.org.cn/), and the registered number is ChiCTR1900026306.

Ultrafine particles (UFPs) usually explosive growth during new particle formation (NPF) events. However, the risk of exposure to UFPs on NPF days has been ignored due to the prevalence of mass-based air quality standards. In this study, the daily deposited doses, i.e., the daily deposited particle number dose (D-PNd), mass dose (D-PMd), and surface area dose (D-PSd), of ambient particles in the human respiratory tract in Beijing were evaluated based on the particle number size distribution (3 nm-10 mu m) from June 2018 to May 2019 utilizing a Multiple-Path Particle Dosimetry Model (MPPD) after the hygroscopic growth of particles in the respiratory tract had been accounted for. Our observations showed a high frequency (72.6%) of NPF on excellent air quality days, with daily mean PM2.5 concentrations less than 35 mu g m(-3). The daily D-PNd on excellent air quality days was com-parable with that on polluted days, although the D-PMd on excellent air quality days was as low as 15.6% of that on polluted days. The D-PNd on NPF days was similar to 1.3 times that on non-NPF days. The D-PNd in respiratory tract regions decreased in the order: tracheobronchial (TB) > pulmonary (PUL) > extrathoracic (ET) on NPF days, while it was PUL > TB > ET on non-NPF days. The number of deposited nucleation mode particles, which were deposited mainly in the TB region (45%), was 2 times higher on NPF days than that on non-NPF days. Our results demonstrated that the deposition potential due to UFPs in terms of particle number concentrations is high in Beijing regardless of the aerosol mass concentration. More toxicological studies related to UFPs on NPF days, especially those targeting tracheobronchial and pulmonary impairment, are required in the future.

Background Hsa_circ_0000345 has been reported to be down-regulated in nasopharyngeal carcinoma (NPC). Whether hsa_circ_0000345 can exert antitumor effect in NPC remains unclear. This study aimed to investigate the possible biological role of hsa_cic_0000345 in suppressing the progression of NPC. Methods Hsa_circ_0000345 expression was detected in normal nasopharynx epithelial cells (NP69) and NPC cell lines (SUNE1, HONE1, 6-10B and HNE1). The influence of hsa_circ_0000345 on cell proliferation, migration and invasion of NPC cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and transwell assays. Quantitative real-time PCR and western blot were performed to examine gene and protein expression, respectively. Luciferase reporter assay was carried out to verify the relationship among hsa_circ_0000345, miR-513a-3p and phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Results Compared with NP69 cells, hsa_circ_0000345 was down-regulated in NPC cells. Moreover, hsa_circ_0000345 overexpression repressed cell proliferation, migration and invasion of SUNE1 cells, whereas hsa_circ_0000345 knockdown promoted cell proliferation, migration and invasion of 6-10B cells. Furthermore, hsa_circ_0000345 promoted PTEN expression by sponging miR-513a-3p. Both miR-513a-3p overexpression and PTEN knockdown promoted cell proliferation, migration and invasion of SUNE1 cells, which were effectively abolished by hsa_circ_0000345 up-regulation. Conclusion Hsa_circ_0000345 inhibits cell proliferation, migration and invasion of NPC cells via miR-513a-3p/PTEN axis, thereby suppressing the progression of NPC. Thus, this work suggests that hsa_circ_0000345 may be a potential biomarker for diagnosis and treatment of NPC.

Background Intussusception recurrence (IR) induced by intestinal lymphoid hyperplasia (ILH) in children is rare, and surgical treatment is the final resort if IR is refractory to medications and non-surgical interventions. To date, only a few case reports have described surgical management of ILH-induced IR in children, all involving bowel resection regardless of whether there are bowel necrosis and perforation. Case presentation A 2-year-old boy was transferred to our department due to IR. His main complaint was abdominal pain. Color Doppler ultrasound confirmed ileocecal intussusception while no other abnormalities were found. A final diagnosis of IR with unknown causes was made. Repeated saline enema reductions and dexamethasone failed to cure the IR. Laparotomy was eventually performed after almost 10 episodes of IR. Intraoperatively, distal ileum thickening with palpable masses without bowel necrosis and perforation was noted. ILH was suspected and a biopsy of the affected intestine was performed. Histopathological analysis confirmed ILH. The intussusception was manually reduced, the terminal ileum and the ileocecal junction were fixed to the paralleled ascending colon and the posterior peritoneum respectively, and no bowel resection was performed. The postoperative recovery was uneventful and no IR was observed during over 5 years of follow-up. Conclusions As far as we are aware, this is the first report of successful surgical treatment of ILH-induced pediatric IR without bowel resection in a child. Our experience suggests bowel resection may be unnecessary if bowel necrosis and perforation are absent.

Inhibition of the pituitary adenylate cyclase 1 receptor (PAC1R) is a novel mechanism that could be used for abortive treatment of acute migraine. Our research began with comparative analysis of known PAC1R ligand scaffolds, PACAP38 and Maxadilan, which resulted in the selection of des(24-42) Maxadilan, 6, as a starting point. C-terminal modifications of 6 improved the peptide metabolic stability in vitro and in vivo. SAR investigations identified synergistic combinations of amino acid replacements that significantly increased the in vitro PAC1R inhibitory activity of the analogs to the pM IC90 range. Our modifications further enabled deletion of up to six residues without impacting potency, thus improving peptide ligand binding efficiency. Analogs 17 and 18 exhibited robust in vivo efficacy in the rat Maxadilan-induced increase in blood flow (MIIBF) pharmacodynamic model at 0.3 mg/kg subcutaneous dosing. The first cocrystal structure of a PAC1R antagonist peptide (18) with PAC1R extracellular domain is reported.

Alzheimer's disease (AD) is a neurodegenerative disorder with notable factors of dysfunction in multiple neurological changes, encompassing neuronal loss in the frontal cortex and hippocampal regions. Dysfunction of proliferation and self-renewal of neural stem cells (NSCs) was observed in AD patients and animals. Thereby, mobilizing endogenous neurogenesis by pharmacological agents would provide a promising route for neurodegeneration. Osthole (Ost), a natural coumarin derivative, has been reported to exert extensive neuroprotective effects in AD. However, whether ost can facilitate endogenous neurogenesis against AD in vivo is still unknown. In this study, by using Morris water maze (MWM) test, hematoxylin-eosin (HE) staining, Nissl staining, immunofluorescence analysis and western blot, we demonstrated that oral administration of ost could improve the learning and memory function, inhibit neuronal apoptosis, elevate the expression of glial cell line derived neurotrophic factor (GDNF), synaptophysin (SYP) and postsynaptic density protein 95 (PSD95). Moreover, ost could remarkably enhance proliferation of NSCs and increase the amount of mature neurons in APP/PS1 transgenic mice. Together, our findings demonstrated that ost possessed the ability of promoting endogenous neurogenesis and ost could be served as a plausible agent to reverse or slow down the progress of AD.

The frequent intake of whole foods and dietary food variety is recommended due to their health benefits, such as prevention of multiple chronic diseases, including cancer, Alzheimer's disease, cardiovascular diseases, and type 2 diabetes mellitus. Often, consuming whole fruits or vegetables showed the enhanced effects than consuming the individual dietary supplement from natural products, which is widely explained by the interactive effects of co-existing phytochemicals in whole foods. Although research relevant to interactive effects among the bioactive compounds mounted up, the mechanism of interaction is still not clear. Especially, biological influence factors such as bioavailability are often neglected. The present review summarizes the progress on the synergistic and antagonistic effects of dietary phytochemicals, the evaluating models for antioxidant interactions, and the possible interaction mechanisms both in vitro and in vivo, and with an emphasis on biological-related molecular mechanisms of phytochemicals. The research on the interaction mechanism is of value for guiding how to take advantage of synergistic effects and avoid antagonistic effects in daily diets or phytochemical-based treatments for preventing chronic diseases.

The elevation of circulating interleukin 6 (IL-6) is one of the major molecular characteristics of endometrial carcinoma. In this study, we investigated the role of coiled-coil domain-containing 68 (CCDC68) in IL-6-associated endometrial carcinoma progression. CCDC68 expression levels and the activation of IL-6 pathway were detected by qPCR and Western blot. Stable CCDC68 knockdown Ishikawa and RL-95 cells were created to investigate cancer cell proliferation, migration, and invasion with or without IL-6 administration. Kaplan-Meier's analysis was used to determine the correlation between CCDC68 expression and overall survival or recurrence-free survival in endometrial carcinoma patients. CCDC68 expression level is significantly uregulated by IL-6 stimulation. Increased CCDC68 expression predicts poor prognosis in endometrial carcinoma patients. CCDC68 knockdown dramatically inhibit IL-6-associated cancer cell proliferation, migration, invasion, and downregulate the expression of proto-oncogenes in endometrial carcinoma cells. CCDC68 acts as a cancer-promoting factor in IL-6-stimulated endometrial carcinoma cells, and blocking the expression of CCDC68 might be a novel therapeutic strategy for the endometrial carcinoma treatment.

Background The prognostic value of 18F-FDG PET/CT in extranodal natural killer/T-cell lymphoma (ENKTL) is not well established. We aimed to develop nomograms for individualized estimates of progression-free survival (PFS) and overall survival (OS) in patients with ENKTL using 18F-FDG PET/CT parameters and clinical parameters. Methods A total of 171 patients with newly diagnosed ENKTL undergoing 18F-FDG PET/CT scanning were retrospectively analyzed. Nomograms were constructed according to multivariate Cox proportional hazards regression. The predictive and discriminatory capacities of the nomograms were then measured using the concordance index (C-index), calibration plots, and Kaplan-Meier curves. The C-index, the area under receiver operating characteristic (ROC) curve (AUC), and decision curve analysis (DCA) were used to contrast the predictive and discriminatory capacities of the nomograms against with the International Prognostic Index (IPI) and Korean Prognostic Index (KPI). Results Multivariate analysis demonstrated that pretreatment SUVmax≥9.5, disease stage II and III-IV, elevated lactate dehydrogenase (LDH), and elevated β2-microglobulin (β2-MG) had the strongest association with unfavorable PFS and OS. In addition, hemoglobin (Hb) p Conclusions This study established nomograms that incorporate pretreatment SUVmax and clinical parameters, which could be effective tools for individualized prognostication of both PFS and OS in patients with newly diagnosed ENKTL.

Background Muscle-invasive bladder cancer (MIBC) patients are subject to unfavorable treatment options and a high recurrence rate. The status of TP53 mutations played an essential role in the progression and the prognosis of MIBC. The present study proposed to investigate the association between TP53 mutations and immunophenotype in MIBC. Results We established an immune prognostic model (IPM) ground on the immune-associated genes derived from variation analysis between wild-type TP53 and mutated TP53 TCGA-MIBC patients, and validated in another cohort from GEO database. Based on IPM, we divided MIBC patients into low and high risk subgroups. The high risk MIBC patients had higher proportions of macrophages M1, and lower proportions of T cells regulatory (Tregs) and activated dendritic cells than the low risk MIBC patients. Moreover, the expression of immune checkpoints genes (PD1, CTLA4, LAG3, HAVCR2 and TIGIT) was higher in the high risk patients than the low risk patients. In clinical application, IPM exhibited better survival prediction than conventional clinical characteristics. Conclusions Our investigation presented practical prognostic significance for MIBC patients and displayed the overarching landscape of the immune response in the MIBC microenvironment. Methods Data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) analysis between the TP53 mutated and wild-type MIBC patients was conducted. The CIBERSORT algorithm was performed to evaluate the proportion of immune cell types. Gene expression profiles from the TCGA and GEO were used as training and testing cohorts to build and validate an immune-related prognostic model (IPM). Genes in the IPM model were first screened by univariate Cox analysis, then filtered by the least absolute shrinkage and selection operator (LASSO) Cox regression. A nomogram was finally established and evaluated by combining both the IPM and other clinical factors.

This study aimed to evaluate the effect of the timing of selective reduction and finishing the number of fetuses on perinatal outcomes in triplets.The study assessed 417 cases of triplets. Perinatal outcomes were compared between selective reduction (SR) performed at 11-14The spontaneous abortion rate was 6.5% and 14.9%, respectively, when SR was performed at 11-14When the starting and finishing numbers of fetuses were the same, the timing of SR could affect the spontaneous abortion rates. When the starting number of fetuses was the same, the timing of SR did not affect the neonatal outcome. However, the finishing number of fetuses was the influencing factor.

Objective: The study aims to analyze the pregnancy outcomes of multiple gestations with preterm premature rupture of membranes (PPROM) that occurred within 24 h after fetal reduction with potassium chloride (KCL). Materials and methods: We identified and evaluated the outcomes of 16 retrospectively recorded multigestational pregnancies that met the inclusion criteria between 2006 and 2016, from the Obstetrics Department of Shandong Provincial Hospital. A total of 16 patients carrying twins or higher order multiple gestations experienced PPROM within 24 h after fetal reduction, and all of them received expectant management after understanding the relevant risks. The maternal and neonatal records were retrospectively collected and reviewed. Every surviving child was followed up to at least 2 years old. Result: Of the 16 cases, 12 cases (75%) ended in successful pregnancy, resulting in the delivery of at least 1 child surviving from a multiple gestational pregnancy. All cases of successful pregnancies were either term (≥37 weeks) or near-term (36+5 weeks) at delivery. And of those 20 infants delivered, only 3 were low birth weight infants (

To assess the temporal changes in the characteristics of ischemic stroke drug clinical trials conducted in mainland China in 2005-2021.A statistical analysis of registered clinical trials on ischemic stroke was performed using the platform of the Center for Drug Evaluation of China National Medical Products Administration, the Chinese Clinical Trial Registry, and ClinicalTrials.gov websites.From January 1, 2005 to August 1, 2021, a total of 384 registered drug clinical trials on ischemic stroke were identified in mainland China. Over time, the number of trials gradually increased each year, with a significant growth in 2014, from 16 in 2013 to 42 in 2014. Phase IV trials (31.8%) accounted for the majority, followed by phase II (16.4%), phase I (10.9%), and phase III (8.6%). In terms of sponsorship, the proportion of investigator-initiated trials (IITs) (60.7%) was higher than industry-sponsored trials (ISTs) (39.3%). Additionally, trials involving traditional Chinese medicines (TCMs) (36.2%) accounted for the largest proportion, followed by trials involving antithrombotic therapy (19.5%) and cerebral protection agents (16.7%). Furthermore, over the past 17 years, the number of leading drug clinical trial units for ischemic stroke in mainland China has continuously increased. The leading principal units from Beijing, Shanghai, Guangdong, Jiangsu, and Liaoning accounted for the majority of the trials (67.4%).In the past 17 years, great progress has been made in the research and development (RD) of drugs and clinical trials for ischemic stroke in mainland China. The most extensive progress was observed in TCMs, antithrombotic therapy, and cerebral protection agents. More clinical trials are needed to confirm whether the newly developed drugs can improve the clinical efficacy of ischemic stroke. Simultaneously, more pharmaceutical RD efforts of innovative drugs are warranted.

Concurrent exposure to ionizing radiation (IR) and psychological stress (PS) may affect the development of adverse health consequences in scenarios such as space missions, radiotherapy and nuclear accidents. IR can induce DNA damage and cell apoptosis in the kidneys, thus potentially leading to renal fibrosis, which is the ultimate outcome of various chronic progressive nephropathies and the morphological manifestation of a continuous coordinated response after renal injury. However, little is known regarding the effects of concurrent IR exposure and PS on renal damage, particularly renal fibrosis. In this study, using a chronic restraint-induced PS (CRIPS) model, we exposed Trp53-heterozygous mice to total body irradiation with 0.1 or 2 Gy 56Fe ions on the eighth day of 28 consecutive days of a restraint regimen. At the end of the restraint period, the kidneys were collected. The histopathological changes and the degree of kidney fibrosis were assessed with H&E and Masson staining, respectively. Fibronectin (FN) and alpha smooth muscle actin (α-SMA), biomarkers of fibrosis, were detected by immunohistochemistry. Analysis of 8-hydroxy-2 deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, was performed with immunofluorescence, and terminal deoxynucleotidyl transferase-mediated nick end labeling assays were used to detect apoptotic cells. Histopathological observations did not indicate significant structural damage induced by IR or CRIPS + IR. Western blotting revealed that the expression of α-SMA was much higher in the CRIPS + IR groups than the CRIPS groups. However, no differences in the average optical density per area were observed for FN, α-SMA and 8-OHdG between the IR and CRIPS + IR groups. No difference in the induction of apoptosis was observed between the IR and CRIPS + IR groups. These results suggested that exposure to IR (0.1 and 2 Gy 56Fe ions), 28 consecutive days of CRIPS or both did not cause renal fibrosis. Thus, CRIPS did not alter the IR-induced effects on renal damage in Trp53-heterozygous mice in our experimental setup.

Clinically, the failure of periodontal therapy stems largely from an inability to control the inflammatory response. Resolution of inflammation is an active, energy-requiring repair process, not merely a passive termination of inflammation. AMP-activated protein kinase (AMPK), a key energy sensor, has been shown to negatively regulate inflammatory signaling pathways. Thus, there is a crucial need for new therapeutic strategies to modulate AMPK and to promote enhanced resolution of inflammation. This study is aimed at investigating the anti-inflammatory effects of ETC-1002 through modulating AMPK in periodontitis.RAW264.7 cells were infected withETC-1002 inhibited the production of proinflammatory cytokines, promoted AMPK phosphorylation, and decreased IETC-1002 exerts anti-inflammatory effects in

Antagonism or agonism of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) prevents weight gain and leads to dramatic weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Based on the genetic evidence supporting GIPR antagonism, we previously developed a mouse anti-murine GIPR antibody (muGIPR-Ab) that protected diet-induced obese (DIO) mice against body weight gain and improved multiple metabolic parameters. This work reconciles the similar preclinical body weight effects of GIPR antagonists and agonists in vivo, and here we show that chronic GIPR agonism desensitizes GIPR activity in primary adipocytes, both differentiated in vitro and adipose tissue in vivo, and functions like a GIPR antagonist. Additionally, GIPR activity in adipocytes is partially responsible for muGIPR-Ab to prevent weight gain in DIO mice, demonstrating a role of adipocyte GIPR in the regulation of adiposity in vivo., Both agonism and antagonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR) lead to weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Here the authors show that this may be explained by desensitization of GIPR activity by chronic GIPR agonism in vitro and in vivo.

Global emergence of Gram-negative bacteria carrying the plasmid-borne resistance genes, blaMBL and mcr, raises a significant challenge to the treatment of life-threatening infections by the antibiotics, carbapenem and colistin (COL). Here, we identify an antirheumatic drug, auranofin (AUR) as a dual inhibitor of metallo-β-lactamases (MBLs) and mobilized colistin resistance (MCRs), two resistance enzymes that have distinct structures and substrates. We demonstrate that AUR irreversibly abrogates both enzyme activity via the displacement of Zn(II) cofactors from their active sites. We further show that AUR synergizes with antibiotics on killing a broad spectrum of carbapenem and/or COL resistant bacterial strains, and slows down the development of β-lactam and COL resistance. Combination of AUR and COL rescues all mice infected by Escherichia coli co-expressing MCR-1 and New Delhi metallo-β-lactamase 5 (NDM-5). Our findings provide potential therapeutic strategy to combine AUR with antibiotics for combating superbugs co-producing MBLs and MCRs., Multi-drug resistant pathogens remain a serious public health threat. Here, Sun and colleagues identify a role for auranofin, which is normally used as a drug for rheumatoid arthritis, for reversing antibiotic resistance to carbapenem and colistin.

Preeclampsia has impacted 3-5% pregnancies among the world and its complications lead to both maternal and fetal morbidity and mortality. However, management of preeclampsia is limited. Nanoparticles targeting chondroitin sulfate A (CSA) can deliver drugs to placenta. Inactivation of soluble fms-like tyrosine kinase (sFlt-1) and nuclear factor-erythroid 2-like 2 (Nrf2) has been proved to alleviate preeclampsia and improve maternal and fetal outcomes. Carboxyl-polyethylene glycol-poly (d,l-lactide) (COOH-PEG5K-PLA8K), cationic lipid DOTAP, and siNrf2 and sisFlt-1 were used to construct the nanoparticles and conjugating peptides targeting CSA was fabricated to it. The expression levels of proteins and RNAs were estimated by qRT-PCR and Western blot assays. ELISA assays were performed to evaluate levels of circulating sFlt-1. The nanoparticles containing siNrf2 and sisFlt-1 are targeted to the placenta trophoblasts and downregulated the expression levels of Nrf2 and sFlt-1 as well as their downstream genes in the placental cells of model mice. Treatment of nanoparticles induced the expression of angiogenic factors in placenta. Knocking down Nrf2 and sFlt-1 synchronously alleviated the preeclampsia and increased the maternal and fetal outcomes in preeclampsia model mice. Nanoparticle-mediated simultaneous downregulation of placental Nrf2 and sFlt1 improved maternal and fetal outcomes in a preeclampsia mouse model.

Background: Subjective cognitive decline (SCD) is considered the earliest symptomatic manifestation of preclinical Alzheimer’s disease (AD). Currently, given the lack of effective and curable pharmacological treatments for AD, non-pharmacological interventions (NPIs) for individuals with SCD may provide a valuable opportunity for the secondary prevention of AD. Objective: This systematic review and meta-analysis, conducted in accordance with the PRISMA guidelines, aimed to investigate the benefits of current NPIs in the population with SCD. Methods: The online electronic databases, including MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, PsycInfo, and CINAHL, were searched to identify randomized controlled trials of NPIs for SCD. Intervention strategies were psychological and health-related education interventions, mind-body therapy, lifestyle modification, cognitive training, and multidomain interventions. Outcomes included subjective memory, objective memory, global cognitive function, psychological well-being, and mood. Study quality was determined using the criteria of the Cochrane collaboration’s tool. The Hedges’ g of change was analyzed. Results: Eighteen studies were included in this review and meta-analysis. Overall, psychological and health-related education interventions exhibited a medium effect on objective memory function (Hedges’ g = 0.53, p = 0.01). Cognitive training led to a small effect on objective memory, which was marginal statistically (Hedges’ g = 0.19, p = 0.05). In addition, cognitive training also significantly improved subjective memory performance (Hedges’ g = 0.49, p = 0.0003) and psychological well-being (Hedges’ g = 0.27, p = 0.03). Conclusion: Overall, the psychological intervention and cognitive training may be beneficial to cognitive function and psychological well-being. NPIs may be effectively implemented in older adults with SCD.

Chaotic monitor alarm management generates a large number of alarms, which result in alarm fatigue. Intensive care unit (ICU) nurses are caretakers of critically ill patients, the effect of alarm management affect patient safety directly.To evaluate the effect of monitor alarm management training based on the theory of planned behaviour for reducing alarm fatigue in intensive care unit nurses.A randomised, single-blind trial. This article follows the requirements of CONSORT statement.The study was conducted from February 2019-May 2019 in a tertiary A-level hospital. 93 ICU clinical nurses were included, and they were randomly assigned into two groups.Nurses in the experimental group (n = 47) received a 12-week alarm management training course based on the theory of planned behaviour. Nurses in the control group (n = 46) received regular training. All nurses' alarm fatigue scores were measured with a questionnaire before and after the study period. Total number of alarms, nonactionable alarms and true crisis alarms were recorded continuously throughout the study period.For baseline comparisons, no significant differences were found. By the analysis of independent samples one-way ANCOVAs, the nurses' adjusted alarm fatigue scores at the post-test in the experimental group were significantly lower than those in the control group (p .001). After the study period, adjusted total number of alarms and nonactionable alarms recorded in the experimental group were both significantly lower than those recorded in the control group (p .001). After the study period, no significant difference between the two groups was noted in the adjusted number of true crisis alarms (p .05). The interventions did not cause adverse events in either group of patients and did not cause adverse events in patients.Intensive care unit nurses' alarm fatigue was effectively decreased by the monitor alarm management training based on the theory of planned behaviour.(1) Monitor alarm training based on the theory of planned behaviour is effective in reducing nonactionable alarms and lowering alarm fatigue in ICU nurses. (2) The intervention considering the social psychological aspects of behaviour is effective in rebuilding the nurses' awareness and behaviour of alarm management. (3) Nurses are the direct users of monitoring technology. Hospital administrators should attach importance to the role of nurses in the medical monitoring system. We suggest that nursing managers implement training programmes in more ICUs in the future to improve alarm management ability and lower alarm fatigue in ICU nurses.

Background and Purpose: We aimed to evaluate the impact of cortical microinfarcts (CMIs) on functional outcome after endovascular treatment in patients with acute ischemic stroke. Methods: In a multicenter registration study for RESCUE-RE (a registration study for Critical Care of Acute Ischemic Stroke After Recanalization), eligible patients with large vessel occlusion stroke receiving endovascular treatment, who had undergone 3T magnetic resonance imaging on admission or within 24 hours after endovascular treatment were analyzed. We evaluated the presence and numbers of CMIs with assessment of axial T1, T2-weighted images, and fluid-attenuated inversion recovery images. The primary outcome was functional dependence or death defined as modified Rankin Scale scores of 3 to 6 at 90 days. Secondary outcomes included early neurological improvement, any intracranial hemorrhage, symptomatic intracranial hemorrhage, and mortality. We investigated the independent associations of CMIs with the outcomes using multivariable logistic regression in overall patients and in subgroups. Results: Among 414 patients (enrolled from July 2018 to May 2019) included in the analyses, 96 (23.2%) patients had at least one CMI (maximum 6). Patients with CMI(s) were more likely to be functionally dependent or dead at 90 days, compared with those without (55.2% versus 37.4%; P P =0.04) and multiple CMIs (CMIs ≥2; adjusted odds ratio, 7.41 [95% CI, 2.48−22.17]; P Conclusions: Acute large vessel occlusion stroke patients receiving endovascular treatment with CMI(s) were more likely to have a poor functional outcome at 90 days, independent of patients’ characteristics. Such associations may be dose-dependent. Registration: URL: http://www.chictr.org.cn ; Unique identifier: ChiCTR1900022154.

The research was performed to delineate how β-sitosterol laurate (β-SLE) consumption influenced serum and hepatic lipids. The results showed that 220 mg/5 mL oil/kg body weight of β-SLE robustly reduced serum total triglyceride and cholesterol levels and the epididymal adipocyte size, and efficiently protected hepatic polyunsaturated fatty acids against lipid peroxidation through superoxide dismutase and glutathione transferase activity enhancement and malondialdehyde level reduction. Based on the changes of fecal cholesterol contents, fecal and hepatic bile acid (BAs) levels, and related protein expression, it was concluded that the mechanisms for lowering serum cholesterol by β-SLE involved (i) the enhanced excretion of fecal cholesterol via down-regulation of intestinal Niemann-Pick C1-like 1 protein; (ii) the increased conversion from cholesterol to primary BAs via up-regulation of cholesterol-7α-hydroxylase and sterol 27-hydroxylase, which was induced by the reduced BAs reabsorption through up-regulating ileal apical sodium-dependent bile acid transporter and ileal bile acid-binding protein.

Environmental monitoring of pollutants is essential to guarantee the human health and maintain the ecosystem. The exploration of both simple and sensitive detection method has aroused widespread attentions. Herein, 2D bimetallic metal organic framework nanosheets (NiZn-MOF NSs) with tunable Ni/Zn ratios were synthesized, and for the first time employed to construct a tyrosinase biosensor. It is revealed that Zn element not only tuned the porosity structure and electronic structure of MOF NSs, but also modified their electrochemical activity. As a result, enzyme immobilization and electrochemical sensing performance of the NiZn-MOF NSs based biosensor were significantly enhanced by a suitable Zn addition. The fabricated tyrosinase biosensor exhibited excellent analytical detections, with a wide linear range from 0.08 μM to 58.2 μM, a high sensitivity of 159.3 mA M−1, and an ultralow detection limit of 6.5 nM. In addition, the proposed biosensing approach also demonstrated good repeatability, superior selectivity, long-term stability, and high recovery for phenol detection in the real tap water samples.

Different chain lengths diacylglycerols (DAG) (long- and medium-chain) were synthesized from peanut and coconut oils. The effects of DAG with different chain lengths on body fat, blood lipids, and lipid metabolism-related enzymes in the liver and adipose tissue of C57BL/6J mice were investigated. Compared to peanut and coconut oils containing triacylglycerol (TAG), DAG-rich oils can significantly reduce the body weight, kidney weight, serum triglyceride (TG) content, hepatic fatty acid synthase (FAS), and Acetyl-CoA carboxylase (ACC) enzyme levels (p < 0.05) in C57BL/6J mice. Therefore, the effect of coconut oil DAG on improving body fat metabolism was probably due to the impact of DAG. Meanwhile, the body weight and serum TG content in coconut oil DAG group were lower than those in peanut oil DAG group. In addition, the spleen weight, hepatic ACC, and lipoprotein lipase (LPL) enzymes in coconut oil DAG group (0.07 ± 0.01 g, 2.08 ± 0.42 ng/mg pro, and 18.44 ± 5.23 ng/mg pro, respectively) were significantly lower than those in peanut oil DAG group. Although coconut oil DAG and peanut oil DAG have different fatty acid compositions, their effects on lipid metabolism showed no significant changes. Coconut oil DAG (peanut oil DAG) showed the improved lipid metabolism than that of coconut oil (peanut oil), which was probably due to the effect of DAG. PRACTICAL APPLICATION: Peanut and coconut oils are common edible oils. The oil containing DAG synthesized decreased the body weight and lipid accumulation in mice. Coconut oil is rich in medium-chain fatty acids, while peanut oil mainly consists of long-chain fatty acids. Due to the different contents of fatty acids, the synthesized structural lipids have different effects on lipid metabolism. Medium-chain triglycerides were considered as agents to alleviate obesity.

BACKGROUND: To compare the outcomes of half-dose verteporfin photodynamic therapy (vPDT) for central serous chorioretinopathy (CSCR) with or without subfoveal fibrin. METHODS: One hundred seventy-three cases of CSCR treated with half-dose vPDT between September 2008 and February 2018 were retrospectively reviewed and classified into two groups: CSCR with subfoveal fibrin (fibrin group) and without subfoveal fibrin (no-fibrin group). The changes in best-corrected visual acuity (BCVA) from baseline and in central macular thickness (CMT) were recorded at 1, 3, and 6 months after the treatment. RESULTS: Forty-eight eyes were included in the fibrin group and 125 eyes in the no fibrin group. There were no statistical differences in the baseline characteristics including age, gender, duration of symptoms, and CMT between the groups. The baseline mean BCVA of the fibrin group was significantly worse than that of the no fibrin group (0.47 ± 0.32 versus 0.32 ± 0.31 in logMAR; p = 0.003). There was no statistically significant difference between the two groups in the improvement of BCVA at each follow-up point (1 month: p = 0.069; 3 months: p = 0.111; 6 months: p = 0.172, respectively) and in the reduction of CMT (1 month: p = 0.367; 3 months: p = 0.767; 6 months: p = 0.496, respectively). In the fibrin group, the rates of complete resolution of the subretinal fibrin at 1, 3, and 6 months after vPDT were 72.9%, 95.8%, 95.8%, respectively. The SRF resolution rate at 1, 3, and 6 months was 72.9%, 89.6% and 91.7% respectively in the fibrin group and was 62.4%, 83.2% and 84.0% in the no fibrin group. There was no significant difference of SRF resolution rate between the two groups at 1 month (p = 0.216), 3 months (p = 0.350), and 6 months (p = 0.228). No ocular adverse event was encountered in both groups. CONCLUSION: Half-dose vPDT was effective and safe for CSCR patients with subfoveal fibrin.

The aim of the study was to investigate the various effects of high linear energy transfer (LET) carbon ion (12C6+) and low LET X-ray radiation on MDA-MB-231 and MCF-7 human breast cancer cells and to explore the underlying mechanisms of radiation sensitivity. Cell proliferation, cell colony formation, cell cycle distribution, cell apoptosis and protein expression levels [double-strand break marker γ-H2AX, cell cycle-related protein cyclin B1, apoptosis-related proteins Bax and Bcl-2, and the Akt/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase B1 (p70S6K) pathway] were detected after irradiation with carbon ions or X-rays at doses of 0, 2, 4 and 8 Gy. Our results showed that the inhibition of cell proliferation and cell colony formation and the induction of G2/M phase arrest, DNA lesions and cell apoptosis/necrosis elicited by carbon ion irradiation were more potent than the effects elicited by X-ray radiation at the same dose. Simultaneously, compared with X-ray radiation, carbon ion radiation induced a marked increase in Bax and prominent decreases in cyclin B1 and Bcl-2 in a dose-dependent manner. Furthermore, the Akt/mTOR/p70S6K pathway was significantly inhibited by carbon ion radiation in both breast cancer cell lines. These results indicate that carbon ion radiation kills MDA-MB-231 and MCF-7 breast cancer cells more effectively than X-ray radiation, which might result from the inhibition of the Akt/mTOR/p70S6K pathway.

Introduction Osthole (Ost) is a coumarin compound that strengthens hippocampal neurons and neural stem cells against Aβ oligomer-induced neurotoxicity in mice, and is a potential drug for the treatment of Alzheimer's disease (AD). However, the effectiveness of the drug is limited by its solubility and bioavailability, as well as by the low permeability of the blood-brain barrier (BBB). In this study, a kind of transferrin-modified Ost liposomes (Tf-Ost-Lip) was constructed, which could improve the bioavailability and enhance brain targeting. Methods Tf-Ost-Lip was prepared by thin-film hydration method. The ability of liposomal formulations to translocate across BBB was investigated using in vitro BBB model. And the protective effect of Tf-Ost-Lip was evaluated in APP-SH-SY5Y cells. In addition, we performed pharmacokinetics study and brain tissue distribution analysis of liposomal formulations in vivo. We also observed the neuroprotective effect of the varying formulations in APP/PS-1 mice. Results In vitro studies reveal that Tf-Ost-Lip could increase the intracellular uptake of hCMEC/D3 cells and APP-SH-SY5Y cells, and increase the drug concentration across the BBB. Additionally, Tf-Ost-Lip was found to exert a protective effect on APP-SH-SY5Y cells. In vivo studies of pharmacokinetics and the Ost distribution in brain tissue indicate that Tf-Ost-Lip prolonged the cycle time in mice and increased the accumulation of Ost in the brain. Furthermore, Tf-Ost-Lip was also found to enhance the effect of Ost on the alleviation of Alzheimer's disease-related pathology. Conclusion Transferrin-modified liposomes for delivery of Ost has great potential for AD treatment.

To assess YLL and mortality burden attributable to non-optimum ambient temperature, we collected mortality and environmental data from June 1, 2012 to December 30, 2017 in Shenzhen. We applied distributed lag nonlinear models with 21 days of lag to examine temperature-YLL and temperature-mortality associations, and calculated the attributable fractions of YLL and deaths for non-optimum temperature, including four subranges, mild cold, mild heat, extreme cold, and extreme heat. Cold and heat were distinguished by the optimum temperature, and each was separated into extreme and mild by cutoffs at 2.5th (12.2 °C) and 97.5th (30.4 °C) temperature percentile further. The optimum temperature was defined as the temperature that had minimum effect on YLL or mortality risk. The optimum temperature for non-accidental YLL was 24.5 °C, and for mortality it was 25.4 °C. Except for the population older than 65 years, the optimum temperature was generally lower in the YLL model than the mortality model. Of the total 61,576 non-accidental deaths and 1,350,835.7 YLL within the study period, 17.28% (95% empirical CI 9.42-25.14%) of YLL and 17.27% (12.70-21.34%) of mortality were attributable to non-optimum temperature. More YLL was caused by cold (10.14%, 3.94-16.36%) than by heat (7.14%, 0.47-13.88%). Mild cold (12.2-24.5 °C) was responsible for far more YLL (8.78%, 3.00-14.61%) than extreme cold (3.5-12.2 °C). As for cardiovascular deaths, only the fractions attributable to overall and cold temperature were significant, with mild cold contributing the largest fraction to YLL (16.31%, 6.85-25.82%) and mortality (16.08%, 9.77-21.22%). Most of the temperature-related YLL and mortality was attributable to mild but non-optimum weather, especially mild cold, while the YLL model implied a more prominent heat effect on premature death. Our findings can supply additional evidence from multiperspectives for health planners to define priorities and make targeted policies for mitigating the burden of adverse temperatures.

BackgroundStroke, especially ischemic stroke (IS), has been a severe public health problem around the world. However, the association between air pollution and ischemic stroke remains ambiguous.MethodsA total of 63, 997 IS cases aged 18 years or above in Shenzhen were collected from 2008 to 2014. We used the time-stratified case-crossover design combining with distributed lag nonlinear model (DLNM) to estimate the association between air pollution and IS onset. Furthermore, this study explored the variability across gender and age groups.ResultsThe cumulative exposure-response curves were J-shaped for SO2, NO2and PM10, and V-shaped for O3, and crossed over the relative risk (RR) of one. The 99th, 50th (median) and 1st percentiles of concentration (μg/m3) respectively were 37.86, 10.06, 3.71 for SO2, 116.26, 41.29, 18.51 for NO2, 145.94, 48.29, 16.14 for PM10, and 111.57, 49.82, 16.00 for O3. Extreme high-SO2, high-NO2, high-PM10, high-O3, and low-O3concentration increased the risk of IS, with the maximumRRvalues and 95%CIs: 1.50(1.22, 1.84) (99th vs median) at 0–12 lag days, 1.37(1.13, 1.67) (99th vs median) at 0–10 lag days, 1.26(1.04, 1.53) (99th vs median) at 0–12 lag days, 1.25(1.04, 1.49) (99th vs median) at 0–14 lag days, and 1.29(1.03, 1.61) (1st vs median) at 0–14 lag days, respectively. The statistically significant minimalRRvalue and 95%CIwas 0.79(0.66,0.94) at 0–10 lag days for extreme low-PM10. The elderly aged over 65 years were susceptible to extreme pollution conditions. Difference from the vulnerability of males to extreme high-SO2, high-NO2and low-O3, females were vulnerable to extreme high-PM10and high-O3. Comparing with the elderly, adults aged 18–64 year were immune to extreme low-NO2and low-PM10. However, no association between CO and IS onset was found.ConclusionsSO2, NO2, PM10and O3exerted non-linear and delayed influence on IS, and such influence varied with gender and age. These findings may have significant public health implications for the prevention of IS.

Human pancreatic stellate cells (PSCs) play a critical role in fibrogenesis during chronic pancreatitis (CP). However, primary PSCs have a short lifespan in vitro, which seriously affects their use in various applications. We have established a stable immortalized human PSC line (HP-1) by RSV promoter/enhancer-driven SV40 T antigen expression in primary activated human PSCs. HP-1 cells express cytoskeleton proteins including glial fibrillary acidic protein (GFAP), α-smooth muscle actin (α-SMA), vimentin and desmin, and are typical of PSCs, which are high transfeciability and viable in 0.5% serum. The cells express receptors such as TGFβR2, PDGFR, TGF-β pseudoreceptor Bambi and PPRPγ that are commonly found in PSCs. HP-1 cells are similar to activated human PSCs in that they have enhanced expression of α-SMA, CTGF, Col1 and TIMP-2 mRNAs or proteins, as well as decreased expression of MMP-1/2 mRNAs or proteins in response to TGF-β1 stimulation. Comparative proteomics revealed 4,537 shared proteins between HP-1 cells and PSCs and no single protein in HP-1 cells versus PSCs. Statistical analysis reveals no significantly difference between HP-1 cells and PSCs in their expression of proteins associated with matrix and matrix remodeling. The similarity between HP-1 cell and PSC is further shown by the finding that only 9 proteins are differentially up-regulated > ± 2-fold in HP-1 cells and 13 proteins are up-regulated > ± 2-fold in PSCs and none of these proteins include ECM proteins, cytokines, growth factors or matrix remodeling regulatory proteins. Therefore, HP-1 cells can be used as an effective tool for the study of PSC-mediated pancreatic fibrosis.

Glycosylated hemoglobin (HbA1c), not routinely screened in blood donors, is associated with morphological, biochemical, and functional abnormalities of red blood cells (RBCs) and with enhanced oxidative stress. We aimed to explore HbA1c levels in blood donors and their effect on RBC storage.An analytical cross-sectional study was conducted on 875 eligible blood donors aged 18-60 years from May 1, 2021, to August 30, 2021. Two selected groups of donors (HbA1c6.5%, n = 10; HbA1c ≥ 6.5%, n = 10) exhibiting as similar as possible baseline values (such as age, sex, and living habits, etc.) were recruited for blood donation in leukoreduced CPDA-1 units. RBC morphological, biochemical, structural, and oxidative stress states were measured during 5-35 days of storage.Elevated HbA1c prevalence was 37%, including 31.7% (277/875) in the prediabetes range (HbA1c 5.7%-6.4%) and 5.4% (47/875) in the diabetes range (HbA1c ≥ 6.5%). Age, body mass index (BMI), smoking, and alcohol consumption were the main factors influencing the HbA1c levels. During storage, high-HbA1c group had abnormal RBC morphology, impaired membrane function, and ion imbalance (higher mean corpuscular volume, distribution width, hemolysis rate, potassium ion efflux, and phosphatidylserine exposure) as compared with low HbA1c group. Additionally, RBC oxidative stress was significantly increased in donors with high HbA1c levels during 21-35 days.Blood donors proportion with abnormal HbA1c levels was relatively high, and donor HbA1c levels may be associated with stored RBCs capacity. Our study provides new insights into the different effects of donor HbA1c levels on RBC storage lesions.

Purpose: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants.Methods: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis.Results: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P =.01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P =.005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs.Conclusion: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes. (C) 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Despite the efficacy of current starvation therapies, they are often associated with some intrinsic drawbacks such as poor persistence, facile tumor metastasis and recurrence. Herein, we establish an extravascular gelation shrinkage-derived internal stress strategy for squeezing and narrowing blood vessels, occluding blood & nutrition supply, reducing vascular density, inducing hypoxia and apoptosis and eventually realizing starvation therapy of malignancies. To this end, a biocompatible composite hydrogel consisting of gold nanorods (GNRs) and thermal-sensitive hydrogel mixture was engineered, wherein GRNs can strengthen the structural property of hydrogel mixture and enable robust gelation shrinkage-induced internal stresses. Systematic experiments demonstrate that this starvation therapy can suppress the growths of PANC-1 pancreatic cancer and 4T1 breast cancer. More significantly, this starvation strategy can suppress tumor metastasis and tumor recurrence via reducing vascular density and blood supply and occluding tumor migration passages, which thus provides a promising avenue to comprehensive cancer therapy., The efficacy of tumour starvation therapy is limited by lack of persistent tumour suppression, tumour metastasis and recurrence. Here, the authors report biocompatible gold nanorods and thermal-sensitive hydrogel to promote narrowing of blood vessels and show this to reduce tumour growth and metastasis.

Intratumoral or intestinal microbiota correlates with tumorigenesis and progression, and microbiota regulation for reinforcing various anti-tumor approaches is of significant importance, which, however, suffers from no precise regulation method and unclear underlying mechanism. Herein, a microbiome metabolism-engineered phototherapy strategy is established, wherein Nb

Objective To perform a meta-analysis of randomized controlled trials to evaluate the efficacy of vitamin D supplementation on thyroid autoimmunity markers in Hashimoto’s thyroiditis (HT). Methods This meta-analysis included randomized controlled clinical trials identified by a systematic search of electronic databases (PubMed®, MEDLINE®, EMBASE, The Cochrane Library, China National Knowledge Infrastructure) from inception to August 2020. All studies included patients with HT that received vitamin D supplementation irrespective of the doses administered or the duration of treatment. The primary and secondary outcome measures were thyroid peroxidase antibody (TPOAb) and/or thyroglobulin antibody (TGAb) titres. Results Eight studies ( n = 652) were included. There was significant heterogeneity between the studies. Using a random-effect model, vitamin D supplementation reduced TPOAb titre (standardized mean difference [SMD]: –1.11; 95% confidence interval [CI]: 1–1.92, –0.29) and TGAb titre (SMD: –1.12; 95% CI: –1.96, –0.28). A subgroup analysis demonstrated that vitamin D supplementation for >3 months resulted in a decrease in TPOAb titre (SMD: –1.66, 95% CI: –2.91, –0.41) but treatment ≤3 months was ineffective. Treatment with vitamin D3 decreased TPOAb titre (SMD: –1.48; 95% CI: –2.53, –0.42) whereas vitamin D did not. Conclusion These data suggest that vitamin D reduces autoantibody titre in patients with HT.

Earlier detection of biomarkers responsible for cancer relapse facilitates more rational cancer treatment regimens to be designed. Herein, we develop a mass cytometry-based strategy for unbiased mining of cell subsets that potentially contribute to cancer recurrence through panoramic examination of the immunophenotypic features and multidrug resistance characteristics. The incorporation of metal tags enables multiplexed information of single cells to be interrogated based on metal fingerprint. Using acute lymphoblastic leukemia (B-ALL) as a showcase, we show overexpressed multidrug resistance biomarkers, i. e., BCRP, Bcl-2, MRP1, and P-gp in B-ALL cells compared with healthy control, and a positive correlation among different multidrug resistance biomarkers. Different cell subsets with multidrug resistance are well-defined, featured with CD34+ CD38+ CD10- and CD34+ CD38+/int CD10+ . Importantly, we uncovered that CD34 expression level is positively correlated to multidrug resistance, indicative of a higher potential of immature cells to induce B-ALL relapse. In addition, the cell subsets positively expressing CD73 and CD304 (CD34+ CD10+ CD304+ ; CD34+ CD38+/int CD10+ CD73+ ) also overexpress multidrug resistance biomarkers, suggesting that they may serve as additional new biomarkers for B-ALL stratification and prognosis. Our data provide the first evidence that highly expressed multidrug resistance biomarkers in certain cell subpopulations with specific immunophenotypes may potentially induce B-ALL recurrence. The incorporation of multidrug resistance features with cell phenotypes using mass cytometry proposed in this study provides a general strategy for risk assessment and the prediction of recurrence of different types of cancers.

Background Disease prediction based on electronic health records (EHRs) is essential for personalized healthcare. But it’s hard due to the special data structure and the interpretability requirement of methods. The structure of EHR is hierarchical: each patient has a sequence of admissions, and each admission has some co-occurrence diagnoses. However, the existing methods only partially model these characteristics and lack the interpretation for non-specialists. Methods This work proposes a time-aware and co-occurrence-aware deep learning network (TCoN), which is not only suitable for EHR data structure but also interpretable: the co-occurrence-aware self-attention (CS-attention) mechanism and time-aware gated recurrent unit (T-GRU) can model multilevel relations; the interpretation path and the diagnosis graph can make the result interpretable. Results The method is tested on a real-world dataset for mortality prediction, readmission prediction, disease prediction, and next diagnoses prediction. Experimental results show that TCoN is better than baselines with 2.01% higher accuracy. Meanwhile, the method can give the interpretation of causal relationships and the diagnosis graph of each patient. Conclusions This work proposes a novel model—TCoN. It is an interpretable and effective deep learning method, that can model the hierarchical medical structure and predict medical events. The experiments show that it outperforms all state-of-the-art methods. Future work can apply the graph embedding technology based on more knowledge data such as doctor notes.