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High-dose-rate (HDR) electronic brachytherapy (EBT) has been shown to be effective for non-melanoma skin cancer (NMSC) in Caucasian patients. However, its efficacy remains unknown in Asian patients. To analyze the clinical outcome of HDR EBT for NMSC in a Taiwanese medical center.Medical records over a 5-year period between January 2015 to December 2019 were retrospectively analyzed.Forty-seven patients with 54 NMSC including 42 basal cell carcinomas (BCCs) and 12 squamous cell carcinomas (SCCs) were treated with HDR EBT. The average age was 73.8 years. The mean radiation dose was 45.3 Gy (40-80 Gy). Mean follow-up duration was 33.1 months. Adequate local control was achieved in 50 lesions (92.6%). Grade 1 acute skin toxicity was noted in 63.0% of lesions, while no tumors had Grade 4 acute toxicity. No ulceration was observed six months after completion of treatment. At the last follow-up visit, all lesions were rated to have "fair" to "excellent" cosmetic outcomes.HDR EBT provides adequate clinical outcomes and cosmetic results for NMSC in Asian patients. Further investigation of the dosage guidelines is needed for Asian patients with NMSC.

Totally laparoscopic total gastrectomy has been developed with difficulty in intracorporeal esophagojejunostomy. Although mechanical stapling has been widely used for intracorporeal esophagojejunostomy, manual suture holds great promise with the emergence of high-resolution 3D vision and robotic surgery. After exploration of how to improve the safety and efficiency of intracorporeal suture for esophagojejunostomy, we recommended the technique of single-layer running "trapezoid-shaped" suture. The cost-effectiveness was analyzed by comparing with conventional mechanical stapling.The study retrospectively reviewed the patients undergoing laparoscopic gastrectomy for gastric cancer from January 2010 to December 2021. The patients were divided into two cohorts based on the methods of intracorporeal esophagojejunostomy: manual suture versus stapling suture. Propensity score matching was performed to match patients from the two cohorts at a ratio of 1:1. Then group comparison was made to determine whether manual suture was non-inferior to stapling suture in terms of operation time, anastomotic complications, postoperative hospital stay, and surgical cost.The study included 582 patients with laparoscopic total gastrectomy. The manual and stapling suture for esophagojejunostomy were performed in 50 and 532 patients, respectively. In manual suture cohort, the median time for the whole operation and digestive tract reconstruction were 300 min and 110 min. There was no anastomotic bleeding and stenosis but two cases of anastomotic leak which occurred at 3 days after surgery. The median length of postoperative hospital stay was 11 days. After propensity score matching, group comparison yielded two variables with statistical significance: time for digestive tract reconstruction and surgery cost. The manual suture cohort spent less money but more time for esophagojejunostomy. Intriguingly, the learning curve of manual suture revealed that the time for digestive tract reconstruction was declined with accumulated number of operations.Laparoscopic single-layer running "trapezoid-shaped" suture appears safe and cost-effective for intracorporeal esophagojejunostomy after total gastrectomy. Although the concern remains about prolonged operation time for beginners of performing the suture method, adequate practice is expected to shorten the operation time based on our learning curve analysis.

To explore the effect of doxycycline on vasculogenic mimicry (VM) formation and the potential mechanism in human pterygium fibroblasts in order to find novel targets for pterygium therapy.First, we demonstrate the existence of VM in 73 pterygium specimens by CD31 and periodic acid Schiff (PAS) dual staining. Then we used cell counting kit-8, clone formation assay and flow cytometry to prove the inhibitory effect of doxycycline on cell proliferation and apoptosis. The VM formation was evaluated through wound healing assay, cell transwell assay and three-dimensional cell culture combined with PAS staining. Finally, we used Western blot to testify the correlation of the VM and the factors in protein level preliminarily.Our results showed that VM existed in human pterygium specimens exactly. Otherwise, in human pterygium fibroblasts, doxycycline induced a dose-dependent inhibitory effect on cell proliferation and apoptosis induction. Besides, doxycycline significantly suppressed vasculogenic mimicry tube formation, cell migration and invasion. Furthermore, doxycycline impaired the expression of MMP-9, MMP-2 and VEGF which may related to pterygium VM formation.Doxycycline decelerated pterygium progression might be through inhibiting VM formation according to the downregulation of MMP-9, MMP-2 and VEGF, which may provide the basis of further studies involving doxycycline for pterygium treatment.

Noncoding RNAs (ncRNAs) regulation of various diseases including cancer has been extensively studied. Reactive oxidative species (ROS) elevated by oxidative stress are associated with cancer progression and drug resistance, while autophagy serves as an ROS scavenger in cancer cells. However, the regulatory effects of ncRNAs on autophagy and ROS in various cancer cells remains complex. Here, we explore how currently investigated ncRNAs, mainly miRNAs and lncRNAs, are involved in ROS production through modulating antioxidant genes. The regulatory effects of miRNAs and lncRNAs on autophagy-related (ATG) proteins to control autophagy activity in cancer cells are discussed. Moreover, differential expression of ncRNAs in tumor and normal tissues of cancer patients are further analyzed using The Cancer Genome Atlas (TCGA) database. This review hypothesizes links between ATG genes- or antioxidant genes-modulated ncRNAs and ROS production, which might result in tumorigenesis, malignancy, and cancer recurrence. A better understanding of the regulation of ROS and autophagy by ncRNAs might advance the use of ncRNAs as diagnostic and prognostic markers as well as therapeutic targets in cancer therapy.

Spinal cord injury (SCI) was a serious nerve injury, which involves complex genetic changes. This paper was intended to investigate the function and mechanism of differentially expressed genes in SCI. The three datasets GSE92657, GSE93561 and GSE189070 of SCI from GEO database were used to identify differentially expressed genes (DEGs). We identified the common DEGs in the three datasets GSE92657, GSE93561 and GSE189070 of SCI from GEO database. Next, a protein-protein interaction (PPI) network of DEGs was constructed. Subsequently, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that DEGs were significantly enriched in immune response, inflammatory response. The expression level of immune-related genes (Arg1, Ccl12, Ccl2, Ifitm2, Ifitm3, and et al.) at different time points of SCI were analyzed in GSE189070 dataset. Next, differentially expressed miRNAs (DE-miRNAs) were identified in SCI compared with normal based on GSE158194 database. DE-miRNA and targeted immune-related genes were predicted by miRwalk, including miR-487b-5p targeted Ifitm3, miR-3072-5p targeted Ccl3, and et al. What’s more, the miR-487b was identified and verified to be down-regulated in Lipopolysaccharide (LPS)-induced BV-2 cell model. Further, the miR-487b inhibited cell inflammation and apoptosis in LPS-induced BV2 cell by targeted Ifitm3. For the first time, our results revealed that miR-487b may play an important regulatory role in SCI by targeted Ifitm3 and provide further evidence for SCI research.

Keloid is a benign tumor with high recurrence rate; accordingly, complete surgical excision with adjuvant radiotherapy is one of the most effective treatments. This study reviewed outcomes of keloid patients receiving surgery and adjuvant radiotherapy in Kaohsiung Medical University Hospital.All patients received radiation dose with 15 Gy, with their first radiotherapy within 24 hours after surgical excision. The end points were recurrence rate and local recurrence-free interval (LRFI), defined clinically as palpable gross tumor over the treatment site and duration from the last day of radiotherapy to disease recurrence.From May 2017 to July 2020, 32 patients with 40 keloid lesions were included. The mean age for these patients was 37.6 years, and the median follow-up time was 15.3 months. The overall recurrence rate was 52.5%, and the median LRFI was 9.7 months. Recurrence rates for males and females were 46.7% and 56% ( P = 0.567), respectively; for head and ear, chest, shoulder and upper extremities, and abdomen and back were 12.5%, 61.5%, 63.6%, and 62.5% ( P = 0.093); for lesions over 20 cm 2 and below 20 cm 2 were 62.5% and 50% ( P = 0.527); and for megavoltage electron beam and kilovoltage photon beam were 56.7% and 40% ( P = 0.361), respectively. Patients were further classified into 2 groups by lesion sites, which showed lower recurrence rate ( P = 0.011) and longer LRFI ( P = 0.028) with lesions over the head and ear than other sites.We found that lesion site might be a prognostic factor for keloid recurrence. Adjuvant radiation dose escalation for high-recurrence risk areas (other than the head and ear) might be required.

Peptides play important roles in regulating biological processes and form the basis of a multiplicity of therapeutic drugs. To date, only about 300 peptides in human have confirmed bioactivity, although tens of thousands have been reported in the literature. The majority of these are inactive degradation products of endogenous proteins and peptides, presenting a needle-in-a-haystack problem of identifying the most promising candidate peptides from large-scale peptidomics experiments to test for bioactivity. To address this challenge, we conducted a comprehensive analysis of the mammalian peptidome across seven tissues in four different mouse strains and used the data to train a machine learning model that predicts hundreds of peptide candidates based on patterns in the mass spectrometry data. We provide in silico validation examples and experimental confirmation of bioactivity for two peptides, demonstrating the utility of this resource for discovering lead peptides for further characterization and therapeutic development.

RationalLung cancer is the most common tumor worldwide, with the highest mortality rate and second highest incidence. Immunotherapy is one of the most important treatments for lung adenocarcinoma (LUAD); however, it has relatively low response rate and high incidence of adverse events. Herein, we explored the therapeutic potential of fibrinogen-like protein 1 (FGL1) for LUAD.MethodsData from GEPIA and ACLBI databases were assessed to explore gene–gene correlations and tumor immune infiltration patterns. A total of 200 patients with LUAD were recruited. FGL1 levels in the serum and cellular supernatant were determined by enzyme-linked immunosorbent assay. In vitro and in vivo experiments were performed to assess the effect FGL1 on the proliferation of LUAD cells. Cocultures were performed to explore the effect of FGL1 knockdown in lung cancer cells on T cells, concerning cytokine secretion and viability. PROMO and hTFtarget databases were used for transcription factor prediction. Quantitative polymerase chain reaction (qPCR), chromatin immunoprecipitation, and dual luciferase reporter assays were performed to validate the identified transcription factor of FGL1. Immunoprecipitation, mass spectrometry and gene ontology analysis were performed to explore the downstream partners of FGL1.ResultsFGL1 expression in LUAD was positively associated with PDL1, but not for PD1 expression. Moreover, FGL1 was positively associated with the CD3D expression and negatively associated with FOXP3, S100A9, and TPSB2 within the tumor site. FGL1 promotes the secretion of interleukin-2 by T cells in vitro, simultaneously inducing their apoptosis. Indeed, YY1 is the upstream molecule of FGL1 was found to be transcriptionally regulated by YY1 and to directly by to MYH9 to promote the proliferation of LUAD cells in vitro and in vivo.ConclusionsFGL1 is involved in the immunological and proliferative regulation of LUAD cells by controlling the secretion of important immune-related cytokines via the YY1–FGL1–MYH9 axis. Hence, targeting FGL1 in LUAD may pave the way for the development of new immunotherapies for tackling this malignancy.

The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global threat. Although non-pharmaceutical interventions have been rigorously and widely implemented, living conditions caused by the pandemic will last until highly effective vaccines are successfully improved and globally administered. Several first-generation COVID-19 vaccines were approved at the end of 2020. However, the COVID-19 pandemic is persisting worldwide. To be clear, the efficiency and the coverage of current vaccines are insufficient, but newly emerging and rapidly spreading variants are the most pressing concern. A second-generation COVID-19 vaccine worth mentioning, NVX-CoV2373, has demonstrated 90% overall efficacy as well as a high level of efficacy against circulating variants in Phase 3 clinical trials. Currently, NVX-CoV2373 is the only vaccine that has proven successful against variants during Phase 3/4 trials. Therefore, developing the next generation of vaccines is a promising strategy to ultimately prevail against SARS-CoV-2. This review provides up-to-date information on COVID-19 vaccines in terms of their efficacy and new platforms and the progression of COVID-19 vaccination. Moreover, this review also summarizes the efficacy of approved COVID-19 vaccines against variants. Lastly, this review highlights the global challenges for COVID-19 vaccines in development and vaccination, and it discusses opportunities for development of future COVID-19 vaccines and vaccination coverage.

Primary malignant melanoma of the gastrointestinal mucosa is a rare tumor. Here, we report a case of a 60-year-old female patient with esophageal malignant melanoma. Combined with the related literature, the clinical manifestations, imaging, histopathological and immunohistochemical features of primary esophageal malignant melanoma were observed and analyzed. Imaging examination with 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18FDG-PET/CT) revealed multiple metastases in the patient's skull, bilateral acetabular, and bilateral cervical lymph nodes, but no radioactive uptake in the primary lesion. Endoscopy showed an area of abnormal pigmentation measuring approximately 0.8 cm in diameter in the lower esophageal mucosa, which was confirmed by pathological biopsy as primary malignant melanoma of the esophagus. The tumor cells are large, round, and diffused in sheets and nests, with visible nucleoli, thick chromatin granules, and abundant eosinophilic cytoplasm; melanin granules can be seen in the cytoplasm. The immune phenotype was as follows: tumor cells had diffuse expression of HMB45, Melan A, and S100. Diagnosing esophageal malignant melanoma using 18FDG-PET/CT imaging presents some difficulties, and new radio-targeted tracers need to be further developed to improve the diagnostic accuracy of this method. The combination of a morphological examination, pathological examination, and immunohistochemistry is helpful for diagnosing primary esophageal malignant melanoma.

The selective antiproliferation to oral cancer cells of Physalis peruviana-derived physapruin A (PHA) is rarely reported. Either drug-induced apoptosis and DNA damage or DNA repair suppression may effectively inhibit cancer cell proliferation. This study examined the selective antiproliferation ability of PHA and explored detailed mechanisms of apoptosis, DNA damage, and repair. During an ATP assay, PHA provided high cytotoxicity to two oral cancer cell lines (CAL 27 and Ca9-22) but no cytotoxicity to two non-malignant oral cells (HGF-1 and SG). This selective antiproliferation of PHA was associated with the selective generation of reactive oxygen species (ROS) in oral cancer cells rather than in non-malignant oral cells, as detected by flow cytometry. Moreover, PHA induced other oxidative stresses in oral cancer cells, such as mitochondrial superoxide generation and mitochondrial membrane potential depletion. PHA also demonstrated selective apoptosis in oral cancer cells rather than non-malignant cells in annexin V/7-aminoactinmycin D and caspase 3/7 activity assays. In flow cytometry and immunofluorescence assays, PHA induced γH2AX expressions and increased the γH2AX foci number of DNA damages in oral cancer cells. In contrast, the mRNA expressions for DNA repair signaling, including homologous recombination (HR) and non-homologous end joining (NHEJ)-associated genes, were inhibited by PHA in oral cancer cells. Moreover, the PHA-induced changes were alleviated by the oxidative stress inhibitor N-acetylcysteine. Therefore, PHA generates selective antiproliferation, oxidative stress, and apoptosis associated with DNA damage induction and DNA repair suppression in oral cancer cells.

Acute myeloid leukemia (AML) is marked by significant unmet clinical need due to both poor survival and high relapse rates where long-term disease control for most patients with relapsed or refractory AML remain dismal. Inspired to bring novel therapeutic options to these patients, we envisioned protein degradation as a potential therapeutic approach for the treatment of AML. Following this course, we discovered and pioneered a novel mechanism of action which culminated in the discovery of CC-90009. CC-90009 represents a novel protein degrader and the first cereblon E3 ligase modulating drug to enter clinical development that specifically targets GSPT1 (G1 to S phase transition 1) for proteasomal degradation. This manuscript briefly summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and efficacy data for CC-90009, which is currently in phase 1 clinical development.

Background:. Cryptococcal meningitis (CM) is one of the most common opportunistic infections caused by Cryptococcus neoformans in human immunodeficiency virus (HIV)-infected patients, and is complicated with significant morbidity and mortality. This study retrospectively analyzed the clinical features, characteristics, treatment, and outcomes of first-diagnosed HIV-associated CM after 2-years of follow-up. Methods:. Data from all patients (n = 101) of HIV-associated CM hospitalized in Shanghai Public Health Clinical Center from September 2013 to December 2016 were collected and analyzed using logistic regression to identify clinical and microbiological factors associated with mortality. Results:. Of the 101 patients, 86/99 (86.9%) of patients had CD4 count

Contemporarily, there has been a growing consumption rate of areca nut (AN) products worldwide, despite the fact that both fresh and processed AN contain various hazardous ingredients, including toxic alkaloids and carcinogenetic aflatoxins. However, there is a dearth of toxicity and potential cancer risk information regarding toxic alkaloids and aflatoxins via consuming AN products. The present study conducted a comprehensive assessment of the combined hazardous effects of AN alkaloids and aflatoxins towards human digestive system, by methods of HPLC analysis, cell study and in vitro digestive system study. The results revealed a synergetic effect of arecoline and aflatoxins was on human gingival normal fibroblast cell of HGF-1 and a proliferation effect on human tongue squamous carcinoma cell of CAL-27. Specifically, the residual arecoline was as high as 91.08 μg·ml

Background The etiology of Rasmussen's encephalitis (RE), a rare chronic neurological disorder characterized by CD8+ T cell infiltration and unihemispheric brain atrophy, is still unknown. Various human herpes viruses (HHVs) have been detected in RE brain, but their contribution to RE pathogenesis is unclear. Methods HHVs infection and relevant immune response were compared among brain tissues from RE, temporal lobe epilepsy (TLE) and traumatic brain injury (TBI) patients. Viral antigen or genome, CD8+ T cells, microglia and innate immunity molecules were analyzed by immunohistochemical staining, DNA dot blot assay or immunofluorescence double staining. Cytokines were measured by multiplex flow cytometry. Cell apoptosis was visualized by TUNEL staining. Viral infection, immune response and the severity of unihemispheric atrophy were subjected to correlation analysis. Results Antigens of various HHVs were prevalent in RE and TLE brains, and the cumulative viral score of HHVs positively correlated with the unihemispheric atrophy in RE patients. CD8+ T cells infiltration were observed in both RE and TLE brains and showed co-localization with HHV antigens, but their activation, as revealed by Granzyme B (GZMB) release and apoptosis, was found only in RE. In comparison to TLE, RE brain tissues contained higher level of inflammatory cytokines, but the interferon-β level, which was negatively correlated with cumulative viral score, was relatively lower. In line with this, the DNA sensor STING and IFI16, rather than other innate immunity signaling molecules, were insufficiently activated in RE. Conclusions Compared with TBI, both RE and TLE had prevalently HHV infection and immune response in brain tissues. However, in comparison to TLE, RE showed insufficient activation of antiviral innate immunity but overactivation of cytotoxic T cells. Our results show the relatively lower level of antiviral innate immunity and overactivation of cytotoxic T cells in RE cases upon HHV infection, the overactivated T cells might be a compensate to the innate immunity but the causative evidence is lack in our study and need more investigation in the future.

Cryptocaryone (CPC) was previously reported as preferential for killing natural products in oral cancer cells. However, its radiosensitizing potential combined with ultraviolet C (UVC) cell killing of oral cancer cells remains unclear. This study evaluates the combined anti-proliferation effect and clarifies the mechanism of combined UVC/CPC effects on oral cancer cells. UVC/CPC shows higher anti-proliferation than individual and control treatments in a low cytotoxic environment on normal oral cells. Mechanistically, combined UVC/CPC generates high levels of reactive oxygen species and induces mitochondrial dysfunction by generating mitochondrial superoxide, increasing mitochondrial mass and causing the potential destruction of the mitochondrial membrane compared to individual treatments. Moreover, combined UVC/CPC causes higher G2/M arrest and triggers apoptosis, with greater evidence of cell cycle disturbance, annexin V, pancaspase, caspases 3/7 expression or activity in oral cancer cells than individual treatments. Western blotting further indicates that UVC/CPC induces overexpression for cleaved types of poly (ADP-ribose) polymerase and caspase 3 more than individual treatments. Additionally, UVC/CPC highly induces γH2AX and 8-hydroxy-2’-deoxyguanosine adducts as DNA damage in oral cancer cells. Taken together, CPC shows a radiosensitizing anti-proliferation effect on UVC irradiated oral cancer cells with combined effects through oxidative stress, apoptosis and DNA damage.

Cross-reactivity with nontuberculous mycobacteria (NTM) species might limit the use of urine lipoarabinomannan (LAM) test to diagnose tuberculosis (TB) in people living with HIV (PLWH). This study aimed to investigate the utility of the LAM test among hospitalized HIV-positive patients.This prospective study enrolled HIV-positive inpatients with any TB symptom or seriously ill patients with advanced immunodeficiency. Urine samples were tested using the Alere Determine LAM Ag, and participants were categorized as confirmed TB, confirmed NTM infection, unclassified mycobacteria infection, and no mycobacteria infection based on microbiologic reference standards.A total of 382 participants were included. The prevalence of confirmed TB and NTM infection was 5.24% (20 of 382) and 4.45% (17 of 382), respectively. The sensitivity and specificity of the urine LAM for TB diagnosis were 65.00% (95% confidence interval [CI] 40.78-84.61) and 89.36% (95% CI 85.68-92.36), respectively. The LAM test for NTM yielded a sensitivity of 58.82% (95% CI 32.92-81.56) and specificity of 88.61% (95% CI 84.87-91.70). Notably, the negative predictive values of the urine LAM for TB and NTM were 97.85% (95% CI 95.63-99.13) and 97.85% (95% CI 95.63-99.13), respectively.Cross-reactivity with NTM cause high false-positive LAM for TB diagnosis in PLWH. The correct identification of mycobacteria species is crucial for deciding treatment strategies.

Chronical hyperuricemia, a severe metabolic disease characterized by increased serum uric acid, urea nitrogen, and creatinine, has a positive correlation with the risks of gouty arthritis, diabetes, hypertension, and kidney damage. Abnormal purine metabolism and reduced uric acid excretion are the major causes of hyperuricemia, which, thus, points to a potential strategy of preventing from or delaying the progress of hyperuricemia-related diseases and its complications by effectively controlling the serum uric acid level. Increasing evidence has revealed that Chinese medicines alleviate hyperuricemia through regulating intestinal flora, which plays a pivotal role in regulating metabolites, including uric acid level. The disease treatment with traditional Chinese medicine is based on syndrome differentiation, and Chinese medicines often have multiple effects and a wide range of targets. In this review, we summarized the anti-hyperuricemia effects and mechanisms of active compounds in Chinese medicines, single Chinese medicinal herbs, and Chinese medicinal prescriptions in regulating the uric acid level via intestinal flora and metabolites, which will be helpful for further study and application of Chinese medicines in hyperuricemia treatment.

Pituitary adenomas are known to cause optic chiasmal compression leading to visual field (VF) defects. Herein, we analysed the factors influencing early VF recovery following transsphenoidal surgery and explored the significance of retinal vessel density parameters in predicting prognoses. We collected data of 50 patients with pituitary adenoma and an abnormal VF prior to surgery. Patients were categorised into VF recovery (n = 25) and non-recovery (n = 25) groups within 1 week postoperatively. The VF, optic chiasm form, tumour volume, retinal thickness, and vessel density parameters were measured. The χ

Background Few data are available regarding the long-term case-fatality rate (CFR) among people living with HIV (PLWH) with nontuberculous mycobacteria (NTM) disease. The aim of this study is to analyze the long-term CFR in patients with NTM disease and to identify risk factors for their death. Methods A retrospective cohort study of 379 cases of microbiologically confirmed NTM disease in PLWH was conducted from January 1, 2012, to December 31, 2020, in Shanghai, China. We used Kaplan–Meier survival analysis and the log-rank test to compare the long-term CFR in patients with disseminated NTM (DNTM) and localized NTM disease. Univariate Cox proportional hazards regression analysis and a stepwise Cox proportional hazards regression model were used to estimate the predictors of long-term CFR. Results The cohort was followed up for a median of 26 months. The total CFR was 15.7% by one year and increased to 22.6% at 5 years after the diagnosis of NTM disease. The 5-year CFR of PLWH with DNTM was significantly higher than that of PLWH with localized NTM (26.7% vs 19.6% for DNTM and localized NTM disease, respectively). Older age [hazard ratio (HR) = 1.04, 95% confidence interval (CI): 1.02–1.06, P CI: 1.21–3.49, P CI: 1.17–3.68, P CI: 1.12–1.55, P CI: 0.82–0.98, P Conclusions NTM was associated with a high long-term CFR in PLWH. Further approaches to prevent NTM disease in PLWH are urgently needed. Graphical Abstract

Background: Rifamycins are the cornerstone of anti-tuberculosis therapy while they are potent inducers of drug metabolizing enzymes. For the first time, we evaluated the effect of rifampicin (RIF) and rifabutin (RBT) on the pharmacokinetics (PK) of dolutegravir (DTG) in patients with HIV and tuberculosis (TB)/ mycobacterium avium complex (MAC) co-infection. Methods: Both HIV/TB (or MAC) co-infected patients and HIV infected patients without TB/MAC were enrolled. Patients in the RIF group received DTG 50 mg twice daily together with 600mg of RIF, while patients in the RBT group received DTG 50 mg once daily together with 300 mg of RBT. The DTG pharmacokinetic profiles in different groups were assessed. Results: A total of 13 subjects in the RIF group, 12 subjects in the RBT group, and 10 subjects in non-TB/MAC group were enrolled. The geometric mean ratio (GMR) of the trough concentration (Ctr) of DTG in the RIF group to non-TB/MAC group was 1.33 [90% confidence interval (CI):0.97 to 1.81], while the GMR of the maximum concentration (Cmax) of DTG was 1.29 (90% CI: 1.23 to 1.36). The GMR of the Ctr of DTG in the RBT group to non-TB/MAC group was 0.41 (90% CI: 0.30 to 0.57), while the GMR of the Cmax of DTG was 0.55 (90% CI: 0.52 to 0.57). Conclusions: Due to the relatively low trough concentrations of DTG with RBT, DTG 50mg once daily together with RBT could only serve as an alternative option for HIV/TB (or MAC) co-infected patients.

Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.

Discovering drug candidates for the modulation of metastasis is of great importance in inhibiting oral cancer malignancy. Although most pomegranate extract applications aim at the antiproliferation of cancer cells, its antimetastatic effects remain unclear, especially for oral cancer cells. The aim of this study is to evaluate the change of two main metastasis characters, migration and invasion of oral cancer cells. Further, we want to explore the molecular mechanisms of action of pomegranate extract (POMx) at low cytotoxic concentration. We found that POMx ranged from 0 to 50 μg/mL showing low cytotoxicity to oral cancer cells. In the case of oral cancer HSC-3 and Ca9-22 cells, POMx inhibits wound healing migration, transwell migration, and matrix gel invasion. Mechanistically, POMx downregulates matrix metalloproteinase (MMP)-2 and MMP-9 activities and expressions as well as epithelial-mesenchymal transition (EMT) signaling. POMx upregulates extracellular signal-regulated kinases 1/2 (ERK1/2), but not c-Jun N-terminal kinase (JNK) and p38 expression. Addition of ERK1/2 inhibitor (PD98059) significantly recovered the POMx-suppressed transwell migration and MMP-2/-9 activities in HSC-3 cells. Taken together, these findings suggest to further test low cytotoxic concentrations of POMx as a potential antimetastatic therapy against oral cancer cells.

To determine the relationship, if any, between body mass index (BMI) and attenuation of the arcuate eminence (AE).Case series with chart review.Tertiary neurotologic referral center.Submillimeter distances were recorded from high-resolution temporal bone computed tomography (CT) scans of 50 patients (100 sides). The AE (defined as the superiormost location of the petrous bone over the otic capsule), the bony apex of the superior semicircular canal (SSC), and the geniculate ganglion (GG) were identified and 3-dimensional distances measured. The height of the AE relative to the bony apex of the superior semicircular canal was determined using Euclidean geometry using the fixed anatomical landmark of the GG as the origin. Correlations between AE and BMI were calculated using Pearson's, linear mixed effects, and sensitivity analysis models.The mean (SD) BMI was 30 (8.1) kg/mContrary to other structures within the lateral skull base, the relative prominence of the arcuate eminence does not correlate with BMI or any other demographic variables.

Background Homeodomain-interacting protein kinase 2 (HIPK2) has increasingly drawn attention as recent researches demonstrated its unique role in the regulation of multiple fundamental processes such as apoptosis, proliferation and DNA damage repair. Most importantly, HIPK2 was shown to play regulatory role in inflammation and influence the phenotype and activity of fibroblasts. In this study, we aimed to evaluate the impact of HIPK2 gene variant on risk of radiation pneumonitis for patients with pulmonary malignancies. Methods 169 lung cancer patients with radiotherapy were included in our prospective study and genotyped by Sanger Sequence method. Multivariable Cox hazard analysis and multiple testing were applied to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of all factors possibly related to the risk of radiation pneumonitis (RP). Results Patients with Mean Lung Dose (MLD) ≥ 15Gy, Lung V20 ≥ 24% had higher risk of RP ≥ grade 2 compared with those counterparts (HR = 1.888, 95% CI: 1.186–3.004, P = 0.007; HR = 2.126, 95% CI: 1.338–3.378, P = 0.001, respectively). Importantly, CC genotype of HIPK2: rs2030712 were strongly related to an increased occurrence of RP ≥ grade 2 (HR = 2.146, 95% CI: 1.215–3.791, P = 0.009). Conclusion HIPK2: rs2030712 was found to be significantly related to RP of grade ≥ 2 in our cohort, and may thus be one of the important predictors of severe RP before radiotherapy, if further validated in larger population. Trial registration Our study was prospective and observational. The research was registered in ClinicalTrials.gov database as NCT02490319.

Reduced doses of antiretroviral (ARV) drugs may lower toxicity while preserving efficacy. We aimed to evaluate the efficacy of reduced doses of both tenofovir disoproxil fumarate (TDF) and efavirenz for the treatment of HIV-1 infection. In this open-label, non-inferiority trial, HIV-1-infected antiretroviral-naive adults were randomly assigned to receive either a lower dose anti-retroviral regimen comprised of TDF (200 mg), efavirenz (400 mg), and standard dose lamivudine (300 mg) or the standard dose regimen. The primary endpoint was the proportion of participants with HIV-1 RNA≤ 50 copies/mL at week 48 using a non-inferiority margin of –10%. At week 48, 79 of 92 (85.9%) participants in the lower dose regimen group and 78 of 92 (84.8%) in the standard dose regimen group achieved HIV-1 RNA≤ 50 copies/mL (treatment difference 1.1%, 95% CI −9.1 to 11.3) in the intention-to-treat analysis. Drug-related adverse events occurred more frequently in the participants receiving the standard dose regimen compared with the lower dose one (63.0% vs 80.4%). Changes in estimated glomerular filtration rate and bone mineral density were comparable between the two groups. The non-inferior efficacy and better safety profile of the lower dose ARV regimen support its use as alternative initial therapy for HIV-1 infected patients.

Background and purpose Recent researches demonstrated that single nucleotide polymorphisms (SNPs) of genes involving inflammation, DNA repair, etc. were associated with risk of radiation pneumonitis (RP). However, these studies were single-centered, from single ethnic origin, without validation from independent cohort studies from other populations. In order to identify clinical valuable SNPs for RP, in this study we selected 19 RP-related SNPs candidates previously published before 2016 for validation in our cohort. Material and methods 359 lung cancer patients with radiotherapy were included in our prospective study (NCT02490319). Peripheral blood samples from these patients were genotyped by MassArray and Sanger Sequence method. Multivariate Cox hazard and other analyses were applied to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of all factors possibly related to the risk of RP. Results Patients with elder age, MLD ≥15 Gy, V20 ≥24% had higher risk of RP ≥grade 3 compared with their counterparts (HR = 2.020, 95% CI: 1.045–3.906, P = 0.037; HR = 2.502, 95% CI: 1.346–4.652, P = 0.004; HR = 2.256, 95% CI: 1.191–4.272, P = 0.013, respectively). Moreover, patients receiving IMRT were associated with decreased incidence of RP (HR = 0.520, 95% CI: 0.280–0.963, P = 0.037). Importantly, CT + TT genotype of IL4: rs2243250 was strongly related to decreased risk of RP ≥grade 3 (HR = 0.195, 95% CI: 0.090–0.424, P = 0.000037, Pc = 0.0006). Conclusion IL4: rs2243250 was validated to be significantly related to RP of grade ≥3 in our cohort. Our results further emphasized the prevalence and clinical value of IL4: rs2243250 on RP, and may thus be one of the important predictors of severe RP before radiotherapy.

To achieve preferential effects against cancer cells but less damage to normal cells is one of the main challenges of cancer research. In this review, we explore the roles and relationships of oxidative stress-mediated apoptosis, DNA damage, ER stress, autophagy, metabolism, and migration of ROS-modulating anticancer drugs. Understanding preferential anticancer effects in more detail will improve chemotherapeutic approaches that are based on ROS-modulating drugs in cancer treatments.

BACKGROUND This study evaluated the imaging features of ganglioneuroma (GN) and assessed the diagnostic value of the enhancement rate (ER) of CT for GN. MATERIAL AND METHODS We retrospectively reviewed records of 49 patients with histopathologically confirmed GN who underwent preoperative contrast-enhanced CT or MRI between 2010 and 2018. The independent samples t test and chi-square test were used. Receiver operating characteristic (ROC) curves were generated to analyze the diagnostic sensitivity (SE) and specificity (SP). Positive predictive value (PPV) and negative predictive value (NPV) were calculated. RESULTS The CT values were 32.59±3.61 Hounsfield units (HU) for plain scans, 38.87±5.09 HU for the arterial phase, and 54.26±8.14 HU for the venous phase, and the incidence of calcification and cysts was 32.6% and 10.2%, respectively. There was no significant difference in CT results and clinical parameters between mediastinal ganglioneuroma (MGN) and retroperitoneal ganglioneuroma (RGN) (p>0.05). The area under the curves (AUCs) for the arterial enhancement rate (AER), venous enhancement rate (VER), and AER/VER combined index in diagnosing GN were 0.735, 0.980, and 0.990, respectively. The VER of 0.2819 exhibited the SE and SP at 92.9% and 92.9%, respectively, to characterize the GN, whereas the AER of 0.1779 had SE and SP of 52.4% and 90.5%, respectively. The SE and SP for the combined index were 88.1% and 100%, respectively. The GN showed hypointensity on T1WI, hyperintense, or slightly high signal on T2WI with the linear hypointensity, and hyperintense on DWI. CONCLUSIONS A hypodense mass was observed for GN on plain scan and presented delayed enhancement on contrast enhancement. VER or AER/VER combination is more accurate than AER for the diagnosis of paravertebral GN.

Purpose: This study evaluates the growth inhibiting potential of our previously described sulfonyl chromen-4-ones (CHW09) compound in X-ray irradiated oral cancer cells.Materials and methods: The g...

Nepenthes plants are regarded as a kind of Traditional Chinese Medicine for several diseases but its anticancer activity remain unclear. The subject of this study is to evaluate the antiproliferation effects on oral cancer cells by Nepenthes plants using ethyl acetate extract of Nepenthes adrianii x clipeata (EANA). Cell viability was detected using MTS assay. Its detailed mechanisms including cell cycle, apoptosis, oxidative stress, and DNA damage were explored by flow cytometry or western blotting. For 24 hours EANA treatment, five kinds of oral cancer cells (CAL 27, Ca9-22, OECM-1, HSC-3, and SCC9) show IC50 values of cell viability ranging from 8 to 17 μg/mL but the viability of normal oral cells (HGF-1) remains over 80%. Subsequently, CAL 27 and Ca9-22 cells with high sensitivity to EANA were chosen to investigate the detailed mechanism. EANA displays the time course and concentration effects for inducing apoptosis based on flow cytometry (subG1 and annexin V analyses) and western blotting [cleaved poly (ADP-ribose) polymerase (c-PARP)]. Oxidative stress and DNA damage were induced by EANA treatments in oral cancer cells through reactive oxygen species (ROS), mitochondrial membrane potential disruption, mitochondrial superoxide, and γH2AX. All these changes of EANA treatments in oral cancer cells were reverted by the ROS scavenger N-acetylcysteine pretreatment. Therefore, EANA induces preferential killing, apoptosis, and DNA damage against oral cancer cells through oxidative stress.

Ten previously undescribed triterpenoid congeners, namely irpeksolactins A–J, together with eighteen known ones, were isolated from the fruiting bodies of the rainforest-dwelling medicinal fungus Irpex lacteus. The structures of all the isolates were characterized by extensive spectroscopic approaches, including 1D & 2D NMR and MS spectroscopic methods. Irpeksolactin J displayed selective and weak cytotoxicity against the human lung cancer cell line A549 and the human hepatocellular carcinoma cell line SMMC-7721.

LY303511 was developed as a negative control of LY294002 without pan-phosphoinositide 3-kinase (PI3K) inhibition. We hypothesize LY303511 generate reactive oxygen species (ROS) to induce apoptosis for killing oral cancer cells. In MTS assay, LY303511 dose-responsively decreases survival in three kinds of oral cancer cells but little damage to normal oral cells (HGF-1). Two oral cancer cells (CAL 27 and SCC-9) with highly sensitivity to LY303511 were used. In 7-aminoactinomycin D (7AAD) assay, LY303511 slightly increases subG1 population in oral cancer cells. In annexin V/7AAD and/or pancaspase assays, LY303511 induces apoptosis in oral cancer cells but HGF-1 cells remains in basal level. In oxidative stress, LY303511 induces ROS and mitochondrial superoxide in oral cancer cells. In 8-oxo-2'-deoxyguanosine assay, LY303511 induces oxidative DNA damage in oral cancer cells. In zebrafish model, LY303511 inhibits CAL 27-xenografted tumor growth. Therefore, LY303511 displays antiproliferation potential against oral cancer cells in vitro and in vivo.

The striatin-interacting phosphatase and kinase (STRIPAK) complexes integrate extracellular stimuli that result in intracellular activities. Previously, we discovered that STRIPAK is a key machinery responsible for loss of the Hippo tumor suppressor signal in cancer. Here, we identified the Hippo-STRIPAK complex as an essential player in the control of DNA double-stranded break (DSB) repair and genomic stability. Specifically, we found that the mammalian STE20-like protein kinases 1 and 2 (MST1/2), independent of classical Hippo signaling, directly phosphorylated zinc finger MYND type-containing 8 (ZMYND8) and hence resulted in the suppression of DNA repair in the nucleus. In response to genotoxic stress, the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway was determined to relay nuclear DNA damage signals to the dynamic assembly of Hippo-STRIPAK via TANK-binding kinase 1-induced (TBK1-induced) structural stabilization of the suppressor of IKBKE 1- sarcolemma membrane-associated protein (SIKE1-SLMAP) arm. As such, we found that STRIPAK-mediated MST1/2 inactivation increased the DSB repair capacity of cancer cells and endowed these cells with resistance to radio- and chemotherapy and poly(ADP-ribose)polymerase (PARP) inhibition. Importantly, targeting the STRIPAK assembly with each of 3 distinct peptide inhibitors efficiently recovered the kinase activity of MST1/2 to suppress DNA repair and resensitize cancer cells to PARP inhibitors in both animal- and patient-derived tumor models. Overall, our findings not only uncover what we believe to be a previously unrecognized role for STRIPAK in modulating DSB repair but also provide translational implications of cotargeting STRIPAK and PARP for a new type of synthetic lethality anticancer therapy.

Anxiety is exceedingly prevalent among individuals with an autism spectrum condition (ASC). While recent literature postulates anxiety as a mechanism encompassing an underlying amygdala-related elevated baseline level of arousal even to nonthreatening cues, whether this same mechanism contributes to anxiety in those with an ASC and supports the transdiagnostic nature of anxiety remains elusive. In this case-control study of 51 youths (26 ASC), we assessed autism and anxiety via the Autism-Spectrum Quotient and the State-Trait Anxiety Inventory, respectively. Hemodynamic responses, including amygdala reactivity, to explicit and implicit (backwardly masked) perception of threatening faces were acquired using functional Magnetic Resonance Imaging (fMRI). For explicit fear, ASC individuals showed significantly greater negative correlations between the amygdala and the attentional deployment-parietal network. For implicit fear, ASC individuals showed significantly stronger correlations of the amygdala with the prefrontal networks, temporal pole, and hippocampus. Additionally, an fMRI-based neurologic signature for anxiety in ASCs was identified via the LibSVM machine learning model using amygdala-centered functional connectivity during the emotional processing of explicit and implicit stimuli. Hypervigilance to implicit threat in ASCs comorbid with anxiety might exacerbate explicit threat reactivity; hence the use of attentional avoidance patterns to restrict affective hyperarousal for explicitly perceived socioemotional stimuli. Consequently, developing an attention-independent behavioral/neural marker identifying anxiety in ASCs is highly warranted. LAY SUMMARY: This study identifies a dissociation of amygdala reactivity dependent on explicit and implicit threat processing. Implicit anxiety in individuals with an autism spectrum condition (ASC) could outweigh explicitly induced threat. When explicitly perceiving socioemotional stimuli, ASC individuals with anxiety might use attentional avoidance patterns to restrict affective hyperarousal.

Intelligent microfluidics is an emerging cross-discipline research area formed by combining microfluidics with machine learning. It uses the advantages of microfluidics, such as high throughput and controllability, and the powerful data processing capabilities of machine learning, resulting in improved systems in biotechnology and chemistry. Compared to traditional microfluidics using manual analysis methods, intelligent microfluidics needs less human intervention, and results in a more user-friendly experience with faster processing. There is a paucity of literature reviewing this burgeoning and highly promising cross-discipline. Therefore, we herein comprehensively and systematically summarize several aspects of microfluidic applications enabled by machine learning. We list the types of microfluidics used in intelligent microfluidic applications over the last five years, as well as the machine learning algorithms and the hardware used for training. We also present the most recent advances in key technologies, developments, challenges, and the emerging opportunities created by intelligent microfluidics.

Marine natural products are abundant resources for antioxidants, but the antioxidant property of the soft corals-derived sinularin and dihydrosinularin were unknown. This study aimed to assess antioxidant potential and antiproliferation effects of above compounds on cancer cells, and to investigate the possible relationships between them. Results show that sinularin and dihydrosinularin promptly reacted with 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-azinobis (3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS), and hydroxyl (•OH), demonstrating a general radical scavenger activity. Sinularin and dihydrosinularin also show an induction for Fe+3-reduction and Fe+2-chelating capacity which both strengthen their antioxidant activities. Importantly, sinularin shows higher antioxidant properties than dihydrosinularin. Moreover, 24 h ATP assays show that sinularin leads to higher antiproliferation of breast, lung, and liver cancer cells than dihydrosinularin. Therefore, the differential antioxidant properties of sinularin and dihydrosinularin may contribute to their differential anti-proliferation of different cancer cells.

Background Talaromyces marneffei (TM) bloodstream infection is common in Acquired Immunodeficiency Syndrome (AIDS) patients with extreme immunodeficiency in Southeast Asia and South China, however, clinical case study on TM bloodstream infection is scarce. We retrospectively analyzed the clinical characteristics of TM bloodstream infection in hospitalized AIDS patients and determined the outcomes of hospitalization after diagnosis in our hospital over the past 5 years. Methods From January 2015 to July 2020, 87 cases of TM detected by blood culture in patients admitted to our center were collected. The admission complaints, blood cells, biochemistry, CD4 and CD8 cell counts and 1,3-β-D-glucan (BDG), procalcitonin (PCT), CRP level on the day of blood culture test, and outcomes during hospitalization were analyzed. Logistic regression analysis was performed for the risk factors for poor prognosis (60 cases). Spearman correlation analysis was used to analyze the correlation between peripheral blood cells, albumin and the time required for TM turnaround in blood culture. The difference was statistically significant when the P value was Results A total of 87 patients were collected, with a median age of 34 years, a median hemoglobin of 94 g/L and CD4 count of 7/μl. The rate of TM bloodstream infection among all in-hospital patients increased from 0.99% in 2015 to 2.09% in 2020(half year). Patients with TM bloodstream infection with CD8 count 200/μl (p = 0.04), and those with BDG 100 pg/mL (p = 0.01). Conclusions TM bloodstream infection is becoming more common in advanced AIDS patients in endemic areas. For those patients with extremely low CD4 and CD8 cell counts below 200/μl is with an increased risk of poor prognosis.

Tumor‑associated macrophages (TAMs) are critical components of the tumor microenvironment that are tightly associated with malignancies in human cancers, including lung cancer. LGK‑974, a small molecular inhibitor of Wnt secretion, was reported to block Wnt/β‑catenin signaling and exert anti‑inflammatory effects by suppressing pro‑inflammatory gene expression in cancer cells. Although it was reported that Wnt/β‑catenin was critical in regulating TAMs, it is still largely unknown whether LGK‑974 regulates tumor malignancies by regulating TAMs. The present study firstly verified that the polarization of TAMs was regulated by LGK‑974. LGK‑974 increased M1 macrophage functional markers and decreased M2 macrophage functional markers. The addition of Wnt3a and Wnt5a, two canonical Wnt signaling inducers, reversed the decrease in M1 macrophage functional markers, including mannose receptor, IL‑10 and Arg1, by activating Wnt/β‑catenin signaling. Conditioned medium from LGK‑974‑modified TAMs inhibited the malignant behaviors in A549 and H1299 cells, including proliferation, colony formation and invasion, by blocking Wnt/β‑catenin signaling. LGK‑974‑modified TAMs blocked the cell cycle at the G1/G0 phase, which was reversed by the addition of Wnt3a/5a, indicating that LGK‑974 regulates the microenvironment by blocking Wnt/β‑catenin signaling. Taken together, the results indicate that LGK‑974 indirectly inhibited the malignant behaviors of A549 and H1299 cells by regulating the inflammatory microenvironment by inhibiting Wnt/β‑catenin signaling in TAMs.

Elevated Wnt/β‐catenin signaling has been commonly associated with tumorigenesis especially colorectal cancer (CRC). Here, an MST4‐pβ‐cateninThr40 signaling axis essential for intestinal stem cell (ISC) homeostasis and CRC development is uncovered. In response to Wnt3a stimulation, the kinase MST4 directly phosphorylates β‐catenin at Thr40 to block its Ser33 phosphorylation by GSK3β. Thus, MST4 mediates an active process that prevents β‐catenin from binding to and being degraded by β‐TrCP, leading to accumulation and full activation of β‐catenin. Depletion of MST4 causes loss of ISCs and inhibits CRC growth. Mice bearing either MST4T178E mutation with constitutive kinase activity or β‐cateninT40D mutation mimicking MST4‐mediated phosphorylation show overly increased ISCs/CSCs and exacerbates CRC. Furthermore, the MST4‐pβ‐cateninThr40 axis is upregulated and correlated with poor prognosis of human CRC. Collectively, this work establishes a previously undefined machinery for β‐catenin activation, and further reveals its function in stem cell and tumor biology, opening new opportunities for targeted therapy of CRC., A novel MST4‐pβ‐cateninThr40 signaling axis essential for maintaining intestinal stem cell (ISC) homeostasis is identified. In response to Wnt signal, MST4 directly phosphorylates β‐catenin at Thr40 to actively block the GSK3β/β‐TrCP‐mediated phosphorylation/degradation of β‐catenin. Genetic activation of the MST4‐pβ‐cateninThr40 axis exacerbates ISC‐driven colorectal cancer (CRC); and hyperactivation of this axis is clinically correlated with poor prognosis.

Introduction Lymphoma is the most common cancer in HIV/AIDS patients. Chemotherapy regiments recommended for lymphomas in HIV-negative patients are also used for lymphomas in HIV/AIDS patients. Little is known about the infections among HIV/AIDS patients with lymphoma undergoing chemotherapy. Methods This retrospective study investigated the incidence, spectrum of and risk factors for infections during chemotherapy in 164 HIV/AIDS patients with lymphoma admitted to Shanghai Public Health Clinical Center from July 2013 to December 2020. Results The median age of the patients was 43 years old; 90.9% (149/164) were male. A total of 112 (68.3%) patients had a CD4 count < 200 cells/μL at lymphoma diagnosis. Diffuse large B-cell lymphoma (56%, 91/164) and Burkitt lymphoma (28%, 46/164) were the two most common subtypes of lymphoma. Among the 137 patients who underwent chemotherapy (total cycles = 749), 58.4% (80/137) of patients experienced a total of 153 episodes of infection, with an incidence rate of 20.4% (153/749). The most commonly seen infections were lung infection (29.2%, 40/137) and febrile neutropenia (27.0%, 37/137). Multivariate analysis showed that grade 4 neutropenia during chemotherapy (OR = 7.128, 95% CI 3.051-16.654, p < 0.001) and duration of antiretroviral treatment at lymphoma diagnosis

Tumor-associated macrophages have emerged as crucial factors for metastases. Microglia are indispensable components of the brain microenvironment and play vital roles in brain metastasis (BM). However, the underlying mechanism of how activated microglia promote brain metastasis of non-small cell lung cancer (NSCLC) remains elusive. Here, we purified cell lines with brain-metastatic tropism and employed a co-culture system to reveal their communication with microglia. By single-cell RNA-sequencing and transcriptome difference analysis, we identified IL6 as the key regulator in brain-metastatic cells (A549-F3) to induce anti-inflammatory microglia via JAK2/STAT3 signaling, which in turn promoted the colonization process in metastatic A549-F3 cells. In our clinical samples, patients with higher levels of IL6 in serum showed higher propensity for brain metastasis. Additionally, the TCGA (The Cancer Genome Atlas) data revealed that NSCLC patients with a lower level of IL6 had a longer overall survival time compared to those with a higher level of IL6. Overall, our data indicate that the targeting of IL6/JAK2/STAT3 signaling in activated microglia may be a promising new approach for inhibiting brain metastasis in NSCLC patients.

This study aims to explore the value of retinal vessel density (VD) in diagnosing optic nerve injuries in patients with pituitary adenomas using optical coherence tomography angiography (OCTA).In this cross-sectional retrospective study, 100 patients with pituitary adenomas and 71 participants for normal controls, who visited the Beijing Tiantan Hospital from January 2019 to May 2021, were enrolled. The OCTA was used to measure retinal thickness and VD, and the correlation of these parameters with visual field (VF) factors was analyzed. Receiver operating characteristic curves were used to compare the value of the above parameters in diagnosing VF abnormalities in the patients with pituitary adenomas; the differences in retinal VD between 41 patients with pituitary adenomas who had normal retinal thicknesses and 41 patients in the normal control group with no statistical differences in gender and age were compared.The radial peripapillary capillary (RPC) density, superficial retinal capillary plexus (SRCP) density, retinal nerve fiber layer thickness, and ganglion cell layer complex thickness correlated with VF parameters (The density of the RPC and SRCP may also be sensitive and specific indicators of VF damage in patients with pituitary adenomas. Measuring retinal VD in patients with pituitary adenomas may be a supplement to help identify VF impairments. In addition, abnormal retinal vascular density may indicate VF impairment in patients who are unable to cooperate with VF examinations.

Colorectal cancer (CRC) is one of the most common digestive tract cancers and ~90% of CRC‑related deaths are caused by metastasis. MicroRNA (miR)‑129 has been reported to be involved in the metastasis of various malignant tumors. However, the role of miR‑129 in CRC metastasis remains unclear. The purpose of the present study was to identify the potential functions and mechanisms of action of miR‑129 in CRC progression. The expression of miR‑129 and sex‑determining region Y‑related high‑mobility group‑box 4 (SOX4) was determined in CRC tissues or cell lines by reverse transcription‑quantitative PCR, western blot or immunofluorescence assays. The mechanism underlying the role of miR‑129 in CRC progression was assessed by MTT, wound healing, Transwell, western blot and dual‑luciferase report assays. The results revealed that miR‑129 was significantly decreased, whereas SOX4 was increased, in CRC tissues and cell lines. SW620 and SW480 cells exhibited a higher proliferation, migration and invasion capacity compared with NCM460 cells. miR‑129 overexpression significantly inhibited cell proliferation, migration, invasion and epithelial‑to‑mesenchymal transition (EMT), and it activated the nuclear factor (NF)‑κB signaling pathway in CRC cells, while the inhibition of miR‑129 exerted opposite effects. Additionally, SOX4 was identified as a direct target gene of miR‑129. Taken together, the findings of the present study suggested that miR‑129 may act as a tumor suppressor in CRC by inhibiting CRC cell proliferation, migration, invasion and EMT, in part through targeting the 3'‑untranslated region of SOX4 mRNA, and the mechanism may involve activation of the NF‑κB signaling pathway.

We previously found that marine sponge-derived manoalide induced antiproliferation and apoptosis of oral cancer cells as well as reactive species generations probed by dichloro-dihydrofluorescein diacetate (DCFH-DA) and MitoSOX Red. However, the sources of cellular and mitochondrial redox stresses and the mutual interacting effects between these redox stresses and apoptosis remain unclear. To address this issue, we examined a panel of reactive species and used the inhibitors of cellular reactive species (N-acetylcysteine (NAC)), mitochondrial reactive species (MitoTEMPO), and apoptosis (Z-VAD-FMK; ZVAD) to explore their interactions in manoalide-treated oral cancer Ca9-22 and CAL 27 cells. Hydroxyl (˙OH), nitrogen dioxide (NO2˙), nitric oxide (˙NO), carbonate radical-anion (CO3˙–), peroxynitrite (ONOO–), and superoxide (O2˙–) were increased in oral cancer cells following manoalide treatments in terms of fluorescence staining and flow cytometry. Cellular reactive species (˙OH, NO2⋅, ˙NO, CO3˙–, and ONOO–) as well as cellular and mitochondrial reactive species (O2˙–) were induced in oral cancer cells following manoalide treatment for 6 h. NAC, MitoTEMPO, and ZVAD inhibit manoalide-induced apoptosis in terms of annexin V and pancaspase activity assays. Moreover, NAC inhibits mitochondrial reactive species and MitoTEMPO inhibits cellular reactive species, suggesting that cellular and mitochondrial reactive species can crosstalk to regulate each other. ZVAD shows suppressing effects on the generation of both cellular and mitochondrial reactive species. In conclusion, manoalide induces reciprocally activation between cellular and mitochondrial reactive species and apoptosis in oral cancer cells.

Epilepsy with comorbid depression has recently attracted increasing attention. Temporal lobe epilepsy (TLE) may represent an increased risk of developing depression, especially if the seizures do not generalize. The two-pore domain potassium channel-TWIK-related K

A 26-year-old female was admitted to the emergency department of thoracic surgery complaining of chest tightness, shortness of breath, and a history of bilateral tuberculosis. A chest Computed Tomography (CT) scan showed bilateral pleural effusion. After that, the patient was implanted with bilateral intercostal drainage tubes. Further analysis of the pleural effusion was conducted to confirm the diagnosis of bilateral chylothorax. We initiated conservative treatment consisting of fasting and total parenteral nutrition. After the failure of conservative treatment, the patient underwent ligation of the thoracic duct by right-sided thoracotomy combined with talc slurry. On the first day postoperatively, the right pleural effusion had decreased significantly, while the left pleural effusion had not. Subsequently, talc slurry was injected into the left thoracic drainage tube of the patient. Bilateral pleural effusion was significantly reduced. Re-examination chest X-ray showed the disappearance of pleural effusion, and the patient was discharged good healthy. Chest X-rays were reexamined one month postoperatively, and the patient's lung was well dilated, with no recurrence of pleural effusion. In this case, it was shown that conservative treatment is the first choice for chylothorax. However, if this proves to be ineffective, early surgical treatment should be considered. Early diagnosis and timely surgical intervention are the key factors to improve the prognosis of patients.

In the early stage of infection in severe burn patients, the killing function of the natural immune cells is continuously low, which causes the immune system to continuously and compensatorily secrete a large amount of cytokines to improve the ability to resist bacterial infection. Once the cytokine secretion is out of control, a cytokine storm will form. In the late stage of severe burn infection, the bone marrow mobilization caused by continuous acute myelodysplasia will be exhausted, the level of immune response will be low, and the secretion of anti-inflammatory factors promoting repair will be increased, which will lead to immune suppression. Cytokine storm after burn infection is caused by excessive proinflammatory stimulation, inadequate inflammatory regulation, or a combination of the two. From the perspective of immunology, this review will briefly summarize the changing process of immune response against pathogenic bacteria after severe burn infection, cytokine storm in the early stage of severe burn infection and the mechanism of occurrence and transformation of immunosuppression in the late stage of severe burn infection. We suggest that future research direction from the following aspects: Mechanism of low bacterial killing function of innate immune cells after severe burns; The mechanism by which acute myeloid hyperplasia leads to myeloid inhibitory cells (MDSC) and nucleated erythrocytosis during the development of cytokine storms; The key regulatory mechanism between macrophage phagocytic dysfunction and cytokine hyperactivity; The role and key regulatory mechanism of destruction of the dynamic balance of M1/M2 macrophages and effector/regulatory T cells in triggering immune suppression.