Safety and clinical efficacy of immune checkpoint inhibitors in advanced gastric cancer in the real world.

BACKGROUND: To evaluate the clinical efficacy and safety of immune checkpoint inhibitors in patients with advanced gastric cancer in the real world. METHODS: The retrospective analysis was conducted on the clinical records of 402 patients with advanced gastric cancer who were admitted to the Nanjing Drum Tower Hospital between December 2017 and April 2022 and who had received immunotherapy. Observation target: drug use, treatment, adverse reaction type and grade, objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), and overall survival (OS). RESULTS: By retrospectively analyzing the data of patients with advanced gastric cancer treated with ICIs previously admitted to our medical center, we found some clinical characteristic factors associated with the occurrence of irAEs as well as the efficacy and prognosis: the presence or absence of hypertension, whether or not to receive targeted therapies can predict the occurrence of immune-related adverse events (irAEs), and the more the presence of irAEs, the better the prognosis. These can help clinicians in clinical drug selection. CONCLUSIONS: The results of this paper show that the occurrence of irAEs is associated with patients' OS. irAEs occurrence can prolong patients' OS. irAEs occurrence may serve as a surrogate marker for ICIs.

A multi-omics analysis-based model to predict the prognosis of low-grade gliomas.

Lower-grade gliomas (LGGs) exhibit highly variable clinical behaviors, while classic histology characteristics cannot accurately reflect the authentic biological behaviors, clinical outcomes, and prognosis of LGGs. In this study, we carried out analyses of whole exome sequencing, RNA sequencing and DNA methylation in primary vs. recurrent LGG samples, and also combined the multi-omics data to construct a prognostic prediction model. TCGA-LGG dataset was searched for LGG samples. 523 samples were used for whole exome sequencing analysis, 532 for transcriptional analysis, and 529 for DNA methylation analysis. LASSO regression was used to screen genes with significant association with LGG survival from the frequently mutated genes, differentially expressed genes, and differentially methylated genes, whereby a prediction model for prognosis of LGG was further constructed and validated. The most frequently mutated diver genes in LGGs were IDH1 (77%), TP53 (48%), ATRX (37%), etc. Top significantly up-regulated genes were C6orf15, DAO, MEOX2, etc., and top significantly down-regulated genes were DMBX1, GPR50, HMX2, etc. 2077 genes were more and 299 were less methylated in recurrent vs. primary LGG samples. Thirty-nine genes from the above analysis were included to establish a prediction model of survival, which showed that the high-score group had a very significantly shorter survival than the low-score group in both training and testing sets. ROC analysis showed that AUC was 0.817 for the training set and 0.819 for the testing set. This study will be beneficial to accurately predict the survival of LGGs to identify patients with poor prognosis to take specific treatment as early, which will help improve the treatment outcomes and prognosis of LGG.

A bibliometric study of the nasopharyngeal cancer immunotherapy knowledge map.

Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors, and stages III and IV are frequently diagnosed. In recent years, immunotherapy has achieved remarkable results in recurrent/metastatic NPC, and many studies related to immunotherapy for NPC have been published. However, to date, no relevant bibliometric studies have been published. The trends and research focus on NPC immunotherapy are analyzed in this study through bibliometric analysis, which is conducive to better understanding the status quo and future trends of immunotherapy for NPC. The Web of Science Core Collection was used to collect literature on NPC immunotherapy. These publications were analyzed using bibliometric methods from the aspects of country/region, institution, author (co-cited author), journal (co-cited journal), references, and keywords to determine the research focus and trends in the field. A total of 510 English studies were published between January 1, 2000 and September 1, 2023. The number of articles published increased rapidly in 2016. China ranked first in the number of publications (n = 254), followed by the United States (n = 127). Sun Yat-sen University had the largest number of publications (n = 74). In terms of authors, Comoli P is the most cited author among the co-cited authors. The journal publishing the largest number of studies on NPC immunotherapy is Frontiers in Oncology (impact factor (2022) = 4.7). Five of the top 10 highly cited publications came from China. Keyword analysis reveals that infiltrating lymphocytes, PD-L1, and the tumor microenvironment are recent research focuses on nasopharyngeal cancer immunotherapy. Immunotherapy research for nasopharyngeal cancer is a recent trend. Nasopharyngeal cancer immunotherapy research has mainly focused on immune checkpoint inhibitors and the tumor microenvironment. Notably, China has made significant contributions to this field.

Initial experience with the enhanced recovery after surgery (ERAS) protocols in gynecologic surgery at an urban academic tertiary medical center.

Background: The enhanced recovery after surgery (ERAS) protocols have been consistently associated with improved patient experience and surgical outcomes. Despite the release of ERAS Society guidelines specific to gynecologic oncology, the adoption of ERAS in gynecology on global level has been disappointingly low and some centers have shown minimal improvement in clinical outcomes after adopting ERAS. The aim of this study is to describe the development and early experience of ERAS protocols in gynecologic surgery at an urban academic tertiary medical center. Methods: This was an observational prospective cohort study. The target patient population included those with low comorbidities who were scheduled to undergo various types of gynecologic surgeries for both benign and malignant diseases between October 2020 and February 2021. Two attending surgeons implemented the protocols for their patients (ERAS cohort) while three attending surgeons maintained the conventional perioperative care for their patients (non-ERAS cohort). Baseline characteristics, surgical outcomes and patients' answers to a 12-question survey were compared. A case-matched comparative analysis was also performed between the ERAS cohort and the historical non-ERAS cohort (those who received the same types of surgical procedures from the two ERAS attending surgeons prior to the implementation of the protocols). Results: A total of 244 patients were evaluated (122 in the ERAS cohort vs. 122 in the non-ERAS cohort). The number of vials of opioid analgesia used during the first two postoperative days was significantly lower whereas the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen was more frequent in the ERAS cohort group. The patients in the ERAS group reported less postoperative pain, feelings of hunger and thirst, and greater amount of exercise postoperatively. These benefits of the ERAS cohort were more pronounced in the patients who underwent laparotomic surgeries than those who underwent laparoscopic surgeries. The case-matched comparative analysis also showed similar results. The length of hospital stay did not differ between those who underwent the ERAS protocols and those who did not. Conclusions: The results of the study demonstrated the safety, clinical feasibility and benefits of the ERAS protocols for patients undergoing gynecologic surgeries for both benign and malignant indications.

Endoscopic Surgery Versus Stereotactic Aspiration in Spontaneous Intracerebral Hemorrhage Treatment: A Systematic Review and Meta-Analysis.

OBJECTIVE: To comprehensively compare the safety and efficacy of endoscopic surgery (ES) and stereotactic aspiration (SA) in patients with spontaneous intracerebral hemorrhage (sICH). METHODS: We searched Web of Science, PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception to July 31, 2023. Studies comparing ES and SA for sICH treatment were also included. Outcome measures included primary outcomes (mortality and good functional outcome [GFO]) and secondary outcomes (evacuation rate, residual hematoma, perihematomal edema (PHE), operation time, volume of intraoperative blood loss, hospital stay duration, intensive care unit stay duration, hospital cost, complications, and reoperation). Subgroup analyses assessed the influence of age, hematoma volume, Glasgow Coma Scale score, and time to surgery on the outcomes. RESULTS: Nine studies (1 randomized controlled trial and 8 observational studies) with 2105 patients (705 and 1400 in the ES and SA groups, respectively) were included in this meta-analysis. The final analysis indicated that compared with SA, ES was associated with enhanced GFO and a higher evacuation rate 1 day post-surgery along with reduced mortality and residual hematoma. Conversely, ES did not confer benefits in terms of perihematomal edema, operation time, intraoperative blood loss volume, or hospital stay duration compared with SA. Subgroup analysis highlighted the significant influences of age and hematoma volume on mortality, whereas hematoma volume and Glasgow Coma Scale score affected GFO. CONCLUSIONS: ES is a safe and effective approach for sICH treatment, leading to improved patient prognosis and quality of life compared to SA.

Age-related secretion of grancalcin by macrophages induces skeletal stem/progenitor cell senescence during fracture healing.

Skeletal stem/progenitor cell (SSPC) senescence is a major cause of decreased bone regenerative potential with aging, but the causes of SSPC senescence remain unclear. In this study, we revealed that macrophages in calluses secrete prosenescent factors, including grancalcin (GCA), during aging, which triggers SSPC senescence and impairs fracture healing. Local injection of human rGCA in young mice induced SSPC senescence and delayed fracture repair. Genetic deletion of Gca in monocytes/macrophages was sufficient to rejuvenate fracture repair in aged mice and alleviate SSPC senescence. Mechanistically, GCA binds to the plexin-B2 receptor and activates Arg2-mediated mitochondrial dysfunction, resulting in cellular senescence. Depletion of Plxnb2 in SSPCs impaired fracture healing. Administration of GCA-neutralizing antibody enhanced fracture healing in aged mice. Thus, our study revealed that senescent macrophages within calluses secrete GCA to trigger SSPC secondary senescence, and GCA neutralization represents a promising therapy for nonunion or delayed union in elderly individuals.

Repeated intratracheal instillation of whole-cigarette smoke condensate to assess lung damage in a rat model.

Cigarette smoke induces an inflammatory response in the lungs by recruiting inflammatory cells, leading to lung diseases such as lung cancer, chronic obstructive pulmonary disease, and pulmonary fibrosis. Existing inhalation exposure methods for assessing the adverse effects of cigarette smoke require expensive equipment and are labor-intensive. Therefore, we attempted to develop a novel method to assess these adverse effects using intratracheal instillation (ITI) of whole cigarette smoke condensate (WCSC). The WCSC (0, 5, 10, or 20 mg/mL) was administered by ITI once daily for 6 or 12 days using an automatic video instillator. Repeated WCSC ITI increased the lung weight, and monocyte chemoattractant protein-1 (MCP-1), neutrophil, and lymphocyte levels within bronchoalveolar lavage fluid compared to the control. In the histopathological analysis of the lung tissue, a mild inflammatory response was observed in the 6 and 12 days 20 mg/mL WCSC exposure groups. The genome-wide RNA-seq expression patterns revealed that inflammatory and immune response-related genes, such as the chemokine signaling pathway, Th1/Th2 cell differentiation, and cytokine-cytokine receptor interaction, were employed following WCSC exposure. In addition, MCP-1 was time-dependent and increased in the 10 mg/mL exposure group compared to the control group. These results suggested that the WCSC might induce the potential pulmonary inflammatory response. Furthermore, we proposed that ITI may be a rapid and effective method of evaluating the adverse effects of WCSC within a short exposure period (less than 2 weeks), and it can be used to evaluate cigarette inhalation toxicity studies as an alternative method.

Sex-based influential factors for dental caries in patients with schizophrenia.

BACKGROUND: Schizophrenia is a common mental disorder that seriously affects patients' daily lives and brings heavy psychological and economic burdens to their families and society. The oral problems of patients with schizophrenia are gradually gaining attention, among which dental caries are among the most common oral diseases. Sex differences may be related not only to the various clinical symptoms of schizophrenia but also to different oral hygiene statuses; therefore, the main purpose of this paper is to investigate sex differences related to influencing factors for dental caries in patients with schizophrenia. METHOD: Inpatients with schizophrenia over 18 years old were included in this study, and multidimensional indicators such as demographics, symptom and cognitive impairment assessments, medications, and the caries index of decayed, missing, and filled teeth (DMFT) were collected. An analysis of sex-based influential factors for dental caries in schizophrenia patients was performed. RESULTS: Four-hundred and ninety-six patients with schizophrenia were included, with a mean age of 46.73 ± 12.23 years, of which 142 were females and 354 were males. The mean DMFT was significantly higher in males (8.81 ± 8.50) than in females (5.63 ± 6.61, p < 0.001), and the odd ratio of caries in males to females was significantly higher as well (OR = 2.305, p < 0.001). The influential factors of caries in male patients were independently associated with age and smoking status, in which current smokers were at the highest risk for developing caries, and different smoking statuses had various influencing factors for caries. The influencing factors for caries in female patients were independently associated with age, antipsychotic dose, PANSS-positive symptoms, and MMSE levels. CONCLUSION: Our findings suggest sex differences exist among influential factors for caries in patients with schizophrenia. These risk factors may even be associated with and affect the treatment and prognosis of psychiatric symptoms in patients. Therefore, oral hygiene management of patients with schizophrenia should be enhanced. These differential factors provide new visions and ideas for formulating individual interventions, treatments, and care priorities.

Association between nickel exposure and body compositions in the United States: a population-based cross-sectional study.

BACKGROUND: Increasing body fat or decreasing muscle and bone mass were associated with worse health outcomes in the adult population. The effects of nickel exposure on body composition are not known. The aim of the current study was to investigate the relationship between urinary nickel levels and body compositions. MATERIALS AND METHODS: Two thousand seven hundred sixty-two participants were included in the analysis from the National Health and Nutrition Examination Surveys of 2017-2018 after excluding participants who have missing data on urinary nickel and those with missing all body mass component data. We used weighted generalized linear models to explore the relationship between urinary nickel and body mass components under interpolating missing covariable values. Simultaneously, sensitivity analyses and subgroup analysis were conducted to verify stability of analysis result. Curve fitting and saturation effect analysis were used to explore the possible nonlinear relationship between urine nickel and body compositions. RESULTS: Among the 2,762 participants, the average urinary nickel level was 1.58 ug/L. The weighted generalized linear models, the sensitivity analyses and subgroup analyses found no significant linear relationship between urinary nickel and body compositions. For body weight, BMI, TLM, ALM, TRF, TOF and BMC, the urine nickel saturation effect values were 0.76, 0.74, 0.5, 0.67, 0.64, 0.48, and 0.45 ug/L, respectively. For each 1 ug/L rise in urinary nickel levels at levels below the turning point, body weight increases (ß = 9.06, 95% CI = 2.75, 15.36, p = 0.01), BMI increases (ß = 3.20, 95% CI = 1.36, 5.05, p = < 0.001), TLM decreases (ß = -47.39, 95% CI = -97.38, 2.59, p = 0.06), ALM decreases (ß = -37.25, 95% CI = -63.25, -11.24, p = 0.01), TRF increases (ß = 20.68, 95% CI = 1.50, 39.86, p = 0.03), TOF increases (ß = 57.92, 95% CI = -0.12, 115.95, p = 0.05), and BMC decreases (ß = -6.84, 95% CI = -12.64, -1.04, p = 0.02). CONCLUSIONS: In summary, our study demonstrated that a dose-response relationship exists between urinary nickel and body compositions, with a low inflection point level of urinary nickel for the saturation effect.

The association between sex hormones and periodontitis among American adults: A cross-sectional study.

Introduction: After adulthood, as a person grows older, the secretion of sex hormones in the body gradually decreases, and the risk of periodontitis increases. But the relationship between sex hormones and periodontitis is still controversial. Methods: We investigated the association between sex hormones and periodontitis among Americans over 30 years old. 4,877 participants containing 3,222 males and 1,655 postmenopausal females who had had periodontal examination and detailed available sex hormone levels, were included in our analysis from the 2009-2014 National Health and Nutrition Examination Surveys cycles. We applied multivariate linear regression models to estimate the connection between sex hormones and periodontitis after converting sex hormones into categorical variables through tertile. Additionally, to ensure the stability of the analysis results, we carried out a trend test, subgroup analysis, and interaction test. Results: After fully adjusting the covariates, estradiol levels were not associated with periodontitis in both males and females with a P for trend = 0.064 and 0.064, respectively. For males, we found that sex hormone-binding globulin was positively associated with periodontitis (tertile3 vs tertile1: OR=1.63, 95% CI=1.17-2.28, p = 0.004, P for trend = 0.005). Congruously, free testosterone (tertile3 vs tertile1: OR=0.60, 95% CI=0.43-0.84, p = 0.003), bioavailable testosterone (tertile3 vs tertile1: OR=0.51, 95% CI=0.36-0.71, p < 0.001), and free androgen index (tertile3 vs tertile1: OR=0.53, 95% CI=0.37-0.75, p < 0.001) was found to be negatively associated with periodontitis. Moreover, subgroup analysis of age found a closer relationship between sex hormones and periodontitis in those younger than 50 years. Conclusion: Our research suggested that males with lower bioavailable testosterone levels affected by sex hormone-binding globulin were at a higher risk of periodontitis. Meanwhile, estradiol levels were not associated with periodontitis in postmenopausal women.

Splicing factor YBX1 regulates bone marrow stromal cell fate during aging.

Senescence and altered differentiation potential of bone marrow stromal cells (BMSCs) lead to age-related bone loss. As an important posttranscriptional regulatory pathway, alternative splicing (AS) regulates the diversity of gene expression and has been linked to induction of cellular senescence. However, the role of splicing factors in BMSCs during aging remains poorly defined. Herein, we found that the expression of the splicing factor Y-box binding protein 1 (YBX1) in BMSCs decreased with aging in mice and humans. YBX1 deficiency resulted in mis-splicing in genes linked to BMSC osteogenic differentiation and senescence, such as Fn1, Nrp2, Sirt2, Sp7, and Spp1, thus contributing to BMSC senescence and differentiation shift during aging. Deletion of Ybx1 in BMSCs accelerated bone loss in mice, while its overexpression stimulated bone formation. Finally, we identified a small compound, sciadopitysin, which attenuated the degradation of YBX1 and bone loss in old mice. Our study demonstrated that YBX1 governs cell fate of BMSCs via fine control of RNA splicing and provides a potential therapeutic target for age-related osteoporosis.

Photochemically-driven highly efficient intracellular delivery and light/hypoxia programmable triggered cancer photo-chemotherapy.

BACKGROUND: Using nanotechnology to improve the efficiency of tumor treatment represents a major research interest in recent years. However, there are paradoxes and obstacles in using a single nanoparticle to fulfill all the requirements of complex tumor treatment. RESULTS: In this paper, a programmed-triggered nanoplatform (APP NPs), which is sequentially responsive to light and hypoxia, is rationally integrated for photoacoustic (PA) imaging-guided synergistic cancer photo-chemotherapy. The nanoplatform is constructed by in situ hybridization of dopamine monomer in the skeleton of PCN-224 and loading prodrug banoxantrone (AQ4N). Upon first-stage irradiation with a 660 nm laser, cellular internalization was effectively promoted by a photosensitizer-mediated photochemical effect. Furthermore, under second-stage irradiation, APP NPs exhibit a notably high photothermal conversion efficiency and sufficient reactive oxygen species (ROS) production for photothermal therapy (PTT) and photodynamic therapy (PDT), respectively, which not only triggers rapid intercellular drug release but also consequently aggravates tumor hypoxia levels, and aggravated hypoxia can further active the cytotoxicity of AQ4N for chemotherapy. Both in vitro and in vivo studies confirm that the dual-stage light guided photo-chemotherapy strategy exhibits a greatly enhanced anticancer effects and superior therapeutic safety. CONCLUSION: This work represents a versatile strategy to construct a dual-stage light induced PDT/PTT and hypoxia-activated chemotherapy nanoplatform and will be promising for the development of multistimuli-responsive nanosystems with programmable functions for precise cancer therapy.

Comparative Analysis of the Pre- and Post-Medication Effects of Antipsychotic Agents on the Blood-Based Oxidative Stress Biomarkers in Patients with Schizophrenia: A Meta-Analysis.

OBJECTIVE: Studies have shown that oxidative stress (OS) is related to the pathophysiology of schizophrenia (SCZ), but whether antipsychotics can induce OS has not been investigated well. Moreover, antipsychotics have differential effects on the OS level modulation, i.e., different types of antipsychotics have different effects on the cellular antioxidants or pro-oxidants. METHODS: We followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines and investigated the OS indicators including both enzymatic and nonenzymatic markers, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), malondialdehyde (MDA), glutathione (GSH), vitamin C, etc., of SCZ patients at baseline and follow-up of mono-medication. RESULTS: Twenty studies met the inclusion criteria, with a total of 1162 patients enrolled at baseline, and 1105 patients completed the follow-up. OS markers were changed after a period of antipsychotic treatment in SCZ patients. The GPx activity and MDA level decreased in the whole blood (P<0.05), also the serum MDA level decreased (P<0.05). For the first-episode SCZ patients, the activity of GPx and the level of MDA decreased, while the level of vitamin C increased (all P<0.05). The levels of MDA in patients receiving atypical antipsychotics decreased (P<0.05), while the level of GSH in patients with typical antipsychotics decreased (P=0.05). CONCLUSION: Antipsychotic medication may cause changes in the levels of OS markers in different blood samples of SCZ patients. However, the available studies might not be sufficient to reveal the underlying facts accurately due to the poor quality of experimental designs in the published literature.

Targeted Wolfram-Doped Polypyrrole for Photonic Hyperthermia-Synergized Radiotherapy.

Single ionizing radiation at a tolerable dose is ineffectual in eliminating malignancies but readily generates harmful effects on surrounding normal tissues. Herein, we intelligently fabricated novel wolfram-doped polypyrrole (WPPy) through a simple oxidative polymerization method with WCl6 as an oxidizing catalyst, which possessed good biocompatibility, high photothermal conversion, and intensive radiosensitivity capacities to concurrently serve as a photothermal reagent and a radiosensitizer for hyperthermia-synergized radiotherapy (RT) against a malignant tumor. In comparison with traditional polypyrrole without noble metal doping, the innovative introduction of WCl6 not only successfully launched the polymerization of a pyrrole monomer but also endowed WPPy with additional radiosensitization. More importantly, after further decoration with an active targeted component (SP94 polypeptide), the obtained WPPy@SP94 significantly increased tumor internalization and accumulation in vitro and in vivo and induced obvious DNA damage as well as robust ROS generation under X-ray irradiation, which meanwhile synergized with strong photonic hyperthermia to effectively inhibit tumor growth by single drug injection. Moreover, such biocompatible WPPy@SP94 showed negligible adverse effects on normal cells and tissues. WPPy@SP94 developed in this study not only expands the category of polypyrrole chemical syntheses but also sheds light on WPPy@SP94-based radiosensitizers for cancer RT.

Mutated lncRNA increase the risk of type 2 diabetes by promoting ß cell dysfunction and insulin resistance.

Islet ß cell dysfunction and insulin resistance are the main pathogenesis of type 2 diabetes (T2D), but the mechanism remains unclear. Here we identify a rs3819316 C > T mutation in lncRNA Reg1cp mainly expressed in islets associated with an increased risk of T2D. Analyses in 16,113 Chinese adults reveal that Mut-Reg1cp individuals had higher incidence of T2D and presented impaired insulin secretion as well as increased insulin resistance. Mice with islet ß cell specific Mut-Reg1cp knock-in have more severe ß cell dysfunction and insulin resistance. Mass spectrometry assay of proteins after RNA pulldown demonstrate that Mut-Reg1cp directly binds to polypyrimidine tract binding protein 1 (PTBP1), further immunofluorescence staining, western blot analysis, qPCR analysis and glucose stimulated insulin secretion test reveal that Mut-Reg1cp disrupts the stabilization of insulin mRNA by inhibiting the phosphorylation of PTBP1 in ß cells. Furthermore, islet derived exosomes transfer Mut-Reg1cp into peripheral tissue, which then promote insulin resistance by inhibiting AdipoR1 translation and adiponectin signaling. Our findings identify a novel mutation in lncRNA involved in the pathogenesis of T2D, and reveal a new mechanism for the development of T2D.

Rapid diagnosis of Talaromyces marneffei infection by metagenomic next-generation sequencing technology in a Chinese cohort of inborn errors of immunity.

Talaromyces marneffei (T. marneffei) is an opportunistic pathogen. Patients with inborn errors of immunity (IEI) have been increasingly diagnosed with T. marneffei in recent years. The disseminated infection of T. marneffei can be life-threatening without timely and effective antifungal therapy. Rapid and accurate pathogenic microbiological diagnosis is particularly critical for these patients. A total of 505 patients with IEI were admitted to our hospital between January 2019 and June 2022, among whom T. marneffei was detected in 6 patients by metagenomic next-generation sequencing (mNGS), and their clinical and immunological characteristics were summarized. We performed a systematic literature review on T. marneffei infections with published immunodeficiency-related gene mutations. All patients in our cohort were confirmed to have genetic mutations in IL12RB1, IFNGR1, STAT1, STAT3, and CD40LG. T. marneffei was detected in both the blood and lymph nodes of P1 with IL12RB1 mutations, and the clinical manifestations were serious and included recurrent fever, weight loss, severe anemia, splenomegaly and lymphadenopathy, all requiring long-term antifungal therapy. These six patients received antifungal treatment, which relieved symptoms and improved imaging findings. Five patients survived, while one patient died of sepsis after hematopoietic stem cell transplantation. The application of mNGS methods for pathogen detection in IEI patients and comparison with traditional diagnosis methods were investigated. Traditional diagnostic methods and mNGS tests were performed simultaneously in 232 patients with IEI. Compared to the traditional methods, the sensitivity and specificity of mNGS in diagnosing T. marneffei infection were 100% and 98.7%, respectively. The reporting time for T. marneffei detection was approximately 26 hours by mNGS, 3-14 days by culture, and 6-11 days by histopathology. T. marneffei infection was first reported in IEI patients with IL12RB1 gene mutation, which expanded the IEI lineage susceptible to T. marneffei. For IEI patients with T. marneffei infection, we highlight the application of mNGS in pathogenic detection. mNGS is recommended as a front-line diagnostic test for rapidly identifying pathogens in complex and severe infections.

Exploring prognostic value and regulation network of PPP1R1A in hepatocellular carcinoma.

Novel and accurate biomarkers are needed for early detection and progression evaluation of hepatocellular carcinoma (HCC). Protein phosphatase 1 regulatory subunit 1A (PPP1R1A) has been studied in cancer biology; however, the expression pattern and biological function of PPP1R1A in HCC are unclear. The differentially expressed genes (DEGs) in HCC were screened by The Cancer Genome Atlas (TCGA) database. Real-time PCR and immunohistochemistry (IHC) assay were used to detect the expression of PPP1R1A in BALB/c mice, human normal tissues and corresponding tumor tissues, especially HCC. Then, Kaplan-Meier analysis of patients with HCC was performed to evaluate the relationship between PPP1R1A expression and prognosis. The transcriptional regulatory network of PPP1R1A was constructed based on the differentially expressed mRNAs, microRNAs and transcription factors (TFs). To explore the downstream regulation of PPP1R1A, the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis and immune infiltration score were performed. A total of 4 DEGs were screened out. PPP1R1A was differentially distributed and expressed in BALB/c mice and human tissues. PPP1R1A expression was higher in normal tissues than that in tumor tissues, and patients with higher PPP1R1A expression had better clinical outcome in HCC. In addition, we constructed miR-21-3p/TAL1/PPP1R1A transcriptional network. Furthermore, PPP1R1A may modulate the activation of PI3K-Akt pathway, cell cycle, glycogen metabolism and the recruitment of M2 macrophage in HCC. This study may help to clarify the function and mechanism of PPP1R1A in HCC and provide a potential biomarker for tumor prevention and treatment.

Mesenchymal-Stem-Cell-Derived Extracellular Vesicles Attenuate Brain Injury in Escherichia coli Meningitis in Newborn Rats.

We recently reported that transplantation of mesenchymal stem cells (MSCs) significantly reduced bacterial growth and brain injury in neonatal meningitis induced by Escherichia coli (E. coli) infection in newborn rats. As a next step, to verify whether the MSCs protect against brain injury in a paracrine manner, this study was designed to estimate the efficacy of MSC-derived extracellular vesicles (MSC-EVs) in E. coli meningitis in newborn rats. E. coli meningitis was induced without concomitant bacteremia by the intra-cerebroventricular injection of 5 × 102 colony-forming units of K1 (-) E. coli in rats, at postnatal day 11. MSC-EVs were intra-cerebroventricularly transplanted 6 h after the induction of meningitis, and antibiotics were administered for three consecutive days starting at 24 h after the induction of meningitis. The increase in bacterial growth in the cerebrospinal fluid measured at 24 h after the meningitis induction was not significantly reduced following MSC-EV transplantation. However, an increase in brain cell death, reactive gliosis, and inflammation following meningitis were significantly attenuated after MSC-EV transplantation. Taken together, our results indicate that MSCs show anti-apoptotic, anti-gliosis, and anti-inflammatory, but not antibacterial effects, in an EV-mediated paracrine manner in E. coli-induced neonatal meningitis.

Acoustic triggered nanobomb for US imaging guided sonodynamic therapy and activating antitumor immunity.

We fabricated an ultrasound activated 'nanobomb' as a noninvasive and targeted physical therapeutic strategy for sonodynamic therapy and priming cancer immunotherapy. This 'nanobomb' was rationally designed via the encapsulation of indocyanine green (ICG) and perfluoropentane (PFP) into cRGD peptide-functionalized nano-liposome. The resulting Lip-ICG-PFP-cRGD nanoparticle linked with cRGD peptide could actively targeted ID8 and TC-1 cells and elicits ROS-mediated apoptosis after triggered by low-intensity focused ultrasound (LIFU). Moreover, the phase change of PFP (from droplets to microbubbles) under LIFU irradiation can produce a large number of microbubbles, which act as intra-tumoral bomber and can detonate explode tumor cells by acoustic cavitation effect. Instant necrosis of tumor cells further induces the release of biologically active damage-associated molecular patterns (DAMPs) to facilitate antitumor immunity. More important, the 'nanobomb' in combination with anti-PD-1checkpoint blockade therapy can significantly improve the antitumor efficacy in a subcutaneous model. In addition, the liposomes may also be used as an imaging probe for ultrasound (US) imaging after being irradiated with LIFU. In summary, the US imaging-guided, LIFU activated ROS production and explosion 'nanobomb' might significantly improve the antitumor efficacy and overcome drug resistance through combination of SDT and immunotherapy, we believe that this is a promising approach for targeted therapy of solid tumor including ovarian cancer.

Analysis of the expression profiles of long noncoding RNAs and messenger RNAs in tongue squamous cell carcinoma.

OBJECTIVE: Long noncoding RNAs (lncRNAs) are involved in the progression of tongue squamous cell carcinoma (TSCC). Therefore, it is necessary to comprehensively investigate the role of lncRNAs in TSCC. STUDY DESIGN: In this study, RNA sequencing was performed to examine the expression profiles of lncRNAs and messenger RNAs (mRNAs) of patients with TSCC. The expression of selected lncRNAs in TSCC and paired adjacent tissues as well as in cell lines was validated via quantitative real-time polymerase chain reaction (qRT-PCR). The cell function of lncRNA iodothyronine deiodinase 2 antisense RNA 1 (DIO2-AS1) overexpression was assessed through 5-(3-carboxymethoxyphenyl)-2-(4.5-dimethyl-thiazoly)-3-(4-sulfophenyl) tetrazolium inner salt and Transwell assays. RESULTS: A total of 342 lncRNAs and 6392 mRNAs were differentially expressed in TSCC tissues compared with paired adjacent tissues. qRT-PCR revealed the increased expression of AC093818.1 and reduced expression of CYP4F35P and DIO2-AS1 in TSCC. Furthermore, DIO2-AS1 overexpression inhibited Cal-27 cell proliferation, migration, and invasion. CONCLUSIONS: We provide evidence that DIO2-AS1 is involved in TSCC progression. This study provides a direction for subsequent research.