Multi-omics Analysis Reveals Key Gut Microbiota and Metabolites Closely Associated with Huntington's Disease.

Dysbiosis of the gut microbiota is closely associated with neurodegenerative diseases, including Huntington's disease (HD). Gut microbiome-derived metabolites are key factors in host-microbiome interactions. This study aimed to investigate the crucial gut microbiome and metabolites in HD and their correlations. Fecal and serum samples from 11 to 26 patients with HD, respectively, and 16 and 23 healthy controls, respectively, were collected. The fecal samples were used for shotgun metagenomics while the serum samples for metabolomics analysis. Integrated analysis of the metagenomics and metabolomics data was also conducted. Firmicutes, Bacteroidota, Proteobacteria, Uroviricota, Actinobacteria, and Verrucomicrobia were the dominant phyla. At the genus level, the presence of Bacteroides, Faecalibacterium, Parabacteroides, Alistipes, Dialister, and Christensenella was higher in HD patients, while the abundance of Lachnospira, Roseburia, Clostridium, Ruminococcus, Blautia, Butyricicoccus, Agathobaculum, Phocaeicola, Coprococcus, and Fusicatenibacter decreased. A total of 244 differential metabolites were identified and found to be enriched in the glycerophospholipid, nucleotide, biotin, galactose, and alpha-linolenic acid metabolic pathways. The AUC value from the integrated analysis (1) was higher than that from the analysis of the gut microbiota (0.8632). No significant differences were found in the ACE, Simpson, Shannon, Sobs, and Chao indexes between HD patients and controls. Our study determined crucial functional gut microbiota and potential biomarkers associated with HD pathogenesis, providing new insights into the role of the gut microbiota-brain axis in HD occurrence and development.

Aggregation-Induced Emission CN-Based Nanoparticles to Alleviate Hypoxic Liver Fibrosis via Triggering HSC Ferroptosis and Enhancing Photodynamic Therapy.

Hypoxia can lead to liver fibrosis and severely limits the efficacy of photodynamic therapy (PDT). Herein, carbon nitride (CN)-based hybrid nanoparticles (NPs) VPSGCNs@TSI for light-driven water splitting were utilized to solve this problem. CNs were doped with selenide glucose (Se-glu) to enhance their red/NIR region absorption. Then, vitamin A-poly(ethylene glycol) (VA-PEG) fragments and aggregation-induced emission (AIE) photosensitizers TSI were introduced into Se-glu-doped CN NPs (VPSGCNs) to construct VPSGCNs@TSI NPs. The introduction of VA-PEG fragments enhanced the targeting of the NPs to activated hepatic stellate cells (HSCs) and reduced their toxicity to ordinary liver cells. VPSGCN units could trigger water splitting to generate O2 under 660 nm laser irradiation, improve the hypoxic environment of the fibrosis site, downregulate HIF-1α expression, and activate HSC ferroptosis via the HIF-1α/SLC7A11 pathway. In addition, generated O2 could also increase the reactive oxygen species (ROS) production of TSI units in a hypoxic environment, thereby completely reversing hypoxia-triggered PDT resistance to enhance the PDT effect. The combination of water-splitting materials and photodynamic materials showed a 1 + 1 > 2 effect in increasing oxygen levels in liver fibrosis, promoting ferroptosis of activated HSCs and reversing PDT resistance caused by hypoxia.

Therapeutic Effectiveness of Leukocyte- and Platelet-rich Fibrin for Diabetic Foot Ulcers: A Retrospective Study.

OBJECTIVE: Diabetic foot ulcer (DFU) is one of the most serious complications of diabetes. Leukocyte- and platelet-rich fibrin (L-PRF) is a second-generation autologous platelet-rich plasma. This study aims to investigate the clinical effects of L-PRF in patients with diabetes in real clinical practice. METHODS: Patients with DFU who received L-PRF treatment and standard of care (SOC) from 2018 to 2019 in Tongji Hospital were enrolled. The clinical information including patient characteristics, wound evaluation (area, severity, infection, blood supply), SOC of DFU, and images of ulcers was retrospectively extracted and analyzed. L-PRF treatment was performed every 7±2 days until the ulcer exhibited complete epithelialization or an overall percent volume reduction (PVR) greater than 80%. Therapeutic effectiveness, including overall PVR and the overall and weekly healing rates, was evaluated. RESULTS: Totally, 26 patients with DFU were enrolled, and they had an ulcer duration of 47.0 (35.0, 72.3) days. The severity and infection of ulcers varied, as indicated by the Site, Ischemia, Neuropathy, Bacterial Infection, and Depth (SINBAD) scores of 2-6, Wagner grades of 1-4, and the Perfusion, Extent, Depth, Infection and Sensation (PEDIS) scores of 2-4. The initial ulcer volume before L-PRF treatment was 4.94 (1.50, 13.83) cm3, and the final ulcer volume was 0.35 (0.03, 1.76) cm3. The median number of L-PRF doses was 3 (2, 5). A total of 11 patients achieved complete epithelialization after the fifth week of treatment, and 19 patients achieved at least an 80% volume reduction after the seventh week. The overall wound-healing rate was 1.47 (0.63, 3.29) cm3/week, and the healing rate was faster in the first 2 weeks than in the remaining weeks. Concurrent treatment did not change the percentage of complete epithelialization or healing rate. CONCLUSION: Adding L-PRF to SOC significantly improved wound healing in patients with DFU independent of the ankle brachial index, SINBAD score, or Wagner grade, indicating that this method is appropriate for DFU treatment under different clinical conditions.

Gradient inflammation in the pancreatic stump after pancreaticoduodenectomy: Two case reports and review of literature.

BACKGROUND: Postoperative pancreatic fistula (POPF) contributes significantly to morbidity and mortality after pancreaticoduodenectomy (PD). However, the underlying mechanisms remain unclear. This study explored this pathology in the pancreatic stumps and elucidated the mechanisms of POPF following PD. CASE SUMMARY: Pathological analysis and 16S rRNA gene sequencing were performed on specimens obtained from two patients who underwent complete pancreatectomy for grade C POPF after PD. Gradient inflammation is present in the pancreatic stump. The apoptosis was lower than that in the normal pancreas. Moreover, neutrophil-dominated inflammatory cells are concentrated in the ductal system. Notably, neutrophils migrated through the ductal wall in acinar duct metaplasia-formed ducts. Additionally, evidence indicates that gut microbes migrate from the digestive tract. Gradient inflammation occurs in pancreatic stumps after PD. CONCLUSION: The mechanisms underlying POPF include high biochemical activity in the pancreas, mechanical injury, and digestive reflux. To prevent POPF and address pancreatic inflammation and reflux, breaking the link with anastomotic dehiscence is practical.

[Effect of Shikonin on Autophagy and Apoptosis of Human Promyelocytic Leukemia Cells].

OBJECTIVE: To explore the effect of shikonin on autophagy and apoptosis of human promyelocytic leukemia cells and its possible mechanism. METHODS: Human promyelocytic leukemia cells NB4 in the logarithmic growth phase were divided into control group (untreated NB4 cells), shikonin group (0.3 µmol/L shikonin treatment), 740Y-P group (15 µmol/L PI3K/Akt/mTOR pathway activator 740Y-P treatment), shikonin+740Y-P group (0.3 µmol/L shikonin and 15 µmol/L 740Y-P co-treatment), after 24 hours of treatment, the cells were used for subsequent experiments. CCK-8 method was used to detect cell viability, monodansylcadaverine (MDC) staining to detect the aggregation of autophagic vesicles, flow cytometry to detect cell apoptosis, and Western blot to detect the expression of Beclin1, LC3, p62, Bax, cleaved caspase-3, Bcl-2 and PI3K/Akt/mTOR pathway related proteins. RESULTS: Compared with the control group, the purple punctate fluorescence intensity, apoptosis rate, Beclin1, LC3-Ⅱ/LC3-Ⅰ, cleaved caspase-3, and Bax protein expression in NB4 cells were increased in the shikonin group, while OD450 value (24, 48 h) and the expressions of Bcl-2 and p62 proteins were decreased (all P < 0.05). Compared with the control group, the purple punctate fluorescence intensity, apoptosis rate, Beclin1, LC3-Ⅱ/LC3-Ⅰ, cleaved caspase-3, and Bax protein expression in NB4 cells were decreased, while OD450 value (24, 48 h) and the expressions of Bcl-2 and p62 proteins were increased in the 740Y-P group (all P < 0.05). Compared with the shikonin group, the purple punctate fluorescence intensity, apoptosis rate, Beclin1, LC3-Ⅱ/LC3-Ⅰ, cleaved caspase-3, and Bax protein expression in NB4 cells were decreased, while OD450 value (24, 48 h) and the expressions of Bcl-2 and p62 proteins were increased in the shikonin+740Y-P group (all P < 0.05). Compared with the control group, the expression of PI3K/Akt/mTOR pathway related proteins p-PI3K, p-Akt, and p-mTOR in NB4 cells were significantly decreased in the shikonin group, while those in the 740Y-P group were increased (all P < 0.05). Compared with the shikonin group, the expressions of p-PI3K, p-Akt, and p-mTOR proteins in NB4 cells were significantly increased in the shikonin+740Y-P group (all P < 0.05). CONCLUSION: Shikonin may promote autophagy and apoptosis of NB4 cells by inhibiting PI3K/Akt/mTOR pathway.

Study on the postoperative visual function recovery of children with concomitant exotropia based on an augmented reality plasticity model.

Objective: This study aimed to investigate the clinical application effect of an augmented reality (AR) plasticity model on the postoperative visual function recovery of children with concomitant exotropia. Methods: Between September 2019 and October 2021, 28 patients with concomitant exotropia who visited Shenzhen Children's Hospital (9 male and 19 female) were enrolled in this study. The average age of the patients was 6.4 ± 1.8 years. Postoperative rehabilitation training was conducted using a personalized AR binocular visual perception plasticity model developed based on the patient's examination results. After 1 month, 3 months, and 6 months of training, the patients returned to the hospital for examinations of perceptual eye position, static zero-order stereopsis, dynamic first-order fine stereopsis, and dynamic second-order coarse stereopsis to compare the changes in eye position control and stereovision function. Results: After 6 months of eye position training, the horizontal perception eye position of the 28 patients was significantly lower than that before training. The difference in eye position at the first and third months compared with that before training was not statistically significant (1st month: z = -2.255, p = 0.024 > 0.017; 3rd month: z = -2.277, p = 0.023 > 0.017; 6th month: z = -3.051, p = 0.002 < 0.017). The difference in vertical perceptual eye position after training compared with that before training was not statistically significant (1st month: z = -0.252, p = 0.801 > 0.017; 3rd month: z = -1.189, p = 0.234 > 0.017; 6th month: z = -2.225, p = 0.026 > 0.017). The difference in 0.8-m static zero-order stereopsis before and after training was not statistically significant (1st month: z = -2.111, p = 0.035 > 0.017; 3rd month: z = -1.097, p = 0.273 > 0.017; 6th month: z = -1.653, p = 0.098 > 0.017). The 1.5-m static zero-order stereopsis was improved after 1 month, 3 months, and 6 months of training compared with that before training (1st month: z = -3.134, p = 0.002 < 0.017; 3rd month: z = -2.835, p = 0.005 < 0.017; 6th month: z = -3.096, p = 0.002 < 0.017). Dynamic first-order fine stereopsis and dynamic second-order coarse stereopsis were measured in the 28 patients before and after training. Patients 1 and 18 had no dynamic first-order fine stereopsis before training, but both regained dynamic stereopsis after 1 month, 3 months, and 6 months of training. Patient 16 had no dynamic first-order fine stereopsis or dynamic second-order coarse stereopsis before training, but first-order and second-order stereopsis had been reconstructed after 1 month, 3 months, and 6 months of training. Conclusion: Concomitant exotropia surgery improved the basic problem of eye position at the ocular muscle level, but the patient's perceptual eye position and visual function defects at the brain visual level remained. This might partly explain the poor postoperative clinical effect. The AR plasticity model can improve patients' horizontal perceptual eye position and multi-dimensional stereoscopic function, and its clinical effect warrants further study.

Insomnia Burden among Informal Caregivers of Hospitalized Lung Cancer Patients and Its Influencing Factors.

Objective: This study aimed to reveal the insomnia burden and relevant influencing factors among informal caregivers (ICs) of hospitalized patients with lung cancer. Methods: A cross-sectional study on ICs of hospitalized patients with lung cancer was conducted from December 31, 2020 to December 31, 2021. ICs' burden was assessed using the Caregiver Reaction Assessment (CRA), Hospital Anxiety and Depression Scale (HADS), and Insomnia Severity Index (ISI). Linear and logistic regression models were used to identify the influencing factors. Results: Among 289 ICs of hospitalized patients with lung cancer, 83 (28.72%), 53 (18.34%), and 14 (4.84%) ICs experienced mild, moderate, and severe insomnia, respectively. The scores concerning self-esteem, lack of family support, financial problems, disturbed schedule, and health problems were 4.32 ± 0.53, 2.24 ± 0.79, 2.84 ± 1.14, 3.63 ± 0.77, and 2.44 ± 0.95, respectively. ICs with higher Activities of Daily Living Scale (ADLS) scores were associated with a lower risk of insomnia, with an odd ratio ( OR) and 95% confidence interval ( CI) of 0.940 (0.898-0.983). Among the ICs, female gender ( OR = 2.597), alcohol consumption ( OR = 3.745), underlying medical conditions ( OR = 11.765), long-term caregiving experience ( OR = 37.037), and higher monthly expenses ( OR = 5.714) were associated with a high risk of insomnia. Conclusion: Of the hospitalized patients with lung cancer, 51.9% experienced insomnia. Patients' ADL, ICs gender, alcohol consumption, underlying medical conditions, caregiving duration, and monthly expenses were influencing factors. Therefore, prompt screening and early intervention for ICs of patients with lung cancer is necessary.

Light controlled self-escape capability of non-cationic carbon nitride-based nanosheets in lysosomes for hepatocellular carcinoma targeting stimulus-responsive gene delivery.

High positive charge-induced toxicity, easy lysosomal degradation of nucleic acid drugs, and poor lesion sites targeting are major problems faced in the development of gene carriers. Herein, we proposed the concept of self-escape non-cationic gene carriers for targeted delivery and treatment of photocontrolled hepatocellular carcinoma (HCC) with sufficient lysosome escape and multiple response capacities. Functional DNA was bound to the surface of biotin-PEG2000-modified graphitic carbon nitride (Bio-PEG-CN) nanosheets to form non-cationic nanocomplexes Bio-PEG-CN/DNA. These nanocomposites could actively target HCC tissue. Once these nanocomplexes were taken up by tumor cells, the accumulated reactive oxygen species (ROS) generated by Bio-PEG-CN under LED irradiation would disrupt the lysosome structure, thereby facilitating nanocomposites escape. Due to the acidic microenvironment and lipase in the HCC tissue, the reversible release of DNA could be promoted to complete the transfection process. Meanwhile, the fluorescence signal of Bio-PEG-CN could be monitored in real time by fluorescence imaging technology to investigate the transfection process and mechanism. In vitro and in vivo results further demonstrated that these nanocomplexes could remarkably upregulate the expression of tumor suppressor protein P53, increased tumor sensitivity to ROS generated by nanocarriers, and realized effective gene therapy for HCC via loading P53 gene.

Carbon Nitride-Based siRNA Vectors with Self-Produced O2 Effects for Targeting Combination Therapy of Liver Fibrosis via HIF-1α-Mediated TGF-ß1/Smad Pathway.

Hypoxia is an important feature, which can upregulate the hypoxia-inducible factor-1α (HIF-1α) expression and promote the activation of hepatic stellate cells (HSCs), leading to liver fibrosis. Currently, effective treatment for liver fibrosis is extremely lacking. Herein, a safe and effective method is established to downregulate the expression of HIF-1α in HSCs via targeted delivery of VA-PEG-modified CNs-based nanosheets-encapsulated (VA-PEG-CN@GQDs) HIF-1α small interfering RNA (HIF-1α-siRNA). Due to the presence of lipase in the liver, the reversible release of siRNA can be promoted to complete the transfection process. Simultaneously, VA-PEG-CN@GQD nanosheets enable trigger the water splitting process to produce O2 under near-infrared (NIR) irradiation, thereby improving the hypoxic environment of the liver fibrosis site and maximizing the downregulation of HIF-1α expression to improve the therapeutic effect, as demonstrated in liver fibrosis mice. Such combination therapy can inhibit the activation of HSCs via HIF-1α-mediated TGF-ß1/Smad pathway, achieving outstanding therapeutic effects in liver fibrosis mice. In conclusion, this study proposes a novel strategy for the treatment of liver fibrosis by regulating the hypoxic environment and the expression of HIF-1α at lesion site.

Treatment of coracoid process fractures combined with acromioclavicular joint dislocation using clavicular hook plate.

BACKGROUND: The injury mechanism of acromioclavicular (AC) dislocation combined with coracoid process (CP) fracture is not clear, and there is no consensus on its treatment. This study was performed to evaluate the diagnosis of CP fractures combined with AC dislocation and the effectiveness of operative treatment using a clavicular hook plate. METHODS: Eighteen patients with CP fractures combined with AC dislocation were treated with a clavicular hook plate from May 2012 to June 2021. The patients comprised 10 male and 8 female patients with an average age of 38 years (range, 16-54 years). The injury was caused by falling in 15 patients, traffic accidents in 2 patients, and falling from a height in 1 patient. The Eyres type of CP fracture was type II in 1 patient, type III in 11 patients, type IV in 3 patients, and type V in 3 patients. The Ogawa type of CP fracture was type I in 17 patients and type II in 1 patient. The Rockwood type of AC dislocation was type V in 1 patient, variation type III in 15 patients, and variation type V in 2 patients. The interval from injury to the operation was 3 days (range, 1-7 days). Postoperative complications and CP fracture healing were recorded. Functional assessment at the last follow-up was performed by an independent reviewer using the Constant score and visual analog scale score. RESULTS: All 18 patients were followed up for a mean period of 49 months (range, 12-123 months). Nine patients had acromion osteolysis and 3 patients had CP fracture nonunion (Eyres type II, III, and V in 1 patient each); however, no patients developed shoulder pain, incision infection, limitation of shoulder movement, clinical symptoms of subcoracoid impingement, or AC dislocation relapse. At the last follow-up, the mean Constant score was 99 (range, 94-100). CONCLUSIONS: The possibility of CP fracture should be considered in patients with AC dislocation to avoid a missed diagnosis. Fixation with a clavicular hook plate is a feasible treatment for CP fracture combined with AC dislocation and provides a satisfactory outcome. CP fracture healing may be related to the fracture morphology.

Gap junction is essential for the antidepressant effects of fluoxetine.

OBJECTIVES: Fluoxetine has been used as the first line for the therapy of depression. However, lack of therapeutic efficacy and time lag still limit the application of fluoxetine. Gap junction dysfunction is a potentially novel pathogenic mechanism for depression. To clarify the mechanism underlying these limitations, we investigated whether gap junction was related to the antidepressant effects of fluoxetine. METHODS AND KEY FINDINGS: After chronic unpredictable stress (CUS), animals showed decreases in gap junction intracellular communication (GJIC). Treatment with fluoxetine 10 mg/kg significantly improved GJIC and anhedonia of rats until six days. These results indicated that fluoxetine improved gap junction indirectly. Furthermore, to test the role of gap junction on antidepressant effects of fluoxetine, we blocked gap junction using carbenoxolone (CBX) infusion in the prefrontal cortex. CBX dampened fluoxetine-induced decrease in immobility time of mice in tail suspension test (TST). CONCLUSIONS: Our study suggested that gap junction dysfunction blocks antidepressant effects of fluoxetine, contributing to understanding the mechanism underlying the time lag of fluoxetine.

Two-photon excited red-green "discoloration" bioprobes for monitoring lipid droplets and lipid droplet-lysosomal autophagy.

Lipid droplets (LDs) and their autophagy by lysosomes are closely related to a variety of physiological and pathological conditions. Therefore, identifying and tracking LDs and the dynamic process of autophagy can provide useful information for the diagnostics and treatment of related diseases. However, few organic small molecule-based fluorescent probes can specifically recognize LDs and dynamically track their autophagy process. Herein, we synthesized a "discoloration" fluorescent bioprobe DPABP-BI with distinguishable features including red fluorescence emission (630 nm), large Stokes shift (145 nm), two-photon excitation and outstanding photostability and biocompatibility. In particular, LDs could be specifically identified via the red fluorescence emission of DPABP-BI (colocalization constant of 0.98), while autophagolysosomes could be visualized via the green fluorescence emission of its acid-hydrolyzed product (colocalization constant of 0.90) to track the autophagy dynamic process. In addition, DPABP-BI enabled the specific recognition of fatty substances in zebrafish larvae. In this study, a two-photon excited red light small molecule probe was constructed to identify LDs and track their autophagy dynamic process by changing the fluorescence emission wavelength.

Role of Peripheral Regulatory T Lymphocytes in Patients with Thyroid Associated Ophthalmopathy During Systemic Glucocorticoid Treatment: A Prospective Observational Study.

OBJECTIVE: Thyroid-associated ophthalmopathy (TAO) is an autoimmune disorder involving the orbital tissue. This study aimed to understand the role of regulatory T cells (Tregs) in TAO during 12-week systemic glucocorticoid (GC) treatment. METHODS: Thirty-two moderate-severe TAO patients with a clinical activity score (CAS) ≥3/7 or with prolonged T2 relaxation time (T2RT) on at least one side of extraocular muscle (EOM) were enrolled. The percentage of the peripheral CD4+CD25(high)CD127(-/low) Tregs was analyzed using flow cytometry before and after the GC treatment. The activity and severity of TAO, T2RT, and the clinical outcomes after the GC treatment were assessed. Their correlation with the peripheral Tregs was investigated. RESULTS: There was no significant association between the baseline Treg fraction and the activity and severity of TAO or the treatment response. A significant reduction of Tregs was observed after the GC therapy merely in patients without any clinical improvement. CONCLUSION: Treg reduction after systemic GC therapy is indicative of a poor therapeutic response. Accordingly, dynamic alterations of Tregs could help to evaluate the effectiveness of the GC treatment.

Two ambuic acid dimers derived from homo-endo Diels-Alder reaction from Pestalotiopsis versicolor.

Two new dimers of ambuic acid, pestaloversicoloric acids A (1) and B (2), and a known derivative, 13(S)-hydroxyambuic acid (3), were isolated from the static fermentation product of Pestalotiopsis versicolor. The structural identification was accomplished via analyses on the data of HR-MS, 1 D and 2 D NMR, and ECD. Different from the well-known exo-type dimer, torreyanic acid, compounds 1 and 2 represent the first example of endo-type product derived from the intermolecular Diels-Alder reaction of two molecules of ambuic acid derivative with the identical absolute stereochemistry.

Olanzapine for the Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting: A Review to Identify the Best Way to Administer the Drug.

Common treatment methods for malignant tumors include surgery, chemotherapy, radiotherapy, immunotherapy, targeted therapy, etc., among which chemotherapy plays an important role. However, chemotherapy brings corresponding side effects while killing tumor cells, and nausea and vomiting are the most common adverse reactions induced by chemotherapy. It not only affects the patient's appetite, resulting in malnutrition and electrolyte disturbances, but also reduces the patient's compliance with treatment, which further aggravates the disease. Thus, it is important to quickly prevent and cure nausea and vomiting induced by chemotherapy (CINV). In addition, with the continuous development of medicine, more and more antiemetic drugs have been developed. At present, the most common antiemetic agents for chemotherapy-induced nausea and vomiting are NK-1R antagonists, 5-HT3R antagonists, and dexamethasone. Surprisingly, olanzapine, often used as a psychotropic drug, has been found to be an effective antiemetic and is similar to other regimens on the safety of medicine. However, although there are numerous studies on the antiemetic effects of olanzapine, its comprehensive application remains unclear. Therefore, this review will elaborate the antiemetic effect of olanzapine in terms of the antiemetic mechanism and the safety, economic cost, dose, administration time, and drug delivery aspects.

Tislelizumab Combined with Carboplatin-Paclitaxel for Treatment of Metastatic or Recurrent Endometrial Cancer: a Retrospective Clinical Study.

BACKGROUND: Metastatic or recurrent endometrial cancers with low survival rate had no standard or limited therapy choice. The aim of our study was to determine the efficiency and safety of tislelizumab combined with carboplatin-paclitaxel as a front-line therapy for patients with metastatic or recurrent endometrial cancer. METHODS: This clinical retrospective cohort study examined 24 Chinese patients with metastasis or recurrence but had not yet received treatment. The therapeutic regimen consisted of 6 cycles of intravenous paclitaxel (175 mg/m2) and carboplatin (target AUC: 5 mg/mL/min) with tislelizumab (200 mg) once every 3 weeks, and then intravenous tislelizumab (200 mg) once every 3 weeks until disease progression or unacceptable toxicity. RESULTS: At the 18-month follow-up, 8 patients were still receiving treatment, 13 were dead, and 3 withdrew. The objective response rate (ORR) was 62.5%, the disease control rate was 75.00%. The ORR was 77.78% for patients positive for PD-L1 and 69.23% for patients positive for MSI-H. The median overall survival time was 11.50 months, and the median progression-free survival time was 6.00 months. Half of the patients experienced 3 - 4 grade adverse events. There were no allergic reactions or treatment-related deaths. CONCLUSIONS: Tislelizumab combined with carboplatin-paclitaxel was used as a front-line therapy, had a beneficial effect and was safe for patients with metastatic or recurrent endometrial cancer.

Long-term survival after immunotherapy and targeted therapy without chemotherapy in an elderly patient with HER2-positive gastroesophageal junction cancer: A case report.

A 74-yr-old man underwent thoracic laparoscopy combined with radical gastrectomy, and the postoperative pathological diagnosis was esophageal and gastric cardia cancer pT3N1M0, pStage IIB. Immunohistochemical staining for HER2 (3+) and PD-L1 (<5%) was positive. Adjuvant chemotherapy was not performed because the patient developed severe thrombocytopenia (platelet counts <30 × 109/L), which was never cured throughout the reporting period. At 10.7 months post-surgery, he suffered metastases in multiple organs, including the peritoneum, liver, lung, and bone. Following two cycles of first-line trastuzumab and pembrolizumab (200 mg), he developed immune-related myositis (G2), myocarditis (G2), and hepatitis (G1). Therefore, pembrolizumab was discontinued. Trastuzumab was administered as a monotherapy; meanwhile, adoptive cytokine-induced killer (CIK) cell infusions were initiated. Eight months after the initial immunotherapy, a solitary brain metastasis was detected, and the patient underwent CyberKnife radiosurgery. For second-line therapy, adoptive CIK cell immunotherapy plus trastuzumab was still used. At the time of reporting, the patient had achieved a complete response (CR) in the brain and liver and a partial response (PR) in the ilium, and he had been followed-up for 36.6 months, much longer than the median survival time for patients with advanced GEJ cancer. We suggest that HER2-targeted therapy and immunotherapy with pembrolizumab or CIK adoptive cell infusions prolonged the overall survival of an elderly patient with HER2-positive GEJ cancer with multiple metastases.

Mangiferin prevents hepatocyte epithelial-mesenchymal transition in liver fibrosis via targeting HSP27-mediated JAK2/STAT3 and TGF-ß1/Smad pathway.

Hepatocytes has been confirmed to undergo EMT and can be converted into myofibroblasts during hepatic fibrogenesis. However, the mechanism of hepatocyte EMT regulation in hepatic fibrosis, particularly through HSP27 (human homologue of rodent HSP25), remains unclear. Mangiferin (MAN), a compound extracted from Mangifera indica L, has been reported to attenuate liver injury. This study aimed to investigate the mechanisms underlying HSP27 inhibition and the anti-fibrotic effect of MAN in liver fibrosis. Our results revealed that the expression of HSP27 was remarkably increased in the liver tissues of patients with liver cirrhosis and CCl4 -induced fibrotic rats. However, HSP27 shRNA treatment significantly alleviated fibrosis. Furthermore, MAN was found to inhibit CCl4 - and TGF-ß1-induced liver fibrosis and reduced hepatocyte EMT. More importantly, MAN decreased HSP27 expression to suppress the JAK2/STAT3 pathway, and subsequently blocked TGF-ß1/Smad signaling, which were consistent with its protection against CCl4 -induced EMT and liver fibrosis. Together, these results suggest that HSP27 may play a crucial role in hepatocyte EMT and liver fibrosis by activating JAK2/STAT3 signaling and TGF-ß1/Smad pathway. The suppression of HSP27 expression by MAN may be a novel strategy for attenuating the hepatocyte EMT in liver fibrosis.

Highly water-dispersible PCN nanosheets as light-controlled lysosome self-promoting escape type non-cationic gene carriers for tumor therapy.

The construction of non-viral gene delivery faces two major challenges: cytotoxicity caused by high cationic charge units and easy degradation by lysosomes. Herein, highly water-dispersible polymeric carbon nitride (PCN) nanosheets were utilized as the core to construct a light-controlled non-cationic gene delivery system with sufficient lysosomal escape ability. In this system, these nanosheets exhibited efficient DNA condensation, outstanding biocompatibility, transfection tracking, light responsiveness and high transfection efficiency. Once PCN-DNA was taken up by the tumor cells, the accumulated ROS generated by photosensitizers (PSs) under light irradiation would destroy the structure of lysosomes, promote the escape of PCN-DNA and increase the efficiency of gene transfection. Simultaneously, the gene transfection process could be tracked in real time through fluorescence imaging technology, which was conducive to investigate the transfection mechanism. In vitro and in vivo experiments further confirmed that PCN nanosheets loaded with the P53 gene were beneficial to the regeneration of the P53 apoptotic pathway, increased tumor sensitivity to PSs, and further induced tumor cell apoptosis. In summary, the highly water-dispersible PCN nanosheets were applied to light-controlled self-escaping gene delivery for the first time, and tumor gene therapy was successfully realized.