Chimeric antigen receptor-T (CAR-T) cell therapy has achieved remarkable efficacies in the treatment of B-cell leukemia/lymphoma and multiple myeloma (MM). Nevertheless, how to maintain a sustainable remission remains a significant concern. One of the underlying factors for the recurrence after CAR-T cell therapy is the acquired resistance in tumor cells to apoptosis. bcl-2 protein belongs to the anti-apoptotic protein family and plays a key role in regulating endogenous apoptosis. The overexpression of bcl-2 indicates a poor prognosis in hematological malignancies such as chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML) and MM. BH3 is a key protein domain involved in the process of programmed cell death, and bcl-2 inhibitors promote tumor cell apoptosis by competitively binding to BH3. bcl-2 inhibitors have been previously verified to sensitize tumor cells to the cytotoxicity of CAR-T cell. This paper reviews the preclinical and clinical results of CAR-T cell in combination with bcl-2 inhibitors for treatment of hematologic malignancies, aiming to intricate molecular mechanisms of the synergistic effect of CAR-T cell combined with bcl-2 inhibitors and further to improve the efficacy of tumor immunotherapy.

Objective To establish a stable,reliable,and clinically relevant porcine model of endotoxin-induced acute respiratory distress syndrome(ARDS).Methods Ten 8-month-old male Bama minipigs were deeply sedated,followed by invasive mechanical ventilation and electrocardiographic monitoring.Lipopolysaccharide(LPS)was intravenously pumped at 600 μg/(kg·h)for 3 hours,then maintained at 15 μg/(kg·h)thereafter.Dynamic monitoring was performed at five time points after LPS injection(LPS 0,1,3,5,and 8 h),including arterial blood gas analysis and chest computed tomography(CT)scans.Pathological examination of lung tissues obtained via bronchoscopic biopsy(HE staining and transmission electron microscopy)was conducted.These indicators were comprehensively used to evaluate the success of the animal model.Results At 5 hours after LPS administration,8 minipigs developed symptoms such as skin cyanosis,elevated body temperature,and respiratory distress.The oxygenation index decreased to<300 mmHg.Chest CT scans showed diffuse pulmonary infiltrates.Histopathology revealed alveolar edema and hyaline membrane formation.Transmission electron microscopy demonstrated disruption of pulmonary blood-air barrier,depletion of lamellar bodies in type Ⅱ pneumocytes,inflammatory cell infiltration,and exudation of plasma proteins and fibrin.Compared with LPS 0 h,at LPS 8 h,the oxygenation index and arterial blood pH were significantly decreased(P<0.001),while blood lactic acid and serum potassium were significantly increased(P<0.05);serum calcium and base excess were significantly decreased(P<0.05),and the lung injury score based on HE-stained lung sections was significantly increased(P<0.01).Conclusion The porcine ARDS model established by continuous LPS injection can dynamically simulate the pathophysiological characteristics and typical pathological manifestations of clinical septic ARDS,making it an effective tool to study the pathogenesis,prevention,and treatment strategies of septic ARDS.

Objective To investigate the differences of perineuronal net(PNN)and parvalbumin(PV)-positive neuron distribution across specific brain regions between young and aged mice.Methods Brains from young(45 days)and aged(350 days)mice(n=4 per group)were fixed with 4％paraformaldehyde,sectioned(50 μm)using a vibratome,and stained with Wisteria floribunda agglutinin(WFA)and PV immunofluorescence.Quantitative analyses of PNN-positive and PV-positive neurons,along with PNN encapsulation of PV-positive neurons,were performed in the anterior cingulate cortex(ACC),somatosensory cortex barrel field layer 4(S1BF L4),striatum(STR),and hippocampal CA2 region.Results Aged mice exhibited no significant changes in PNN-positive or PV-positive neuron counts in ACC,S1BF L4,or STR compared to young mice,but showed significantly increased PNN encapsulation of PV-positive neurons.In hippocampal CA2,PNN-positive neurons increased significantly without PV-positive neuron alterations.Conclusion The differences in PNN-PV neuron interactions and PNN density exist in specific brain regions of young and aged mice.

Objective:To review the diagnosis, treatment and quality of life of patients with primary immune thrombocytopenia (ITP) in seven medical centers in some areas of Hubei Province.Methods:A retrospective analysis was conducted on age, disease course, symptoms, diagnosis, and treatment status (including testing items, drug selection, and adverse reactions) of patients with ITP in seven medical centers in Hubei Province from January 2020 to December 2022. An online survey was conducted on the quality of life of patients using the ITP Patient Assessment Questionnaire (ITP-PAQ) .Results:Among the 1033 patients, those with newly diagnosed, persistent, and chronic ITP accounted for 39.8%, 19.1%, and 41.1%, respectively. Most patients exhibit varying degrees of bleeding. Regarding treatment, corticosteroids and thrombopoietin drugs are the most commonly chosen treatment drugs for ITP, and the adverse reactions to treatment mainly include diarrhea, liver dysfunction, and thrombosis. The ITP-PAQ survey of 125 patients revealed that ITP significantly impairs their life quality. Patients with ITP scored significantly lower in fatigue, sleep, fear, exercise, work, and social aspects.Conclusion:A relatively high proportion of patients with ITP progressed to the chronic phase. Corticosteroids and thrombopoietin drugs are the two main treatment drugs for ITP patients. The quality of life of patients with ITP is significantly reduced in multiple dimensions.

Objective:To analyze the clinical characteristics of adult patients with phytosterolemia presenting with thrombocytopenia as the initial manifestation.Methods:A retrospective analysis was conducted on eight adult patients with phytosterolemia who visited Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, from December 2020 to December 2023.Results:① The participants consisted of 2 (25%) male and 6 (75%) female patients, with a median age at diagnosis of 55 years (range: 29-66 years). The median duration from the discovery of thrombocytopenia to diagnosis was 10 years (range: 0.2-50 years). ② Compared with the normal control group (30 healthy adult volunteers) and the immune thrombocytopenia (ITP) control group (20 patients with ITP), patients with phytosterolemia exhibited significantly higher mean platelet volume and large platelet ratio. Peripheral blood smears revealed that the mean platelet diameter and the proportion of large platelets (diameter> 4 μm) were significantly higher in patients with phytosterolemia than those in the normal and ITP control groups ( P<0.01). ③ After a low-plant-sterol diet and ezetimibe treatment, five patients demonstrated decreased serum sitosterol and campesterol levels, increased hemoglobin concentration and platelet counts, and reduced platelet volume. Conclusion:Adult-onset phytosterolemia presenting with thrombocytopenia as the initial manifestation is prone to misdiagnosis. The presence of hemolytic anemia, splenomegaly, increased large platelets and schistocytes on peripheral blood smears, and xanthomas are crucial diagnostic indicators. Restricting dietary plant sterol intake and using ezetimibe to inhibit sterol absorption effectively lowers serum plant sterol levels and improves hematological abnormalities.

OBJECTIVE: To explore the therapeutic effects and underlying mechanisms of Dendrobium officinale (Tiepi Shihu) extract (DOE) on insomnia. METHODS: Forty-two male Sprague-Dawley rats were randomly divided into 6 groups (n=7 per group): normal control, model control, melatonin (MT, 40 mg/kg), and 3-dose DOE (0.25, 0.50, and 1.00 g/kg) groups. Rats were raised in a strong-light (10,000 LUX) and -noise (>80 db) environment (12 h/d) for 16 weeks to induce insomnia, and from week 10 to week 16, MT and DOE were correspondingly administered to rats. The behavior tests including sodium pentobarbital-induced sleep experiment, sucrose preference test, and autonomous activity test were used to evaluate changes in sleep and emotions of rats. The metabolic-related indicators such as blood pressure, blood viscosity, blood glucose, and uric acid in rats were measured. The pathological changes in the cornu ammonis 1 (CA1) region of rat brain were evaluated using hematoxylin and eosin staining and Nissl staining. Additionally, the sleep-related factors gamma-aminobutyric acid (GABA), glutamate (GA), 5-hydroxytryptamine (5-HT), and interleukin-6 (IL-6) were measured using enzyme linked immunosorbent assay. Finally, we screened potential sleep-improving receptors of DOE using polymerase chain reaction (PCR) array and validated the results with quantitative PCR and immunohistochemistry. RESULTS: DOE significantly improved rats' sleep and mood, increased the sodium pentobarbital-induced sleep time and sucrose preference index, and reduced autonomic activity times (P<0.05 or P<0.01). DOE also had a good effect on metabolic abnormalities, significantly reducing triglyceride, blood glucose, blood pressure, and blood viscosity indicators (P<0.05 or P<0.01). DOE significantly increased the GABA content in hippocampus and reduced the GA/GABA ratio and IL-6 level (P<0.05 or P<0.01). In addition, DOE improved the pathological changes such as the disorder of cell arrangement in the hippocampus and the decrease of Nissel bodies. Seven differential genes were screened by PCR array, and the GABA_A receptors (Gabra5, Gabra6, Gabrq) were selected for verification. The results showed that DOE could up-regulate their expressions (P<0.05 or P<0.01). CONCLUSION DOE demonstrated remarkable potential for improving insomnia, which may be through regulating GABA_A receptors expressions and GA/GABA ratio.
Animals ; Dendrobium/chemistry* ; Rats, Sprague-Dawley ; Male ; Sleep Initiation and Maintenance Disorders/blood* ; Plant Extracts/therapeutic use* ; Receptors, GABA-A/metabolism* ; Noise/adverse effects* ; Light/adverse effects* ; gamma-Aminobutyric Acid/metabolism* ; Sleep/drug effects* ; Rats ; Receptors, GABA/metabolism*

This study aims to delve into the influences and underlying mechanisms of Banxia Xiexin Decoction(BXD) on the proliferation, apoptosis, invasion, and migration of colon cancer cells. Firstly, the components of BXD in blood were identified by UPLC-MS/MS, and subsequently the content of these components were determined by HPLC. Then, different concentrations of BXD were used to treat both the normal intestinal epithelial cells(NCM460) and the colon cancer cells(HT29 and HCT116). The cell viability and apoptosis were examined by the cell counting kit-8(CCK-8) and flow cytometry, respectively. Western blot was employed to determine the expression of the apoptosis regulators B-cell lymphoma-2(Bcl-2) and Bcl-2-associated X(Bax). The cell wound healing assay and Transwell assay were employed to measure the cell migration and invasion, respectively. Additionally, Western blot was employed to determine the expression levels of epithelial-mesenchymal transition(EMT)-associated proteins, including epithelial cadherin(E-cadherin), neural cadherin(N-cadherin), and vimentin. The protein and mRNA levels of the factors in the poly(ADP-ribose) glycohydrolase(PARG)/poly(ADP-ribose) polymerase 1(PARP1)/nuclear factor kappa-B p65(NF-κB p65) signaling pathway were determined by Western blot and RT-qPCR, respectively. The results demonstrated that following BXD intervention, the proliferation of HT29 and HCT116 cells was significantly reduced. Furthermore, BXD promoted the apoptosis, enhanced the expression of Bcl-2, and suppressed the expression of Bax in colon cancer cells. At the same time, BXD suppressed the cell migration and invasion and augmented the expression of E-cadherin while diminishing the expression of N-cadherin and vimentin. In addition, BXD down-regulated the protein and mRNA levels of PARG, PARP1, and NF-κB p65. In conclusion, BXD may inhibit the malignant phenotypes of colon cancer cells by mediating the PARG/PARP1/NF-κB signaling pathway.
Colonic Neoplasms/pathology* ; Drugs, Chinese Herbal/pharmacology* ; Phenotype ; Signal Transduction/drug effects* ; Cell Proliferation/drug effects* ; Apoptosis ; Cell Movement/drug effects* ; Neoplasm Invasiveness ; HCT116 Cells ; Proto-Oncogene Proteins c-bcl-2/biosynthesis* ; Humans ; Poly (ADP-Ribose) Polymerase-1 ; Glycoside Hydrolases ; bcl-2-Associated X Protein ; NF-kappa B p50 Subunit

OBJECTIVE: To investigate the effect of the sequence of intermediate instrumentation and distraction-reduction of the injured vertebra on the surgical efficacy of short-segment percutaneous pedicle screw fixation for thoracolumbar burst fractures with high rate of spinal canal encroachment. METHODS: From January 2016 to January 2022, 38 patients with thoracolumbar burst fractures with high rate of spinal canal encroachment (spinal canal encroachment rate >40%, complete posterior longitudinal ligament, no flipping bone block in the posterior marginal of the vertebra) without spinal cord injury who were were treated with short-segment percutaneous pedicle screw fixation were retrospectively analyzed. During the operation, 18 cases were used distraction-reduction first and then intermediate instrumentation on injured vertebral and sequential distraction-reduction again(the distraction-reduction first group) including 8 females and 10 males with a mean age of 46.5 (38.5, 50.0) years old, and the other 20 cases were used intermediate instrumentation on injured vertebral first and then direct distraction-reduction(the intermediate instrumentation first group) including 10 males and 10 females with a mean age of 46.0 (35.8, 50.8) years. The anterior height ratio of the injured vertebra, local Cobb's angle of the injured vertebrae, the spinal canal encroachment rate, and the improvement rate of spinal canal encroachment were compared and evaluated. RESULTS: All patients were followed up for more than 1 year, and no complications such as spinal cord and root injury, screw loosening and screw rod fracture were found. The anterior height ratio of the injured vertebra, local Cobb' angle of the injured vertebra in the two groups were significantly improved compared with preoperative data(P<0.05), and those at 3 months and 1 year after operation was lost compared with that at the previous time point(P<0.05). Although the spinal canal encroachment rate of the two groups 1 day and 1 year after operation was improved compared with that before operation(P<0.05), the improvement of spinal canal volume in the distraction-reduction first group was significantly better than that in the intermediate instrumentation first group (P<0.01). CONCLUSION In the treatment of patients with thoracolumbar fractures with high rate of spinal canal encroachment, short-segment percutaneous pedicle screw internal fixation with distraction-reduction first and then intermediate instrumentation and sequential distraction-reduction again can more effectively reduce the bony encroachment in the spinal canal and achieve indirect decompression effect better.
Humans ; Female ; Male ; Adult ; Middle Aged ; Spinal Fractures/surgery* ; Thoracic Vertebrae/surgery* ; Lumbar Vertebrae/surgery* ; Fracture Fixation, Internal/instrumentation* ; Pedicle Screws ; Retrospective Studies ; Spinal Canal/surgery*