Emerging role of immunogenic cell death in cancer immunotherapy: Advancing next-generation CAR-T cell immunotherapy by combination.

Immunogenic cell death (ICD) is a stress-driven form of regulated cell death (RCD) in which dying tumor cells' specific signaling pathways are activated to release damage-associated molecular patterns (DAMPs), leading to the robust anti-tumor immune response as well as a reversal of the tumor immune microenvironment from "cold" to "hot". Chimeric antigen receptor (CAR)-T cell therapy, as a landmark in anti-tumor immunotherapy, plays a formidable role in hematologic malignancies but falls short in solid tumors. The Gordian knot of CAR-T cells for solid tumors includes but is not limited to, tumor antigen heterogeneity or absence, physical and immune barriers of tumors. The combination of ICD induction therapy and CAR-T cell immunotherapy is expected to promote the intensive use of CAR-T cell in solid tumors. In this review, we summarize the characteristics of ICD, stress-responsive mechanism, and the synergistic effect of various ICD-based therapies with CAR-T cells to effectively improve anti-tumor capacity.

Kimura disease in children: A report of 11 cases and review of the literature.

Introduction: Kimura disease (KD), also known as eosinophilic hyperplastic lymphoid granuloma, is a rare benign chronic inflammatory condition, which is featured with the painless progressive mass located in the subcutaneous area of the head and neck region, elevated peripheral blood eosinophils, and raised serum immunoglobulin E (IgE) levels. KD is uncommon in clinical practice, especially with low incidence in children, so it often leads to misdiagnosis or missed diagnosis in pediatric patients. Methods: The clinical data of 11 pediatric patients with KD in the authors' institution were retrospectively analyzed. Results: There were 11 pediatric patients with KD enrolled in total, including 9 male patients and 2 female patients (sex ratio 4.5:1). The median age at diagnosis stood at 14 years (range 5-18 years), the initial symptoms in all patients included painless subcutaneous masses and focal swelling, the duration of symptoms ranged from 1 month to 10 years, and the average duration was 24.45 months. Six patients had single lesions, and 5 had multiple lesions. The highest proportion of lesion regions were parotid gland (n = 5, 31.3%) and retroauricular (n = 5, 31.3%), followed by cervical lymph nodes (n = 4, 25%), and others (n = 2,12.5; elbow n = 1; back n = 1). The eosinophil absolute count elevated in all patients, ranging from 0.71×109/L to 10.35 ×109/L (normal range 0.02-0.52×109/L). IgE levels were increased in all 7 patients who underwent serum immunoglobulin examination (normal range <100 IU/mL). Three patients received oral corticosteroid treatment while 2 relapsed. Three patients received surgical resection combined with oral corticosteroid treatment, and no patient relapsed. The other 3 patients received surgery and radiotherapy, surgery combined with corticosteroid and cyclosporin and corticosteroid combined with leflunomide respectively, and no patient relapsed. Conclusion: Base on the study, it is found that Kimura disease is rare and may have the atypical symptoms in pediatric patients, combination therapy is recommended to reduce recurrence, and long-term follow-up should be performed.

RAB3D/MDM2/ß-catenin/c-MYC axis exacerbates the malignant behaviors of acute myeloid leukemia cells in vitro and in vivo.

RAB3D, a small Ras-like GTPase involved in regulating secretory pathway, plays a cancer-promoting role in several solid tumors. However, its role in leukemogenesis remains unknown yet. Acute myeloid leukemia (AML) is a common acute leukemia with a high mortality. Here, we found the higher expression of RAB3D in bone marrow mononuclear cells derived from AML patients (n = 54) versus healthy participants (n = 20). The following loss- and gain-of-function experiments demonstrated that RAB3D promoted growth, enhanced colony formation and accelerated G1/S transition of U937, THP-1 and KG-1 AML cells. RAB3D silencing inhibited tumorigenesis of AML cells in vivo and delayed AML cells-induced death of mice. Interestingly, the expression of RAB3D is positively correlated with that of an oncogene mouse double minute 2 (MDM2) in bone marrow mononuclear cells of AML patients (r = 0.923, p < 0.001). Intracellular MDM2 was conjugated with more ubiquitins and degraded faster when RAB3D was silenced. A commonly therapeutic target of AML, ß-catenin signaling, was activated by RAB3D overexpression, but deactivated after MDM2 was silenced. The RAB3D-induced proliferation acceleration and ß-catenin activation were abolished by MDM2 knockdown, implying that RAB3D function by stabilizing MDM2. In addition, c-MYC, a ß-catenin downstream effector, was recruited directly to the RAB3D gene promoter (-360/-349 and -136/-125 sites) and induced its transcription. Collectively, this study demonstrates that RAB3D may exacerbate the malignant behaviors of AML cells through forming a positive feedback loop with MDM2/ß-catenin/c-MYC signaling. RAB3D might be a novel target of clinical AML treatment.

Risk Factors for Mortality and Antimicrobial Regimens in Pediatric Intensive Care Unit Patients with Carbapenem-Resistant Enterobacteriaceae Infections: A Six-Year Retrospective Study.

Purpose: Limited data are available on the characteristics, risk factors, and antimicrobial treatment of critically ill pediatric patients with carbapenem-resistant Enterobacteriaceae (CRE) infections. This study was to identify the risk factors for 30-day mortality in pediatric intensive care unit (PICU) patients with CRE infections and compare the clinical outcomes of different antimicrobial regimens. Methods: A retrospective, observational cohort study was performed on patients admitted to the PICU with positive CRE cultures between January 2016 and December 2021. Results: For the 56 patients, the overall 30-day mortality was 50% (n=28). Multivariable logistic regression analysis revealed that pediatric critical illness score (PCIS; HR = 0.879; 95% CI, 0.827-0.935; P < 0.001) and serum albumin levels (HR = 0.921; 95% CI, 0.860-0.987; P = 0.019) were independently associated with 30-day mortality. At the same time, there was no significant difference in 30-day mortality (42.9% versus 45.5%, P = 0.854) or clinical efficiency rate (53.4% versus 40.9%, P = 0.374) between with and without polymyxin B therapy. Conclusion: The study revealed PCIS and serum albumin levels were the independent mortality-related risk factors of CRE infections in critically ill pediatric patients. Treatment with polymyxin B could not reduce 30-day mortality. Future prospective cohort studies are needed to investigate the optimal antimicrobial regimens for CRE infection in PICU patients.

[Risk factors for acute kidney injury after hematopoietic stem cell transplantation in children: a retrospective study]. / å„¿ç«¥é€ è¡€å¹²ç»†èƒžç§»æ¤åŽæ€¥æ€§è‚¾æŸä¼¤ç›¸å ³å±é™©å› ç´ çš„å›žé¡¾æ€§ç ”ç©¶.

OBJECTIVES: To investigate the risk factors for acute kidney injury (AKI) after hematopoietic stem cell transplantation (HSCT) in children. METHODS: A retrospective analysis was performed on the medical data of 111 children who underwent HSCT from January 2018 to January 2020. A multivariate logistic regression analysis was used to identify the risk factors for AKI. The Kaplan-Meier survival analysis was used to compare the prognosis in children with different grades of AKI. RESULTS: Graft-versus-host disease (grade Ⅱ-Ⅳ) (OR=4.406, 95%CI: 1.501-12.933, P=0.007), hepatic veno-occlusive disease (OR=4.190, 95%CI: 1.191-14.740, P=0.026), and thrombotic microangiopathy (OR=10.441, 95%CI: 1.148-94.995, P=0.037) were closely associated with the development of AKI after HSCT. The children with stage Ⅲ AKI had a lower 1-year survival rate than those without AKI or with stage Ⅰ AKI or stage Ⅱ AKI (28.6%±12.1% vs 82.8%±5.2%/81.7%±7.4%/68.8%±11.6%; P<0.05). CONCLUSIONS: Children with stage Ⅲ AKI after HSCT have a higher mortality rate. Graft-versus-host disease, hepatic veno-occlusive disease, and thrombotic microangiopathy are closely associated with the development of AKI after HSCT.