Dual Role of CXCL8 in Maintaining the Mesenchymal State of Glioblastoma Stem Cells and M2-Like Tumor-Associated Macrophages.

PURPOSE: The dynamic interplay between glioblastoma stem cells (GSC) and tumor-associated macrophages (TAM) sculpts the tumor immune microenvironment (TIME) and promotes malignant progression of glioblastoma (GBM). However, the mechanisms underlying this interaction are still incompletely understood. Here, we investigate the role of CXCL8 in the maintenance of the mesenchymal state of GSC populations and reprogramming the TIME to an immunosuppressive state. EXPERIMENTAL DESIGN: We performed an integrative multi-omics analyses of RNA sequencing, GBM mRNA expression datasets, immune signatures, and epigenetic profiling to define the specific genes expressed in the mesenchymal GSC subsets. We then used patient-derived GSCs and a xenograft murine model to investigate the mechanisms of tumor-intrinsic and extrinsic factor to maintain the mesenchymal state of GSCs and induce TAM polarization. RESULTS: We identified that CXCL8 was preferentially expressed and secreted by mesenchymal GSCs and activated PI3K/AKT and NF-κB signaling to maintain GSC proliferation, survival, and self-renewal through a cell-intrinsic mechanism. CXCL8 induced signaling through a CXCR2-JAK2/STAT3 axis in TAMs, which supported an M2-like TAM phenotype through a paracrine, cell-extrinsic pathway. Genetic- and small molecule-based inhibition of these dual complementary signaling cascades in GSCs and TAMs suppressed GBM tumor growth and prolonged survival of orthotopic xenograft-bearing mice. CONCLUSIONS: CXCL8 plays critical roles in maintaining the mesenchymal state of GSCs and M2-like TAM polarization in GBM, highlighting an interplay between cell-autonomous and cell-extrinsic mechanisms. Targeting CXCL8 and its downstream effectors may effectively improve GBM treatment.

Expenditure projections for community home-based care services for older adults with functional decline in China.

INTRODUCTION: Difficulty in identifying the functional status of older adults creates an imbalance between the supply and demand for community home-based care. Using a multi-level functional classification system to guide care cost measurement may optimize care resources and meet diverse eldercare demands. METHODS: The Markov model was used to project the older population size in different functional decline (FD) statuses. The project cost and the man-hour costing method were combined to forecast the cost of community home-based care for older adults with FD. RESULTS: The projected cost of eldercare increased from 1668.623 billion yuan in 2020 to 2836.754 billion yuan in 2035. By 2035, the total cost for community-based home care for those in pathological development of FD statuses such as "viability disorder," "acute disease," "somatic functional disorder," and "sub-disorder" was projected to be 1094.591 billion, 433.855 billion, 1256.236 billion, and 52.072 billion yuan, respectively, which is 1.24, 1.58, 1.78, and 0.49 times higher than the results by the man-hour costing method. Family caregiving costs are about three times those of professional caregivers. CONCLUSION: The escalating cost of providing graded care for older adults, particularly by family caregivers, presenting a significant evidence for the need to optimize resource allocation and develop a robust human resources plan for community home-based care.

Association between multimorbidity trajectories, healthcare utilization, and health expenditures among middle-aged and older adults: China Health and Retirement Longitudinal Study.

BACKGROUND: To identify the latent groups of multimorbidity trajectories among middle-aged and older adults and examine their associations with healthcare utilization and health expenditures. METHODS: We included adults aged ≥45 years who participated in the China Health and Retirement Longitudinal Study from 2011 to 2015 and were without multimorbidities (<2 chronic conditions) at baseline. Multimorbidity trajectories underlying 13 chronic conditions were identified using group-based multi-trajectory modeling based on the latent dimensions. Healthcare utilization included outpatient care, inpatient care, and unmet healthcare needs. Health expenditures included healthcare costs and catastrophic health expenditures (CHE). Random-effects logistic regression, random-effects negative binomial regression, and generalized linear regression models were used to examine the association between multimorbidity trajectories, healthcare utilization, and health expenditures. RESULTS: Of the 5548 participants, 2407 developed multimorbidities during follow-up. Three trajectory groups were identified among those with new-onset multimorbidity according to the increasing dimensions of chronic diseases: "digestive-arthritic" (N = 1377, 57.21 %), "cardiometabolic/brain" (N = 834, 34.65 %), and "respiratory/digestive-arthritic" (N = 196, 8.14 %). All trajectory groups had a significantly increased risk of outpatient care, inpatient care, unmet healthcare needs, and higher healthcare costs than those without multimorbidities. Notably, participants in the "digestive-arthritic" trajectory group had a significantly increased risk of incurring CHE (OR = 1.70, 95%CI: 1.03-2.81). LIMITATIONS: Chronic conditions were assessed using self-reported measures. CONCLUSIONS: The growing burden of multimorbidity, especially multimorbidities of digestive and arthritic diseases, was associated with a significantly increased risk of healthcare utilization and health expenditures. The findings may help in planning future healthcare and managing multimorbidity more effectively.

Clinicopathologic Features and Genomic Signature of De Novo CD5 + Diffuse Large B-Cell Lymphoma : A Multicenter Collaborative Study.

De novo CD5 + diffuse large B-cell lymphoma (DLBCL) has poor survival in the era of immunochemotherapy. Accurate gene-based typing and prognostic stratification can enhance the development of effective individualized treatments. Therefore, we conducted a multicenter retrospective study to evaluate the clinicopathologic characteristics, genomic profiles, and prognostic parameters of 61 patients with CD5 + DLBCL and 60 patients with CD5 - DLBCL, with the goal of facilitating accurate prognostic stratification and potential individualized treatment strategies. Compared with patients with CD5 - DLBCL, older age, advanced stage, higher incidence of central nervous system involvement, and MYC/BCL-2 and p53 overexpression were more prevalent in CD5 + DLBCL. Most patients with CD5 + DLBCL had lymph nodes with non-germinal center B-cell-like or activated B-cell-like subtype according to immunohistochemistry or Lymph2Cx assay. Next-generation sequencing showed that the proportion of MCD subtype (based on the co-occurrence of MYD88 and CD79B mutations) in the CD5 + DLBCL cohort was higher than that in the CD5 - DLBCL cohort (54.2% vs. 13.0%, P =0.005). Compared with the CD5 - cohort, CD5 + DLBCL patients showed poor 5-year overall survival (70.9% vs. 39.0%, P <0.001). Kaplan-Meier survival analysis indicated that cell of origin, MYC/BCL-2, p53, and BCL-6 expression did not have a prognostic impact on patients with CD5 + DLBCL. Multivariate analysis showed that age above 76 years, advanced stage, higher incidence of central nervous system involvement, and hypoalbuminemia were independent factors for poor prognosis in CD5 + DLBCL patients. In summary, CD5 + DLBCL displays poor prognosis, distinctive clinicopathologic characteristics and predominant genetic features of activated B-cell-like and MCD subtypes with worse survival outcome.

The transitions and predictors of cognitive frailty with multi-state Markov model: a cohort study.

BACKGROUND: Cognitive frailty (CF) is characterized by the simultaneous presence of physical frailty and cognitive impairment. Previous studies have investigated its prevalence and impact on different adverse health-related outcomes. Few studies have focused on the progression and reversibility of CF and their potential predictors. METHODS: Data were derived from the China Health and Retirement Longitudinal Study (CHARLS). A total of 4051 older adults with complete data on three waves of the survey (2011, 2013, and 2015) were included and categorized into four groups: normal state (NS), cognitive impairment (CI) only, physical frailty (PF) only and CF (with both PF and CI). A multi-state Markov model was constructed to explore the transitions and predicting factors of CF. RESULTS: The incidence and improvement rates of CF were 1.70 and 11.90 per 100 person-years, respectively. The 1-year transition probability of progression to CF in those with CI was higher than that in the PF population (0.340 vs. 0.054), and those with CF were more likely to move to PF (0.208). Being female [hazard ratio (HR) = 1.46, 95%CI = 1.06, 2.02)], dissatisfied with life (HR = 4.94, 95%CI = 1.04, 23.61), had a history of falls (HR = 2.36, 95%CI = 1.02, 5.51), rural household registration (HR = 2.98, 95%CI = 1.61, 5.48), multimorbidity (HR = 2.17, 95%CI = 1.03, 4.59), and depression (HR = 1.75, 95%CI = 1.26, 2.45) increased the risk of progression to CF, whereas literacy (HR = 0.46, 95%CI = 0.33, 0.64) decreased such risk. Depression (HR = 0.43, 95%CI = 0.22, 0.84) reduced the likelihood of CF improvement, whereas literacy (HR = 2.23, 95%CI = 1.63, 3.07) increased such likelihood. CONCLUSIONS: Cognitive frailty is a dynamically changing condition in older adults. Possible interventions aimed at preventing the onset and facilitating the recovery of cognitive frailty should focus on improving cognitive function in older adults.

Heterogeneous adverse childhood experiences and cognitive function in an elderly Chinese population: a cohort study.

OBJECTIVE: To identify the heterogeneity of adverse childhood experiences (ACEs) as well as their association with cognitive function in an elderly Chinese population. DESIGN: A retrospective cohort study. PARTICIPANTS: The data were from the latest wave of the China Health and Retirement Longitudinal Study and a total of 7222 participants aged ≥60 were included. PRIMARY AND SECONDARY OUTCOME MEASURES: Latent class analysis was used to identify the classes characterised by 11 types of ACEs. Cognitive function was measured by the Mini-Mental State Examination (MMSE) and cognitive impairment was defined by education-specific threshold MMSE scores. Logistic models were constructed to examine the relationship between ACE classes and cognitive impairment. Several childhood and adulthood confounding factors were considered. RESULTS: Three ACE latent classes were identified. Of them, 76.09% were in the 'Low ACEs' class, 15.43% were in the 'Household dysfunction' class and 8.49% were in the 'Child maltreatment' class. The people in the 'Low ACEs' class seemed to have better childhood family financial situations and higher education levels. The population in the 'Household dysfunction' class tended to live in rural areas and have a higher proportion of men, whereas people in the 'Child maltreatment' class showed a significantly higher proportion of women and higher levels of chronic diseases. 'Child maltreatment' was related to a higher risk of cognitive impairment (OR=1.37, 95% CI: 1.12 to 1.68), while the risk of 'Household dysfunction' was not significantly different from that of the 'Low ACEs' participants (OR=1.06, 95% CI: 0.90 to 1.26). CONCLUSIONS: The findings supported differences in cognitive function in elderly Chinese people exposed to different types of ACEs.

Prognostic value of hemoglobin combined with Geriatric Nutritional Risk Index scores in patients undergoing postoperative radiotherapy for esophageal squamous cell carcinoma.

Aims: To investigate the prognostic value of hemoglobin combined with geriatric nutritional risk index (GNRI) scores in patients undergoing postoperative radiotherapy for esophageal squamous cell carcinoma (ESCC). Patients & methods: Patients who underwent esophagectomy and postoperative radiotherapy were included in this retrospective study. Their preoperative hemoglobin and GNRI were collected to establish hemoglobin-GNRI (H-GNRI) scores, and their association with OS was evaluated. Results: Patients with high H-GNRI scores had better prognosis than those with low scores (p < 0.001). Differentiation (p = 0.001), T classification (p = 0.010), N classification (p = 0.001) and H-GNRI score (p = 0.018) were independent prognostic factors for all patients. Conclusion: H-GNRI score is an independent prognostic factor for the survival of patients with ESCC managed by surgery and postoperative radiotherapy.

Coexistence of gastric gastrointestinal stromal tumor, intro-abdominal and retroperitoneal liposarcomas -a case report.

BACKGROUND: Gastric gastrointestinal stromal tumor (GIST), intro-abdominal and retroperitoneal neoplasms are distinct tumors arising from different cell layers; therefore, coexistence of such tumors is relatively rare. CASE PRESENTATION: A man complained of early satiety for 2 mouths, whose upper gastrointestinal (GI) endoscopy showed a tumor arising from the greater curvature of gastric body and extending into the lumen. Abdominal computed tomography (CT) revealed coexistence of gastric, intro-abdominal and retroperitoneal masses. Wedge resection for gastric tumor, resection for intro-abdominal and retroperitoneal tumors were done. The postoperative histological examination suggested simultaneous development of a gastric GIST, intro-abdominal and retroperitoneal myxoid liposarcomas. CONCLUSION: Although both GISTs and liposarcomas originate from mesenchymal tissues, simultaneous development of a gastric GIST, intro-abdominal and retroperitoneal liposarcomas is the first such case to be reported in the literature.

Gastroduodenal intussusception and pylorus obstruction induced by a c-KIT-negative gastric gastrointestinal stromal tumor: case report and review of the literature.

INTRODUCTION: Gastrointestinal stromal tumors (GISTs) are infrequently reported to cause gastroduodenal intussusception, especially in the cases with complete pylorus obstruction. GISTs comprise only 1 - 3 % of all gastrointestinal tract tumors, and most of them strongly express the c-KIT protein. Approximately 5 % of GISTs show negative staining of c-KIT. CASE PRESENTATION: A 69-year-old man complained of acute abdominal pain accompanied with nausea and vomiting for 6 hours. Emergency endoscopic examination, upper gastroenterography, and computed tomography scan suggested gastroduodenal intussusception and pylorus obstruction induced by a gastric GIST. Laparoscopic exploration and wedge resection of the tumor were performed in the patient. Postoperative histological examination showed a gastric GIST with c-KIT-negative expression. CONCLUSION: Herein, we report the unique findings of a c-KIT-negative gastric GIST presenting with gastroduodenal intussusception and pylorus obstruction. We also reviewed the English language literature of gastroduodenal intussusception induced by GISTs and put our case in the context of the previously reported cases.