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Potential Biological and Genetic Links Between Dementia and Osteoporosis: A Scoping Review
No full textBackground: The biological mediators for the epidemiologic overlap between osteoporosis and dementia are unclear. We undertook a scoping review of clinical studies to identify genetic and biological factors linked with these degenerative conditions, exploring the mechanisms and pathways connecting both conditions.
Methods: Studies selected (1) involved clinical research investigating genetic factors or biomarkers associated with dementia or osteoporosis, and (2) were published in English in a peer-reviewed journal between July 1993 and March 2025. We searched Medline Ovid, Embase, PsycINFO, the Cochrane Library, the Web of Science databases, Google Scholar, and the reference lists of studies following the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR).
Results: Twenty-three studies were included in this review. These explored the role of the APOE polymorphism (n = 2) and the APOE4 allele (n = 13), associations between TREM2 mutation and late onset AD (n = 1), and associations between amyloid beta and bone remodeling (n = 1); bone-related biomarkers like DKK1, OPG, and TRAIL as predictors of cognitive change (n = 2); extracellular vesicles as bone-brain communication pathways (1); and the role of dementia-related genes (n = 1), AD-related CSF biomarkers (n = 1), and parathyroid hormone (PTH) (n = 1) in osteoporosis-dementia pathophysiology.
Conclusions: Bone-related biomarkers active in the Wnt/β-Catenin pathway (Dkk1 and sclerostin) and the RANKL/RANK/OPG pathway (OPG/TRAIL ratio) present consistent evidence of involvement in AD and osteoporosis development. Reports proposing APOE4 as a causal genetic link for both osteoporosis and AD in women are not corroborated by newer observational studies. The role of Aβ toxicity in osteoporosis development is unverified in a large clinical study
Cytokine Release Syndrome and Neurotoxicity Following CD19 CAR-T in B-Cell Lymphoma.
No full textChimeric antigen receptor T cell (CAR-T) therapy is an effective treatment for relapsed-refractory large B-cell lymphoma (LBCL). However, toxicities, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), remain significant concerns. Analyze temporal trends, risk factors, and associations between these toxicities and their severity. In this registry study by the Center for International Blood and Marrow Transplant Research, we studied CRS and ICANS in 1916 LBCL patients treated with commercial CAR-T therapies (axicabtagene ciloleucel 74.9%, tisagenlecleucel 25.1%) between 2018 and 2020. Outcomes include development of CRS/ICANS, timing and severity according to ASTC grading, overall survival (OS). Risk factors were assessed using Cox proportional hazards model. Among patients developing CRS (75.2%), 11.3% had grade ≥3 CRS. Among patients developing ICANS (43.5%), 47.7% had grade ≥3 ICANS. Among patients developing CRS, severe CRS rates decreased from 14.0% in 2018 to 9.2% in 2020 (P\u3c .01). However, the proportion of severe ICANS in patients who developed ICANS remained statistically unchanged (41.5% in 2018 to 53.7% in 2020, P= .10). CRS and ICANS were correlated: 57.1% of patients with CRS also experienced ICANS, and CRS was reported in 97.5% of ICANS cases, suggesting a potential continuum between toxicities. Axicabtagene ciloleucel was associated with higher risk of any grade CRS (OR, 4.6; 95% CI, 3.65 to 5.81) and ICANS (OR, 5.85; 95% CI, 4.48 to 7.64) as well as early and severe forms of both complications. Older age, lower performance status, and elevated lactate dehydrogenase levels prior to infusion also variably predicted these toxicities. In a landmark analysis starting 30 days postinfusion, patients with severe CRS or severe ICANS had shorter OS compared to those without these toxicities. High grades of CRS improved over time likely related to earlier intervention, development of ICANS is intrinsically related with CRS. These findings underscore the need for effective strategies to mitigate these toxicities and improve CAR-T safety
Mutant p53 Variants Differentially Impact Replication Initiation and Activate cGAS-Sting To Affect Immune Checkpoint Inhibition
No full textPrior research shows that Akt-dependent phosphorylation of TopBP1 in S phase results in the switch of TopBP1/Treslin binding to TopBP1/E2F1 binding, which is important to prevent replication re-initiation in late S and G2 phases. Here, we demonstrate that contact, but not conformational, mutant p53 can override this switch by binding to both TopBP1 and Treslin, thereby facilitating persistent TopBP1/Treslin interaction in late S and G2 phases, which ultimately leads to over-firing of replication initiation. This increases micronuclei formation, which is further enhanced by genotoxic stressors such as doxorubicin, PARP inhibitors, or ATR inhibitors. Consequently, contact mutant p53 increases the sensitivity of cancer cells to a TopBP1-BRCT7/8 inhibitor combined with PARP or ATR inhibitors. Importantly, contact mutant p53 induces micronuclei formation and MRE11 expression, thereby activating cGAS-STING pathway and enhancing response to immune checkpoint inhibition. This finding is validated in murine mammary tumor allografts and further corroborated by clinical data
Ertapenem as an Antibiotic Prophylaxis for Colectomies and Laparotomies: A Systematic Review
No full textIntroduction: Given concerns for antibiotic resistance, broader spectrum antibiotic agents such as ertapenem are being used for pre-operative prophylaxis. We hypothesize that pre-operative ertapenem prior to laparotomies and colectomies is superior at decreasing surgical site infections (SSIs) compared with other widely used antibiotic agents.
Methods: Medline, Embase, the Cochrane Library, and Web of Science were queried for studies until February 02, 2025. Studies were excluded if they did not evaluate ertapenem as a pre-operative antibiotic prophylaxis in patients undergoing laparotomy or colectomy, the outcome was not SSIs, or it represented a review of prior publications. Three reviewers independently extracted relevant articles, and two performed risk-of-bias analyses.
Results: Of 6,389 abstracts identified, 9 studies remained after full-text review. Seven of the included studies were observational (78%), and two (22%) were randomized controlled trials (RCTs). The median number of patients enrolled was 499 (inter-quartile range 253, 5192). Study populations included colorectal surgery (n = 8) and trauma patients undergoing laparotomy (n = 1). Ertapenem was compared with single-agent second-generation cephalosporins such as cefotetan, cefuroxime, and cefoxitin and to a single-agent penicillin with or without a combined β-lactamase inhibitor (i.e., ampicillin-sulbactam). In total, five (56%) studies showed that ertapenem was superior in preventing SSIs, decreasing SSI rates by as much as 59% (adjusted odds ratio = 0.41 [0.28-0.61]; p \u3c 0.001).
Conclusion: Approximately half of the studies (56%) demonstrated that ertapenem was superior to other commonly used antibiotic prophylaxis regimens in decreasing SSI after laparotomies and colectomies. However, most studies were observational. Therefore, RCTs, especially in trauma, are needed
Skewed Adaptive Immune Responses Are Involved in Alpha-1 Antitrypsin Deficiency Emphysema
No full textAdvances in Idiopathic Pulmonary Fibrosis Diagnosis and Treatment
No full textSignificant advances have been made in diagnosing and treating idiopathic pulmonary fibrosis (IPF) in the last decade. The incidence and prevalence of IPF are increasing, and morbidity and mortality remain high despite the two Food and Drug Administration (FDA)-approved medications, pirfenidone and nintedanib. Hence, there is an urgent need to develop new diagnostic tools and effective therapeutics to improve early, accurate diagnosis of IPF and halt or reverse the progression of fibrosis with a better safety profile. New diagnostic tools such as transbronchial cryobiopsy and genomic classifier require less tissue and generally have good safety profiles, and they have been increasingly utilized in clinical practice. Advances in artificial intelligence-aided diagnostic software are promising, but challenges remain. Both pirfenidone and nintedanib focus on growth factor-activated pathways to inhibit fibroblast activation. Novel therapies targeting different pathways and cell types (immune and epithelial cells) are being investigated. Biomarker-based personalized medicine approaches are also in clinical trials. This review aims to summarize recent diagnostic and therapeutic development in IPF
Military Inhalational Exposures Outside the Theater of Conflict and Chronic Respiratory Symptoms
No full textImportance: Deployment to Afghanistan and Southwest Asia has been associated with adverse respiratory health outcomes. However, the impact of inhalational exposures (eg, vapor, dust, gas, fumes), which are known correlates of reduced lung function and future chronic lung disease, during military service time outside this deployment period has not been assessed.
Objective: To assess military inhalational exposures during nonwartime routine activities and their associations with chronic respiratory symptoms.
Design, setting, and participants: This cross-sectional study used data from the US Department of Veterans Affairs Service and Health Among Deployed Veterans study. US veterans who served between October 7, 2001, and February 28, 2017; deployed to Afghanistan or Southwest Asia; and living near 6 Veterans Affairs sites were randomly selected from Defense Manpower Data Center records. Participants completed interviewer-administered multi-item questionnaires about 29 exposures related to active duty military service time when not deployed. Onsite visits occurred between April 27, 2018, and March 13, 2020, and analyses were performed between April 1, 2023, and February 10, 2025.
Exposure: Inhalation exposures during active duty military service time.
Main outcomes and measures: The main outcomes were chronic respiratory symptoms of dyspnea, wheeze in the previous 12 months, and chronic bronchitis. Using factor analysis, the 29 exposures were reduced to 20 items and categorized into 5 factors. Responses were scored ordinally (0, 1, 2) according to exposure prevalence and duration. Generalized linear modeling was used to explore associations between exposures and chronic respiratory symptoms.
Results: The sample included 1712 veterans (median [IQR] age, 37 [33-45] years; 1522 male [88.9%]) who had military service other than during their deployment to Afghanistan or Southwest Asia. The median (IQR) total active duty military service duration was 77 (57-128) months, with 82.8% of their service time spent outside the theater of conflict. The prevalence of dyspnea, chronic bronchitis, and wheeze was 7.0% (117 participants), 7.1% (121 participants), and 15.2% (260 participants), respectively. The most commonly reported exposure categories were combustion and ground dust (1014 participants [59.2%]), aircraft maintenance (812 participants [47.4%]), and heavy equipment maintenance (783 participants [45.7%]). Adjusted multivariable analyses identified significant associations between heavy equipment maintenance exposures and dyspnea (odds ratio [OR], 1.33; 95% CI, 1.06-1.68) and wheeze (OR, 1.29; 95% CI, 1.10-1.52). Aircraft maintenance exposures were significantly associated with wheeze (OR, 1.22; 95% CI, 1.01-1.47). No statistically significant associations were found between these exposures and chronic bronchitis.
Conclusions and relevance: This cross-sectional study shows significant associations between heavy equipment maintenance and aircraft maintenance inhalation exposures outside of deployment with chronic respiratory symptoms among US veterans. These findings suggest that certain military inhalational exposures may contribute to the development of chronic lung disease and that policy interventions to reduce such exposures may protect the long-term respiratory health of military personnel
Oxidative Stress Promotes Lipid-Laden Macrophage Formation via CYP1B1
No full textEmerging evidence suggests that lipid-laden macrophages (LLM) participate in lung damage in various clinical conditions. However, the mechanisms involved in LLM formation are not fully understood. In this study, we aimed to investigate the link between reactive oxygen species (ROS) and LLM formation. We found that ROS triggered by cigarette smoke extract (CSE) or H2O2 significantly promoted LLM formation. Given the key role of ROS in LLM formation, we further demonstrated that LLM formation is induced by various ROS-producing stimuli, including bacteria, oxidized low-density lipoprotein (OxLDL), hyperoxia, and E-cigarette vapor extract (EVE). Meanwhile, cytochrome P450 family-1 subfamily B member 1 (CYP1B1) was highly upregulated in lung macrophages from chronic obstructive pulmonary disease (COPD) patients and CSE-treated macrophages. Functionally, CYP1B1 contributes to the CSE-induced lipid accumulation and LLM formation. CYP1B1 expression and LLM formation were effectively suppressed by antioxidant N-acetylcysteine (NAC) and carvedilol. The formation of LLM was also associated with classically activated M1 but not the M2 state. CSE-induced LLM showed time-dependent alterations in inflammatory response and phagocytic ability. In summary, our study highlights the role of oxidative stress in LLM formation. CYP1B1 contributes to ROS-induced LLM formation and may serve as a therapeutic target for reducing LLM-induced lung damage
