Journal of Investigative Medicine最新文献

Extrapulmonary tuberculosis (EPTB) is an important public health problem due to its diverse clinical presentations, diagnostic complexities, and significant impact on patient outcomes and public health. Our study aimed to understand the sociodemographic, clinical, and laboratory characteristics as well as diagnostic and treatment modalities of adult patients with EPTB. This is a multicentric retrospective study that covers patients with EPTB cases followed up from January 2015 to December 2022 among tuberculosis (TB) dispensaries and Infectious Diseases and Clinical Microbiology clinics of 15 hospitals located in various regions of Turkey. The study included 64.6% women with a mean age of 44 years and a mortality rate of 3.5% within 1 year of diagnosis. Initial constitutional symptoms were predominantly fatigue (57%) and anorexia (53.7%). The most commonly affected sites were the lymph nodes (49.1%) and pleura (9.7%). The lumbar region was particularly involved in cases with spinal TB. Diagnostic findings included acid-fast bacilli positivity in 27.5% of cases, tuberculosis polymerase chain reaction positivity in 41%, elevated adenosine deaminase levels in 91.2% (especially in pleural and peritoneal fluids), and mycobacterial culture positivity in 40.9%. Pathology slides showed granulomatous inflammation in 97.7%. Increased C-reactive protein (CRP) levels correlated with the number of organs affected. Anti-TB treatment-related hepatotoxicity was detected in 8.9% of patients. In this study, it is important to note that the lumbar region is predominantly affected with involvement in spinal region. CRP level was consistent with the number of organ involvements and was one of the most critical results of this study.

Endocrine disruptive chemicals (EDCs) are considered as the potential attributes for the increasing trend in obesity and metabolic syndrome (MS) through disruption of sex hormones, particularly in women. We evaluated the association of understudied EDC compounds with total testosterone (TT), sex hormone-binding globulin (SHBG), obesity, and MS. A population-based cross-sectional study was conducted using the National Health and Nutrition Examination Survey datasets collected during the years 2013-2016. Women of age ≥15 years with urinary measurements of nonpersistent EDCs, including bisphenol, triclosan, triclocarban, dichlorophenol, and paraben compounds were included in this study. Data were analyzed using the modified Poisson models to estimate the adjusted relative risk (RR) and 95% confidence interval (CI). The associations were also validated by considering TT and SHBG concentrations as the outcomes. The study included 1974 women with 11% high TT, 10.5% low SHBG, 40% obesity, and 46.2% MS. A medium to high exposure to bisphenol-A (RR = 1.64; 95% CI: 1.14, 2.35, p = 0.009), bisphenol-F (RR = 1.83; 95% CI: 1.35, 2.49, p < 0.001), bisphenol-S (RR = 1.83; 95% CI: 1.35, 2.49, p = 0.041) and 2, 4- dichlorophenol (RR = 1.61; 95% CI: 1.06, 2.45, p = 0.026) were associated with low SHBG but not with high TT. In addition, high exposure to triclosan was also inversely associated with SHBG concentrations (regression coefficient = -0.09; 95% CI: -0.15, -0.02, p = 0.013). However, these EDCs were found to be associated with SHBG, obesity, and MS according to menopausal status. High exposure to certain nonpersistent EDCs was associated with low SHBG, obesity, and MS according to menopausal status.

Early onset colorectal cancer (EO-CRC) is increasing. We investigated the risk factors for ER-CRC compared to late onset colorectal cancer (LO-CRC). CRC patients between the years 1999 and 2021 were retrospectively evaluated. Data regarding demographics, comorbidities, malignancies, and mortality were collected. Data were retrieved using the MdClone platform from a large Health Maintenance Organization. The cohort was subdivided into EO-CRC (age ≤ 50 years) and LO-CRC (age ≥ 51 years) groups. 61,679 patients diagnosed with CRC were included in our analysis, 30,456 (49.4%) males, and 4891 (7.9%) Arabs, with an average age at diagnosis of 70.1 ± 13.1 years. 5561 (9%) patients were included in the EO-CRC group. Over the last decades, higher rates of EO-CRC were diagnosed compared to the previous decade, 9.8% vs 8.3%, p < 0.001. A higher percentage of EO-CRC patients were females (52.8% vs 50.4%), had a family history of CRC (9.9% vs 5.5%), were Arabs (18.7% vs 6.9%), and were smokers (32.7% vs 30.2%) compared to LO-CRC patients. Significantly lower rates of comorbidities such as ischemic heart disease, diabetes mellitus, hypertension, obesity, and iron deficiency anemia were found among EO-CRC patients, with a lower all-cause mortality (27.7% vs 63.1%, p < 0.001). 348 (6.3%) of the EO-CRC patients had another Lynch-related cancer until age 50 years compared to 45 (0.1%) at the LO-CRC. Young individuals with increased risk for CRC need special consideration and should be referred early for screening and endoscopic investigation, particularly those with a family history of CRC, smokers, and those of Arab ethnicity.

Hyperglycemia, one of the major risk factors for atherosclerosis, leads to the accumulation of advanced glycation end products (AGEs), contributing to cardiovascular complications. Such accumulation may accelerate the progression of vascular disease in patients with diabetes. Reverse cholesterol transport (RCT) protein, ATP-binding membrane cassette transporters A1 and G1 (ABCA1 and ABCG1) and cholesterol 27-hydroxylase facilitate cholesterol removal from macrophages. AGE inhibits RCT by reducing the expression of ABCA1 and ABCG1. This study aimed to evaluate whether plasma from poorly controlled adolescents with type 1 diabetes (T1D) disrupts cholesterol homeostasis in human monocytes/macrophages. Twenty healthy controls (HCs) and 20 patients with type 1 diabetes mellitus (T1DM), 10-19 years old, were enrolled. Naïve THP-1 macrophages were exposed to plasma from each HC and patient with T1D. Following incubation, mRNA for cholesterol efflux (ABCA1, ABCG1, and 27-hydroxylase) and cholesterol uptake (CD36, ScR-A1, lectin oxidized low-density lipoprotein (LOX)-1, and CXCL16) were isolated. Foam cell formation was quantified to confirm the pro-atherogenic effects of T1D plasma on macrophages. Results showed that T1D plasma had an elevated level of N-(carboxymethyl)-lysine-modified proteins and upregulated CXCL16 and, to a lesser degree, ScR-A1. This change in gene expression in the presence of T1D plasma is associated with increased lipid accumulation and foam cell formation by THP-1 macrophages. In our study, these cells' uptake of an AGE product occurred mainly through the SR-A1 and CXCL16 receptors, leading to increased intracellular oxidized low-density lipoprotein. We conclude that AGEs may contribute to accelerated atherosclerosis in diabetes through effects on both forward and reverse cholesterol movement.

Triple-positive breast cancer (TPBC) is a type of breast cancer that overexpresses estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). Dysregulation of ER signaling has been implicated in the pathogenesis of breast cancer. ERα activation triggers the production of second messengers, including cAMP, leading to the activation of signals such as PI3K/AKT or Ras/MAPK. Ruxolitinib is a specific inhibitor of JAK1/JAK2. MK-2206 is an allosteric inhibitor of the Akt. The limitations of the use of ruxolitinib and MK-2206 as single agents necessitate the development of combination therapies with other drugs. This study is the first to investigate the effects of combining ruxolitinib with MK-2206 on MAPK and PI3K/AKT signaling in BT474 breast cancer cells. In addition, this work aimed to increase the anticancer effects of cotreatment with MK-2206 and ruxolitinib. Ruxolitinib, MK-2206, and their combination reduced cell viability in a dose- and time-dependent manner, as determined by MTT assays after 48 h of treatment. Colony formation and wound healing assays demonstrated that MK-2206 exhibited a synergistic anti-proliferative effect. The effects of ruxolitinib, MK-2206, and their combination on PI3K/AKT and MAPK signaling were assessed via western blotting. Ruxolitinib and MK-2206 combined treatment inhibit cell death in BT474 cells by downregulating ERα, Src-1, ERK1/2, SAPK/JNK, and c-Jun. Our results revealed the relationships among the ERα, PI3K/AKT, and MAPK signaling pathways in ER+ breast cancer cells. Understanding the interactions among ERα, PI3K-AKT-mTOR, and MAPK could lead to novel combination therapies.

While some studies have suggested better outcomes for critically ill patients with balanced solutions over normal saline, the best type of intravenous fluid to use for stroke patients remains unknown. Using a retrospective chart review of 2015-2019 Get with the Guidelines^® data at a single academic medical center, this study sought to determine whether balanced solutions or normal saline are associated with risk of hemorrhagic transformation or 90-day disability in patients with acute ischemic stroke treated with intravenous thrombolysis. Exposure was the type of intravenous fluid and outcomes were modified Rankin scale (mRS) ≤2 at 90 days and hemorrhagic transformation. Multivariate analysis controlled for age, demographics, medical history, time to tissue plasminogen activator (tPA), and admission stroke scale. We identified 302 patients who received thrombolysis, of which 166 patients had mRS data at 90 days. In univariate analysis, exposure to any balanced solution was associated with increased 90-day disability (odds ratio (OR) 4.3, 95% confidence interval (CI) 3.8-4.9) and hemorrhagic transformation (OR 2.0, 95% CI 1.3-2.2). In multivariate analysis, exposure to a balanced solution at any time was associated with increased 90-day disability (OR 6.3, 95% CI 2.4-17.0, p < 0.01), but not hemorrhagic transformation. Thus, this observational trial demonstrated that exposure to balanced solutions is associated with an increased risk of disability at 90 days and possibly hemorrhagic transformation in patients with acute ischemic stroke treated with intravenous thrombolysis. This data would suggest that normal saline is a preferred solution in these patients, though larger future trials are needed.

Cell therapy has emerged as a prominent leader in regenerative medicine, offering potential solutions for various disorders, including infertility. Half of all infertility cases are related to male factors. The objective of this study is to systematically summarize the existing knowledge regarding studies on stem cell-based therapy for the regeneration of impaired spermatogenesis. Initial searching was performed through main databases (e.g., PubMed, Scopus, Cochrane Library, and Embase) until December 2023. Articles conducted on stem cell transplantation into the testis of infertile models were considered. The titles and abstracts of articles were carefully evaluated and screened by independent authors. Nonrelated articles were deleted. The desired outcomes of infertility treatment after stem cell transplantation were attentively evaluated in the final selected articles. In the primary search, 3237 published studies were identified. Finally, 39 studies were included based on the eligibility criteria. In all studies except for two articles, all the outcomes considered, including germ cells/spermatogonia stem cell differentiation, spermatogenesis restoration, defective testicular tissue regeneration, improved sperm quality parameters, and hormonal levels, as well as increased expression of fertility-related markers and fertility rate, were observed after stem cell transplantation. Transplantation of stem cells, especially MSCs could be a safe and effective method for the treatment of male infertility patients, such as azoospermic cases. Further research to investigate the efficiency of different stem cell sources, providing nutrient conditions for the isolation and differentiation of stem cells, and exploring the paracrine effects of MSCs in male infertility therapy, could be useful.

Kidney transplantation is a pivotal treatment for end-stage renal disease. However, renal ischemia-reperfusion injury (IRI) during surgery significantly impacts graft function. Despite unclear molecular mechanisms, no specific therapies or preventative measures are available. Gene expression profiles from renal biopsies before and after IRI were downloaded from public databases. Differentially expressed genes were identified using the Wilcoxon rank-sum test and weighted gene co-expression network analysis. Ferroptosis-associated genes were screened using the FerrDb database. The genes with the highest connectivity were identified via the protein-protein interaction (PPI) network and upstream regulatory miRNAs were found through the gene-miRNA network. A mouse renal IRI model was constructed for transcriptome sequencing and quantitative real-time polymerase chain reaction (qRT-PCR) validation to elucidate the relationship between key ferroptosis genes and regulatory miRNAs in renal IRI. Differential analysis identified 15 ferroptosis-associated genes (TNFAIP3, IL6, KLF2, EGR1, JUN, ZFP36, GDF15, CDKN1A, HSPB1, BRD2, PDK4, DUSP1, SLC2A3, DDIT3, and CXCL2) involved in renal IRI regulation. In animal experiments, ferroptosis-related genes were also upregulated in the model group. Enrichment analysis and hematoxylin-eosin pathological staining suggested these genes are primarily involved in renal inflammatory responses. PPI network analysis revealed IL6 as the gene with the highest connectivity, and the gene-miRNA network indicated IL6 might be regulated by miR-let-7a. Animal experiments revealed decreased miR-let-7a and increased IL6 levels in the model group, identifying potential therapeutic targets. MiR-let-7a regulates ferroptosis in renal IRI by targeting IL6, highlighting IL6 as a crucial gene in the ferroptosis process of renal IRI.

NKG2D chimeric antigen receptor (CAR)-modified T cells (NKG2D CAR-T cells) have been reported to be preclinically efficient in several tumors, but little is known whether NKG2D CAR-T cells co-expressing IL21 (IL21-NKG2D CAR-T cells) display greater antitumor activity in multiple myeloma (MM). In this study, the lentivirus has been produced for expression of the IL21 sequence linked to the extracellular NKG2D sequence with the signal peptide linked through the CD8α hinge-transmembrane domain to the 4-1BB molecule fused with the CD3-ζ chain signaling domain, and the engineered IL21-NKG2D CAR-T cells and NKG2D CAR-T cells were constructed. The CAR expression on CAR-T cells was assessed by flow cytometry, and the killing effects of CAR-T cells on MM were assessed by the cytotoxicity assay and ELISA assay. Moreover, xenograft models were also established to evaluate the ability of IL21-NKG2D-CAR-T cells to eliminate MM in vivo. Our results indicated that NKG2D CAR-T cells had dramatic cytotoxicity on MM cells in vitro, and co-expression of IL-21 significantly increased the cytotoxicity of NKG2D CAR-T cells on MM cells. Remarkably, we found that dexamethasone enhanced the cytotoxicity of IL21-NKG2D CAR-T cells on MM cells. Furthermore, IL21-NKG2D CAR-T cells also displayed significant anti-myeloma activity in vivo. In conclusion, IL21-NKG2D CAR-T cells had dramatic cytotoxicity on MM cells in vitro and in vivo, and a system to apply IL21-NKG2D CAR-T cells and low dosage of dexamethasone for the future study of the targeted therapy for MM has been established.

The occurrence of sepsis-associated acute kidney injury (SA-AKI) predicts a worse prognosis. We aimed to assess the impact of acetaminophen use on short-term mortality in patients with SA-AKI. A total of 6563 patients diagnosed with SA-AKI from the 2008 to 2019 Medical Information Mart for Intensive Care IV (MIMIC-IV) database were enrolled in this retrospective cohort study. The Cox regression model was utilized to analyze the associations of acetaminophen with 30-day mortality and in-hospital mortality. Additional propensity score matching (PSM) analysis was performed regarding patients with acetaminophen use versus those without. Of these patients, 30-day mortality occurred in 1421 (21.65%) patients and in-hospital mortality in 1246 (18.99%) patients. Patients who used acetaminophen were associated with a reduced risk of 30-day mortality (hazard ratio (HR) = 0.80, 95% confidence interval (CI): 0.71-0.90) and in-hospital mortality (HR = 0.72, 95% CI: 0.63-0.82). The PSM analysis demonstrated that acetaminophen use was still related to a reduced risk of 30-day mortality and in-hospital mortality. Subgroup analysis showed that the relationships between acetaminophen and 30-day mortality and in-hospital mortality were consistent across subgroups (p < 0.05). The use of acetaminophen has an association with lower short-term mortality in patients with SA-AKI.