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With advances in tissue typing, organ preservation techniques, and clinical surgery, organ transplantation has gained popularity as a treatment option for various end-stage diseases. Allogeneic transplantation has been widely adopted and extensively researched in clinical practice. Despite significant breakthroughs and progress in immunosuppression, this procedure is still associated with several adverse reactions and complications. Therefore, there is a continuing need to explore new immunological approaches to provide fresh insights and guidance for clinical transplantation. CD8+ T cells, traditionally known for their cytotoxic function and their ability to recognize transplanted organs as "non-self entities, display cytotoxicity. However, recent studies have unveiled that CD8+ T cells have various subtypes and functions that extend beyond conventional cytotoxicity. These CD8+ T cell subtypes include Effector CD8+ T cells, Memory CD8+ T cells, and CD8Treg cells. This review examines the immune regulatory mechanisms of CD8i T cells in allogeneic transplantation and discusses the potential applications of CD8+ T cells in treating tumors in transplant recipients who are receiving immunosuppressive therapy. These findings offer theoretical guidance for reducing post-transplant rejection reactions and improving adverse prognoses, offering new hope for improved clinical survival rate. [ABSTRACT FROM AUTHOR]

The article discusses the Warburg effect, a phenomenon where cancer cells use glycolysis instead of oxidative phosphorylation for energy production. It explores the reasons why cancer cells expel lactate instead of utilizing it and how the Warburg effect can be targeted for cancer treatment. The article suggests that dysfunctional mitochondria and epigenetic remodeling play a role in cell dedifferentiation and tumorigenesis. It also discusses the potential use of mitochondrial uncouplers as a therapeutic strategy. Further research is needed to understand the molecular mechanisms and validate the efficacy of these treatments. [Extracted from the article]

Uncoupling of mitochondrial respiration by chemical uncouplers has proven effective in ameliorating obesity, insulin resistance, and hyperglycemia. However, development of uncoupler-based therapy remains challenging due to its potentially lethal adverse effects. Here, we identify pyruvate dehydrogenase (PDH) as a key modifier of the toxicity profile of 2, 4-dinitrophenol (DNP), a prototypical mitochondrial uncoupler. PDH activation by dichloroacetic acid (DCA) protects mice from DNP-induced hyperlactacidemia, hyperthermia, and death while preserving the ability of DNP to promote fuel oxidation and improve insulin sensitivity in mice. Mechanistically, PDH activation switches on mitochondrial glucose oxidation to accommodate increased glycolytic flux, leading to reduced lactate secretion during uncoupler treatments. We devised a chemical screening strategy and discovered compound 6j as a dual-action compound that simultaneously activates PDH and uncouples mitochondrial respiration. Compound 6j exhibits an excellent efficacy and safety profile in restoring glucose homeostasis in diabetic mice. This work establishes a new principle to safely harness the power of chemical uncouplers for the treatment of metabolic disease. [ABSTRACT FROM AUTHOR]

Gossypol is known to be a polyphenolic compound toxic to animals. However, its molecular targets are far from fully characterized. To evaluate the physiological and molecular effects of gossypol, we chose turbot (Scophthalmus maximus L.), a carnivorous fish, as our model species. Juvenile turbots (7.83 ± 0.02 g) were fed diets containing gradient levels of gossypol at 0 (G0), 600 (G1), and 1,200 (G2) mg/kg diets for 11 wk. After the feeding trial, fish growth, body protein, and fat contents were significantly reduced in the G2 group compared with those of the G0 group (P < 0.05). Gossypol had little impact on digestive enzyme activities and intestine morphology. However, gossypol caused liver fibrosis and stimulated chemokine and proinflammatory cytokine secretions. More importantly, gossypol suppressed target of rapamycin (TOR) signaling and induced endoplasmic reticulum (ER) stress pathway in both the feeding experiment and cell cultures. Our results demonstrated that gossypol inhibited TOR signaling and elevated ER stress pathways both in vivo and in vitro, thus providing new mechanism of action of gossypol in nutritional physiology. [ABSTRACT FROM AUTHOR]

Early detection is the key to improve the prognosis of kidney cancer. This study profiled and identified differentially expressed serum proteins in stage T1a renal cell carcinoma (RCC) using isobaric tags for relative and absolute quantification (iTRAQ)-based mass spectrometry. A total amount of 99 serum samples including 29 patients with ccRCC, 24 patients with a benign kidney mass, 28 patients with another type of urological tumor (20 cases of transitional cell carcinoma and 8 cases of prostate cancer or a male genital tumor), and 18 healthy controls were subjected to iTRAQ-based mass spectrometry. ProteinPilot software was used to identify the differentially expressed serum proteins in RCC compared to the other three populations. Hierarchical clustering analysis according to The Cancer Genome Atlas (TCGA) RCC database was then performed as the cross-platform validation. Immunohistochemistry was performed to verify the expression of selected proteins in tissue samples from these subjects. iTRAQ identified 27 differentially expressed serum proteins in the RCC patients, and 11 of these proteins were cross validated in RCC tissues from the TCGA database. The expression of C1QC, C1QB, S100A8, S100A9, ceruplasmin, and lumican was verified and associated with the tumor stage and/or grade. There were 27 differentially expressed proteins in early-stage RCC identified by iTRAQ; among them, the expression of C1QC, C1QB, S100A8, S100A9, ceruplasmin, and lumican were associated with the tumor stage and/or grade. Further studies are needed to confirm these data for their use as biomarkers for the early detection of RCC. [ABSTRACT FROM AUTHOR]

In order to investigate the two members of the EF-hand Ca2+ binding protein S100 family, S100A8 and S100A9, in renal cell carcinoma (RCC), serum samples were collected from patients with RCC, transitional cell carcinoma in the kidney, benign renal masses and normal controls. The samples were analyzed by isobaric tags for relative and absolute quantification technology to identify the differential expression of S100A8 and S100A9 in the respective groups. Hierarchical clustering analysis was then conducted for the samples and the relevant selected gene. The cross-platform analysis for the external validation was performed by means of The Cancer Genome Atlas database, containing the gene/microRNA expression pattern and clinical information of patients with RCC. Immunohistochemical staining was used to verify the expression of S100A8 and S100A9 in the four groups. As a result, serum and mRNA expression levels of S100A8 and S100A9 were found to be upregulated in patients with RCC compared with the other three groups, which was consistent with the result of the upregulated expression of mRNA levels in RCC tissue. The overexpression of S100A8 and S100A9 in cancer cells was also confirmed by immunohistochemistry. In addition, bioinformatics revealed that let-7, a microRNA formerly identified as an inhibiting factor of RCC was downregulated in RCC, which contrasted with S100A8. It was also complementary to the sequence at the 3' untranslated region terminal of S100A8. Therefore, indicating that S100A8 and S100A9 may serve as biomarkers for the detection of RCC. [ABSTRACT FROM AUTHOR]

Background: Prostate-specific antigen (PSA) screening is growing in popularity in China, but its impact on biopsy characteristics and outcomes are poorly understood. Objective: Our objective was to characterize prostate biopsy outcomes and trends in Chinese men over a 10-year period, since the increasing use of PSA tests. Methods: All men (n = 1,650) who underwent prostate biopsy for PCa at Huashan Hospital, Shanghai, China from 2003-2011 were evaluated. Demographic and clinical information was collected for each patient, including age, digital rectal examination (DRE), transrectal ultrasound (prostate volume and nodule), total prostate-specific antigen (tPSA) levels and free PSA ratio (fPSA/tPSA) prior to biopsy. Prostate biopsy was performed using six cores before October 2007 or ten cores thereafter. Logistic regression and multivariate analysis were used to evaluate our data. Results: The overall positive rate of prostate biopsy for PCa was 47% and the rate decreased significantly over the years from 74% in 2003 to 33% in 2011 (P-trend = 0.004) . Age at diagnosis was slightly increased (P-trend = 0.04) while fPSA/tPSA was significantly decreased (P-trend = 1.11x10-5). A statistically significant trend was not observed for tPSA levels, prostate volume, or proportion of positive nodule. The model including multiple demographic and clinical variables (i.e., age, DRE, tPSA, fPSA/tPSA and transrectal ultrasound results) (AUC = 0.93) statistically outperformed models that included only PSA (AUC = 0.85) or fPSA/tPSA (AUC = 0.66) to predict PCa risks (P<0.05). Similar results were observed in a subgroup of men whose tPSA levels were lower than 20 ng/mL (AUC = 0.87, vs. AUC of tPSA = 0.62, P<0.05). Conclusions: Detection rates of PCa and high-grade PCa among men that underwent prostate biopsy at the institution has decreased significantly in the past 10 years, likely due to increasing use of PSA tests. Predictive performance of demographic and clinical variables of PCa was excellent. These variables should be used in clinics to determine the need for prostate biopsy. [ABSTRACT FROM AUTHOR]

Purpose We evaluated the effectiveness and safety of holmium YAG laser lithotripsy with a semirigid ureteroscope for ureteral calculi in a prospective cohort of 697 patients.Patients and Methods Holmium YAG laser lithotripsy was performed with a semirigid ureteroscope in 697 inpatients between September 2002 and January 2006. Calculi were located in the distal ureter in 382 patients (54.8), the midureter in 143 (20.5), and the proximal ureter in 172 (24.7). Patients were assessed 2 to 24 weeks postoperatively with repeat plain radiography, ultrasonography, intravenous urography, or some combination.Results The overall stone-free rate was 92.2, the rate being 100 for calculi in the distal ureter (N 382), 97.9 for calculi in the midureter (N 140), and 70.3 for calculi in the proximal ureter (N 121). Complications occurred in 13 patients (1.9). Postoperative ureteral stricture developed in five patients (0.72) and was managed surgically.Conclusions Holmium YAG laser lithotripsy with a semirigid ureteroscope is a highly effective and safe treatment for ureteral calculi, especially those in the distal ureter and midureter. [ABSTRACT FROM AUTHOR]

Loss of estrogen receptor (ER) pathway activity promotes breast cancer progression, yet how this occurs remains poorly understood. Here, we show that serine starvation, a metabolic stress often found in breast cancer, represses estrogen receptor alpha (ERa) signaling by reprogramming glucose metabolism and epigenetics. Using isotope tracing and time-resolved metabolomic analyses, we demonstrate that serine is required to maintain glucose flux through glycolysis and the TCA cycle to support acetyl-CoA generation for histone acetylation. Consequently, limiting serine depletes histone H3 lysine 27 acetylation (H3K27ac), particularly at the promoter region of ER pathway genes including the gene encoding ERα, ESR1. Mechanistically, serine starvation impairs acetyl-CoA-dependent gene expression by inhibiting the entry of glycolytic carbon into the TCA cycle and down-regulating the mitochondrial citrate exporter SLC25A1, a critical enzyme in the production of nucleocytosolic acetyl-CoA from glucose. Consistent with this model, total H3K27ac and ERα expression are suppressed by SLC25A1 inhibition and restored by acetate, an alternate source of acetyl-CoA, in serine-free conditions. We thus uncover an unexpected role for serine in sustaining ER signaling through the regulation of acetyl-CoA metabolism. [ABSTRACT FROM AUTHOR]

Background: Penoscrotal extramammary Paget's disease is a rare, slow-growing neoplasm with high frequency of local recurrence.Aims: The aim of this study was to investigate the difference in clinicopathological characteristics between first-time and recurrent penoscrotal Paget's disease, and to discover the potential risk factors of recurrence.Methods: Between January 2007 and February 2014, a total of 164 Chinese patients with biopsy-proven tramammary Paget's diseaseex in penis and scrotum underwent wide local resection in our institution. Among them, 142 patients with first-time disease and other 22 patients with recurrent disease were enrolled in this retrospective analysis.Results: The median duration of symptoms was much shorter in recurrent disease than in first-timers (3 vs. 24 months, P < 0.001). Patients with recurrent disease tended to have lower lesion exudation rates (27.3% vs. 51.8%, P= 0.032). In addition, patients with distant stage were more likely to obtain recurrent disease compared with first-time disease (P = 0.005). Through immunohistochemical detection of extramammary Paget's specimen, we found that HER2/neu protein expression in the recurrent group was significantly higher than first-timers (P = 0.036).Limitations: In this study, the information on familial history of most patients was insufficient. Moreover, due to the lack of follow-up data of our included cases, we were unable to evaluate the prognosis after diagnosis of extramammary Paget's disease.Conclusion: Patients with penoscrotal Paget's disease, especially those with shorter duration of symptoms, exudation of lesions, distant-stage, Paget cells infiltrating into adnexa, and HER2/neu expression, should be followed up more carefully after surgery, as they were more likely to suffer recurrence. [ABSTRACT FROM AUTHOR]

Background: Neo-adjuvant hormone therapy (NHT) following radical prostatectomy (RP) or radiotherapy has been utilized in the multimodal approach to patients with intermediate- to high-risk prostate cancer (PCa). Herein, we performed a systematic review and meta-analysis of published randomized trials to evaluate the clinical efficacy of NHT. Methods: Literatures were searched from PubMed, EMBASE, Web of Science, and Cochrane Library for comparing neo-adjuvant therapy group (NHT plus radiotherapy or radical prostatectomy) with traditional therapy (radiotherapy or prostatectomy) alone. Quality of the research was assessed on the basis of the Cochrane's risk of bias of randomized controlled trial. Comparable information were obtained from eligible trials and assembled for meta-analysis up to 31 August 2014. RevMan 5.2 software was used for statistical analysis. Results: Fifteen randomized controlled trials (RCTs) (total 5,194 patients) were included in this study. Meta-analysis showed there was a significant improvement in overall survival (OS) (Odds ratio (OR) = 1.51, 95% confidence interval (CI) 1.22 to 1.87, P = 0.0002), positive surgical margin (PSM) rate (OR = 0.30, 95% CI 0.24 to 0.38, P < 0.00001), and biochemical disease-free survival (bDFS) (OR = 1.95, 95% CI 1.13 to 3.39, P = 0.02), but no significant difference in disease-free survival (OR = 1.52, 95% CI 0.90 to 2.59, P = 0.12) and clinical disease-free survival (cDFS) (OR = 0.96, 95% CI 0.22 to 4.18, P = 0.95). Heterogeneity and risk of bias were observed between different studies. Conclusions: Patients with aggressive prostate cancer would better benefit from the receipt of neo-adjuvant therapy. Physicians should make individualized treatment strategies according to adverse reactions, financial capacities, and personal wishes. [ABSTRACT FROM AUTHOR]

Estrogen may help to preserve renal function in chronic kidney disease. This study examined whether estrogen administration or deprivation affected the split renal function in rats subjected to chronic unilateral ureteral obstruction (UUO). Fifteen adult female Sprague-Dawley rats were randomly divided into three groups. Low- and high-estrogen groups were modeled by female castration or estrogen intraperitoneal injection, respectively, and the rats in the normal-estrogen group were untreated. Intermittent split renal function [glomerular filtration rate (GFR)] examination was performed on rats on days 2, 6 and 16 after UUO surgery via single-photon emission computed tomography (SPECT/CT). Routine hematoxylin and eosin (H&E) staining, immunohistochemistry, pathology examination and electron microscopy were performed to compare the histological differences. Low-, normal- and high-estrogen groups were successfully established (P<0.001). In the acute stage, the GFR of the contralateral healthy kidney showed a greater compensatory rise in the normal- and high-estrogen groups than in the low-estrogen group (P<0.05). In the chronic stage, the GFR of the obstructed kidney continued to decrease with the GFR of the high-estrogen group being significantly better preserved than that of the low-estrogen group (P<0.05). The GFR of the contralateral kidney compensated to the greatest extent in the high-estrogen group (P=0.01), and the total GFR was significantly superior (P<0.05). Routine H&E examination showed significant histological changes following surgery. The low-estrogen group had significant renal interstitial fibrosis compared with the normal- and high-estrogen groups (P<0.05), as observed by immunohistochemical (IHC) examination of transforming growth factor-β (TGF-β) and α-smooth muscle actin (α-SMA). Electron-microscopic (EM) examination also differentiated between groups. In conclusion, estrogen administration and deprivation significantly affected renal function. Estrogen may preserve the split renal function (GFR) in rats with chronic UUO. [ABSTRACT FROM AUTHOR]