Main mechanisms and clinical implications of alterations in energy expenditure state among patients with pheochromocytoma and paraganglioma: A review.

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors with diverse clinical presentations. Alterations in energy expenditure state are commonly observed in patients with PPGL. However, the reported prevalence of hypermetabolism varies significantly and the underlying mechanisms and implications of this presentation have not been well elucidated. This review discusses and analyzes the factors that contribute to energy consumption. Elevated catecholamine levels in patients can significantly affect substance and energy metabolism. Additionally, changes in the activation of brown adipose tissue (BAT), inflammation, and the inherent energy demands of the tumor can contribute to increased resting energy expenditure (REE) and other energy metabolism indicators. The PPGL biomarker, chromogranin A (CgA), and its fragments also influence energy metabolism. Chronic hypermetabolic states may be detrimental to these patients, with surgical tumor removal remaining the primary therapeutic intervention. The high energy expenditure of PPGL has not received the attention it deserves, and an accurate assessment of energy metabolism is the cornerstone for an adequate understanding and treatment of the disease.

Clinical features and risk factors for postoperative recurrence in patients with Cushing's syndrome of different etiologies.

The clinical characteristics of Cushing's syndrome (CS) vary with etiology, and few studies have investigated the risk factors affecting CS recurrence after surgery. This retrospective study involved 202 patients diagnosed with CS between December 2012 and December 2022. The patients were divided into three groups according to etiology: Cushing's disease (CD), adrenocortical adenoma (ACA), and ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS). Of the patients with CS, 41.9% had hypokalemia and 15.0% had hypophosphatemia. The cortisol levels were negatively correlated with blood potassium, blood chlorine, and blood phosphorus. Moreover, 22.4% of patients had an abnormal heart structure, 11.2% had centripetal remodeling, 5.6% had centripetal hypertrophy, and 5.6% had centrifugal hypertrophy. The overall recurrence rate of CS caused by pituitary tumors and adrenal adenoma was 25.7%. The recurrence times were longer in the ACA group versus the CD group, in patients < 50 years of age versus in patients ≥ 50 years old group, and in patients with CD with tumors ≥ 1 cm versus tumors < 1 cm. Age, preoperative cortisol level, postoperative cortisol level, and absolute neutrophil value were closely related to postoperative recurrence, and etiology was an independent predictor of tumor recurrence in patients with CS. The results of this study showed that CS caused by different etiologies showed different clinical manifestations, blood electrolyte characteristics, and that CS could affect patient cardiac structure and function. Etiology is an independent predictor of tumor recurrence in patients with CS.

Targeting DGAT1 inhibits prostate cancer cells growth by inducing autophagy flux blockage via oxidative stress.

Impaired macroautophagy/autophagy flux has been implicated in the treatment of prostate cancer (PCa). However, the mechanism underlying autophagy dysregulation in PCa remains unknown. In the current study, we investigated the role of diacylglycerol acyltransferases 1 (DGAT1) and its potential effects on cellular energy homeostasis and autophagy flux in PCa. The results of immunohistochemical staining suggested that DGAT1 expression was positively corrected with tumor stage and node metastasis, indicating DGAT1 is an important factor involved in the development and progression of PCa. Furthermore, targeting DGAT1 remarkably inhibited cell proliferation in vitro and suppressed PCa growth in xenograft models by triggering severe oxidative stress and subsequently autophagy flux blockage. Mechanically, DGAT1 promoted PCa progression by maintaining cellular energy homeostasis, preserving mitochondrial function, protecting against reactive oxygen species, and subsequently promoting autophagy flux via regulating lipid droplet formation. Moreover, we found that fenofibrate exhibits as an upstream regulator of DGAT1. Fenofibrate performed its anti-PCa effect involved the aforementioned mechanisms, and partially dependent on the regulation of DGAT1. Collectively. These findings indicate that DGAT1 regulates PCa lipid droplets formation and is essential for PCa progression. Targeting DGAT1 might be a promising method to control the development and progression of PCa. Schematic representation of DGAT1 affects autophagy flux by regulating lipid homeostasis and maintaining mitochondrial function in prostate cancer (PCa). PCa is characterized up-regulation of DGAT1, leading to the translocation of free fatty acids into lipid droplets, thereby preventing PCa cell from lipotoxicity. Inhibition of DGAT1 suppresses growth of PCa by inducing oxidative stress and subsequently autophagy flux blockage. Further, the current results revealed that fenofibrate exhibits as an upstream regulator of DGAT1, and fenofibrate plays an anti-PCa role partially dependent on the regulation of DGAT1, suggesting a potential therapeutic approach to ameliorate this refractory tumor.

Identification of key genes and pathways in adrenocortical carcinoma: evidence from bioinformatic analysis.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis. The disease originates from the cortex of adrenal gland and lacks effective treatment. Efforts have been made to elucidate the pathogenesis of ACC, but the molecular mechanisms remain elusive. To identify key genes and pathways in ACC, the expression profiles of GSE12368, GSE90713 and GSE143383 were downloaded from the Gene Expression Omnibus (GEO) database. After screening differentially expressed genes (DEGs) in each microarray dataset on the basis of cut-off, we identified 206 DEGs, consisting of 72 up-regulated and 134 down-regulated genes in three datasets. Function enrichment analyses of DEGs were performed by DAVID online database and the results revealed that the DEGs were mainly enriched in cell cycle, cell cycle process, mitotic cell cycle, response to oxygen-containing compound, progesterone-mediated oocyte maturation, p53 signaling pathway. The STRING database was used to construct the protein-protein interaction (PPI) network, and modules analysis was performed using Cytoscape. Finally, we filtered out eight hub genes, including CDK1, CCNA2, CCNB1, TOP2A, MAD2L1, BIRC5, BUB1 and AURKA. Biological process analysis showed that these hub genes were significantly enriched in nuclear division, mitosis, M phase of mitotic cell cycle and cell cycle process. Violin plot, Kaplan-Meier curve and stage plot of these hub genes confirmed the reliability of the results. In conclusion, the results in this study provided reliable key genes and pathways for ACC, which will be useful for ACC mechanisms, diagnosis and candidate targeted treatment.

Mechanisms of bariatric surgery for weight loss and diabetes remission.

Obesity and type 2 diabetes(T2D) lead to defects in intestinal hormones secretion, abnormalities in the composition of bile acids (BAs), increased systemic and adipose tissue inflammation, defects of branched-chain amino acids (BCAAs) catabolism, and dysbiosis of gut microbiota. Bariatric surgery (BS) has been shown to be highly effective in the treatment of obesity and T2D, which allows us to view BS not simply as weight-loss surgery but as a means of alleviating obesity and its comorbidities, especially T2D. In recent years, accumulating studies have focused on the mechanisms of BS to find out which metabolic parameters are affected by BS through which pathways, such as which hormones and inflammatory processes are altered. The literatures are saturated with the role of intestinal hormones and the gut-brain axis formed by their interaction with neural networks in the remission of obesity and T2D following BS. In addition, BAs, gut microbiota and other factors are also involved in these benefits after BS. The interaction of these factors makes the mechanisms of metabolic improvement induced by BS more complicated. To date, we do not fully understand the exact mechanisms of the metabolic alterations induced by BS and its impact on the disease process of T2D itself. This review summarizes the changes of intestinal hormones, BAs, BCAAs, gut microbiota, signaling proteins, growth differentiation factor 15, exosomes, adipose tissue, brain function, and food preferences after BS, so as to fully understand the actual working mechanisms of BS and provide nonsurgical therapeutic strategies for obesity and T2D.

Association of alcohol consumption with all-cause mortality, new-onset stroke, and coronary heart disease in patients with abnormal glucose metabolism-Findings from a 10-year follow-up of the REACTION study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and diabetic complications threaten human health seriously. Healthy lifestyles can lower the risk of cardiovascular disease (CVD) and long-term complications. However, the relationship between alcohol consumption and CVD mortality is still controversial, and there is a lack of evidence from large-scale longitudinal studies in the Chinese population. Based on the REACTION study (Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal Study), this paper explores the association between alcohol consumption and all-cause mortality, stroke, and coronary heart disease (CHD) in patients with abnormal glucose metabolism during a 10-year follow-up period to provide evidence for lifestyle counselling for these patients. METHODS: First, baseline data were collected from the REACTION study cohort in Changchun, Jilin Province, China, in 2011-2012. A questionnaire survey was performed among patients with abnormal glucose metabolism aged over 40 years. The frequency of their alcohol intake, the type of alcohol, and the amount of alcohol consumed daily were surveyed. Physical and biochemical examinations were also performed. Then, through the Primary Public Health Service System of Jilin Province, we collected outcomes during the 10-year follow-up up to October 1, 2021, including all-cause mortality, stroke, and CHD. Next, we conducted logistic regression to analyze the relationship between baseline alcohol consumption and 10-year outcomes, and risk ratio (RR) and 95% CI were calculated by adjusting for different clinical indicators. A p value < 0.05 was considered statistically significant. RESULTS: A total of 4855 patients with T2DM and prediabetes (35.2% men and 64.8% women) were included in the baseline analysis. Outcomes of 3521 patients during the 10-year follow-up were obtained, including 227 deaths, 296 new-onset strokes and 445 new-onset CHD. Occasional drinking (less than once a week) was associated with a reduced 10-year all-cause mortality, with an RR of 0.511 (95% CI [0.266, 0.982]) after adjustment for age, gender, medical history, and lifestyles and an RR of 0.50 (95% CI [0.252, 0.993]) in a fully adjusted model including additional biochemical indicators. In addition, heavy alcohol consumption (≥30 g/day for men and ≥15 g/day for women) was significantly associated with an increased incidence of stroke, with an RR of 2.503 (95% CI [1.138, 5.506]) after the adjustment for age, gender, medical history, lifestyles, and biochemical indicators. No significant association was found between alcohol consumption and new-onset CHD. CONCLUSIONS: For patients with abnormal glucose metabolism, occasional drinking (less than once a week) reduces the risk of all-cause mortality, while heavy alcohol consumption (≥30 g/day for men and ≥15 g/day for women) significantly increases the risk of new-onset stroke. They should avoid heavy alcohol intake, but light alcohol consumption or occasional drinking is acceptable. Additionally, it is crucial to control blood glucose and blood pressure and keep performing physical activities.

Pathogenesis, clinical features, and treatment of plurihormonal pituitary adenoma.

Plurihormonal pituitary adenoma (PPA) is a type of pituitary tumor capable of producing two or more hormones and usually presents as an aggressive, large adenoma. As yet, its pathogenesis remains unclear. This is the first study to systematically summarize the underlying pathogenesis of PPA. The pathogenesis is related to plurihormonal primordial stem cells, co-transcription factors, hormone co-expression, differential gene expression, and cell transdifferentiation. We conducted a literature review of PPA and analyzed its clinical characteristics. We found that the average age of patients with PPA was approximately 40 years, and most showed only one clinical symptom. The most common manifestation was acromegaly. Currently, PPA is treated with surgical resection. However, recent studies suggest that immunotherapy may be a potentially effective treatment.

Benign thyroid disease and the risk of breast cancer: An updated systematic review and meta-analysis.

Background: The correlation between benign thyroid disease (BTD) and breast cancer (BC) has long been discussed. However, the definite relationship and potential mechanism between them are still disputed. The current meta-analysis aimed at performing a comprehensive assessment of the relationship between different types of benign thyroid disease and the risk of breast cancer, furthermore, assessing whether benign thyroid disease exerts an influence on the aggressiveness of breast cancer. Method: A systematic literature search (PubMed, Web of Science, MEDLINE, and Embase databases) identified studies to evaluate the correlation between BTD and BC risk. Data were analyzed using version 16.0 STATA software, including the odds ratio (OR) and its corresponding 95% confidence intervals (CIs). Publication bias and quality assessment were conducted for the included studies. Result: Overall, 18 studies involving 422,384 patients with BTD were incorporated. The outcome showed that autoimmune thyroiditis (OR: 2.56, 95%CI: 1.95-3.37, I2 = 0.0%, p=0.460), goiter (OR: 2.13, 95%CI: 1.19-3.79, I2 = 80.6%, p=0.000), and Graves' disease (OR: 5.01, 95%CI: 1.49-16.82, I2 = 0.0%, p=0.358) was connected with a higher risk of BC. Both hypothyroidism (OR: 0.82, 95%CI: 0.64-1.04, I2 = 85.0%, p=0.000) and hyperthyroidism (OR: 1.07, 95%CI: 0.93-1.24, I2 = 24.9%, p=0.206) had no significant association with the risk of BC. Additionally, the pooled analysis showed no apparent correlation between BTD and aggressiveness of BC. However, subgroup analysis indicated a positive relationship between BTD and aggressiveness of BC in the Europe subgroup (HR: 2.05, 95%CI: 1.32-3.17, I2 = 86.4%, p=0.000). Conclusion: Autoimmune thyroiditis, goiter, and Graves' disease are connected with an increased risk of BC. Furthermore, subgroup analysis suggested that BTD increases the aggressiveness of BC in the European population geographically. Nevertheless, further research is needed to prove these discoveries.

Treatment of Primary Pigmented Nodular Adrenocortical Disease.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS), which mainly occurs in children and young adults. Treatment options with proven clinical efficacy for PPNAD include adrenalectomy (bilateral or unilateral adrenalectomy) and drug treatment to control hypercortisolemia. Previously, the main treatment of PPNAD is bilateral adrenal resection and long-term hormone replacement after surgery. In recent years, cases reports suggest that unilateral or subtotal adrenal resection can also lead to long-term remission in some patients without the need for long-term hormone replacement therapy. Medications for hypercortisolemia, such as Ketoconazole, Metyrapone and Mitotane et.al, have been reported as a preoperative transition for in some patients with severe hypercortisolism. In addition, tryptophan hydroxylase inhibitor, COX2 inhibitor Celecoxib, somatostatin and other drugs targeting the possible pathogenic mechanisms of the disease are under study, which are expected to be applied to the clinical treatment of PPNAD in the future. In this review, we summarize the recent progress on treatment of PPNAD, in which options of surgical methods, research results of drugs acting on possible pathogenic mechanisms, and the management during gestation are described in order to provide new ideas for clinical treatment.

Mechanism, diagnosis, and treatment of cyclic Cushing's syndrome: A review.

Cushing's syndrome (CS) is caused by hypercortisolemia, leading to the occurrence of characteristic clinical symptoms. A small number of patients with CS have periodic and intermittent increases in cortisol levels, resulting in recurrent episodes of clinical symptoms. Such patients are known as having cyclic CS (CCS). The cortisol secretion cycle of patients with CCS is unpredictable, and laboratory tests often show negative results during the normal cortisol secretion period; therefore, the diagnosis and treatment of the disease are currently difficult. Although the pathogenesis of CCS remains uncertain, recent studies have suggested that it may be closely related to hypothalamic factors, feedback mechanisms, and tumor infarction. Our review summarizes the current state of research on the potential mechanisms, diagnosis, and treatment of CS and provides an outlook for future studies.

Antidiabetic medications and the risk of prostate cancer in patients with diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Antidiabetic medications (ADMs) may modify prostate cancer (PCa) risk in patients with diabetes mellitus (DM). Accordingly, the current study assessed the possible associations between ADMs and the risk of PCa in diabetics. METHODS: A systematic literature search (PubMed, Embase and Cochrane Library) identified studies evaluating the associations between ADMs and incidence of PCa. A meta-analysis followed PRISMA was performed using odds ratio (OR) with 95% confidence interval (CI) as effect measures. RESULTS: In total of 47 studies involving 3094,152 patients with diabetes were included. Results of meta-analysis of the observational studies suggested no significant association between metformin, thiazolidinediones, sulfonylureas, insulin or dipeptidyl peptidase-4 inhibitors administration and the risk of PCa (All p-values > 0.05). Separate analysis of randomized controlled trials (RCTs) revealed a significant reduction in PCa risk with thiazolidinediones (OR = 0.55, p = 0.04) or glucagon-like peptide-1 receptor agonists (GLP-1RA) administration (OR = 0.53, p = 0.006), whereas no significant association was found in SGLT2 inhibitors (p = 0.3). CONCLUSION: Thiazolidinediones or GLP-1RA administration may have benefits in PCa based on RCTs, however, further research is needed to confirm these findings.

Liquid biopsy in prostate cancer: current status and future challenges of clinical application.

PURPOSE: Liquid biopsy refers to the detection and analysis of the components from biological fluids non-invasively, including circulating tumor cells, nucleic acids, and extracellular vesicles (EVs). It is necessary to review the clinical value of liquid biopsy assays in PC and explore its potential application. MATERIALS AND METHODS: We systematically reviewed of PubMed was performed to identify relevant literature on potential clinical applications of circulating tumor cells, circulating nucleic acids, and EVs in prostate cancer (PC). RESULTS: Liquid biopsy has emerged as a powerful tool to elucidate dynamic genomic, transcriptomic, and epigenomic tumor profiling in real-time. Here, the potential clinical applications of liquid biopsy include early detection, prognosis of survival, assessment of treatment response, and mechanisms of drug resistance in PC. CONCLUSIONS: Liquid biopsy provides great value in diagnosis, prognosis, and treatment response in PC. Characterization of liquid biopsy components provides benefits both to unravel underlying resistance mechanisms and to exploit novel clinically actionable targets in PC. In addition, we suggest that analysis of multiparametric liquid biopsies should be analyzed comprehensively, assisting in monitoring tumor characteristics in real-time, guiding therapeutic selection, and early therapeutic switching during disease progression.

Advances in Understanding the Roles of CD244 (SLAMF4) in Immune Regulation and Associated Diseases.

Proteins in the signaling lymphocytic activating molecule (SLAM) family play crucial roles in regulating the immune system. CD244 (SLAMF4) is a protein in this family, and is also a member of the CD2 subset of the immunoglobulin (Ig) superfamily. CD244 is a cell surface protein expressed by NK cells, T cells, monocytes, eosinophils, myeloid-derived suppressor cells, and dendritic cells. CD244 binds to the ligand CD48 on adjacent cells and transmits stimulatory or inhibitory signals that regulate immune function. In-depth studies reported that CD244 functions in many immune-related diseases, such as autoimmune diseases, infectious diseases, and cancers, and its action is essential for the onset and progression of these diseases. The discovery of these essential roles of CD244 suggests it has potential as a prognostic indicator or therapeutic target. This review describes the molecular structure and function of CD244 and its roles in various immune cells and immune-related diseases.

Quantifying observational evidence for risk of dementia following androgen deprivation therapy for prostate cancer: an updated systematic review and meta-analysis.

BACKGROUND: Androgen deprivation therapy (ADT) administration was recently reported and might be positively associated with dementia. However, the existing studies showed controversial results. The aim of this study was to evaluate the relationship between ADT and the risk of dementia through a meta-analysis. METHODS: Original articles published up to March 2020 were retrieved from Embase, Pubmed, the Cochrane library, and Web of Science for studies focusing on associations between ADT for prostate cancer (PCa) and incidence of dementia. A meta-analysis was conducted using a hazard ratio (HR) and 95% confidence interval (CI) as effect measures. Heterogeneity between the studies was examined using I2 statistics. Subgroup analyses, sensitivity analyses, and meta-regression were conducted, and publication bias was assessed by Egger's test. RESULTS: Thirteen studies were included in this systematic review. Eleven cohort studies involving 339,400 cases and 436,851 controls were included in the main meta-analysis. ADT administration was associated with a 21% increase in dementia risk (pooled HR = 1.21, 95% CI: 1.13-1.30, P < 0.001). Subgroup analyses based on ADT types showed that luteinizing hormone-releasing hormone agonists (HR = 1.14, P < 0.001), bilateral orchiectomy (HR = 1.42, P < 0.001), oral antiandrogens (HR = 1.35, P = 0.138), and combined androgen blockade (HR = 1.22, P = 0.097) were positively related to subsequent risk of dementia, although the differences were not statistically significant with oral antiandrogens and combined androgen blockade. CONCLUSIONS: The current study indicated that ADT administration, no matter with types of ADT, is associated with the risk of dementia in patients with PCa. Future studies are needed to determine whether ADT causes dementia or is merely associated with increased risk.

Eight rare urinary disorders in a patient with Kallmann syndrome: A case report.

RATIONALE: Kallmann syndrome (KS) is a rare inherited genetic disorder characterized by hypogonadotropic hypogonadism and hyposmia/anosmia. Early diagnosis is the key to timely treatment and improvement of prognosis in patients with KS. As the most common complication of KS, renal agenesis can provide clues to early diagnosis and treatment for KS. In this article, we report a case of KS with 8 rare urinary disorders for the first time. PATIENT CONCERNS: A 19-year-old Chinese man presented with 8 rare urinary disorders and a history of bilateral cryptorchidism came to us for micropenis, hyposmia, and delayed puberty. DIAGNOSIS: The patient presented with hyposmia, low levels of sex hormones and showed a weak response to the GnRH stimulation test leading to a diagnosis of KS. Two missense mutations were found in further whole-exome sequencing: 1) Kallmann syndrome 1 (KAL1) gene in exon11, c.1600G > A, p. Val534Ile; 2) Prokineticin receptor 2 (PROKR2) gene in exon 2, c.533G > A, p. Trp178Ser. which led to a diagnosis of KS. INTERVENTIONS: The patient underwent replacement therapy of human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG). The patient had previously undergone six surgeries for cryptorchidism and urinary disorders. OUTCOMES: The patient's puberty retardation was effectively alleviated. His serum testosterone (T) reached a normal level (8.280 nmol/mL). During the follow-up period, he presented with Tanner stage II pubic hair development. CONCLUSION: In this article, we report 8 rare urinary disorders with missense mutations of KAL1 and PROKR2 in a case of KS. Among them, bilateral giant kidneys, urinary extravasation of right renal, bilateral megalo-ureters, left ureteral terminal obstruction, bilateral renal cyst and bladder emptying disorder are reported for the first time, which enrich the integrity of urinary disorder types and provide clues to genetic counseling in patients with KS.

20(S)-Ginsenoside Rg3 Protects Kidney from Diabetic Kidney Disease via Renal Inflammation Depression in Diabetic Rats.

20(S)-Ginsenoside Rg3 (20(S)-Rg3) has been shown to induce apoptosis by interfering with several signaling pathways. Furthermore, it has been reported to have anticancer and antidiabetic effects. In order to detect the protective effect of 20(S)-Rg3 on diabetic kidney disease (DKD), diabetic rat models which were established by administering high-sugar, high-fat diet combined with intraperitoneal injection of streptozotocin (STZ), and age-matched wild-type (WT) rat were given 20(S)-Rg3 for 12 weeks, with three groups: control group (normal adult rats with saline), diabetic group (diabetic rats with saline), and 20(S)-Rg3 treatment group (diabetic rats with 20(S)-Rg3 (10 mg/kg body weight/day)). The biochemical indicators and the changes in glomerular basement membrane and mesangial matrix were detected. TUNEL staining was used to detect glomerular and renal tubular cell apoptosis. Immunohistochemical staining was used to detect the expression of fibrosis factors and inflammation factors in rat kidney tissues. Through periodic acid-Schiff staining, we observed that the change in renal histology was improved and renal tubular epithelial cell apoptosis decreased significantly by treatment with 20(S)-Rg3. Plus, the urine protein decreased in the rats with the 20(S)-Rg3 treatment. Fasting blood glucose, creatinine, total cholesterol, and triglyceride levels in the 20(S)-Rg3 treatment group were all lower than those in the diabetic group. Mechanistically, 20(S)-Rg3 dramatically downregulated the expression of TGF-ß1, NF-κB65, and TNF-α in the kidney. These resulted in a significant prevention of renal damage from the inflammation. The results of the current study suggest that 20(S)-Rg3 could potentially be used as a novel treatment against DKD.

Cardiovascular effects of growth hormone (GH) treatment on GH-deficient adults: a meta-analysis update.

BACKGROUND: It is still unclear whether growth hormone (GH) replacement is able to improve cardiovascular parameters in adults with GH deficiency (AGHD) from the updated clinical trials reported to date. METHODS AND RESULTS: We systematically reviewed clinical trials of GH treatment on AGHD patients in recent decade, and evaluated the effects of GH on cardiovascular parameters assessed by echocardiography. 11 clinical trials were identified in 3 bibliographic databases. We conducted a combined analysis of effects on four aspects: General indicators: baseline heart rate (BHR), peak heart rate (PHR), systolic blood pressure (SBP), diastolic blood pressure (DBP); Cardiac structure: left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), left ventricular interventricular septum (LVIS), left ventricular mass (LVM), left ventricular posterior wall (LVPW); Cardiovascular function: deceleration time of E wave (DT), E/A ratio (E/A), ejection fraction (EF), NT-BNP; Life quality: peak VO2, VE/VCO2 slope. Overall effect size was used to evaluate significance, and weighted mean difference after GH treatment was given to appreciate size of the effect. GH treatment was associated with a significant increase in BHR (3.03[2.00, 4.06]), LVIS (0.50[0.43, 0.57]), LVPW (0.50[0.43, 0.57]), and EF (2.12[1.34, 2.90]). Overall effect sizes were negative significant for DBP (- 1.19[- 2.33, - 0.05]), LVEDV (- 9.84[- 16.53, - 3.15]), NT-BNP (- 206.34[- 308.95, - 103.72]), and VE/VCO2 slope (- 2.31[- 2.92, - 1.71]). CONCLUSIONS: As assessed by echocardiography, GH administration may improve the general vital signs and life quality of AGHD patients, based on the positive effect on BHR and negative effects on DBP and VE/VCO2 slope. Also, GH treatment would influence the structure of heart with positive effects on LVIS, LVPW and negative effect on LVEDV, which together with the increase of EF and decrease of NT-BNP, then resulting in improving the systolic function of AGHD patients.

Inappropriate Antidiuretic Hormone Secretion and Cerebral Salt-Wasting Syndromes in Neurological Patients.

The differential diagnosis of syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cerebral salt-wasting syndrome (CSWS) in patients with neurological disorders has been a perplexing clinical controversy. The purpose of this review is to summarize the characteristics and risk factors of patients with different types of neurological disorders complicated by hyponatremia (HN) and review various methods to distinguish SIADH from CSWS. Common neurological disorders with high rates of HN include subarachnoid hemorrhage (SAH), traumatic brain injuries, stroke, cerebral tumors, central nervous system (CNS) infections, and Guillain-Barré syndrome (GBS), which have their own characteristics. Extracellular volume (ECV) status of patients is a key point to differentiate SIADH and CSWS, and a comprehensive assessment of relevant ECV indicators may be useful in differentiating these two syndromes. Besides, instead of monitoring the urinary sodium excretion, more attention should be paid to the total mass balance, including Na+, K+, Cl-, and extracellular fluid. Furthermore, the dynamic detection of fractional excretions (FE) of urate before and after correction of HN and a short-term infusion of isotonic saline solution may be useful in identifying the etiology of HN. As for brain natriuretic peptide (BNP) or N-terminal prohormone of BNP (NT-proBNP), more prospective studies and strong evidence are needed to determine whether there is a pertinent and clear difference between SIADH and CSWS.

Overcoming EZH2 Inhibitor Resistance by Taxane in PTEN-Mutated Cancer.

Rationale: The Polycomb group (PcG) protein EZH2 is implicated in cancer progression due to its frequent overexpression in many cancer types and therefore is a promising therapeutic target. Forkhead box transcription factor-1 (FOXO1) is a tumor suppressor that is often transcriptionally downregulated in human cancers such as prostate cancer although the underlying regulatory mechanisms remain elusive. Methods: Analysis of EZH2 ChIP-seq and ChIP-on-chip data in various cell types was performed. ChIP-qPCR, RT-qPCR, and western blot analyses were conducted to determine the mechanism by which EZH2 represses FOXO1 expression. Immunohistochemistry was employed to assess the correlation between EZH2 and FOXO1 protein expression in prostate cancer patient specimens. In vitro MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) and animal experiments were performed to determine the anti-cancer efficacy of EZH2 inhibitor alone or in combination of docetaxel, a chemotherapy agent of the taxane family, and dependency of the efficacy on FOXO1 expression. Results: We demonstrated that EZH2 binds to the FOXO1 gene promoter. EZH2 represses FOXO1 gene expression at the transcriptional level. EZH2 protein level inversely correlated with FOXO1 protein expression in prostate cancer patient specimens. This repression requires the methyltransferase activity and the functional PRC2 complex. While effectively inducing loss of viability of PTEN-positive 22Rv1 prostate cancer cells, EZH2 inhibitor failed to inhibit growth of PTEN-negative C4-2 prostate cancer cells. Co-treatment with docetaxel overcame EZH2 inhibitor resistance in PTEN-negative cancer cells in vitro and in mice. This effect was largely mediated by docetaxel-induced nuclear localization and activation of FOXO1. Conclusions: This study identifies FOXO1 as a bona fide repression target of EZH2 and an essential mediator of EZH2 inhibition-induced cell death. Our findings suggest that EZH2 repression of FOXO1 can be targeted by EZH2 inhibitor as a monotherapy for PTEN-proficient cancers or in combination with taxane for treatment of cancers with PTEN mutation or deletion.

Small cell lung cancer starting with diabetes mellitus: Two case reports and literature review.

BACKGROUND: Small-cell lung cancer (SCLC) is a type of fatal tumor that is increasing in prevalence. While these are unpleasant facts to consider, it is vitally important to be informed, and it is important to catch the disease early. Typically, lung cancer does not show severe clinical symptoms in the early stage. Once lung cancer has progressed, patients might present with classical symptoms of respiratory system dysfunction. Thus, the prognosis of SCLC is closely related to the early diagnosis of the disease. Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is related to cancer occurrence, especially for SCLC with the presence of Cushing's syndrome, which is dependent on markedly elevated ACTH and cortisol levels. CASE SUMMARY: In the current report, we describe two middle-age patients who were originally diagnosed with diabetes mellitus with no classical symptoms of lung cancer. The patients were eventually diagnosed with SCLC, which was confirmed by bronchoscopic biopsy and histopathology. SCLC-associated diabetes was related to EAS, which was an endogenous ACTH-dependent form of Cushing's syndrome with elevated ACTH and cortisol levels. Multiple organ metastases were found in Patient 1, while Patient 2 retained good health at 2 years follow-up. EAS symptoms including thyroid dysfunction, hypercortisolism and glucose intolerance were all resolved after anticancer treatment. CONCLUSION: In conclusion, SCLC might start with diabetes mellitus and increased cortisol and hypokalemia or other EAS symptoms. These complex clinical features were the most significant factors to deteriorate a patient's condition. Early diagnosis and treatment from clinicians were essential for the anti-cancer treatment for patients with SCLC.