Muscle plasticity is influenced by renal function and caloric intake through the FGF23-vitamin D axis.

Skeletal muscle, the main metabolic engine in the body of vertebrates, is endowed with great plasticity. The association between skeletal muscle plasticity and two highly prevalent health problems: renal dysfunction and obesity, which share etiologic links as well as many comorbidities, is a subject of great relevance. It is important to know how these alterations impact on the structure and function of skeletal muscle because the changes in muscle phenotype have a major influence on the quality of life of the patients. This literature review aims to discuss the influence of a nontraditional axis involving kidney, bone, and muscle on skeletal muscle plasticity. In this axis, the kidneys play a role as the main site for vitamin D activation. Renal disease leads to a direct decrease in 1,25(OH)2-vitamin D, secondary to reduction in renal functional mass, and has an indirect effect, through phosphate retention, that contributes to stimulate fibroblast growth factor 23 (FGF23) secretion by bone cells. FGF23 downregulates the renal synthesis of 1,25(OH)2-vitamin D and upregulates its metabolism. Skeletal production of FGF23 is also regulated by caloric intake: it is increased in obesity and decreased by caloric restriction, and these changes impact on 1,25(OH)2-vitamin D concentrations, which are decreased in obesity and increased after caloric restriction. Thus, both phosphate retention, that develops secondary to renal failure, and caloric intake influence 1,25(OH)2-vitamin D that in turn plays a key role in muscle anabolism.

Effect of caloric restriction on phosphate metabolism and uremic vascular calcification.

Caloric restriction (CR) is known to have multiple beneficial effects on health and longevity. To study the effect of CR on phosphorus metabolism and vascular calcification (VC), rats were fed normal or restricted calories (67% of normal). The phosphorus content of the diets was adjusted to provide equal phosphorus intake independent of the calories ingested. After 50 days of CR, rats had negative phosphorus balance, lower plasma phosphorus, glucose, triglycerides, and leptin, and higher adiponectin than rats fed normal calories. Uremia was induced by 5/6 nephrectomy (Nx). After Nx, rats were treated with calcitriol (80 ng/kg ip every other day) and high-phosphorus diets (1.2% and 1.8%). No differences in aortic calcium content were observed between rats that ate normal or restricted calories before Nx in either rats that received 1.2% phosphorus (11.5 ± 1.7 vs. 10.9 ± 2.1 mg/g tissue) or in rats that received 1.8% phosphorus (12.5 ± 2.3 vs. 12.0 ± 2.9 mg/g of tissue). However, mortality was significantly increased in rats subjected to CR before Nx in both the 1.2% phosphorus groups (75% vs. 25%, P = 0.019) and 1.8% phosphorus groups (100% vs. 45%, P < 0.001). After calcitriol administration was stopped and phosphorus intake was normalized, VC regressed rapidly, but no significant differences in aortic calcium were detected between rats that ate normal or restricted calories during the regression phase (5.7 ± 2.7 and 5.2 ± 1.5 mg/g tissue). In conclusion, CR did not prevent or ameliorate VC and increased mortality in uremic rats.

Mesothelial-to-mesenchymal transition as a possible therapeutic target in peritoneal metastasis of ovarian cancer.

Peritoneal dissemination is the primary metastatic route of ovarian cancer (OvCa), and is often accompanied by the accumulation of ascitic fluid. The peritoneal cavity is lined by mesothelial cells (MCs), which can be converted into carcinoma-associated fibroblasts (CAFs) through mesothelial-to-mesenchymal transition (MMT). Here, we demonstrate that MCs isolated from ascitic fluid (AFMCs) of OvCa patients with peritoneal implants also undergo MMT and promote subcutaneous tumour growth in mice. RNA sequencing of AFMCs revealed that MMT-related pathways - including transforming growth factor (TGF)-ß signalling - are differentially regulated, and a gene signature was verified in peritoneal implants from OvCa patients. In a mouse model, pre-induction of MMT resulted in increased peritoneal tumour growth, whereas interfering with the TGF-ß receptor reduced metastasis. MC-derived CAFs showed activation of Smad-dependent TGF-ß signalling, which was disrupted in OvCa cells, despite their elevated TGF-ß production. Accordingly, targeting Smad-dependent signalling in the peritoneal pre-metastatic niche in mice reduced tumour colonization, suggesting that Smad-dependent MMT could be crucial in peritoneal carcinomatosis. Together, these results indicate that bidirectional communication between OvCa cells and MC-derived CAFs, via TGF-ß-mediated MMT, seems to be crucial to form a suitable metastatic niche. We suggest MMT as a possible target for therapeutic intervention and a potential source of biomarkers for improving OvCa diagnosis and/or prognosis. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions.

Peritoneal adhesions (PAs) are fibrotic bands formed between bowel loops, solid organs, and the parietal peritoneum, which may appear following surgery, infection or endometriosis. They represent an important health problem with no effective treatment. Mesothelial cells (MCs) line the peritoneal cavity and undergo a mesothelial-to-mesenchymal transition (MMT) under pathological conditions, transforming into myofibroblasts, which are abundant in peritoneal fibrotic tissue. The aim of this study was to investigate if peritoneal MCs undergo a MMT contributing to the formation of post-surgical adhesions. Biopsies from patients with PAs were analysed by immunohistochemistry, immunofluorescence, and quantitative RT-PCR. A mouse model of PAs based on ischaemic buttons was used to modulate MMT by blocking the transforming growth factor-beta (TGF-ß) pathway. The severity of adhesions and MMT-related marker expression were studied. We observed myofibroblasts derived from the conversion of MCs in submesothelial areas of patients with PAs. In addition, MMT-related markers were dysregulated in adhesion zones when compared to distant normal peritoneal tissue of the same patient. In animal experiments, blockage of TGF-ß resulted in molecular reprogramming of markers related to the mesenchymal conversion of MCs and in a significant decrease in the severity of the adhesions. These data indicate for the first time that MMT is involved in PA pathogenesis. This finding opens new therapeutic strategies to interfere with adhesion formation by modulating MMT with a wide range of pharmacological agents.

Evaluating the response to glatiramer acetate in relapsing-remitting multiple sclerosis (RRMS) patients.

BACKGROUND: In patients with relapsing-remitting multiple sclerosis (RRMS), a scoring system based on new magnetic resonance imaging (MRI) active lesions, relapses and sustained disability progression after a 1-year treatment with IFNß predicted patient disability progression over time; however, this score had not been tested in patients receiving glatiramer acetate (GA). OBJECTIVE: The objective of this study was to evaluate whether this previous scoring system can also be applied to patients treated with GA. METHODS: This was a prospective, longitudinal study of 151 RRMS patients treated with GA. Their scores were constructed, based on the clinical and MRI activity after 1 year of therapy. Regression analysis was performed, in order to identify the response variables. RESULTS: The total possible score range was 0-3. Patients with a score of ≥ 2 and those with clinical activity (with or without MRI activity) during their first year of treatment were at increased risk of continuing with relapses and/or sustained disability in the next 2 years (odds ratio (OR): 38.8; p < 0.0001 and OR: 7.8; p < 0.009, respectively). CONCLUSIONS: In RRMS patients treated with GA, a combination of clinical activity measures may have prognostic value for identifying patients with disease activity in the next 2 years of therapy.

Carcinoma-associated fibroblasts derive from mesothelial cells via mesothelial-to-mesenchymal transition in peritoneal metastasis.

Peritoneal dissemination is a frequent metastatic route for cancers of the ovary and gastrointestinal tract. Tumour cells metastasize by attaching to and invading through the mesothelial cell (MC) monolayer that lines the peritoneal cavity. Metastases are influenced by carcinoma-associated fibroblasts (CAFs), a cell population that derives from different sources. Hence, we investigated whether MCs, through mesothelial-mesenchymal transition (MMT), were a source of CAFs during peritoneal carcinomatosis and whether MMT affected the adhesion and invasion of tumour cells. Biopsies from patients with peritoneal dissemination revealed the presence of myofibroblasts expressing mesothelial markers in the proximity of carcinoma implants. Prominent new vessel formation was observed in the peritoneal areas harbouring tumour cells when compared with tumour-free regions. The use of a mouse model of peritoneal dissemination confirmed the myofibroblast conversion of MCs and the increase in angiogenesis at places of tumour implants. Treatment of omentum MCs with conditioned media from carcinoma cell cultures resulted in phenotype changes reminiscent of MMT. Adhesion experiments demonstrated that MMT enhanced the binding of cancer cells to MCs in a ß1-integrin-dependent manner. Scanning electron microscopy imaging showed that the enhanced adhesion was mostly due to increased cell-cell interaction and not to a mere matrix exposure. Invasion assays suggested a reciprocal stimulation of the invasive capacity of tumour cells and MCs. Our results demonstrate that CAFs can derive from mesothelial cells during peritoneal metastasis. We suggest that MMT renders the peritoneum more receptive for tumour cell attachment/invasion and contributes to secondary tumour growth by promoting its vascularization.

Percutaneous Tibial Nerve Stimulation in the Treatment of Refractory Idiopathic Overactive Bladder Syndrome: A Retrospective Cohort Study.

BACKGROUND: Overactive bladder (OAB) is a syndrome defined as urinary urgency, accompanied by increased frequency and nocturia with or without urge incontinence, in the absence of urinary tract infection or other obvious pathology. The standard therapies are anticholinergic agents, selective beta-3 adrenoreceptor agonists, or intradetrusor injections of botulinum toxin (BTX-A). For patients with contraindications for BTX-A or drug therapies, percutaneous tibial nerve stimulation (PTNS) may be used. PTNS shows fewer side effects than anticholinergic drugs and costs less than BTX-A. The primary outcome of this study was to assess the efficacy of PTNS in women with refractory OAB. METHODS: Women with refractory OAB undergoing PTNS at our tertiary referral center from 2017 to 2019 were included. The validated German Female Pelvic Floor Questionnaire and a micturition protocol were filled out before and after PTNS. PTNS was applied weekly for 12 weeks. RESULTS: Improvements in OAB symptoms were seen in daily micturition frequency, urgency, and urgency incontinence from pre- to post-PTNS (p < 0.006). Impairments to quality of daily life were significantly (p < 0.0002) less severe after PTNS. There was a significant reduction in daytime voiding frequency from a median of nine to five (p < 0.0001). CONCLUSIONS: Substantial reductions in OAB symptoms, daily micturition frequency, urgency, and urgency incontinence were found in patients with refractory OAB after PTNS.

Supplementary dydrogesterone is beneficial as luteal phase support in artificial frozen-thawed embryo transfer cycles compared to micronized progesterone alone.

Introduction: The number of frozen embryo transfers increased substantially in recent years. To increase the chances of implantation, endometrial receptivity and embryo competency must be synchronized. Maturation of the endometrium is facilitated by sequential administration of estrogens, followed by administration of progesterone prior to embryo transfer. The use of progesterone is crucial for pregnancy outcomes. This study compares the reproductive outcomes and tolerability of five different regimens of hormonal luteal phase support in artificial frozen embryo transfer cycles, with the objective of determining the best progesterone luteal phase support in this context. Design: This is a single-center retrospective cohort study of all women undergoing frozen embryo transfers between 2013 and 2019. After sufficient endometrial thickness was achieved by estradiol, luteal phase support was initiated. The following five different progesterone applications were compared: 1) oral dydrogesterone (30 mg/day), 2) vaginal micronized progesterone gel (90 mg/day), 3) dydrogesterone (20 mg/day) plus micronized progesterone gel (90 mg/day) (dydrogesterone + micronized progesterone gel), 4) micronized progesterone capsules (600 mg/day), and (5) subcutaneous injection of progesterone 25 mg/day (subcutan-P4). The vaginal micronized progesterone gel application served as the reference group. Ultrasound was performed after 12-15 days of oral estrogen (≥4 mg/day) administration. If the endometrial thickness was ≥7 mm, luteal phase support was started, up to six days before frozen embryo transfer, depending on the development of the frozen embryo. The primary outcome was the clinical pregnancy rate. Secondary outcomes included live birth rate, ongoing pregnancy, and miscarriage and biochemical pregnancy rate. Results: In total, 391 cycles were included in the study (median age of study participants 35 years; IQR 32-38 years, range 26-46 years). The proportions of blastocysts and single transferred embryos were lower in the micronized progesterone gel group. Differences among the five groups in other baseline characteristics were not significant. Multiple logistic regression analysis, adjusting for pre-defined covariates, showed that the clinical pregnancy rates were higher in the oral dydrogesterone only group (OR = 2.87, 95% CI 1.38-6.00, p=0.005) and in the dydrogesterone + micronized progesterone gel group (OR = 5.19, 95% CI 1.76-15.36, p = 0.003) compared to micronized progesterone gel alone. The live birth rate was higher in the oral dydrogesterone-only group (OR = 2.58; 95% CI 1.11-6.00; p=0.028) and showed no difference in the smaller dydrogesterone + micronized progesterone gel group (OR = 2.49; 95% CI 0.74-8.38; p=0.14) compared with the reference group. Conclusion: The application of dydrogesterone in addition to micronized progesterone gel was associated with higher clinical pregnancy rate and live birth rate and then the use of micronized progesterone gel alone. DYD should be evaluated as a promising LPS option in FET Cycles.

Rapamycin downregulates α-klotho in the kidneys of female rats with normal and reduced renal function.

Both mTOR and α-klotho play a role in the pathophysiology of renal disease, influence mineral metabolism and participate in the aging process. The influence of mTOR inhibition by rapamycin on renal α-klotho expression is unknown. Rats with normal (controls) and reduced (Nx) renal function were treated with rapamycin, 1.3 mg/kg/day, for 22 days. The experiments were conducted with rats fed 0.6% P diet (NP) and 0.2% P diet (LP). Treatment with rapamycin promoted phosphaturia in control and Nx rats fed NP and LP. A decrease in FGF23 was identified in controls after treatment with rapamycin. In rats fed NP, rapamycin decreased mRNA α-klotho/GADPH ratio both in controls, 0.6±0.1 vs 1.1±0.1, p = 0.001, and Nx, 0.3±0.1 vs 0.7±0.1, p = 0.01. At the protein level, a significant reduction in α-klotho was evidenced after treatment with rapamycin both by Western Blot: 0.6±0.1 vs 1.0±0.1, p = 0.01, in controls, 0.7±0.1 vs 1.1±0.1, p = 0.02, in Nx; and by immunohistochemistry staining. Renal α-klotho was inversely correlated with urinary P excretion (r = -0.525, p = 0.0002). The decrease in α-klotho after treatment with rapamycin was also observed in rats fed LP. In conclusion, rapamycin increases phosphaturia and down-regulates α-klotho expression in rats with normal and decreased renal function. These effects can be observed in animals ingesting normal and low P diet.

Association of Beta-Thalassaemia and Hypogonadotropic Hypogonadism.

Thalassaemic syndromes are among the most common haemoglobinopathies and are associated with high morbidity and mortality. Because of the various treatments, a secondary endocrinopathy due to iron overload-haemosiderosis-can occur, causing hypopituitarism leading to hypogonadotropic hypogonadism (HH) and infertility. We present a case of secondary amenorrhoea in a patient with beta-thalassaemia and a history of multiple therapies in her adolescence, such as multiple transfusions, chemotherapy, and allogeneic bone marrow transplantation, who presented with HH and premature ovarian insufficiency.

Oral Acid Load Down-Regulates Fibroblast Growth Factor 23.

Increased dietary acid load has a negative impact on health, particularly when renal function is compromised. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that is elevated during renal failure. The relationship between metabolic acidosis and FGF23 remains unclear. To investigate the effect of dietary acid load on circulating levels of FGF23, rats with normal renal function and with a graded reduction in renal mass (1/2 Nx and 5/6 Nx) received oral NH4Cl for 1 month. Acid intake resulted in a consistent decrease of plasma FGF23 concentrations in all study groups when compared with their non-acidotic control: 239.3 ± 13.5 vs. 295.0 ± 15.8 pg/mL (intact), 346.4 ± 19.7 vs. 522.6 ± 29.3 pg/mL (1/2 Nx) and 988.0 ± 125.5 vs. 2549.4 ± 469.7 pg/mL (5/6 Nx). Acidosis also decreased plasma PTH in all groups, 96.5 ± 22.3 vs. 107.3 ± 19.1 pg/mL, 113.1 ± 17.3 vs. 185.8 ± 22.2 pg/mL and 504.9 ± 75.7 vs. 1255.4 ± 181.1 pg/mL. FGF23 showed a strong positive correlation with PTH (r = 0.877, p < 0.0001) and further studies demonstrated that acidosis did not influence plasma FGF23 concentrations in parathyroidectomized rats, 190.0 ± 31.6 vs. 215 ± 25.6 pg/mL. In conclusion, plasma concentrations of FGF23 are consistently decreased in rats with metabolic acidosis secondary to increased acid intake, both in animals with intact renal function and with decreased renal function. The in vivo effect of metabolic acidosis on FGF23 appears to be related to the simultaneous decrease in PTH.

When diamniotic twins suddenly become monoamniotic twins: spontaneous septostomy of the dividing membrane.

In twin pregnancies, amnionicity and chorionicity are crucial as they strongly determine prenatal and perinatal management. First trimester ultrasound allows a highly reliable diagnosis of amnionicity and chorionicity, making it an internationally accepted standard in antenatal care. However, in rare cases, amnionicity can change from diamniotic to monoamniotic throughout pregnancy, substantially impacting perinatal management. We report the case of a confirmed monochorionic diamniotic twin pregnancy with a diagnosis of spontaneous septostomy of the dividing membrane (SSDM) at 28 weeks of gestation, resulting in a pseudomonoamniotic pregnancy. Even though SSDM is a rare condition and its sonographic diagnosis might be challenging, it should be considered if, in a known diamniotic pregnancy, there is a sudden failure to visualise the intertwin membrane truly separating both twins.

A rare presentation of isolated right-sided pleural effusion in the context of ovarian hyperstimulation syndrome: A case report.

An isolated pleural effusion as the sole manifestation of early ovarian hyperstimulation syndrome (OHSS) is rare. A 38-year-old woman who had undergone in vitro fertilization presented with OHSS. Six days after transvaginal oocyte pickup, she presented with only an isolated right-sided pleural effusion and restricted respiratory capacity. A thoracentesis was successfull. Clinicians must be aware of unilateral pleural effusion, with a higher incidence on the right side, as a single-symptom presentation of OHSS. The case reported here illustrates the diversity and severity of OHSS.

Increased 1,25(OH)2-Vitamin D Concentrations after Energy Restriction Are Associated with Changes in Skeletal Muscle Phenotype.

The influence of energy restriction (ER) on muscle is controversial, and the mechanisms are not well understood. To study the effect of ER on skeletal muscle phenotype and the influence of vitamin D, rats (n = 34) were fed a control diet or an ER diet. Muscle mass, muscle somatic index (MSI), fiber-type composition, fiber size, and metabolic activity were studied in tibialis cranialis (TC) and soleus (SOL) muscles. Plasma vitamin D metabolites and renal expression of enzymes involved in vitamin D metabolism were measured. In the ER group, muscle weight was unchanged in TC and decreased by 12% in SOL, but MSI increased in both muscles (p < 0.0001) by 55% and 36%, respectively. Histomorphometric studies showed 14% increase in the percentage of type IIA fibers and 13% reduction in type IIX fibers in TC of ER rats. Decreased size of type I fibers and reduced oxidative activity was identified in SOL of ER rats. An increase in plasma 1,25(OH)2-vitamin D (169.7 ± 6.8 vs. 85.4 ± 11.5 pg/mL, p < 0.0001) with kidney up-regulation of CYP27b1 and down-regulation of CYP24a1 was observed in ER rats. Plasma vitamin D correlated with MSI in both muscles (p < 0.001), with the percentages of type IIA and type IIX fibers in TC and with the oxidative profile in SOL. In conclusion, ER preserves skeletal muscle mass, improves contractile phenotype in phasic muscles (TC), and reduces energy expenditure in antigravity muscles (SOL). These beneficial effects are closely related to the increases in vitamin D secondary to ER.

Conservative management of an extensive renal graft subcapsular hematoma arising during living donor nephrectomy. Role of Doppler sonographic posttransplant follow-up.

We report a case of subcapsular hematoma (SH) of a kidney graft arising during minimal-incision living-donor nephrectomy. SH covered at least two-thirds of the cortical surface. Capsulotomy was not done because it was deemed too risky. In the immediate postoperative period, a rapid deterioration of graft function was observed associated with Doppler sonographic evidence of graft compression. However, in the following days, spontaneous resolution of SH and progressive improvement of Doppler findings was observed, which preceded full recovery of graft function. Conservative management seemed a valid approach of this complication in this case where Doppler sonography proved essential for the follow-up.

Waist Circumference as a Preventive Tool of Atherogenic Dyslipidemia and Obesity-Associated Cardiovascular Risk in Young Adults Males: A Cross-Sectional Pilot Study.

Although the correlation coefficient between body mass index (BMI) and poor lipid profile has been reported, representing a cardiovascular risk, the need to find new early detection markers is real. Waist circumference and markers of atherogenic dyslipidemia are not usually measured in medical review appointments. The present study aimed to investigate the relationship between central adiposity and cardiovascular risk. This was a cross-sectional pilot study of 57 young males (age: 35.9 ± 10.85, BMI: 32.4 ± 6.08) recruited from community settings and allocated to non-obese or obese attending to their waist circumference. Total cholesterol (TC), high-density lipoproteins (HDL-C), and low-density lipoproteins (LDL-C) cholesterol and triglycerides (TG) were measured from plasma samples. Patients with at least 100 cm of waist circumference had significantly increased TC, LDL-C, non-HDL-C, and triglycerides and lower levels of HDL-C. The three atherogenic ratios TC/HDL-C, LDL-C/HDL-C, and TG/HDL-C were all optimal in non-obese patients. LDL-C/HDL-C and TG/HDL-C were significantly higher and over the limit when assessing for atherogenic dyslipidemia. The number of patients at risk for cardiovascular events increases 2.5 folds in obese compared to non-obese. Measurement of waist circumference could be adopted as a simpler valid alternative to BMI for health promotion, to alert those at risk of atherogenic dyslipidemia.

Effects of Self-Weighing During Weight Loss Treatment: A 6-Month Randomized Controlled Trial.

OBJECTIVE: To examine the effectiveness of self-weighing for weight loss in men for 6 months. METHODS: In the present study, 54 men, mean age of 40.1 ± 11.1 years, with overweight or obesity, were recruited and randomly assigned into two groups: control group (CG), without weight self-monitoring and intervention group (IG), with weight self-monitoring. Both groups received the same nutritional and educational advice and the establishment of a weight target to reach in the weight loss program. Subjects of IG also had individualized motivating content to improve self-management for 24 weeks. Anthropometric indices were measured at baseline and weekly for 24 weeks. RESULTS: When the group assigned after randomization was introduced in the analysis, its influence was significant in weight loss (F1.52 = 19.465, ± 2 = 0.272, p < 0.001) and in the decrease in body fat percentage (F1.52 = 8,306, ± 2 = 0.132, p < 0.01). CONCLUSION: Study results indicate that self-weighing can help patients to lose additional weight. Our findings have implications in the emerging area of the behavioral approach of patients undergoing weight-loss treatment, as well as clinical care processes. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT04032249.

Caloric Intake in Renal Patients: Repercussions on Mineral Metabolism.

The aim of this paper is to review current knowledge about how calorie intake influences mineral metabolism focussing on four aspects of major interest for the renal patient: (a) phosphate (P) handling, (b) fibroblast growth factor 23 (FGF23) and calcitriol synthesis and secretion, (c) metabolic bone disease, and (d) vascular calcification (VC). Caloric intake has been shown to modulate P balance in experimental models: high caloric intake promotes P retention, while caloric restriction decreases plasma P concentrations. Synthesis and secretion of the phosphaturic hormone FGF23 is directly influenced by energy intake; a direct correlation between caloric intake and FGF23 plasma concentrations has been shown in animals and humans. Moreover, in vitro, energy availability has been demonstrated to regulate FGF23 synthesis through mechanisms in which the molecular target of rapamycin (mTOR) signalling pathway is involved. Plasma calcitriol concentrations are inversely proportional to caloric intake due to modulation by FGF23 of the enzymes implicated in vitamin D metabolism. The effect of caloric intake on bone is controversial. High caloric intake has been reported to increase bone mass, but the associated changes in adipokines and cytokines may as well be deleterious for bone. Low caloric intake tends to reduce bone mass but also may provide indirect (through modulation of inflammation and insulin regulation) beneficial effects on bone. Finally, while VC has been shown to be exacerbated by diets with high caloric content, the opposite has not been demonstrated with low calorie intake. In conclusion, although prospective studies in humans are needed, when planning caloric intake for a renal patient, it is important to take into consideration the associated changes in mineral metabolism.

Direct regulation of fibroblast growth factor 23 by energy intake through mTOR.

To test the hypothesis that fibroblast growth factor 23 (FGF23) is directly regulated by energy intake, in vivo and in vitro experiments were conducted. Three groups of rats were fed diets with high (HC), normal (NC) and low (LC) caloric content that resulted in different energy intake. In vitro, UMR106 cells were incubated in high (HG, 4.5 g/l) or low glucose (LG, 1 g/l) medium. Additional treatments included phosphorus (P), mannitol, rapamycin and everolimus. Intestinal absorption of P and plasma P concentrations were similar in the three groups of rats. As compared with NC, plasma FGF23 concentrations were increased in HC and decreased in the LC group. A significant correlation between energy intake and plasma FGF23 concentrations was observed. In vitro, mRNA FGF23 was significantly higher in UMR106 cells cultured in HG than in LG. When exposed to high P, mRNA FGF23 increased but only when cells were cultured in HG. Cells incubated with HG and mechanistic target of rapamycin (mTOR) inhibitors expressed low mRNA FGF23, similar to the values obtained in LG. In conclusion, this study shows a direct regulation of FGF23 production by energy availability and demonstrates that the mTOR signaling pathway plays a central role in this regulatory system.

Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) Promotes Uterine Serous Cancer Cell Proliferation and Cell Cycle Progression.

Uterine serous carcinoma (USC) is the most aggressive form of endometrial cancer, with poor survival rates and high recurrence risk. Therefore, the purpose of this study was to identify therapeutic targets that could aid in the management of USC. By analyzing endometrial cancer samples from The Cancer Genome Atlas (TCGA), we found Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) to be highly expressed in USC and to correlate with poorer overall survival. UCHL1 silencing reduced cell proliferation in vitro and in vivo, cyclin B1 protein levels and cell cycle progression. Further studies showed that UCHL1 interacts with cyclin B1 and increases cyclin B1 protein stability by deubiquitination. Treatment of USC-bearing mice with the UCHL1-specific inhibitor reduced tumor growth and improved overall survival. Our findings suggest that cyclin B1 is a novel target of UCHL1 and targeting UCHL1 is a potential therapeutic strategy for USC.