The proteomic and particle composition of human platelet lysate for cell therapy products.

Following health agencies warning, the use of animal origin supplements should be avoided in biological products proposed as therapy in humans. Platelet lysate and several other growth factors sources are alternatives to replace fetal calf serum, the current gold standard in clinical-grade cell culture. However, the platelet supplement's content lacks data due to different production methods. The principle behind these products relays on the lysis of platelets that release several proteins, some of which are contained in heterogeneous granules and coordinate biological functions. This study aims to analyze the composition and reproducibility of a platelet lysate produced with a standardized method, by describing several batches' protein and particle content using proteomics and dynamic light scattering. Proteomics data revealed a diversified protein content, with some related to essential cellular processes such as proliferation, morphogenesis, differentiation, biosynthesis, adhesion, and metabolism. It also detected proteins responsible for activation and binding of transforming growth factor beta, hepatocyte growth factor, and insulin-like growth factor. Total protein, biochemical, and growth factors quantitative data showed consistent and reproducible values across batches. Novel data on two major particle populations is presented, with high dispersion level at 231 ± 96 d.nm and at 30 ± 8 d.nm, possibly being an important way of protein trafficking through the cellular microenvironment. This experimental and descriptive analysis aims to support the content definition and quality criteria of a cell supplement for clinical applications.

Diabetes and Colorectal Cancer Risk: Clinical and Therapeutic Implications.

Several epidemiological studies have identified diabetes as a risk factor for colorectal cancer (CRC). The potential pathophysiological mechanisms of this association include hyperinsulinemia, insulin-like growth factor (IGF) axis, hyperglycemia, inflammation induced by adipose tissue dysfunction, gastrointestinal motility disorder, and impaired immunological surveillance. Several studies have shown that underlying diabetes adversely affects the prognosis of patients with CRC. This review explores the novel anticancer agents targeting IGF-1R and receptor for advanced glycation end products (RAGE), both of which play a vital role in diabetes-induced colorectal tumorigenesis. Inhibitors of IGF-1R and RAGE are expected to become promising therapeutic choices, particularly for CRC patients with diabetes. Furthermore, hypoglycemic therapy is associated with the incidence of CRC. Selection of appropriate hypoglycemic agents, which can reduce the risk of CRC in diabetic patients, is an unmet issue. Therefore, this review mainly summarizes the current studies concerning the connections among diabetes, hypoglycemic therapy, and CRC as well as provides a synthesis of the underlying pathophysiological mechanisms. Our synthesis provides a theoretical basis for rational use of hypoglycemic therapies and early diagnosis and treatment of diabetes-related CRC.

INSULIN-LIKE GROWTH FACTORS IN THE SERUM OF PATIENTS WITH PAPILLARY THYROID CANCER.

OBJECTIVE: The aim is to study the level of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-2 (IGF-2) in the blood serum of patients with papillary thyroid cancer, depending on the main clinical and morphological features of the disease. PATIENTS AND METHODS: Materials and methods: The material was the information about 60 patients with papillary thyroid cancer (group 1). In group 2 there were 10 patients without oncopathology. All patients underwent clinical examination after total thyroidectomy before special treatment (radioiodine therapy): ultrasound diagnosis of the neck, confirmed diagnosis of papillary thyroid cancer by morphological examination of operative material. All patients underwent anthropometric studies (height, weight), on the basis of which the body mass index (BMI) was calculated. The study program also included determination of the level of thyroid-stimulating hormone of the pituitary gland (TSH), thyroglobulin (TG), antibodies to thyroglobulin (AB-TG). It was also determined the serum glucose level. In order to assess insulin resistance, the HOMA-IR index was calculated. All patients were tested for serum IGF-1 and IGF-2. RESULTS: Results: In the blood serum of patients with papillary thyroid cancer in 63% of patients the level of IGF-1 and in 85% - IGF-2 was probably higher than in the control group. There is a relationship between the level of IGF-1, IGF-2 and elevated level of proliferating factor - insulin in the serum of patients with papillary thyroid cancer. This may indicate an aggressive potential of the disease (i.e. clinical data on the prevalence of papillary thyroid cancer coincide with laboratory data). There was found a relationship between the expression of IGF-1, IGF-2 and insulin: at elevated levels of insulin> 24.9 µIU/ml, IGF-1 increases 4.2 times, and IGF-2 - 2.5 times. Evaluation of the relationship between the level of IGF-1 and IGF-2 and cervical lymph node involvement shows that in the absence of lesion (N0) there is an increase in these indicators by 2.2 and 1.8 times, respectively. CONCLUSION: Conclusions: The signaling system of insulin-like growth factors (IGF-1 and IGF-2) plays an important role in the occurrence and progression of malignant tumors. It is especially true for papillary thyroid cancer, so its components can be considered as potential diagnostic and prognostic markers of the disease and targets for anticancer therapy.

Characteristics of follicular dynamics and reproductive hormone profiles during oestrous cycles of jennies over an entire year.

Although donkeys have been domesticated for over 6,000 years, limited information is available concerning their reproductive physiology, especially under intensive rearing conditions. The aims of this experiment were to study follicular dynamics and reproductive hormone variation in jennies during the inter-ovulatory interval in different seasons. A total of 12 continuous cycles of six Dezhou Black (DB) donkey jennies were examined in four different seasons. The diameters of the six largest follicles of each jenny were measured daily by ultrasonography, and blood samples were collected at fixed times for reproductive hormone assays. The results demonstrated that most jennies displayed regular oestrous cycles in all seasons. The follicular dynamics were similar in Spring, Summer and Winter, while the jennies had longer oestrous cycles with delayed follicular deviation and dominant selection in Autumn. At least two follicular waves were observed in each oestrous cycle, throughout the study, but two jennies presented oestrous cycles with three follicular waves in the Autumn. The numbers of follicular waves were consistent with the numbers of FSH surges. Oestrous characteristics of the jennies in a large herd were also analysed. The results showed that the rates of regular oestrous cycles were 83.1% (265/319), 89.6% (215/240), 80.2% (235/293) and 77.1% (178/231), with 26.4% (70/265), 19.5% (42/215), 22.1% (52/235) and 23.0% (41/178) double ovulation rates in Spring, Summer, Autumn and Winter, respectively. The results presented may be useful for donkey farms in the design of breeding strategies.

High Intensity Interval Exercise Increases Platelet and Transforming Growth Factor-ß Yield in Platelet-Rich Plasma.

BACKGROUND: Platelet-rich plasma (PRP) is an emerging orthobiologic treatment for musculoskeletal conditions like osteoarthritis. Two studies have demonstrated the influence of longer duration exercise on PRP composition, but no study has ever explored the impact of high intensity interval exercise (HIIE) on PRP content. OBJECTIVE: To quantify cellular and growth factor content changes in PRP after 4 minutes of HIIE. DESIGN: Controlled laboratory pilot study. SETTING: Academic sports medicine center. PARTICIPANTS: Ten healthy volunteers (5 male, 5 female). INTERVENTION: Volunteers had PRP prepared from 15 mL of whole blood using a single spin, plasma-based system (autologous conditioned plasma [ACP]) immediately before and after 4 minutes of HIIE on a stationary exercise bike (Tabata protocol). MAIN OUTCOME MEASURE: The PRP was sent for complete blood counts and enzyme-linked immunosorbent assay (ELISA) to quantify transforming growth factor (TGF)-ß, platelet-derived growth factor (PDGF), insulin-like growth factor (IGF)-1, and vascular endothelial growth factor (VEGF). RESULTS: Mean platelet count in PRP increased from 367.4 ± 57.5 k/µL to 497.7 ± 93.3 k/µL after 4 minutes of HIIE (P < .001). TGF-ß also increased from 8237.2 ± 7676.5 pg/mL to 21 535.7 ± 4062.6 pg/mL postexercise (P = .004). The other cellular components (leukocytes, red blood cells, and mean platelet volume) and growth factors (PDGF, IGF-1, and VEGF) were not significantly changed. CONCLUSIONS: A short 4-minute bout of HIIE significantly increased the total platelet count and TGF-ß concentration in PRP.

Targeted Analysis of Three Hormonal Systems Identifies Molecules Associated with the Presence and Severity of NAFLD.

AIMS: To investigate circulating levels and liver gene expression of 3 hormonal pathways associated with obesity, insulin resistance, and inflammation to identify leads towards potential diagnostic markers and therapeutic targets in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: We compared circulating levels of (1) proglucagon-derived hormones (glucagon-like peptide [GLP]-1, GLP-2, glicentin, oxyntomodulin, glucagon, major proglucagon fragment [MPGF]), (2) follistatins-activins (follistatin-like [FSTL]3, activin B), (3) IGF axis (insulin-like growth factor [IGF]-1, total and intact IGF binding protein [IGFBP]-3 and IGFBP-4, and pregnancy-associated plasma protein [PAPP]-A) in 2 studies: (1) 18 individuals with early stage NAFLD versus 14 controls (study 1; early NAFLD study) and in (2) 31 individuals with biopsy proven NAFLD (15 with simple steatosis [SS] and 16 with nonalcoholic steatohepatitis [NASH]), vs 50 controls (24 lean and 26 obese) (study 2). Liver gene expression was assessed in 22 subjects (12 controls, 5 NASH, 5 NASH-related cirrhosis). RESULTS: Patients in early stages of NAFLD demonstrate higher fasting MPGF and lower incremental increase of glicentin during oral glucose tolerance test than controls. In more advanced stages, FSTL3 levels are higher in NASH than simple steatosis and, within NAFLD patients, in those with more severe lobular and portal inflammation. The IGF-1/intact IGFBP-3 ratio is lower in patients with liver fibrosis. Genes encoding follistatin, activin A, activin B, and the IGF-1 receptor are higher in NASH. CONCLUSION: MPGF and glicentin may be involved in early stages of NAFLD, whereas FSTL3 and IGF-1/intact IGFBP3 in the progression to NASH and liver fibrosis respectively, suggesting potential as diagnostic markers or therapeutic targets.

Production-related contaminants (pesticides, antibiotics and hormones) in organic and conventionally produced milk samples sold in the USA.

OBJECTIVE: Consumption of cow's milk, which is associated with diet and health benefits, has decreased in the USA. The simultaneous increase in demand for more costly organic milk suggests consumer concern about exposure to production-related contaminants may be contributing to this decline. We sought to determine if contaminant levels differ by the production method used. DESIGN: Half-gallon containers of organic and conventional milk (four each) were collected by volunteers in each of nine US regions and shipped on ice for analysis. Pesticide, antibiotic and hormone (bovine growth hormone (bGH), bGH-associated insulin-like growth factor 1 (IGF-1)) residues were measured using liquid or gas chromatography coupled to mass or tandem mass spectrometry. Levels were compared against established federal limits and by production method. SETTING: Laboratory analysis of retail milk samples. RESULTS: Current-use pesticides (5/15 tested) and antibiotics (5/13 tested) were detected in several conventional (26-60 %; n 35) but not in organic (n 34) samples. Among the conventional samples, residue levels exceeded federal limits for amoxicillin in one sample (3 %) and in multiple samples for sulfamethazine (37 %) and sulfathiazole (26 %). Median bGH and IGF-1 concentrations in conventional milk were 9·8 and 3·5 ng/ml, respectively, twenty and three times that in organic samples (P < 0·0001). CONCLUSIONS: Current-use antibiotics and pesticides were undetectable in organic but prevalent in conventionally produced milk samples, with multiple samples exceeding federal limits. Higher bGH and IGF-1 levels in conventional milk suggest the presence of synthetic growth hormone. Further research is needed to understand the impact of these differences, if any, on consumers.

Development of a Parallel Reaction Monitoring-MS Method To Quantify IGF Proteins in Dogs and a Case of Nonislet Cell Tumor Hypoglycemia.

Nonislet-cell tumor hypoglycemia (NICTH) is a rare paraneoplastic phenomenon well described in dogs and humans. Tumors associated with NICTH secrete incompletely processed forms of insulin-like growth factor-II (IGF-II), commonly named big IGF-II. These forms have increased bioavailability and interact with the insulin and IGF-I receptor causing hypoglycemia and growth-promoting effects. Immunoassays designed for human samples have been used to measure canine IGF-I and -II, but they possess some limitations. In addition, there are no validated methods for measurement of big IGF-II in dogs. In the present study, a targeted parallel reaction monitoring MS-based method previously developed for cats has been optimized and applied to simultaneously quantify the serum levels of IGF-I, IGF-II, and IGFBP-3, and for the first time, the levels of big IGF-II in dogs. This method allows the absolute quantification of IGF proteins using a mixture of QPrEST proteins previously designed for humans. The method possesses good linearity and repeatability and has been used to evaluate the IGF-system in a dog with NICTH syndrome. In this dog, the levels of big IGF-II decreased by 80% and the levels of IGF-I and IGFBP-3 increased approximately 20- and 4-times, respectively, after removal of the tumor.

The role of pregnancy, perinatal factors and hormones in maternal cancer risk: a review of the evidence.

An understanding of the origin of cancer is critical for cancer prevention and treatment. Complex biological mechanisms promote carcinogenesis, and there is increasing evidence that pregnancy-related exposures influence foetal growth cell division and organ functioning and may have a long-lasting impact on health and disease susceptibility in the mothers and offspring. Nulliparity is an established risk factor for breast, ovarian, endometrial and possibly pancreatic cancer, whilst the risk of kidney cancer is elevated in parous compared with nulliparous women. For breast, endometrial and ovarian cancer, each pregnancy provides an additional risk reduction. The associations of parity with thyroid and colorectal cancers are uncertain. The timing of reproductive events is also recognized to be important. Older age at first birth is associated with an increased risk of breast cancer, and older age at last birth is associated with a reduced risk of endometrial cancer. The risks of breast and endometrial cancers increase with younger age at menarche and older age at menopause. The mechanisms, and hormone profiles, that underlie alterations in maternal cancer risk are not fully understood and may differ by malignancy. Linking health registries and pooling of data in the Nordic countries have provided opportunities to conduct epidemiologic research of pregnancy exposures and subsequent cancer. We review the maternal risk of several malignancies, including those with a well-known hormonal aetiology and those with less established relationships. The tendency for women to have fewer pregnancies and at later ages, together with the age-dependent increase in the incidence of most malignancies, is expected to affect the incidence of pregnancy-associated cancer.

Endometrial gene expression in primiparous dairy cows at the end of the voluntary waiting period is affected by nutrition: Total mixed ration vs increasing levels of herbage allowance.

The study postulated that differential nutritional management during the early lactation period would be reflected in endometrial expression of genes related to embryo growth at the end of the voluntary waiting period. Thus, the effect of the combined use of total mixed ration (TMR) and grazing under different herbage allowances during the first 75 days post-partum (DPP) on endometrial gene expression was evaluated in primiparous dairy cows. Cows were blocked by body weight, age and body condition score and randomly assigned to three grazing treatments: high (HA, 30 kg DM per cow per day), medium (MA, 15 kg DM per cow per day) and low (LA, 7.5 kg DM per cow per day) herbage allowance (mixed pasture, 2,600 kg DM per ha) plus 8 kg DM of supplement or TMR (55% forage, 45% concentrate) fed ad libitum (TMR) from calving to 75 DPP. At 57 DPP, cows were synchronized for oestrus (day 0, 68 DPP) and at day 7, endometrial biopsies were obtained. The nutritional treatment did not affect insulin, IGF-1 and leptin concentrations on days 0, 4 or 7. Expression of IGF1, IGFBP3, IGFBP4, ADIPOR1 and ADIPOR2 mRNA was significantly affected by the nutritional treatment. Endometrial IGF1 and IGFBP4 mRNA were twofold greater in TMR and HA than MA and LA cows. Expression of IGFBP3 and ADIPOR1 mRNAs was greater in TMR and HA than MA cows, but did not differ from LA cows. All groups had greater expression of ADIPOR2 mRNA than MA cows. This study provided solid evidence of the importance of nutritional management during early lactation on uterine environment at the end of the voluntary waiting period. The greater expression of genes related to embryo growth and uterine function (IGF system, progesterone and adiponectin receptors) in cows fed diets maximizing energy intake suggests a favourable environment for embryonic growth, which may explain the improved reproductive performance of cows in good energy balance.

Trajectories of function and biomarkers with age: the CHS All Stars Study.

BACKGROUND: Multimorbidity is a major driver of physical and cognitive impairment, but rates of decline are also related to ageing. We sought to determine trajectories of decline in a large cohort by disease status, and examined their correspondence with biomarkers of ageing processes including growth hormone, sex steroid, inflammation, visceral adiposity and kidney function pathways. METHODS: We have followed the 5888 participants in the Cardiovascular Health Study (CHS) for healthy ageing and longevity since 1989-90. Gait speed, grip strength, modified mini-mental status examination (3MSE) and the digit symbol substitution test (DSST) were assessed annually to 1998-99 and again in 2005-06. Insulin-like growth hormone (IGF-1), dehydroepiandrosterone sulphate (DHEAS), interleukin-6 (IL-6), adiponectin and cystatin-C were assessed 3-5 times from stored samples. Health status was updated annually and dichotomized as healthy vs not healthy. Trajectories for each function measure and biomarker were estimated using generalized estimating equations as a function of age and health status using standardized values. RESULTS: Trajectories of functional decline showed strong age acceleration late in life in healthy older men and women as well as in chronically ill older adults. Adiponectin, IL-6 and cystatin-C tracked with functional decline in all domains; cystatin-C was consistently associated with functional declines independent of other biomarkers. DHEAS was independently associated with grip strength and IL-6 with grip strength and gait speed trajectories. CONCLUSIONS: Functional decline in late life appears to mark a fundamental ageing process in that it occurred and was accelerated in late life regardless of health status. Cystatin C was most consistently associated with these functional declines.

Association of perfluoroalkyl substances exposure in utero with reproductive hormone levels in cord blood in the Hokkaido Study on Environment and Children's Health.

BACKGROUND: Exposure to perfluoroalkyl substances (PFASs) may disrupt reproductive function in animals and humans. Although PFASs can cross the human placental barrier, few studies evaluated the effects of prenatal PFAS exposure on the fetus' reproductive hormones. OBJECTIVE: To explore the associations of prenatal exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) with cord blood reproductive hormones. METHODS: In the prospective birth cohort (Sapporo cohort of the Hokkaido study), we included 189 mother-infant pairs recruited in 2002-2005 with both prenatal maternal and cord blood samples. PFOS and PFOA levels in maternal blood after the second trimester were measured via liquid chromatography-tandem mass spectrometry. We also measured cord blood levels of the fetuses' reproductive hormones, including estradiol (E2), total testosterone (T), progesterone (P4), inhibin B, insulin-like factor 3, steroid hormone binding globulin, follicle-stimulating hormone, and luteinizing hormone, and prolactin (PRL). RESULTS: The median PFOS and PFOA levels in maternal serum were 5.2ng/mL and 1.4ng/mL, respectively. In the fully adjusted linear regression analyses of the male infants, maternal PFOS levels were significantly associated with E2 and positively, and T/E2, P4, and inhibin B inversely; PFOA levels were positively associated with inhibin B levels. Among the female infants, there were significant inverse associations between PFOS levels and P4 and PRL levels, although there were no significant associations between PFOA levels and the female infants' reproductive hormone levels. CONCLUSIONS: These results suggest that the fetal synthesis and secretion of reproductive hormones may be affected by in utero exposure to measurable levels of PFOS and PFOA.

The insulin-like growth factor system in multiple myeloma: diagnostic and therapeutic potential.

Multiple myeloma (MM) is a highly heterogeneous plasma cell malignancy. The MM cells reside in the bone marrow (BM), where reciprocal interactions with the BM niche foster MM cell survival, proliferation, and drug resistance. As in most cancers, the insulin-like growth factor (IGF) system has been demonstrated to play a key role in the pathogenesis of MM. The IGF system consists of IGF ligands, IGF receptors, IGF binding proteins (IGFBPs), and IGFBP proteases and contributes not only to the survival, proliferation, and homing of MM cells, but also MM-associated angiogenesis and osteolysis. Furthermore, increased IGF-I receptor (IGF-IR) expression on MM cells correlates with a poor prognosis in MM patients. Despite the prominent role of the IGF system in MM, strategies targeting the IGF-IR using blocking antibodies or small molecule inhibitors have failed to translate into the clinic. However, increasing preclinical evidence indicates that IGF-I is also involved in the development of drug resistance against current standard-of-care agents against MM, including proteasome inhibitors, immunomodulatory agents, and corticoids. IGF-IR targeting has been able to overcome or revert this drug resistance in animal models, enhancing the efficacy of standard-of-care agents. This finding has generated renewed interest in the therapeutic potential of IGF-I targeting in MM. The present review provides an update of the impact of the different IGF system components in MM and discusses the diagnostic and therapeutic potentials.

Instability of IGF-IGFBP complex as a cause of the different performance of serum and EDTA-plasma after storage: EDTA-plasma is preferable for evaluating bioactive IGF especially in the mouse.

OBJECTIVE: The insulin-like growth factor (IGF) signaling pathway is recognized as a potential target for treating several cancers, and strategies targeting the IGF type 1 receptor (IGF-1R) have been evaluated in many clinical trials. These suggested that the pretreatment level of circulating free IGF gives an estimate of IGF bioactivity and might be a predictive biomarker of the response to anti-IGF-1R antibodies. However, there is no defined protocol for measuring free and bioactive IGF concentrations, partly because the measurement procedures, including sample collection and handling, have not been standardized. We investigated the effects of sample collection methods and storage conditions on bioactive IGF measurement using a modified kinase receptor activation (KIRA) assay in human and mouse samples. DESIGN: Blood samples were obtained from healthy men and women, and from healthy male and female wild-type BALB/c mice. Serum and ethylenediaminetetraacetic acid (EDTA)-plasma samples were collected and used immediately or stored in small quantities at 4 °C or -80 °C for 3, 7, or 14 days. A bioassay directed against the phosphorylated IGF-1R using western blot analysis was developed as a modification of the KIRA assay, in which the level of phosphorylation of IGF-1R represented the IGF bioactivity in blood samples. RESULTS: The levels of bioactive IGFs in mouse serum stored at 4 °C increased markedly in a time-dependent manner; the increase was slightly reduced in samples stored at -80 °C. Analysis of mouse EDTA-plasma stored at 4 °C showed a similar pattern, but the time-dependent increase was less than in the serum samples. By contrast, the levels of bioactive IGFs in EDTA-plasma stored at -80 °C were stable over 14 days. The levels of human bioactive IGFs in both serum and EDTA-plasma stored at 4 °C increased slightly with time, but the increases were much smaller than in mouse samples. The levels of human bioactive IGF in both serum and EDTA-plasma stored at -80 °C were stable over 14 days. CONCLUSIONS: The use of EDTA-plasma avoids the problems with long-term storage. Therefore, EDTA-plasma should be used when measuring circulating IGF bioactivity, especially in mouse samples. All samples should be stored at -80 °C when long-term storage is unavoidable. Because of the large difference in the stability of the IGF-IGF-binding protein complex between the human and mouse in vitro, all samples should be handled carefully to ensure the accurate evaluation of IGF bioactivity, especially in mouse samples.

Long-term cardiac abnormalities after cranial radiotherapy in childhood cancer survivors.

BACKGROUND: Cardiac morbidity is an important late effect in long-term childhood cancer survivors (CCS) treated with cardiotoxic agents or radiotherapy (RT) on the chest. However, there is limited data on the long-term cardiac sequelae in CCS who only received cranial RT. We hypothesized that cranial RT might negatively influence cardiac structure and function. METHODS AND RESULTS: We studied 13 CCS [mean age 30.8 (18.1-39.3) years, 7 males] who received RT only on the head for a cranial tumor and 36 age- and sex-matched healthy sibling controls. Echocardiographic follow-up was performed at median 21.7 (12.6-30.8) years after diagnosis. CCS had lower indexed diastolic LV volumes [56.0 (31.4-68.3) vs. 60.5 (41.9-94.3) mL/m(2), p = 0.024]. CCS also had reduced LV systolic and diastolic function, reflected by lower systolic LV myocardial velocities (5.3 ± 0.9 vs. 7.1 ± 1.7 cm/s, p = 0.001) and longitudinal deformation (- 17.3 ± 3.1 vs. - 20.7 ± 2.0%, p < 0.001), as well as lower diastolic LV myocardial velocities (- 10.7 ± 1.7 vs. - 12.2 ± 1.5 cm/s, p = 0.006) and deformation speed (1.1 ± 0.3 vs. 1.5 ± 0.2 1/s, p = 0.005). Additionally, in CCS insulin-like growth factor levels [15.4 (9.2-34.6) vs. 24.4 (14.8-55.5) nmol/L, p = 0.007] were lower. CONCLUSION: Cranial RT in CCS is associated with smaller cardiac volumes and reduced systolic and diastolic LV function. This off target effect of RT might be related to lower insulin-like growth factor levels.

Dietary supplementation with tributyrin alleviates intestinal injury in piglets challenged with intrarectal administration of acetic acid.

Tributyrin (TBU) is a good dietary source of butyrate and has beneficial effects on the maintenance of normal intestinal morphology. The present study tested the hypothesis that dietary TBU supplementation could alleviate intestinal injury in the acetic acid (ACA)-induced porcine model of colitis. A total of eighteen piglets (25 d old) were randomly allocated to one of three treatment groups (control, ACA and TBU). The control and ACA groups were fed a basal diet and the TBU group was fed the basal diet supplemented with 0·1 % TBU. On day 15 of the trial, under anaesthesia, a soft catheter was inserted into the rectum of piglets (20-25 cm from the anus), followed by administration of either saline (control group) or ACA (10 ml of 10 % ACA solution for ACA and TBU groups). On day 22 of the trial, after venous blood samples were collected, piglets were killed to obtain mid-ileum and mid-colon mucosae. Compared with the control group, the ACA group exhibited an increase (P< 0·05) in lymphocyte counts, creatinine, PGE2, and malondialdehyde concentrations and diamine oxidase and inducible NO synthase activities in the plasma and lymphocyte density in the colon and a decrease in insulin concentrations and glutathione peroxidase activity, ileal villus height:crypt depth ratios and goblet cell numbers in the colon. These adverse effects of ACA were attenuated by TBU supplementation. Moreover, TBU prevented the ACA-induced increase in caspase-3 levels while enhancing claudin-1 protein and epidermal growth factor receptor (EGFR) mRNA expression in the colonic mucosa. Collectively, these results indicate that dietary supplementation with 0·1 % TBU alleviates ACA-induced intestinal injury possibly by inhibiting apoptosis, promoting tight-junction formation and activating EGFR signalling.

Growth factors expression in hyaluronic acid fat graft myringoplasty.

OBJECTIVES/HYPOTHESIS: To investigate the effect of hyaluronic acid (HA) associated to fat graft on growth factors expression during the healing process of tympanic membrane (TM) perforations in guinea pigs using the hyaluronic acid fat graft myringoplasty (HAFGM) technique. STUDY DESIGN: Prospective randomized animal study. METHODS: Thirty guinea pigs were divided equally into three groups: group I (control group), group II (fat graft myringoplasty technique), and group III (HAFGM technique). TMs were perforated on day 1 and then sampled on days 0, 3, 8, and 21 and tested for the expression of: epidermal growth factor (EGF), insulin-like growth factor (IGF), tumor necrosis factor α (TNF α), vascular endothelial growth factor (VEGF), and keratinocyte growth factor (KGF). Five perforated TMs were taken at day 0 from group I to serve as a reference level. RESULTS: Group III showed an increased expression of all tested growth factors, except for KGF. EGF was highest in the early healing process; then IGF peaked at day 8 with statistically significant increase compared to groups I and II. TNF α in group III was significantly higher than group I throughout the study, with a peak level at day 21. VEGF was significantly higher in group III compared to group I at days 3 and 21. Neovascularization and scarless TM closure was obtained in group III, while spontaneous closure was associated with thin-layered and scarred TM in group I. CONCLUSIONS: HA association to fat graft in perforated TM increases the expression of the endogenous growth factors, suggesting that such an association is advantageous for healing. LEVEL OF EVIDENCE: N/A.

Growth factors in human serum during operative tibial lengthening with the Ilizarov method.

Despite the widespread clinical use of distraction osteogenesis for limb lengthening, the cellular and molecular mechanisms by which this surgical treatment promotes new bone formation in humans are not well understood. The aim of the research was to study the levels of growth factors (GFs) in the serum of patients that were undergoing tibial lengthening with the Ilizarov method of distraction osteogenesis. Those were patients with unilateral congenital discrepancy of the tibia (n = 12), unilateral posttraumatic tibial shortening (n = 7), and healthy patients that underwent cosmetic bilateral tibial lengthening (n = 10). The study established that unlike the congenital group, the posttraumatic group and healthy subjects showed a significantly evident increase in the levels of angiogenic GFs in their serum on day 10 of distraction. In the congenital group, the changes were not significant at this time point. The levels of TGF-α, TGF-ß1, and TGF-ß2 tended to decrease on day 10 of distraction and on day 30 of the post-distraction period in the cosmetic and posttraumatic groups while they grew in the congenital group. Most dynamic changes in the GFs levels during tibial lengthening were noted in the subjects undergoing cosmetic lengthening, and the least ones were in the congenital group.

Hormones and endocrine disruptors in human seminal plasma.

Seminal plasma represents a unique environment for maturation, nutrition, and protection of male germ cells from damaging agents. It contains an array of organic as well as inorganic chemicals, encompassing a number of biologically and immunologically active compounds, including hormones. Seminal plasma contains also various pollutants transferred from outer environment known as endocrine disruptors. They interfere with hormones at the receptor level, act as inhibitors of their biosynthesis, and affect hormone regulation.In this minireview, the main groups of hormones detected in seminal plasma are summarized. Seminal gonadal steroids were investigated mostly with aim to use them as biomarkers of impaired spermatogenesis (sperm count, motility, morphology). Concentrations of hormones in the seminal plasma often differ considerably from the blood plasma levels in dependence on their origin. In some instances (dihydrotestosterone, estradiol), their informative value is higher than determination in blood.Out of peptide hormones detected in seminal plasma, peptides of transforming growth factor beta family, especially antimullerian hormone, and oligopeptides related to thyrotropin releasing hormone have the high informative value, while assessment of seminal gonadotropins and prolactin does not bring advantage over determination in blood.Though there is a large body of information about the endocrine disruptors' impact on male reproduction, especially with their potential role in decline of male reproductive functions within the last decades, there are only scarce reports on their presence in seminal plasma. Herein, the main groups of endocrine disruptors found in seminal plasma are reviewed, and the use of their determination for investigation of fertility disorders is discussed.

Response of the insulin-like growth factor (IGF) system to IGF-IR inhibition and androgen deprivation in a neoadjuvant prostate cancer trial: effects of obesity and androgen deprivation.

CONTEXT: Prostate cancer patients at increased risk for relapse after prostatectomy were treated in a neoadjuvant study with androgen deprivation therapy (ADT) in combination with cixutumumab, an inhibitory fully human monoclonal antibody against IGF receptor 1 (IGF-IR). OBJECTIVE: A clinical trial with prospective collection of serum and tissue was designed to test the potential clinical efficacy of neoadjuvant IGF-IR blockade combined with ADT in these patients. The effect of body mass index (BMI) on response of IGF-IR/insulin components to IGF-IR blockade was also examined. DESIGN: Eligibility for the trial required the presence of high-risk prostate adenocarcinoma. Treatment consisted of bicalutamide, goserelin, and cixutumumab for 13 weeks before prostatectomy. Here we report on an analysis of serum samples from 29 enrolled patients. Changes in IGF and glucose homeostasis pathways were compared to control samples from patients in a concurrent clinical trial of neoadjuvant ADT alone. RESULTS: Significant increases were seen in GH (P = .001), IGF-I (P < .0001), IGF-II (P = .003), IGF binding protein (IGFBP)-3 (P < .0001), C-peptide (P = .0038), and insulin (P = .05) compared to patients treated with ADT alone. IGFBP-1 levels were significantly lower in the cixutumumab plus ADT cohort (P = .001). No significant changes in blood glucose were evident. Patients with BMIs in the normal range had significantly higher GH (P < .05) and IGFBP-1 (P < 0.5) levels compared to overweight and obese patients. CONCLUSIONS: Patients with IGF-IR blockade in combination with ADT demonstrated significant changes in IGF and glucose homeostasis pathway factors compared to patients receiving ADT alone. In the patients receiving combination therapy, patients with normal BMI had serum levels of glucose homeostasis components similar to individuals in the ADT-alone cohort, whereas patients with overweight and obese BMIs had serum levels that differed from the ADT cohort.