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Background Intrahepatic cholangiocarcinoma (iCCA) is a lethal primary liver tumor characterized by clinical aggressiveness, poor prognosis, and scarce therapeutic possibilities. Therefore, new treatments are urgently needed to render this disease curable. Since cumulating evidence supports the oncogenic properties of the Heat Shock Factor 1 (HSF1) transcription factor in various cancer types, we investigated its pathogenetic and therapeutic relevance in iCCA. Methods Levels of HSF1 were evaluated in a vast collection of iCCA specimens. The effects of HSF1 inactivation on iCCA development in vivo were investigated using three established oncogene-driven iCCA mouse models. In addition, the impact of HSF1 suppression on tumor cells and tumor stroma was assessed in iCCA cell lines, human iCCA cancer-associated fibroblasts (hCAFs), and patient-derived organoids. Results Human preinvasive, invasive, and metastatic iCCAs displayed widespread HSF1 upregulation, which was associated with a dismal prognosis of the patients. In addition, hydrodynamic injection of a dominant-negative form of HSF1 (HSF1dn), which suppresses HSF1 activity, significantly delayed cholangiocarcinogenesis in AKT/NICD, AKT/YAP, and AKT/TAZ mice. In iCCA cell lines, iCCA hCAFs, and patient-derived organoids, administration of the HSF1 inhibitor KRIBB-11 significantly reduced proliferation and induced apoptosis. Cell death was profoundly augmented by concomitant administration of the Bcl-xL/Bcl2/Bcl-w inhibitor ABT-263. Furthermore, KRIBB-11 reduced mitochondrial bioenergetics and glycolysis of iCCA cells. Conclusions The present data underscore the critical pathogenetic, prognostic, and therapeutic role of HSF1 in cholangiocarcinogenesis.

Background and Objectives: Aberrant upregulation of fatty acid synthase (FASN), catalyzing de novo synthesis of fatty acids, occurs in various tumor types, including human hepatocellular carcinoma (HCC). Although FASN oncogenic activity seems to reside in its pro-lipogenic function, cumulating evidence suggests that FASN’s tumor-supporting role might also be metabolic-independent. Materials and Methods: In the present study, we show that FASN inactivation by specific small interfering RNA (siRNA) promoted the downregulation of the S-phase kinase associated-protein kinase 2 (SKP2) and the consequent induction of p27KIP1 in HCC cell lines. Results: Expression levels of FASN and SKP2 directly correlated in human HCC specimens and predicted a dismal outcome. In addition, forced overexpression of SKP2 rendered HCC cells resistant to the treatment with the FASN inhibitor C75. Furthermore, FASN deletion was paralleled by SKP2 downregulation and p27KIP1 induction in the AKT-driven HCC preclinical mouse model. Moreover, forced overexpression of an SKP2 dominant negative form or a p27KIP1 non-phosphorylatable (p27KIP1-T187A) construct completely abolished AKT-dependent hepatocarcinogenesis in vitro and in vivo. Conclusions: In conclusion, the present data indicate that SKP2 is a critical downstream effector of FASN and AKT-dependent hepatocarcinogenesis in liver cancer, envisaging the possibility of effectively targeting FASN-positive liver tumors with SKP2 inhibitors or p27KIP1 activators.

Polyporus dermoporus mushroom, native to Brazil, is produced under natural conditions in the unexplored reserve of Mata da Estrela-Rio Grande do Norte-RN. These mushrooms were delipidated with chloroform:methanol (2:1 v/v), extracted with water at 100 °C, and fractionated with ethanol (one and three volumes) and then centrifuged. The ethanol precipitation showed a high total sugar level of 64.8% and 1% of protein. This precipitate contained a high glucan level, characterized by chemical methods and by NMR of 13C and 1H and spectroscopy. The 13C NMR spectrum of these mushroom extracts showed the presence of β-glucose by a signal at 103.25 ppm. Studies with these glucans were made to elucidate antioxidant and anti-inflammatory activities. This extract of glucans inhibited the lipid peroxidation (42.9%) and superoxide radicals (83.3%) at 67 μg/mL. However, the inhibition of hydroxyl radical by the extract of this mushroom was 96% at 267 μg/mL. The action of this extract on induced pleurisy showed a 92.5% and 68.7% reduction in polymorphonuclears cells and nitric oxide, respectively, at 30 mg/kg. The glucans reduced the croton oil-induced ear edema by 65.6% at 30 mg/kg.

Background. Intensive transfusion schedule and iron-chelating therapy prolonged and improved quality of life in patients with β-thalassemia (β-T) major. However, this led to an increased risk of developing impaired glucose tolerance or diabetes. In this study we analyzed variables associated with the occurrence of impaired glucose tolerance or diabetes in patients with β-T major. Methods. 388 Sardinian patients were included. Age, gender, duration of chelation therapy, body mass index, and markers of pancreatic and extrapancreatic autoimmunity were analyzed. Results. Multiple logistic regression analysis showed that anti-thyroid peroxidase (TPO) antibodies (Ab) (OR = 3.36; p = 0.008 ) and male gender (OR = 1.98; p = 0.025 ) were significantly associated with glucose impairment, while the other variables were not. Ferritin levels were significantly higher in TPOAb positive compared to TPOAb negative patients (4870 ± 1665 μg/L versus 2922 ± 2773 μg/L; p < 0.0001 ). Conclusions. In patients with β-T major a progressive damage of insulin-producing cells due to secondary hemosiderosis appears to be the most reasonable mechanism associated with glucose metabolism disorders. The findings need to be confirmed with additional well designed studies to address the question of whether TPOAb may have a role in the management of these patients.

Background. Type 1 diabetes (T1D) and type 2 diabetes (T2D) have been linked to Helicobacter pylori infection, although results are conflicting. No previous study addressed a possible link between H. pylori infection and latent autoimmune diabetes in adults (LADA). In this study, a correlation among H. pylori infection and the risk of autoimmune diabetes in comparison with T2D was investigated. Methods. Sera from 234 LADA patients, 105 patients with late-onset T1D, and 156 patients with T2D were analyzed for anti-H. pylori and the cytotoxin-associated antigen (CagA) IgG antibodies. Results. H. pylori seroprevalence was comparable in LADA (52%), late-onset T1D (45%), and T2D (49%) with no gender differences. The seroprevalence of CagA IgG was significantly higher in autoimmune diabetes (late-onset T1D: 45%, LADA: 40%) compared to T2D (25%; p<0.028). Conclusions. Although H. pylori seroprevalence was similar in LADA, T1D, and T2D, anti-CagA positivity was significantly increased among patients with autoimmune diabetes, suggesting that more virulent H. pylori strains might be a trigger for immune mechanisms involved in their pathogenesis.

Factors influencing the pattern of Helicobacter pylori infection among children living in adjacent urban and rural areas of northern Sardinia, Italy, were compared. The seroprevalence of H. pylori infection was 22% (625 of 2810 children) in the study population and was significantly higher among children in rural areas (37%) than in urban areas (13%) (odds ratio [OR], 3.8; 95% confidence interval [CI], 3.2-4.7; P < .005). This difference was consistent within each age group. In rural areas, children who had dogs were at greatest risk for H. pylori infection (OR, 1.8; 95% CI, 1.3-2.6; P < .05). No association was seen between H. pylori seropositivity and a history of breast-feeding. Urban children attending day care centers had a higher prevalence of infection (17%) than did those who never attended (12%) (OR, 1.5; 95% CI, 1.1-2.0; P < .05). The epidemiology of H. pylori infection is complex; even within the same geographic area, different factors influence acquisition of H. pylori infection.

It has been suggested that Helicobacter pylori infection may, in some instances, be a zoonosis. The aim of this study was to evaluate the prevalence of H. pylori infection in Sardinian shepherds and their families in relation to exposure to sheep and sheep dogs. Sardinian shepherds and a control group of blood donors completed detailed questionnaires regarding demographics, childhood and current economic status, and the presence of symptoms related to the upper gastrointestinal tract. H. pylori status was determined by a sensitive ELISA for anti-H. pylori IgG and by western blot for anti-CagA IgG. A subgroup of shepherds had upper gastrointestinal endoscopy with biopsy to assess the severity of the gastritis. H. pylori infection in Sardinian shepherds approached 100% and was positively related to animal contact (98% of shepherds, 73% of family members without regular direct animal contact compared to 43% of blood donors) (P < 0.001). Importantly, the family members shared the same childhood with the shepherds but choose different careers (e.g., teachers, nurses, business) and did not have regular contact with sheep. In conclusion, the prevalence of H. pylori infection in Sardinian shepherds is among the highest in the world and is associated with direct contact with sheep and sheep dogs. These results suggest that the cycle of H. pylori infection might, in certain circumstances, include phases in the environment, animals (sheep or dogs) and human beings.

Helicobacter pylori (H. pylori) DNA has been identified in human livers and has been implicated in chronic liver disease and liver cancer. To better understand the role of H pylori in primary sclerosing cholangitis (PSC), 25 patients with end-stage PSC and 31 controls were studied. Genomic DNA was extracted from microdissected hilar hepatic ducts of liver explants and was amplified for H pylori DNA. Serum was tested for H pylori antibodies. Helicobacter DNA was detected in 9 of the 56 (16%) patients by 16SrRNA PCR (an additional case [for a total of 18%] was antibody positive). Seven of the 9 cases identified by polymerase chain reaction were positive for the CagA gene, confirming they were H pylori. Seven of the 25 (28%) patients with PSC and 3 of the 31 (9.7%) controls were positive for Helicobacter (P=.087). H pylori DNA was detected in microdissected hilar biliary epithelium in more PSC patients than controls, supporting the hypothesis that bile reflux from the duodenum into the biliary tract might carry H pylori organisms into the proximal biliary system, possibly contributing to PSC development and/or progression in some patients.

OBJECTIVES: When and how Helicobacter pylori ( H. pylori) originally entered the human population as well as how the infection is transmitted in different communities is unknown. We previously showed that Sardinian shepherds had almost a 100% prevalence of H. pylori and that the prevalence was higher than that of their same-household siblings. AIM: To examine whether H. pylori infection might be transmitted from sheep. METHODS: Milk and gastric tissue were cultured and analyzed by PCR amplification using three sets of primers Helicobacter genus–specific 16S rRNA and two sets of primers specific for H. pylori vacA gene. RESULTS: Helicobacter DNA was demonstrated in 60% (38/63) of milk samples and in 30% (6/20) of sheep tissue samples. H. pylori vacA gene was amplified in five of 38 milk samples, and in two of six sheep tissue samples respectively. H. pylori were cultured from sheep milk and tissue samples and confirmed as H. pylori on the basis of colony morphology, positive biochemical reactions, and negative Gram stain. Sequence analysis of 16S rRNA PCR products from these isolates demonstrated 99% identity with H. pylori. CONCLUSIONS: Together, the presence of H. pylori in sheep stomach in the absence of associated gastritis and recovery of H. pylori from sheep milk and gastric tissue suggest that sheep may be a natural host for H. pylori.

Higher serological prevalence rates of Helicobacter pylori (Hp) infection have been reported in patients with autoimmune thyroiditis (AT), and it has been suggested that monoclonal antibodies against Cag-A positive Hp strains can cross-react with follicular cells of the thyroid gland. We studied the prevalence of AT and thyroid functional status in patients who underwent gastroscopy for dyspeptic symptoms. Patients were tested for TSH, free thyroid hormones, and antithyroglobulin and antithyroperoxidase antibodies (ATPO). Hp positivity was determined using urea breath test (UBT). Serum samples from 302 patients (59.9% women) were evaluated. One hundred ninety-one subjects (63.2%) were Hp-negative, and 111 of 302 (36.8%) were Hp-positive. Forty-three of 191 Hp-negative patients (22.5%; 95% CI, 17.1-29.0%) had an increase of either antibody, compared to 30 of 111 (27.0%; 95% CI, 19.6-36.0%) Hp-positive patients (P = 0.40). Similar results were obtained using positivity for both antibodies (7.3 vs. 7.2%; P = 1) or for ATPO (18.8 vs. 21.6%; P = 0.54). The prevalences of hypothyroidism (4.7 vs. 5.5%) or hyperthyroidism (5.8 vs. 5.5%) were also similar (P = 0.95). Hormonal levels were not different in the two groups (P > 0.22 in all cases). The previously reported association between AT and Hp infection was not observed in our study. Infection by Hp does not appear to increase the risk of AT in individuals with dyspeptic symptoms, and screening for this condition in patients with a positive UBT is not indicated.