Impact of hormone receptor status and tumor subtypes of breast cancer in young BRCA carriers.

BACKGROUND: Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer; however, limited evidence exists on its prognostic impact on prognosis of young patients harboring a pathogenic variant (PV) in the BRCA1 and/or BRCA2 genes. PATIENTS AND METHODS: This international, multicenter, retrospective cohort study included young patients (aged ≤40 years) diagnosed with invasive breast cancer and harboring germline PVs in BRCA genes. We investigated the impact of hormone receptor status on clinical behavior and outcomes of breast cancer. Outcomes of interest [disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival (OS)] were first investigated according to hormone receptor expression (positive versus negative), and then according to breast cancer subtype [luminal A-like versus luminal B-like versus triple-negative versus human epidermal growth factor receptor 2 (HER2)-positive breast cancer]. RESULTS: From 78 centers worldwide, 4709 BRCA carriers were included, of whom 2143 (45.5%) had hormone receptor-positive and 2566 (54.5%) hormone receptor-negative breast cancer. Median follow-up was 7.9 years. The rate of distant recurrences was higher in patients with hormone receptor-positive disease (13.1% versus 9.6%, P < 0.001), while the rate of second primary breast cancer was lower (9.1% versus 14.7%, P < 0.001) compared to patients with hormone receptor-negative disease. The 8-year DFS was 65.8% and 63.4% in patients with hormone receptor-positive and negative disease, respectively. The hazard ratio of hormone receptor-positive versus negative disease changed over time for DFS, BCSS, and OS (P < 0.05 for interaction of hormone receptor status and survival time). Patients with luminal A-like breast cancer had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-year DFS: 60.8% in luminal A-like versus 63.5% in triple-negative versus 65.5% in HER2-positive and 69.7% in luminal B-like subtype). CONCLUSIONS: In young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor-positive versus negative disease warrant consideration in counseling patients on treatment, follow-up, and risk-reducing surgery.

High- and intermediate-risk susceptibility variants in melanoma families from the Mediterranean area: A multicentre cohort from the MelaNostrum Consortium.

BACKGROUND: Most of large epidemiological studies on melanoma susceptibility have been conducted on fair skinned individuals (US, Australia and Northern Europe), while Southern European populations, characterized by high UV exposure and dark-skinned individuals, are underrepresented. OBJECTIVES: We report a comprehensive pooled analysis of established high- and intermediate-penetrance genetic variants and clinical characteristics of Mediterranean melanoma families from the MelaNostrum Consortium. METHODS: Pooled epidemiological, clinical and genetic (CDKN2A, CDK4, ACD, BAP1, POT1, TERT, and TERF2IP and MC1R genes) retrospective data of melanoma families, collected within the MelaNostrum Consortium in Greece, Italy and Spain, were analysed. Univariate methods and multivariate logistic regression models were used to evaluate the association of variants with characteristics of families and of affected and unaffected family members. Subgroup analysis was performed for each country. RESULTS: We included 839 families (1365 affected members and 2123 unaffected individuals). Pathogenic/likely pathogenic CDKN2A variants were identified in 13.8% of families. The strongest predictors of melanoma were ≥2 multiple primary melanoma cases (OR 8.1; 95% CI 3.3-19.7), >3 affected members (OR 2.6; 95% CI 1.3-5.2) and occurrence of pancreatic cancer (OR 4.8; 95% CI 2.4-9.4) in the family (AUC 0.76, 95% CI 0.71-0.82). We observed low frequency variants in POT1 (3.8%), TERF2IP (2.5%), ACD (0.8%) and BAP1 (0.3%). MC1R common variants (≥2 variants and ≥2 RHC variants) were associated with melanoma risk (OR 1.4; 95% CI 1.0-2.0 and OR 4.3; 95% CI 1.2-14.6, respectively). CONCLUSIONS: Variants in known high-penetrance genes explain nearly 20% of melanoma familial aggregation in Mediterranean areas. CDKN2A melanoma predictors were identified with potential clinical relevance for cancer risk assessment.

Antitumoral gene-based strategy involving nitric oxide synthase type III overexpression in hepatocellular carcinoma.

Hepatocellular carcinoma develops in cirrhotic liver. The nitric oxide (NO) synthase type III (NOS-3) overexpression induces cell death in hepatoblastoma cells. The study developed gene therapy designed to specifically overexpress NOS-3 in cultured hepatoma cells, and in tumors derived from orthotopically implanted tumor cells in fibrotic livers. Liver fibrosis was induced by CCl4 administration in mice. The first-generation adenoviruses were designed to overexpress NOS-3 or green fluorescent protein, and luciferase complementary DNA under the regulation of murine alpha-fetoprotein (AFP) and Rous Sarcoma Virus (RSV) promoters, respectively. Both adenovirus and Hepa 1-6 cells were used for in vitro and in vivo experiments. Adenoviruses were administered through the tail vein 2 weeks after orthotopic tumor cell implantation. AFP-NOS-3/RSV-luciferase increased oxidative-related DNA damage, p53, CD95/CD95L expression and caspase-8, -9 and -3 activities in cultured Hepa 1-6 cells. The increased expression of CD95/CD95L and caspase-8 activity was abolished by Nω-nitro-l-arginine methyl ester hydrochloride, p53 and CD95 small interfering RNA. AFP-NOS-3/RSV-luciferase adenovirus increased cell death markers, and reduced cell proliferation of established tumors in fibrotic livers. The increase of oxidative/nitrosative stress induced by NOS-3 overexpression induced DNA damage, p53, CD95/CD95L expression and cell death in hepatocellular carcinoma cells. The effectiveness of the gene therapy has been demonstrated in vitro and in vivo.

Rheological Flow Behavior of Structural Polysaccharides from Edible Tender Cladodes of Wild, Semidomesticated and Cultivated 'Nopal' (Opuntia) of Mexican Highlands.

The aim of this study was to quantify the content of polysaccharides of edible tender cladodes (nopalitos) of three species of Opuntia and to evaluate the rheological flow behavior of isolated polysaccharides. A completely randomized experimental design was used to characterize a wild (O. streptacantha), a semidomesticated (O. megacantha) and a domesticated (O. ficus-indica) species. Mucilage content was higher (4.93 to 12.43 g 100 g-1 dry matter), tightly bound hemicelluloses were lower (3.32 to 1.81 g 100 g-1 dry matter) and pectins and loosely bound hemicelluloses were not different in wild than in domesticated species. Aqueous solution/suspensions of mucilage, pectins, hemicellulose and cellulose of all species showed non-Newtonian behavior under simple shear flow. The flow behavior of the structural polysaccharides was well described by the Ostwald de-Waele model. Pectins and mucilages exhibited the highest consistency indexes (K values ranged from 0.075 to 0.177 Pasn) with a moderated shear-thinning behavior (n values ranged from 0.53 to 0.67). Cellulose dispersions exhibited the most shear-thinning behavior (n values ranged from 0.17 to 0.41) and hemicelluloses showed a tendency to Newtonian flow (n values ranged from 0.82 to 0.97). The rheological flow properties of these polysaccharides may be useful to improve the textural and sensory qualities of some foods and pharmaceutical materials. Moreover, they can emerge as functional ingredients mainly due to the nutraceutical properties that have been attributed to nopalitos.

Clinical and Surgical Outcomes of Endoscopic Endonasal Approach for Giant Pituitary Adenomas: Analysis of Predictive Factors.

BACKGROUND: Giant pituitary adenomas (GPAs) are defined as tumors with ≥40 mm in any maximum diameter, and these tend to invade multiple intracranial compartments. Hence, treatment remains a surgical challenge. OBJECTIVE: To describe the clinical and surgical outcomes of the endoscopic endonasal approach (EEA) for GPA in a pituitary referral center in Latin America and to analyze associated predictive factors. METHODS: 37 patients with histologically-confirmed GPA treated solely through the EEA between a 2-year period were included. Preoperative and postoperative clinical and neuroimaging findings; surgical morbidity and mortality; and binary logistic regression analysis to assess predictive factors were analyzed. RESULTS: Preoperative visual impairment prevalence was 97.3%. Mean tumor volume was 32 cc and gross total resection rate was 40.5%. Favorable visual acuity and visual fields outcome rate was 75% and 82.9%, respectively. In the multivariate analysis, bilateral cavernous sinus invasion (P = 0.018) and postoperative cerebrospinal fluid (CSF) leak (P = 0.036) were associated with an unfavorable visual acuity outcome, while radiation therapy (P = 0.035) was for visual fields. Similarly, intraoperative CSF leak was a predictive factor for postoperative CSF leak (10.8%) (P = 0.042) and vascular injury (13.5%) (P = 0.048). CONCLUSIONS: In this first Mexican clinical series, we demonstrated that the EEA is a safe and effective technique for GPA, although early diagnosis and prompt intervention may promote further visual function preservation without significant endocrine morbidity.

Rheological properties of ethyl cellulose-monoglyceride-candelilla wax oleogel vis-a-vis edible shortenings.

The gelation process, elasticity, and mechanical recovery after shear were studied in mixed oleogels of ethylcellulose (EC), monoglycerides (MG), and candelilla wax (CW). EC oleogels produced without MG showed grainy texture due to incomplete dissolution of crystalline fractions of raw EC in the vegetable oil (150 °C). These fractions were eliminated by dissolving the raw EC/MG mixture in ethanol, evaporating the solvent, dispersing, and dissolving the solid residue in the vegetable oil (150 °C) prior gelation. The EC polymeric network, and MG, and CW crystals had a positive interaction on the elasticity of mixed oleogels. Mixed oleogels produced under static conditions showed a 100 % of elasticity recovery after shearing, a phenomenon associated with an EC interchain hydrogen bonding mediated by hydroxyl groups of MGs. This tentatively resulted from the formation of junction zones of the type EC-[MG]n-EC. The rheological behavior of these olegels was remarkably close to that of commercial shortenings.

[Induction treatment by combining immunoglobulins, plasmapheresis and rituximab in hypersensitive patients receiving cadaveric renal allograft]. / Tratamiento de inducción combinando inmunoglobulinas, plasmaféresis y rituximab en pacientes hipersensibilizados que reciben trasplante renal de cadáver.

In our Universitary Hospital of Canarias we iniciated in May 2008 a induction therapy protocol for sensitized patients receiving cadaveric renal graft using intravenous immunoglobulins, plasmapheresis and rituximab plus immunosuppression with prednisone, tacrolimus and mycophenolate mofetil. We present the results of four patients. Everyone had anti-HLA antibodies rate (PRA by CDC) more than 75%, were on a waiting list during 4 to 17 years and follow-up time was 10-14 months after transplantation. Patient and graft survival in this period was 100%. Only one patient suffered a humoral acute rejection and another one cellular rejection, in both cases reversible with treatment. During the first year, no evidence of de novo donor-specific antibodies was detected. All patients had significantly reduced the CD19+ cells percentage after infusion of rituximab. Neurological symptoms suggestive of progressive multifocal leukoencephalopathy or serious viral infections after transplantation have not been observed. Additionally, no immediate side effects were observed after administration of medication. In summary, induction therapy by combining immunoglobulin, plasmapheresis and rituximab in hypersensitive patients allows the realization of deceased kidney transplantation with good results in the short and medium-term without serious side effects. It remains to know whether this success will continue in the long term.

3D printer waste, a new source of nanoplastic pollutants.

Plastics pollution has been recognized as a serious environmental problem. Nevertheless, new plastic uses, and applications are still increasing. Among these new applications, three-dimensional resin printers have increased their use and popularity around the world showing a vertiginous annual-sales growth. However, this technology is also the origin of residues generation from the alcohol cleaning procedure at the end of each printing. This alcohol/resin mixture can originate unintentionally very small plastic particles that usually are not correctly disposed, and as consequence, could be easily released to the environment. In this work, the nanoparticle generation from 3D printer's cleaning procedure and their physicochemical characterization is reported. Nano-sized plastic particles are easily formed when the resin residues are dissolved in alcohol and placed under UV radiation from sunlight. These nanoparticles can agglomerate in seawater showing an average hydrodynamic diameter around 1 µm, whereas the same nanoparticles remain dispersed in ultrapure water, showing a hydrodynamic diameter of ≈300 nm. The formed nanoparticles showed an isoelectric point close to pH 2, which can facilitate their interaction with other positively charged pollutants. Thus, these unexpected plastic nanoparticles can become an environmental issue and public health risk.

Adverse events of ERCP at San José Hospital of Bogotá (Colombia).

Endoscopic retrograde cholangiopancreatography (ERCP) has become the preferred treatment method for hepatobiliary and pancreatic disease. Despite technological progress this technique continues to account for the greatest morbidity and mortality caused by digestive endoscopic procedures. ERCP carries a risk of pancreatitis, perforation, hemorrhage, cholangitis and cardiopulmonary events occurring in upto 10% of patients in referral centers, implying a mortality of up to 1%, not including therapeutic failures or the need for re-intervention. A greater mortality rate has been demonstrated in prospective studies rather than in retrospective studies, but overall, the number of complications described in the literature is much lower than the number of complications that actually occur.A descriptive prospective study was conducted at San José Hospital from April 1, 2006 to April 30, 2007 in patients who underwent an ERCP and had a 1-month follow-up. A total of 381 patients were included; 9 (2.3%) were excluded, and of the remaining 372 there was an overall success in 79.6% of cases, 8.3% had a second intervention, 7.6% developed complications (pancreatitis, perforation, hemorrhage, cholangitis, pain, intolerance to sedatives, and cardiopulmonary events), and 4.3% were failed ERCP studies. The mortality rate of the ERCP procedure was 0.8%.ERCP-related complications were determined at a teaching center, and this suggests the need to implement centers of excellence in order to improve the efficacy of the procedure.

[Causes of hospital mortality due to brain haemorrhage in patients with arteriovenous malformation]. / Causas de la mortalidad hospitalaria por hemorragia cerebral en pacientes con malformacion arteriovenosa.

AIM: To determine the causes of mortality in cases of brain haemorrhage among patients with arteriovenous malformations (AVM) treated in a tertiary hospital. PATIENTS AND METHODS: The patients with AVM who died over the period 1990-2014 were selected from a prospective register of vascular malformations. Demographic aspects, localisation of the AVM, associated aneurysms and previous treatments were reviewed. Three main causes of death were established: initial bleeding/rebleeding, those related with the treatment of the AVM and other causes not related with AVM. RESULTS: A total of 400 patients were treated for AVM, 216 (54%) with a ruptured AVM, of whom 26 (12.1%) died as a result of a brain haemorrhage. The mean age of the group of patients who died was 48.8 years (range: 8-78 years). Twenty (76.9%) were admitted in coma (Glasgow Coma Scale < 9). In five cases (19.2%), bleeding was due to an associated aneurysm. A very high percentage (38.5%) had the AVM in the posterior fossa. Three patients had previously received non-curative treatments for the AVM in other medical centres. Of the total number, six (23.1%) received endovascular/surgical treatment in our hospital, and we have assumed that, due to the indication or owing to the time in which it was carried out, the cause of death was treatment-related, although two young patients underwent surgery with bilateral mydriasis. One patient died due to an associated glioblastoma, and the others, 19 (76%), due to rebleeding or to the initial brain damage. CONCLUSION: Knowing the causes of mortality can help improve the clinical outcome, above all in cases in which an early treatment could be indicated.

TITLE: Causas de la mortalidad hospitalaria por hemorragia cerebral en pacientes con malformacion arteriovenosa.Objetivo. Conocer las causas de la mortalidad en la hemorragia cerebral de los pacientes con malformaciones arteriovenosas (MAV) tratadas en un hospital terciario. Pacientes y metodos. De un registro prospectivo de malformaciones vasculares se han seleccionado los pacientes que fallecieron con MAV en el periodo 1990-2014. Se han revisado aspectos demograficos, localizacion de la MAV, aneurismas asociados y tratamientos previos. Se han establecido tres causas principales de muerte: sangrado inicial/resangrado, relacionadas con el tratamiento de la MAV y otras causas no relacionadas con la MAV. Resultados. Se trato a 400 pacientes de MAV, 216 (54%) con MAV rotas, de los que fallecieron 26 (12,1%) por hemorragia cerebral. La media de edad del grupo de pacientes fallecidos fue de 48,8 años (rango: 8-78 años). Veinte (76,9%) ingresaron en coma (escala de coma de Glasgow < 9). En cinco casos (19,2%), el sangrado se debio a un aneurisma asociado. Un porcentaje muy elevado (38,5%) tenia la MAV en la fosa posterior. Tres pacientes habian recibido previamente en otros centros tratamientos no curativos de la MAV. Del total, seis (23,1%) recibieron tratamiento endovascular/quirurgico en nuestro hospital, y hemos asumido que, por la indicacion o por el momento en que se realizo, la causa de la muerte se relacionaba con el tratamiento, aunque dos pacientes jovenes se operaron con midriasis bilateral. Un paciente fallecio por un glioblastoma asociado, y el resto, 19 (76%), por el resangrado o el daño cerebral inicial. Conclusion. El conocimiento de las causas de mortalidad puede contribuir a mejorar el resultado clinico, sobre todo en los casos en que podria estar indicado un tratamiento precoz.

Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells.

Nitric oxide (NO) plays a relevant role during cell death regulation in tumor cells. The overexpression of nitric oxide synthase type III (NOS-3) induces oxidative and nitrosative stress, p53 and cell death receptor expression and apoptosis in hepatoblastoma cells. S-nitrosylation of cell death receptor modulates apoptosis. Sorafenib is the unique recommended molecular-targeted drug for the treatment of patients with advanced hepatocellular carcinoma. The present study was addressed to elucidate the potential role of NO during Sorafenib-induced cell death in HepG2 cells. We determined the intra- and extracellular NO concentration, cell death receptor expression and their S-nitrosylation modifications, and apoptotic signaling in Sorafenib-treated HepG2 cells. The effect of NO donors on above parameters has also been determined. Sorafenib induced apoptosis in HepG2 cells. However, low concentration of the drug (10nM) increased cell death receptor expression, as well as caspase-8 and -9 activation, but without activation of downstream apoptotic markers. In contrast, Sorafenib (10 µM) reduced upstream apoptotic parameters but increased caspase-3 activation and DNA fragmentation in HepG2 cells. The shift of cell death signaling pathway was associated with a reduction of S-nitrosylation of cell death receptors in Sorafenib-treated cells. The administration of NO donors increased S-nitrosylation of cell death receptors and overall induction of cell death markers in control and Sorafenib-treated cells. In conclusion, Sorafenib induced alteration of cell death receptor S-nitrosylation status which may have a relevant repercussion on cell death signaling in hepatoblastoma cells.

Clinical and prognostic value of serum procollagen levels in chronic alcoholic liver disease.

Liver fibrogenesis involves the synthesis of collagen fibrils and proteoglycans by various types of liver cells, including Ito cells, transitional cells, myofibroblasts and hepatocytes. Synthesis of collagen fibrils follows a complex metabolic pathway with intermediate products such as type III procollagen (III-PC). Serum levels of III-PC may reflect the activity of the fibrogenetic process. We analysed the relationship between the serum levels of III-PC (N-terminal peptide) and diverse clinical, biochemical and histological parameters of 77 alcoholic patients (27 cirrhotics), comparing them with those of 15 age- and sex-matched controls. A highly significant difference was obtained between controls and patients (P less than 0.0001), but no differences were observed between cirrhotics and non-cirrhotics. Serum III-PC significantly correlated with clinical and biochemical data of liver function derangement (prothrombin activity, serum albumin, bilirubin, gynecomastia, ascites, encephalopathy, edema, splenomegaly); with the duration of ethanol addiction and with MCV. Sixty patients were followed up for a period ranging between 3 and 1056 days (mean = 356 days); 9 of them died. Patients with III-PC levels above 38 ng/ml had a significantly higher mortality (P = 0.006) than those with levels under 38 (log rank test). Thus, serum III-PC may be a useful tool in the clinical evaluation and prognostic assessment of patients with chronic alcoholic liver disease.

Spirulina maxima prevents fatty liver formation in CD-1 male and female mice with experimental diabetes.

The dietary administration of 5% Spirulina maxima (SM) during four weeks to diabetic mice, starting one week after a single dose of alloxan, 250 mg/Kg body weight, prevented fatty liver production in male and female animals. The main action of SM was on triacylglycerol levels in serum and liver. There was also a moderate hypoglycemia in male mice. The thiobarbituric acid reactive substances also decreased in serum and liver after SM administration. There was also a decrease in the percentage of HDL in diabetic mice that was reverted by the SM administration. The sum of LDL + VLDL percentages was also partially normalized in diabetic animals by the SM administration. An additional observation was the lower incidence of adherences between the liver and the intestine loops in the diabetic mice treated with SM compared with diabetic mice without SM. Male and female mice showed differences to diabetes susceptibility and response to SM, the female being more resistant to diabetes induction by alloxan and more responsive to the beneficial effects of SM. It is worth future work of SM on humans looking for better quality of life and longer survival of diabetic patients.

Arthrospira maxima prevents the acute fatty liver induced by the administration of simvastatin, ethanol and a hypercholesterolemic diet to mice.

An evident fatty liver, corroborated morphologically and chemically, was produced in CD-1 mice after five daily doses of simvastatin 75 mg/Kg body weight, a hypercholesterolemic diet and 20 percent ethanol in the drinking water. After treating the animals, they presented serum triacylglycerols levels five times higher than the control mice, total lipids, cholesterol and triacylglycerols in the liver were 2, 2 and 1.5 times higher, respectively, than in control animals. When Arthrospira maxima was given with diet two weeks prior the onset of fatty liver induction, there was a decrement of liver total lipids (40%), liver triacylglycerols (50%) and serum triacylglycerols (50%) compared to the animals with the same treatment but without Arthrospira maxima. In addition to the mentioned protective effect, the administration of this algae, produced a significant increase (45%) in serum high density lipoproteins. The mechanism for this protective effect was not established in these experiments.

[Pseudohypoparathyroidism: a familial case]. / Pseudohipoparatiroidismo: un caso familiar.

The pseudohypoparathyroidism is a rare disease which progresses with hypocalcemia despite the high levels of PTH. Clinically, there are three different types of pseudohypoparathyroidism, depending on the urinary elimination of AMPc, the presence of Albright's osteodystrophy and the response to exogenous PTH. It is detected occasionally, as it was the case of the family that we present here, in which 6 of the 9 members from the two last generations were affected by this entity.

Cannabinoid receptor type 1 activation by arachidonylcyclopropylamide in rat aortic rings causes vasorelaxation involving calcium-activated potassium channel subunit alpha-1 and calcium channel, voltage-dependent, L type, alpha 1C subunit.

Cannabinoids are key regulators of vascular tone, some of the mechanisms involved include the activation of cannabinoid receptor types 1 and 2 (CB); the transient receptor potential cation channel, subfamily V, member 1 (TRPV1); and non-(CB(1))/non-CB2 receptors. Here, we used the potent, selective CB(1) agonist arachidonylcyclopropylamide (ACPA) to elucidate the mechanism underlying vascular tone regulation. Immunohistochemistry and confocal microscopy revealed that CB(1) was expressed in smooth muscle and endothelial cells in rat aorta. We performed isometric tension recordings in aortic rings that had been pre-contracted with phenylephrine. In these conditions, ACPA caused vasorelaxation in an endothelium-independent manner. To confirm that the effect of ACPA was mediated by CB(1) receptor, we repeated the experiment after blocking these receptors with a selective antagonist, AM281. In these conditions, ACPA did not cause vasorelaxation. We explored the role of K(+) channels in the effect of ACPA by applying high-K(+) solution to induce contraction in aortic rings. In these conditions, the ACPA-induced vasorelaxation was about half that observed with phenylephrine-induced contraction. Thus, K(+) channels were involved in the ACPA effect. Furthermore, the vasorelaxation effect was similarly reduced when we specifically blocked calcium-activated potassium channel subunit alpha-1 (KCa1.1) (MaxiK; BKCa) prior to adding ACPA. Finally, ACPA-induced vasorelaxation was also diminished when we specifically blocked the calcium channel, voltage-dependent, L type, alpha 1C subunit (Ca(v)1.2). These results showed that ACPA activation of CB(1) in smooth muscle caused vasorelaxation of aortic rings through a mechanism involving the activation of K(Ca)1.1 and the inhibition of Ca(v)1.2.

[Intracerebral pial arteriovenous fistula with giant venous varix]. / Fistula arteriovenosa intracraneal pial con variz gigante.

TITLE: Fistula arteriovenosa intracraneal pial con variz gigante.