DNA repair pathways to regulate response to chemoradiotherapy in patients with locally advanced head and neck cancer.

Platinum-based chemoradiotherapy (CRT) is a preferred standard of care for locally advanced head and neck cancer (HNC). However, survival benefit is small, with substantial toxicity and biomarkers of CRT resistance that could guide treatment selection and spare morbidity. Increased DNA repair in solid tumors may contribute to cancer cells' ability to survive in genotoxic stress environments afforded by therapy. We assessed mRNA expression levels of DNA repair-related genes BRCA1, RAP80, 53 binding protein 1 (53BP1), mediator of DNA damage checkpoint 1 (MDC1), and RNF8. We correlated our findings with response and overall survival in 72 head and neck patients treated with weekly carboplatin AUC 2 and radiotherapy. Complete response (CR) to CRT was 50 % in patients with low levels of 53BP1 compared to 6.3 % in patients with high levels (p = 0.0059). Of high BRCA1 mRNA expressors, 41.2 % had CR compared to 29.4 % of low expressors (p = 0.72). For a small group of patients with low 53BP1 and either high BRCA1 or RAP80, CRs were 66.7 and 71.4 %, respectively. A trend for better overall survival (OS) was found for patients with low 53BP1 (15 vs 8 m; p = 0.056). Our findings highlight the potential usefulness of 53BP1 mRNA as a predictive biomarker of response and overall survival in HNC patients treated with chemoradiotherapy. Those with high 53BP1 expression could derive only a meager benefit from treatment. Analysis of BRCA1 and RAP80 could further reinforce the predictive value of 53BP1. Although this was a retrospective study with small sample size, it could inform larger translational studies in HNC.

Testing monophyly of the freshwater fish Leporinus (Characiformes, Anostomidae) through molecular analysis.

Monophyly of the genus Leporinus (Characiformes: Anostomidae) was tested by sequencing and analysing a total of 4732 bp, including two mitochondrial [cytochrome oxidase subunit 1 (CO1) and cytochrome b (Cytb)] and three nuclear [myosin heavy chain 6 cardiac muscle alpha (Myh6), recombination activating gene 1 (RAG1) and recombination activating gene 2 (RAG2)] loci for 22 species of Leporinus, or c. 25% of all described species in the genus. Phylogenetic tree analyses (maximum parsimony, maximum likelihood and Bayesian species tree) indicate Leporinus to be paraphyletic, with monophyly being rejected by both Kishino-Hasegawa and Shimodaira-Hasegawa tests. The sequenced species of Leporinus are distributed across five clades that are interleaved among other anostomid genera. Several taxonomic changes are suggested as being necessary to restore monophyly for the group. The clade containing the type species, Leporinus fasciatus, should be considered Leporinus sensu stricto and at least three new genera should be described for other species currently considered part of Leporinus.

Intensification of treatment with pegylated interferon alfa in patients coinfected with HIV and HBV genotype H or G being treated with a tenofovir/emtricitabine-containing regimen.

BACKGROUND/AIMS: The most common HBV genotypes in HIV-coinfected patients in Mexico are H and G; the response to treatment for these genotypes is unknown. The aim of the study was to examine the effectiveness of intensification with pegylated interferon (PEG-IFN) alfa-2a or alfa-2b in HBV/HIV-coinfected patients treated with a tenofovir/emtricitabine (TDF/FTC) backbone in an HIV clinic in Mexico City. METHODOLOGY: We performed a single-arm open-label trial involving HBV/HIV-coinfected patients. Patients with chronic hepatitis B who were HBeAg positive were treated with TDF/FTC-containing regimen. Treatment was intensified by addition of PEG-IFN alfa-2b or alfa-2a for 24 weeks. The primary endpoint of effectiveness, assessed after 24 weeks, was suppression of HBV DNA to <60 IU/mL. RESULTS: We enrolled 29 patients; 27 (93%) were men. HBV genotypes were F in 2 (6.9%), A in 2 (6.9%), G in 10 (34.5%), and H in 15 (51.7%). The primary endpoint was present in 17 (58%) patients (95% CI 29.7%­70.8%). CONCLUSIONS: Intensification with PEG-IFN alfa-2a or alfa-2b is effective and well tolerated in patients with chronic hepatitis B who are HBeAg positive, have genotype H or G, and are coinfected with HIV while they are being treated with TDF/FTC-containing regimen.

Molecular phylogeny of Threskiornithidae (Aves: Pelecaniformes) based on nuclear and mitochondrial DNA.

The family Threskiornithidae includes 13 genera and 32 species, and it is traditionally divided into 2 subfamilies: Plataleinae and Threskiornithinae. We present a phylogenetic reconstruction to test the monophyly of currently accepted subfamilies, including 15 species from both subfamilies and 10 genera of family Threskiornithidae. Phylogenetic trees were inferred on the basis of the mitochondrial 16S rRNA gene and the nuclear intron 7 of ß-fibrinogen. Threskiornithidae was recovered as a monophyletic group. Plataleinae formed a monophyletic group, but nested within Threskiornithinae, which was thus paraphyletic. Two major phylogenetic groups were identified: the 'endemic New World clade', including genera endemic to the American continent, and the 'widespread clade', comprising the remaining species. These phylogenetic groups diverged about 39-42 million years ago, i.e., before the separation of South America and Antarctica. Our results agree with an initial vicariance due to Gondwana break-up and subsequent colonization of species from the Old World to the New World.

Allergic sensitization increases contractile responses to 5-HT in guinea pig aorta.

Epidemiological and clinical studies suggest that asthma is associated with adverse cardiovascular outcomes, but its mechanism is uncertain. 5-Hydroxytryptamine (5-HT) is a mediator involved in asthma and in cardiovascular functioning. Thus, in the present study, we explored whether allergic sensitization in guinea pigs modifies 5-HT-induced contractile responses and 5-HT2A receptor expression in thoracic aorta rings. We found that sensitization produced a significant increase of 100 microM 5-HT-induced contractions of aorta rings (~27 % greater contraction than in non-sensitized animals, p<0.05). Preincubation with 10 nM ketanserin (a 5-HT2A receptor antagonist) reduced by ~30 % (p=0.003) and ~36 % (p=0.005) the area under the curve of 5-HT-induced contractions in aortas from non-sensitized and sensitized animals, respectively. There were no differences between sensitized and non-sensitized animals with respect to mRNA (qPCR) and protein (Western blot) expression of 5-HT2A receptor in thoracic aortas. We concluded that in this guinea pig model of asthma, allergic sensitization is not confined to airways, but also affects arterial contractile responses to 5-HT; changes in the expression of the 5-HT2A receptor appear not to be involved in this phenomenon.

[Prevalence of neutropenic enterocolitis in adults with severe neutropenia and associated mortality.]. / Prevalencia de enterocolitis neutropénica en adultos con neutropenia grave y mortalidad asociada.

BACKGROUND: Neutropenic enterocolitis (NEC) is characterized by inflammatory damage and necrosis of the intestinal mucosa, mainly of the terminal ileum and the cecum. It is more frequent in patients with leukemia and/or undergoing antineoplastic chemotherapy, and the main risk factor is neutropenia <1000/mm3. OBJECTIVE: To know the prevalence of NEC and the mortality associated with it in adults with hematologic conditions and neutropenia <1000/mm3. MATERIAL AND METHODS: All adult patients who were hospitalized for malignant hematologic conditions with neutropenia <1000/mm3 were enrolled in the study; those with neutropenia >1000/mm3 were excluded. The diagnosis of NEC was based on the clinical data and imaging tests (abdominal plain X-rays and CT scan). Demographics of all patients were collected, as well as the data related with the course and treatment of the underlying hematologic condition and the NEC. RESULTS: 117 patients were enrolled in the study; 75.2% of them with some type of acute leukemia. The diagnosis of NEC was made in 8 patients (6.8%). NEC occurred in 10.5% of the patients with acute myeloid leukemia and in 8.0% of those with acute lymphocytic leukemia. Three patients died, which resulted in a 37.5% mortality rate. No association was found between the severity of neutropenia and the onset of NEC or NEC-related mortality. CONCLUSIONS: The prevalence of NEC in patients with hematologic conditions admitted for severe neutropenia is 6.8% and the mortality rate associated with this complication is 37.5%.

[Colonic poliposis and acromegaly. Colonoscopy prevalence and detection]. / Pólipos colónicos y acromegalia. Prevalencia y detección por colonoscopia.

BACKGROUND: The prevalence of colorectal polyps in the general population is 10%. Hormonal alterations in acromegaly stimulates adenomatose polyps development making that increase it prevalence. Colonoscopy has elevated sensibility and specificity in detection of colorectal adenomas. OBJECTIVE: Identify colonic polyps in patients with acromegaly and establish the importance of colonoscopy as a detection method. MATERIAL AND METHODS: Retrospective, observational and descriptive study made in Colon and Rectum Surgery Department from March 2000 to March 2007 in patients with acromegaly and colonoscopy. Analyzed variables were: gender,age, endoscopy findings and histopathological results. Descriptive statistics were used to analysis of results. RESULTS: Thirty-two patients were included: 14 (44%) men, 18 (56%) women. The mean age was 48 (range 22 to 75 years old). In 9 (28%) patients were detected colorectal polyps, predominately in the sigmoid. Fifteen polyps lesion were found: 7 (46.6%) adenomas: 5 (33.3%) tubular and 2 (13.3) villous, 6 (40%) hyperplasic, 1 (6.6%) inflammatory and 1 (6.6%) carcinoma. Colonoscopy was complete in 30 (93.7%) patients. CONCLUSIONS: The prevalence of colonic polyps inpatients with acromegaly undergoing colonoscopy,was 28%, higher than expected in the general population. Colonoscopy constitutes an important diagnosis technique in early neoplasia detection.

[Non Hodgkin lymphoma of the sigmoid colon: case report]. / Linfoma no Hodgkin de sigmoides: reporte de un caso.

Non-Hodgkin lymphoma (NHL) occurs in extranodal location in approximately 20% of patients with limited stage, high-grade disease. Colon is infrequently involved as a primary location, accounting for 4% of all extranodal NHL and far less than 1% of all colonic malignancies. Colonic NHL differs significantly in terms of presentation, therapy and outcome relative to other more common gastrointestinal sites, like stomach or small bowel. The most common location is the cecum (60-74% of cases), while the sigmoid is involved in 2.5-14%. Largely related to the lack of specific signs and symptoms, patients frequently present advanced locoregional disease. Moreover, more than half of patients require an emergent surgery, usually due to pain, bleeding, or obstruction. Therapy usually involves resection of the affected colon and regional lymph nodes followed by adjuvant chemotherapy or/and radiotherapy. Utilizing this approach 5 years survival rates range between 27-55%. We present a 59 years old man with weight loss,abdominal pain, palpable mass and intestinal obstruction. A sigmoidectomy was realized with histopathologic report of NHL. Systemic adjuvant chemotherapy and abdominal radiation were administered. After a 6 month follow-up from initial procedure he is now asymptomatic with Karnofsky of 90. Therefore a surgeon should consider the possibility of NHL when evaluating such patients.

The Mexican consensus on nonalcoholic fatty liver disease. / Consenso mexicano de la enfermedad por hígado graso no alcohólico.

Nonalcoholic fatty liver disease (NAFLD) affects nearly one third of the population worldwide. Mexico is one of the countries whose population has several risk factors for the disease and its prevalence could surpass 50%. If immediate action is not taken to counteract what is now considered a national health problem, the medium-term panorama will be very bleak. This serious situation prompted the Asociación Mexicana de Gastroenterología and the Asociación Mexicana de Hepatología to produce the Mexican Consensus on Fatty Liver Disease. It is an up-to-date and detailed review of the epidemiology, pathophysiology, clinical forms, diagnosis, and treatment of the disease, whose aim is to provide the Mexican physician with a useful tool for the prevention and management of nonalcoholic fatty liver disease.

The rat trkC locus encodes multiple neurogenic receptors that exhibit differential response to neurotrophin-3 in PC12 cells.

Members of the Trk tyrosine kinase family have recently been identified as functional receptors of the NGF family of neurotrophins. Here we show the rat trkC locus to be complex, encoding at least four distinct polypeptides. Three of the encoded polypeptides are full-length receptor tyrosine kinases that differ by novel amino acid insertions in the kinase domain. A fourth protein is a truncated receptor that lacks the catalytic domain. Tyrosine phosphorylation, cross-linking, and ligand binding assays indicate that TrkC receptors interact with NT-3 and not with the related neurotrophins NGF, BDNF, xNT-4, or hNT-5. Furthermore, high and low affinity NT-3-binding sites are associated with the TrkC receptors. Stable and transient expression of TrkC receptors in PC12 cells indicates that the neurite outgrowth response elicited by NT-3 is dramatic in receptors lacking the novel kinase insert (gp150trkC) but absent in receptors containing the 14 amino acid insert in the kinase domain (gp150trkC14). These data suggest that the trkC locus encodes receptors that may be capable of mediating different biological responses within the cell. This could have important implications in understanding the role of neurotrophins in the development of the vertebrate nervous system.

The Mexican consensus on the diagnosis and treatment of ulcerative colitis. / Consenso mexicano para el diagnóstico y tratamiento de la colitis ulcerosa crónica idiopática.

The guidelines presented herein are an updated version of the recommendations published in 2007. Since then, there has been a rapid advance in the knowledge about the pathophysiology of ulcerative colitis and its therapeutic options. New drugs have been approved, novel targeted therapies have emerged, and new strategies have been developed to improve the previously available approaches to the disease. The aim of the present consensus is to promote the current knowledge of and Mexican perspective on the epidemiology, diagnosis, and medical and surgical treatment of chronic idiopathic ulcerative colitis. The final vote on the statements and their ultimate modifications were carried out at the consensus working group meeting. Evidence was evaluated through the GRADE classification.

Update on biosimilars in inflammatory bowel disease: Position and recommendations in Mexico. / Actualización sobre los medicamentos biocomparables en la enfermedad inflamatoria intestinal: posición y recomendación en México.

The biotechnology-derived medicines known as biosimilars are defined as non-originator treatments that have demonstrated quality, efficacy, and safety comparable to the reference biologic drug. Clinical trials have shown that the infliximab biosimilar, CT-P13, and the candidates for the adalimumab biosimilars, ABP 501 and ZRC 3197, are not significantly different, with respect to efficacy and safety, from the originator drugs in patients with other autoimmune diseases. However, controversy has arisen over the use of biosimilars in inflammatory bowel disease, due to the incipient evidence not only in patients with no previous biotechnology treatment, but also in patients in remission, that could be switched to a biosimilar for non-medical reasons. The present review is the first critical analysis by different specialists in the area of gastroenterology on the use of biosimilars in inflammatory bowel disease, the evidence on interchangeability, the extrapolation of indications, efficacy, safety, immunogenicity, and the clinical impact of the Mexican health regulations. The aim of our review was to make the positioning and recommendations of these new therapeutic options known, given that they have a potential cost-benefit for both patients and healthcare institutions.

The Mexican consensus on the treatment of hepatitis C. / Consenso Mexicano para el Tratamiento de la Hepatitis C.

The aim of the Mexican Consensus on the Treatment of HepatitisC was to develop clinical practice guidelines applicable to Mexico. The expert opinion of specialists in the following areas was taken into account: gastroenterology, infectious diseases, and hepatology. A search of the medical literature was carried out on the MEDLINE, EMBASE, and CENTRAL databases through keywords related to hepatitisC treatment. The quality of evidence was subsequently evaluated using the GRADE system and the consensus statements were formulated. The statements were then voted upon, using the modified Delphi system, and reviewed and corrected by a panel of 34 voting participants. Finally, the level of agreement was classified for each statement. The present guidelines provide recommendations with an emphasis on the new direct-acting antivirals, to facilitate their use in clinical practice. Each case must be individualized according to the comorbidities involved and patient management must always be multidisciplinary.

Somatostatin is required for masculinization of growth hormone-regulated hepatic gene expression but not of somatic growth.

Pulsatile growth hormone (GH) secretion differs between males and females and regulates the sex-specific expression of cytochrome P450s in liver. Sex steroids influence the secretory dynamics of GH, but the neuroendocrine mechanisms have not been conclusively established. Because periventricular hypothalamic somatostatin (SST) expression is greater in males than in females, we generated knockout (Smst(-/-)) mice to investigate whether SST peptides are necessary for sexually differentiated GH secretion and action. Despite marked increases in nadir and median plasma GH levels in both sexes of Smst(-/-) compared with Smst(+/+) mice, the mutant mice had growth curves identical to their sibling controls and retained a normal sexual dimorphism in weight and length. In contrast, the liver of male Smst(-/-) mice was feminized, resulting in an identical profile of GH-regulated hepatic mRNAs between male and female mutants. Male Smst(-/-) mice show higher expression of two SST receptors in the hypothalamus and pituitary than do females. These data indicate that SST is required to masculinize the ultradian GH rhythm by suppressing interpulse GH levels. In the absence of SST, male and female mice exhibit similarly altered plasma GH profiles that eliminate sexually dimorphic liver function but do not affect dimorphic growth.

Human dirofilariasis in the eyelid caused by Dirofilaria repens: An imported case. / Dirofilariasis palpebral causada por Dirofilaria repens: un caso importado.

CLINICAL CASE: The case concerns a 33-year-old Ukrainian woman, who came to the Ophthalmology Emergency Service, stating that she had a «worm¼ under the skin of her upper left eyelid that wriggled at night and bit her. A complete examination revealed a subcutaneous foreign body, which showed a filarial appearance and seemed to crawl under the skin. It was surgically removed to discover a live parasite, PCR-identified as Dirofilaria repens. DISCUSSION: Humans are accidental hosts in the cycle of Dirofilaria. There are only 8 reported cases of subcutaneous infection in Spain. Due to global warming, D. repens has become an emerging infectious agent in Central Europe countries such as Ukraine. The findings in this case are discussed.

The place of targeted therapies in the management of non-small cell bronchial carcinoma. Molecular markers as predictors of tumor response and survival in lung cancer.

This review highlights the numerous molecular biology findings in the field of lung cancer with potential therapeutic impact in both the near and distant future. Abundant pre-clinical and clinical data indicate that BRCA1 mRNA expression is a differential modulator of chemotherapy sensitivity. Low levels predict cisplatin sensitivity and antimicrotubule drug resistance, and the opposite occurs with high levels. The main core of recent research has centered on epidermal growth factor receptor (EGFR) mutations and gene copy numbers. For the first time, EGFR mutations have been shown to predict dramatic responses in metastatic lung adenocarcinomas, with a threefold increase in time to progression and survival in patients receiving EGFR tyrosine-kinase inhibitors. Evidence has also been accumulated on the crosstalk between estrogen and EGFR receptor pathways, paving the way for clinical trials of EGFR tyrosine-kinase inhibitors plus aromatase inhibitors. Understanding the relevance of these findings can help to change the clinical practice in oncology towards customizing chemotherapy and targeted therapies, leading to improvement both in survival and in cost-effectiveness.

Resistance to arsenic compounds in microorganisms.

Arsenic ions, frequently present as environmental pollutants, are very toxic for most microorganisms. Some microbial strains possess genetic determinants that confer resistance. In bacteria, these determinants are often found on plasmids, which has facilitated their study at the molecular level. Bacterial plasmids conferring arsenic resistance encode specific efflux pumps able to extrude arsenic from the cell cytoplasm thus lowering the intracellular concentration of the toxic ions. In Gram-negative bacteria, the efflux pump consists of a two-component ATPase complex. ArsA is the ATPase subunit and is associated with an integral membrane subunit, ArsB. Arsenate is enzymatically reduced to arsenite (the substrate of ArsB and the activator of ArsA) by the small cytoplasmic ArsC polypeptide. In Gram-positive bacteria, comparable arsB and arsC genes (and proteins) are found, but arsA is missing. In addition to the wide spread plasmid arsenic resistance determinant, a few bacteria confer resistance to arsenite with a separate determinant for enzymatic oxidation of more-toxic arsenite to less-toxic arsenate. In contrast to the detailed information on the mechanisms of arsenic resistance in bacteria, little work has been reported on this subject in algae and fungi.

Aberrant gene methylation and bronchial dysplasia in high risk lung cancer patients.

INTRODUCTION: The risk for lung cancer is incremented in high degree dysplasia (HGD) and in subjects with hypermethylation of multiple genes. We sought to establish the association between them, as well as to analyze the DNA aberrant methylation in sputum and in bronchial washings (BW). METHODS: Cross sectional study of high risk patients for lung cancer in whom induced sputum and autofluorescence bronchoscopy were performed. The molecular analysis was determined on DAPK1, RASSF1A and p16 genes using Methylation-specific PCR. RESULTS: A total of 128 patients were enrolled in the study. Dysplasia lesions were found in 79 patients (61.7%) and high grade dysplasia in 20 (15.6%). Ninety eight patients out of 128 underwent molecular analysis. Methylation was observed in bronchial secretions (sputum or BW) in 60 patients (61.2%), 51 of them (52%) for DAPK1, in 20 (20.4%) for p16 and in three (3.1%) for RASSF1A. Methylated genes only found in sputum accounted for 38.3% and only in BW in 41.7%, and in both 20.0%. In the 11.2% of the patients studied, HGD and a hypermethylated gene were present, while for the 55.1% of the sample only one of both was detected and for the rest of the subjects (33.6%), none of the risk factors were observed. CONCLUSIONS: Our data determines DNA aberrant methylation panel in bronchial secretions is present in a 61.2% and HGD is found in 15.6%. Although both parameters have previously been identified as risk factors for lung cancer, the current study does not find a significative association between them. The study also highlights the importance of BW as a complementary sample to induced sputum when analyzing gene aberrant methylation.

Efficacy of high loading doses of liposomal amphotericin B in the treatment of experimental invasive pulmonary aspergillosis.

This study aimed to investigate whether initial treatment of experimental pulmonary aspergillosis with high loading doses can be used as an alternative to standard therapeutic regimens. Steroid-immunosuppressed rats, infected intratracheally with Aspergillus fumigatus, received either amphotericin B deoxycholate (d-AmB) 1 mg/kg/day, liposomal amphotericin B (L-AmB) 5 mg/kg/day, or underwent a 3-day course of L-AmB 10 mg/kg, or 10 mg/kg for the first 3 or 4 days of treatment, followed by 3 mg/kg until the end of treatment. Therapy started 24 h after fungal challenge and lasted for 7 days. Compared to controls, survival was improved significantly in animals receiving any L-AmB regimen (p

5-HT Receptor Antagonism Attenuates the Ischemia-Reperfusion Injury After Rabbit Lung Preservation.

The success of lung transplantation is threatened by the appearance of ischemia-reperfusion injury, which is characterized by increased vascular permeability. 5-Hydroxytryptamine (5-HT; serotonin) is known to produce microvascular leakage in the systemic circulation, but its possible role in ischemia-reperfusion injury after lung preservation has not been reported. In this work we measured the release of 5-HT during a 24-hour rabbit lung preservation, and the effect of methiothepin (antagonist of the majority of 5-HT receptors) and SB204741 (antagonist of 5-HT2B/2C receptors) on the modified capillary filtration coefficient (mKf,c) was evaluated at the end of this period. Our results showed that the highest release rate of 5-HT occurred during the first 15 minutes after the lung harvesting and progressively decreased in the following time intervals. The baseline mKf,c greatly increased after 24 hours of lung preservation, and this increment was partially reduced by methiothepin and even more by SB204741. We concluded that 5-HT may play an important role in the ischemia-reperfusion process after lung preservation.