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Triple-negative breast cancer (TNBC) and ovarian carcinomas (OvCas) with BRCA1 promoter methylation (BRCA1meth) respond more poorly to alkylating agents compared to those bearing mutations in BRCA1 and BRCA2 (BRCAmut). This is a conundrum given the biologically equivalent homologous recombination deficiency (HRD) induced by these genetic and epigenetic BRCA perturbations. We dissected this problem through detailed genomic analyses of TNBC and OvCa cohorts and experimentation with patient-derived xenografts and genetically engineered cell lines. We found that despite identical downstream genomic mutational signatures associated with BRCA1meth and BRCAmut states, BRCA1meth uniformly associates with poor outcomes. Exposure of BRCA1meth TNBCs to platinum chemotherapy, either as clinical treatment of a patient or as experimental in vivo exposure of preclinical patient derived xenografts, resulted in allelic loss of BRCA1 methylation and increased BRCA1 expression and platinum resistance. These data suggest that, unlike BRCAmut cancers, where BRCA loss is a genetically "fixed" deficiency state, BRCA1meth cancers are highly adaptive to genotoxin exposure and, through reversal of promoter methylation, recover BRCA1 expression and become resistant to therapy. We further found a specific augmented immune transcriptional signal associated with enhanced response to platinum chemotherapy but only in patients with BRCA-proficient cancers. We showed how integrating both this cancer immune signature and the presence of BRCA mutations results in more accurate predictions of patient response when compared to either HRD status or BRCA status alone. This underscores the importance of defining BRCA heterogeneity in optimizing the predictive precision of assigning response probabilities in TNBC and OvCa. Breaking down BRCA heterogeneity: Loss of BRCA1 or BRCA2 (BRCA) activity is common in triple-negative breast cancer (TNBC) and ovarian cancer (OvCa); however, the type of alteration can result in different treatment responses. Here, Menghi et al. examined the differences in response to platinum therapy of patients with TNBC and OvCa who had BRCA loss or genetic alterations as compared to promotor methylation of BRCA. They saw that both patients and mice with promotor methylation were able to adaptively lose methylation, gain BRCA1 expression, and acquire resistance to platinum therapy. These findings have broad implications in using BRCA alteration status to better predict patient. [ABSTRACT FROM AUTHOR]

We report on whole-exome sequencing (WES) of 213 melanomas. Our analysis established NF1, encoding a negative regulator of RAS, as the third most frequently mutated gene in melanoma, after BRAF and NRAS. Inactivating NF1 mutations were present in 46% of melanomas expressing wild-type BRAF and RAS, occurred in older patients and showed a distinct pattern of co-mutation with other RASopathy genes, particularly RASA2. Functional studies showed that NF1 suppression led to increased RAS activation in most, but not all, melanoma cases. In addition, loss of NF1 did not predict sensitivity to MEK or ERK inhibitors. The rebound pathway, as seen by the induction of phosphorylated MEK, occurred in cells both sensitive and resistant to the studied drugs. We conclude that NF1 is a key tumor suppressor lost in melanomas, and that concurrent RASopathy gene mutations may enhance its role in melanomagenesis. [ABSTRACT FROM AUTHOR]

Although urbanization poses severe threats to biodiversity, some wildlife groups manage to thrive within urban areas. Among wildlife, birds are a highly diverse, charismatic and well-known group, establishing complex communities in human settlements around the world, making them suitable bioindicators. However, it is often difficult to have historical species lists that allow understanding current urban ecology trends. In this paper, we compile the available bird records, including unpublished information, for one of the best studied and well vegetated urban areas in México: the city of Xalapa. We gathered records for 329 species, representing ~30 % of the national avifauna in this medium-sized neotropical city. This important avian diversity in the city of Xalapa is mostly due to its environmental heterogeneity, underlining the relevance of its location, and the nature of its surroundings. The information provided in this paper will not only provide an environmental education baseline and represent a starting point for ornithologists, but will represent a reference document on the birds that have been recorded within the limits of Xalapa in the last three decades. [ABSTRACT FROM AUTHOR]

Objective: To determine prospectively the causes of upper GI hemorrhage (UGIH) in alcoholics, focusing on the prevalence of alcoholic gastropathy, and to compare the etiology of bleeding in patients who drink alcohol to that of nondrinkers. Methods: From August 1, 1990 through September 9, 1994, all patients evaluated by the gastroenterology consultative service at a large inner-city hospital presenting with UGIH were prospectively identified. Patients had to have a subnormal hematocrit on or within 12 h of admission or a fall of at least 5 points from a previous baseline determination to be included. Upper GI endoscopy was performed in all patients within 48 h of admission. Alcohol use was quantitated as chronic (80 g or more per day for at least 1 month), binge, occasional, or none. Results: Over the 4-yr study period, 727 patients met the inclusion criteria, and of these, 212 (29%) were classified as chronic alcohol users. Overall, peptic ulcer disease was the most common cause of bleeding (60%). Gastropathy (diffuse subepithelial hemorrhage) was considered etiological in only 32 patients (4%). The most common causes of gastropathy were portal hypertension in 22 patients and nonsteroidal anti-inflammatory drug use in five. Only three patients were identified in whom alcoholic gastropathy was considered etiological; in these patients, bleeding was mild and self-limited. When the causes of bleeding were compared between drinkers and nondrinkers, drinkers were more likely to bleed from varices (p = 0.024) or other portal hypertension-related causes (p < 0.01), whereas peptic ulcer was more common in nondrinkers compared with chronic users (67 vs 53%; p < 0.01). Esophagitis (p = 0.95) and Mallory-Weiss tear (p = 0.15) prevalences were not significantly different between the two groups. Conclusion: In the actively drinking patient, the most common causes of UGIH are peptic ulcer and disorders related to portal... [ABSTRACT FROM AUTHOR]

Objective: Although the presence of oropharyngeal (OP) candidiasis plays an important role in the evaluation of human immunodeficiency virus (HIV)-infected patients with esophageal symptoms, there is little information on the utility of OP findings in patients with esophageal ulceration. Methods: Over a 54-month period, all HIV-infected patients with esophageal ulceration had careful inspection of the oropharynx at the time of presentation with esophageal complaints and at endoscopy. HIV-infected patients without esophageal ulceration undergoing endoscopy during the last 30 months had OP findings similarly documented. OP ulceration was not routinely biopsied. The cause of esophageal ulceration was determined based on clinical, endoscopic, and histopathological findings. Results: Of the 124 patients identified with esophageal ulcer, 14 (11%) had coexistent OP ulceration: herpes simplex virus, four; idiopathic esophageal ulcer, four; cytomegalovirus, three; herpes simplex virus and cytomegalovirus, two; idiopathic and cytomegalovirus, one. Four patients had OP ulcer without esophageal ulcer; only one of these patients had esophageal symptoms. All OP lesions healed with therapy for the esophageal ulcer. Twenty-eight patients with esophageal ulcer had OP candidiasis (23%); 21 of these patients (75 %) also had Candida esophagitis. The sensitivity and specificity of OP ulcer for esophageal ulcer were 11% and 97%, respectively. The positive and negative predictive values of OP candidiasis for esophageal candidiasis were 90% and 82%, respectively. Conclusions: OP ulceration is uncommon in patients with esophageal ulceration, with the exception of herpes simplex virus esophagitis. OP candidiasis is common in patients with underlying esophageal ulcer, potentially resulting in diagnostic confusion. OP candidiasis appears to be a moderately useful diagnostic marker for Candida esophagitis. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about a study on mucosal biopsies by R. W. Goodgame et al published in a 1993 issue of the "American Journal of Gastroentorology."