Synchronous gastric and duodenal metastases from head and neck squamous cell carcinoma: a unique presentation of upper gastrointestinal bleeding.

Metastatic disease to the stomach or duodenum is an infrequent diagnosis, and head and neck squamous cell carcinoma (HNSCC) is one of the least common primary malignancies that lead to gastric or duodenal metastases. We report the case of a 65-year-old man with human immunodeficiency virus infection and previously diagnosed HNSCC who presented with melena. The patient had a percutaneous endoscopic gastrostomy tube placed 3 months prior to his presentation. Laboratory testing was significant for normocytic anemia and a digital rectal examination was positive for melena. Esophagogastroduodenoscopy revealed numerous cratered nodules with contact bleeding in the stomach as well as the duodenum that appeared malignant. Biopsies of the gastric and duodenal nodules were positive for p40 and CK 5/6, consistent with metastatic squamous cell carcinoma

Recruitment of Pontin/Reptin by E2f1 amplifies E2f transcriptional response during cancer progression

Changes in gene expression during tumorigenesis are often considered the consequence of de novo mutations occurring in the tumour. An alternative possibility is that the transcriptional response of oncogenic transcription factors evolves during tumorigenesis. Here we show that aberrant E2f activity, following inactivation of the Rb gene family in a mouse model of liver cancer, initially activates a robust gene expression programme associated with the cell cycle. Slowly accumulating E2f1 progressively recruits a Pontin/Reptin complex to open the chromatin conformation at E2f target genes and amplifies the E2f transcriptional response. This mechanism enhances the E2f-mediated transactivation of cell cycle genes and initiates the activation of low binding affinity E2f target genes that regulate non-cell-cycle functions, such as the Warburg effect. These data indicate that both the physiological and the oncogenic activities of E2f result in distinct transcriptional responses, which could be exploited to target E2f oncogenic activity for therapy

Recruitment of Pontin/Reptin by E2f1 amplifies E2f transcriptional response during cancer progression

Changes in gene expression during tumorigenesis are often considered the consequence of de novo mutations occurring in the tumour. An alternative possibility is that the transcriptional response of oncogenic transcription factors evolves during tumorigenesis. Here we show that aberrant E2f activity, following inactivation of the Rb gene family in a mouse model of liver cancer, initially activates a robust gene expression programme associated with the cell cycle. Slowly accumulating E2f1 progressively recruits a Pontin/Reptin complex to open the chromatin conformation at E2f target genes and amplifies the E2f transcriptional response. This mechanism enhances the E2f-mediated transactivation of cell cycle genes and initiates the activation of low binding affinity E2f target genes that regulate non-cell-cycle functions, such as the Warburg effect. These data indicate that both the physiological and the oncogenic activities of E2f result in distinct transcriptional responses, which could be exploited to target E2f oncogenic activity for therapy

In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma

Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase

FSP1 is a glutathione-independent ferroptosis suppressor

Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids1,2. To date, ferroptosis has been believed to be controlled only by the phospholipid hydroperoxide-reducing enzyme glutathione peroxidase 4 (GPX4)3,4 and radical-trapping antioxidants5,6. However, elucidation of the factors that underlie the sensitivity of a given cell type to ferroptosis7 is critical to understand the pathophysiological role of ferroptosis and how it may be exploited for the treatment of cancer. Although metabolic constraints8 and phospholipid composition9,10 contribute to ferroptosis sensitivity, no cell-autonomous mechanisms have been identified that account for the resistance of cells to ferroptosis. Here we used an expression cloning approach to identify genes in human cancer cells that are able to complement the loss of GPX4. We found that the flavoprotein apoptosis-inducing factor mitochondria-associated 2 (AIFM2) is a previously unrecognized anti-ferroptotic gene. AIFM2, which we renamed ferroptosis suppressor protein 1 (FSP1) and which was initially described as a pro-apoptotic gene11, confers protection against ferroptosis elicited by GPX4 deletion. We further demonstrate that the suppression of ferroptosis by FSP1 is mediated by ubiquinone (also known as coenzyme Q10 (CoQ10)): the reduced form, ubiquinol, traps lipid peroxyl radicals that mediate lipid peroxidation, whereas FSP1 catalyses the regeneration of CoQ10 using NAD(P)H. Pharmacological targeting of FSP1 strongly synergizes with GPX4 inhibitors to trigger ferroptosis in a number of cancer entities. In conclusion, the FSP1–CoQ10–NAD(P)H pathway exists as a stand-alone parallel system, which co-operates with GPX4 and glutathione to suppress phospholipid peroxidation and ferroptosis

Promozione e riqualificazione dei distretti energetici della Toscana: analisi energetica di un edificio pilota di edilizia sovvenzionata

L’argomento di tesi nasce dalla collaborazione tra A.P.E.S. (Azienda Pisana di Edilizia Popolare)s.c.p.a. e il Dipartimento di Energetica dell’ Università degli Studi di Pisa per la riqualificazione energetica di un edificio di edilizia residenziale pubblica. Si è realizzato dei modelli di calcolo che rispettano il fabbisogno Energetico pur mantenendo il costo al mq previsto dalle norme

The Timeliness of Financial Reporting: An Empirical Legal Study of Russian Banks

The timeliness of financial reporting has been an important topic in the accounting literature for decades. There is a tradeoff between the timeliness of reporting and the value of the information being reported. Prior to the advent of the Internet, reporting had to be done using print media. However, now that many companies post their annual and quarterly reports on the Internet, it is possible to report in a more timely fashion than has previously been possible. The problem is that companies in some countries do not make full use of this disclosure tool. They sometimes take many months to make the information available to the general public. The present empirical legal study examines the timeliness of financial reporting in the Russian banking sector and compares it to the SEC benchmark

HOW SERIOUS IS TAX EVASION? AN EMPIRICAL LEGAL STUDY

This article reports on a survey of undergraduate and graduate business students in a university inSouth Florida. The survey sought to determine the relative seriousness of tax evasion compared to more than 70 other offenses. The survey found that tax evasion was not considered to be as serious as most other offenses. One policy implication of the survey findings is that, if one begins with the premise that the punishment should fit the crime, the punishment for tax evasion should be reduced, since the current severity of punishment for tax evasion is often greater than the punishment meted out for comparable offenses

Antibiotic treatment of wild type mice decreases bacterial load and does not produce overt immunological changes.

<p>(A) The average fold change in 16 s rDNA copies was quantified by qPCR from stool of wildtype mice treated with antibiotics and sucralose (n=5) or sucralose alone (n=3). Data shown is the fold change in 16S copies after 13 days of treatment. Error bars represent the SD. (B) The weight of mice treated with sucralose only (black line) or sucralose and antibiotics (dotted line) is shown over the course of treatment. Dot represents the mean of the population and error bars are the SD from the mean. (C) Percentages of activated splenic CD4+ T cells (defined as shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0034478#pone-0034478-g001" target="_blank">Figure 1D</a>) in mice treated with sucralose only or sucralose and antibiotics is shown. Each dot represents a single mouse. (D–E) Histological sections of the esophagus (D) and small bowel (E) are shown for mice treated with sucralose only (−antibiotics) or sucralose and antibiotics (+antibiotics). A 10× objective was used for esophagus and a 40× objective was used to analyze small bowel.</p

Antibiotic Treatment of Ndfip1 cKOs from Birth Does Not Reduce Inflammation.

<p>(A–D) Representative flow cytometry plots of cells isolated from the esophagus (A) and small bowel (C) of Ndfip1-cKO and control animals treated from birth to 5 weeks. Graphs of the percentages of eosinophils (Siglec F+) and CD4+ T cells in esophagus (B) or small bowel (D) from all mice in the experiment are shown. (E) Representative flow plots illustrating the percentage of activiated cells among splenic CD4+ gated T cells. (F) Percentages of activated T cells in the spleens of all mice treated with antibiotics from birth to 5 weeks are shown.</p