Ovarian cancer risk in premenopausal and perimenopausal women treated with Tamoxifen: a case–control study

As tamoxifen stimulates ovarian steroidogenesis in premenopausal women, induces ovulation and increases the incidence of benign ovarian cysts, there has been concern that it might also increase ovarian cancer risk in women treated premenopausally. In a national case–control study in Britain, treatment histories were collected for 158 cases of ovarian cancer after breast cancer diagnosed at ages under 55 years and 464 controls who had breast cancer at these ages without subsequent ovarian cancer. Risk of ovarian cancer was not raised for women overall who had taken tamoxifen (odds ratio (OR)=0.9, 95% confidence interval (CI) 0.6–1.3) or for those treated when premenopausal (OR=1.0, 95% CI 0.6–1.6) or perimenopausal (OR=0.7, 95% CI 0.2–2.4). There was also no relation of risk to daily dose, duration or cumulative dose of tamoxifen, or time since last use. There was, however, a significantly raised risk in relation to non-hormonal chemotherapy. The results suggest that tamoxifen treatment of premenopausal or perimenopausal women does not materially affect ovarian cancer risk, but that non-hormonal chemotherapy might increase risk

Acyl-Protein Thioesterase 2 Catalizes the Deacylation of Peripheral Membrane-Associated GAP-43

An acylation/deacylation cycle is necessary to maintain the steady-state subcellular distribution and biological activity of S-acylated peripheral proteins. Despite the progress that has been made in identifying and characterizing palmitoyltransferases (PATs), much less is known about the thioesterases involved in protein deacylation. In this work, we investigated the deacylation of growth-associated protein-43 (GAP-43), a dually acylated protein at cysteine residues 3 and 4. Using fluorescent fusion constructs, we measured in vivo the rate of deacylation of GAP-43 and its single acylated mutants in Chinese hamster ovary (CHO)-K1 and human HeLa cells. Biochemical and live cell imaging experiments demonstrated that single acylated mutants were completely deacylated with similar kinetic in both cell types. By RT-PCR we observed that acyl-protein thioesterase 1 (APT-1), the only bona fide thioesterase shown to mediate deacylation in vivo, is expressed in HeLa cells, but not in CHO-K1 cells. However, APT-1 overexpression neither increased the deacylation rate of single acylated GAP-43 nor affected the steady-state subcellular distribution of dually acylated GAP-43 both in CHO-K1 and HeLa cells, indicating that GAP-43 deacylation is not mediated by APT-1. Accordingly, we performed a bioinformatic search to identify putative candidates with acyl-protein thioesterase activity. Among several candidates, we found that APT-2 is expressed both in CHO-K1 and HeLa cells and its overexpression increased the deacylation rate of single acylated GAP-43 and affected the steady-state localization of diacylated GAP-43 and H-Ras. Thus, the results demonstrate that APT-2 is the protein thioesterase involved in the acylation/deacylation cycle operating in GAP-43 subcellular distribution

Minimally invasive vs. open segmental resection of the splenic flexure for cancer: a nationwide study of the Italian Society of Surgical Oncology-Colorectal Cancer Network (SICO-CNN)

Background Evidence on the efficacy of minimally invasive (MI) segmental resection of splenic flexure cancer (SFC) is not available, mostly due to the rarity of this tumor. This study aimed to determine the survival outcomes of MI and open treatment, and to investigate whether MI is noninferior to open procedure regarding short-term outcomes. Methods This nationwide retrospective cohort study included all consecutive SFC segmental resections performed in 30 referral centers between 2006 and 2016. The primary endpoint assessing efficacy was the overall survival (OS). The secondary endpoints included cancer-specific mortality (CSM), recurrence rate (RR), short-term clinical outcomes (a composite of Clavien-Dindo > 2 complications and 30-day mortality), and pathological outcomes (a composite of lymph nodes removed >= 12, and proximal and distal free resection margins length >= 5 cm). For these composites, a 6% noninferiority margin was chosen based on clinical relevance estimate. Results A total of 606 patients underwent either an open (208, 34.3%) or a MI (398, 65.7%) SFC segmental resection. At univariable analysis, OS and CSM were improved in the MI group (log-rank test p = 0.004 and Gray's tests p = 0.004, respectively), while recurrences were comparable (Gray's tests p = 0.434). Cox multivariable analysis did not support that OS and CSM were better in the MI group (p = 0.109 and p = 0.163, respectively). Successful pathological outcome, observed in 53.2% of open and 58.3% of MI resections, supported noninferiority (difference 5.1%; 1-sided 95%CI - 4.7% to infinity). Successful short-term clinical outcome was documented in 93.3% of Open and 93.0% of MI procedures, and supported noninferiority as well (difference - 0.3%; 1-sided 95%CI - 5.0% to infinity). Conclusions Among patients with SFC, the minimally invasive approach met the criterion for noninferiority for postoperative complications and pathological outcomes, and was found to provide results of OS, CSM, and RR comparable to those of open resection

Carcinogenicidad del DDT

22 páginas, 6 figuras y 1 tabla estadística[EN] The experimental studies on the possible carcinogenicity of 1,1,1-trichloro-2,2-bis (chlorophenyl)ethane (DDT) in mice indicate that: (1) lifetime exposure to technical DDT results in a high incidence of hepatomas in males at concentration of 2, 10, 50 and 250 ppm, and in females at a concentration of 250 ppm: (2) DDT-induced hepatomas rarely metastasize and in many instances do not show obvious signs of invasiveness; in mice exposed to 250 ppm DDT, however, they could be related to a considerable shortening of the life span, (3) the capacíty of DDT to induce liver tumors ís related to the dose administered, as well as to the duration of the administration, (4) the persistence of DDT-induced hepatomas does not depend on the continuous administration of DDT-induced hepatomas do not regress but continue to grow after cessation of the treatment; and (5) wíth lifetime exposure, on e of the two main metabolites of DDT p,p´-l,l-dichloro-2,2-bis(p-chlorophenylethylene (DDE), caused a hight incidence of hepatomas in both sexes, and the other, p,p'-l,l-dichloro-2,2-bis(p-chlorophenylethane (DDD), caused a high incidence of lung tumors. The results of long-term studies carried out in other animal species indicate a borderline carcinogenic effect of DDT in rats, which has been confirmed by more recent studies , and no effect in hamsters. The few available studíes in man refer to a small number of individuals and for too limited an observation period to allow any conclusion regarding a possible carcinogenic effect of DDT in man. [ES] Los estudios expe rimentales sobre la carcinogenícídad del DDT indican : 1. La exposición durante toda la vida de los ratones eleva la incidencia de hepatomas en machos a todas las dosis y en las hembras tan sólo en la dosis más elevada. 2. Los hepatomas no producen metástasis y hay una sensible disminución del tiempo de vida en los animales expuestos a 250 p.p.m. 3. La capacidad de inducción de tumores hepáticos es directamente proporcional a la dosis administrada , así como a la duración. 4. La discontinuidad en la administración no influye en la inducción de tumores (ya que la suspensión del tratamiento no implica suspensión de exposición). 5. El p,p'-DDE produce una incidencia en ambos casos de hepatomas y el p,p'-DDD una in cidencia de tumores de pulmón. Los resultados en los estudios de larga duración llevados a cabo en otras especies indican un limitado efecto cancerígeno en ratas, lo cual ha sido confirmado en recientes estudios, y sin efecto en cricetos. Los pocos estudios desarrollados en hombre referidos a un bajo número de individuos y en un período de observación limitado no nos permiten llegar a la conclusión del posible efecto cancerígeno del DDT en el hombre.Peer reviewe

Engineered mononuclear variants in Bacillus cereus metallo-beta-lactamase BcII are inactive.

Metallo-beta-lactamases (MbetaLs) are zinc enzymes able to hydrolyze almost all beta-lactam antibiotics, rendering them inactive, at the same time endowing bacteria high levels of resistance. The design of inhibitors active against all classes of MbetaLs has been hampered by their structural diversity and by the heterogeneity in metal content in enzymes from different sources. BcII is the metallo-beta-lactamase from Bacillus cereus, which is found in both the mononuclear and dinuclear forms. Despite extensive studies, there is still controversy about the nature of the active BcII species. Here we have designed two mutant enzymes in which each one of the metal binding sites was selectively removed. Both mutants were almost inactive, despite preserving most of the structural features of each metal site. These results reveal that neither site isolated in the MbetaL scaffold is sufficient to render a fully active enzyme. This suggests that only the dinuclear species is active or that the mononuclear variants can be active only if aided by other residues that would be metal ligands in the dinuclear species

Conceptos De Marketing Estratégico-AM121-201502

El curso de conceptos de marketing estratégico es un cuso de carácter teórico-práctico dirigido a los estudiantes de 2do ciclo muestra al alumno el panorama general de la actividad los conceptos claves detrás de la gestión de marketing actual la forma en que las diversas variables que lo componen interactúan y las últimas tendencias que lo influyen. El curso desarrolla la competencia general de pensamiento innovador en nivel 1 y la competencia especifica de análisis de mercado en nivel 1 dado que luego del curso el alumno cuenta con una sólida base teórica general para profundizar en cada uno de los aspectos puntuales de la disciplina a lo largo del resto de su formación académica

Peptide T-AraC Conjugates. Solid Phase Synthesis and Biological Activity of N4-(acylpeptidyl)-AraC

Due to the capability of peptidyl derivatives of araC to behave as prodrugs of this antimetabolite, and because of the well known biological properties of peptide T and its analogues (in particular that of targeting CD4+ cells), new peptide T-araC conjugates were prepared and tested in vitro for antiproliferative activity. The aim was that of specifically delivering the antitumor drug to CD4+ cells. N4-(Acylpeptidyl)-derivatives of araC were synthesized by a new general approach involving solid-phase synthesis, which allows mild conditions, avoids the usually required protection of the glycoside portion of nucleosides and affords high yields of the final products. After the demonstration that peptide T-araC conjugates were able to activate chemotaxis by binding CD4 receptor on monocyte membranes, the antiproliferative activity was evaluated against a panel of leukemia lymphoma and carcinoma cell lines derived from human tumors, three CD4+ cell lines included. Title compounds resulted effective as antiproliferative agents at concentrations 4- to 10-fold higher than those of araC alone, did not preferentially inhibit CD4+ cells and proved stable not only in cell culture medium containing 20% FCS, but also in human plasma. All this suggests their potential utility in vivo