Mapping IPF helps identify geographic regions at higher risk for disease development and potential triggers.

BACKGROUND AND OBJECTIVE: The relationship between IPF development and environmental factors has not been completely elucidated. Analysing geographic regions of idiopathic pulmonary fibrosis (IPF) cases could help identify those areas with higher aggregation and investigate potential triggers. We hypothesize that cross-analysing location of IPF cases and areas of consistently high air pollution concentration could lead to recognition of environmental risk factors for IPF development. METHODS: This retrospective study analysed epidemiological and clinical data from 503 patients registered in the Observatory IPF.cat from January 2017 to June 2019. Incident and prevalent IPF cases from the Catalan region of Spain were graphed based on their postal address. We generated maps of the most relevant air pollutant PM2.5 from the last 10 years using data from the CALIOPE air quality forecast system and observational data. RESULTS: In 2018, the prevalence of IPF differed across provinces; from 8.1 cases per 100 000 habitants in Barcelona to 2.0 cases per 100 000 in Girona. The ratio of IPF was higher in some areas. Mapping PM2.5 levels illustrated that certain areas with more industry, traffic and shipping maintained markedly higher PM2.5 concentrations. Most of these locations correlated with higher aggregation of IPF cases. Compared with other risk factors, PM2.5 exposure was the most frequent. CONCLUSION: In this retrospective study, prevalence of IPF is higher in areas of elevated PM2.5 concentration. Prospective studies with targeted pollution mapping need to be done in specific geographies to compile a broader profile of environmental factors involved in the development of pulmonary fibrosis.

Adenovirus Infection in Hospitalized Children with Acute Respiratory Infection in Jordan.

BACKGROUND: The most common clinical manifestation of adenovirus (AdV) infection is acute respiratory illness (ARI). Specific AdV species associated with ARI hospitalizations are not well defined in the Middle East. METHODS: A viral surveillance study was conducted among children <2 years hospitalized in Amman, Jordan, from March 2010 to March 2013. Nasal and throat respiratory specimens were obtained from enrolled children and tested for viruses using a real-time reverse-transcription quantitative polymerase chain reaction. AdV-positive specimens were typed by partial hexon gene sequencing. Demographic and clinical features were compared between AdV detected as single pathogen versus co-detected with other respiratory viruses, and between AdV-B and AdV-C species. RESULTS: AdV was detected in 475/3168 (15%) children hospitalized with ARI; of these, 216 (45%) specimens were successfully typed with AdV-C as the most common species detected (140/216; 65%). Children with AdV-single detection (88/475; 19%) had a higher frequency of fever (71% vs. 56%; P=0.015), diarrhea (18% vs. 11%; p=0.048), and/or seizures/abnormal movements (14% vs. 5%; p=0.003). Children with AdV co-detected with other viruses more likely required oxygen support [adjusted odds ratio (aOR) 1.91 (95% CI: 1.08, 3.39), P = 0.027] than those with AdV-single detection. Children with AdV-C had higher odds of co-detections with other viruses compared with those with AdV-B [aOR 4.00 (95% CI: 1.91, 8.44), P < 0.001]. CONCLUSION: Clinical differences were identified between AdV-single and AdV co-detected with other viruses, and between AdV-B and AdV-C. Larger studies with AdV typing are needed to determine additional epidemiological and clinical differences between specific AdV species and types.

The Clinical Characteristics, Severity, and Seasonality of RSV Subtypes Among Hospitalized Children in Jordan.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infection (ARI) in young children worldwide. Multiple factors affect RSV disease severity, and data regarding differences between RSV subtypes severity are controversial. This study aimed to evaluate the clinical characteristics, seasonality and severity of RSV subtypes in children. METHODS: As part of a prospective ARI surveillance study conducted from March 2010 to March 2013 in Amman, Jordan, children less than 2 years with fever and/or respiratory symptoms were enrolled. Demographic and clinical characteristics were collected through parental interviews and medical chart review. The treating physician collected severity score data at admission. Nasal and throat swabs were collected and tested. Multivariable regression models were used to compare the odds of increased disease severity across a priori selected predictors of interest. RESULTS: Overall, 1397/3168 (44%) children were RSV positive, with a mean age of 5.3 months (±4.8 SD), 59.7% were male, 6.4% had an underlying medical condition (UMC), 63.6% were RSV-A positive, 25.2% were RSV-B positive, 0.6% were positive for both, and 10.6% could not be typed. Both RSV subtypes peaked in January-March of each year. RSV A-positive children were more likely to present with decreased appetite but less likely to have viral co-detection than RSV B-positive children. Independent factors associated with RSV disease severity included cycle threshold value, vitamin D level, age, UMC, prematurity and severity score, but not RSV subtypes. CONCLUSION: RSV subtypes co-circulated and had similar severity profiles; future preventive and treatment measures should target both subtypes.

Human adenovirus species in children with acute respiratory illnesses.

BACKGROUND: Human adenovirus (HAdV) species B, C, and E are commonly associated with acute respiratory illnesses (ARI). We sought to determine the association between HAdV species and ARI severity in children over one respiratory season at Monroe Carell Jr. Children's Hospital at Vanderbilt. METHODS: We conducted a retrospective cohort study of children with HAdV from a provider-ordered BioFire® FilmArray Respiratory Pathogen Panel 2.0 (RPP) from 05/2018-06/2019. Type-specific PCR assays for HAdV-B3, B7, B11, B14, B16, B21, HAdV-C1, C2, C5, C6, and HAdV-E4 were performed. Demographics, clinical characteristics, and outcome data were compared between HAdV species. RESULTS: Of 4514 respiratory specimens collected, 2644 (59 %) had at least one pathogen detected by RPP, and 384 (15 %) were HAdV-positive; 342 (89 %) were available for research testing with 306 (89 %) specimens from unique symptomatic individuals; 237 (77 %) were positive for the following species: 104 (44 %) HAdV-B, 114 (48 %) HAdV-C, 9 (4%) HAdV-E, and 10 (4%) with co-detection between species. The majority with identified HAdV species were seen in the ED (62 %), and approximately one-third were hospitalized. Patients with HAdV-C were more likely to be younger, hospitalized, and have a higher frequency of seizures compared to HAdV-B. CONCLUSION: HAdV-C and HAdV-B were the most common species detected, with differences in clinical characteristics and outcomes noted. Additional studies with larger sample sizes focusing on a high-risk pediatric population are necessary to determine if differences in illness severity across individual HAdV types exist to guide further type-specific HAdV vaccine development.

Genomic action of permanently charged tamoxifen derivatives via estrogen receptor-alpha.

Tamoxifen is a selective estrogen receptor modulator widely used in oncology and reproductive endocrinology. In order to decrease its non-desirable effects and elucidate mechanisms of action, permanently charged tamoxifen derivatives (PCTDs) have been reported. Whether PCTDs have genomic effects remains controversial. Since the clinical relevance of tamoxifen, the necessity to have new anticancer drugs, and in order to gain insights into the mechanisms of action of PCTDs, we obtained six quaternary ammonium salts derived from tamoxifen including three new compounds. We characterized them by nuclear magnetic resonance, X-ray diffraction, electron microscopy, and/or high performance liquid chromatography, and detected them in cell lysates by liquid chromatography coupled to mass spectrometry. We evaluated their binding to estrogen receptor-alpha (ERalpha, their effect on the transcriptional activity mediated by ERalpha (gene reporter assays), and the proliferation of cancer cells (MCF-7 and cells from a cervical cancer primary culture). Structural studies demonstrated the expected identity of the molecules. All PCTDs did bind to ERalpha, one of them induced ERalpha-mediated transcription while two others inhibited such genomic action. Accordingly, PCTDs were detected in cell lysates. PCTDs inhibited cell proliferation, noteworthy, two of them displayed higher inhibition than tamoxifen. Structure-activity analysis suggests that PCTDs permanent positive charge and the length of the aliphatic chain might be associated to the biological responses studied. We suggest genomic effects as a mechanism of action of PCTDs. The experimental approaches here used could lead to a better design of new therapeutic molecules and help to elucidate molecular mechanisms of new anticancer drugs.

Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch syndrome fibroblasts.

Recently, mutations in the RNA polymerase III subunit A (POLR3A) have been described as the cause of the neonatal progeria or Wiedemann-Rautenstrauch syndrome (WRS). POLR3A has important roles in transcription regulation of small RNAs, including tRNA, 5S rRNA, and 7SK rRNA. We aim to describe the cellular and molecular features of WRS fibroblasts. Cultures of primary fibroblasts from one WRS patient [monoallelic POLR3A variant c.3772_3773delCT (p.Leu1258Glyfs*12)] and one control patient were cultured in vitro. The mutation caused a decrease in the expression of wildtype POLR3A mRNA and POLR3A protein and a sharp increase in mutant protein expression. In addition, there was an increase in the nuclear localization of the mutant protein. These changes were associated with an increase in the number and area of nucleoli and to a high increase in the expression of pP53 and pH2AX. All these changes were associated with premature senescence. The present observations add to our understanding of the differences between Hutchinson-Gilford progeria syndrome and WRS and opens new alternatives to study cell senesce and human aging.

Spatial Navigation Is Distinctively Impaired in Persistent Postural Perceptual Dizziness.

Objective: To determine whether performance in a virtual spatial navigational task is poorer in persistent postural perceptual dizziness (PPPD) patients than in healthy volunteers and patients suffering other vestibular disorders. Methods: Subjects were asked to perform three virtual Morris water maze spatial navigational tasks: (i) with a visible target, (ii) then with an invisible target and a fixed starting position, and finally (iii) with an invisible target and random initial position. Data were analyzed using the cumulative search error (CSE) index. Results: While all subjects performed equally well with a visible target, the patients with PPPD (n = 19) performed poorer (p < 0.004) in the invisible target/navigationally demanding tasks (CSE median of 8) than did the healthy controls (n = 18; CSE: 3) and vestibular controls (n = 19; CSE: 4). Navigational performance in the most challenging setting allowed us to discriminate PPPD patients from controls with an area under the receiver operating characteristic curve of 0.83 (sensitivity 78.1%; specificity 83.3%). PPPD patients manifested more chaotic and disorganized search strategies, with more dispersion in the navigational pool than those of the non-PPPD groups (standard distance deviation of 0.97 vs. 0.46 in vestibular controls and 0.20 in healthy controls; p < 0.001). Conclusions: While all patients suffering a vestibular disorder had poorer navigational abilities than healthy controls did, patients with PPPD showed the worst performance, to the point that this variable allowed the discrimination of PPPD from non-PPPD patients. This distinct impairment in spatial navigation abilities offers new insights into PPPD pathophysiology and may also represent a new biomarker for diagnosing this entity.

Dispositivo de barrera protectora con presión negativa utilizado en urgencias odontológicas durante la pandemia de COVID-19 / Negative pressure protective barrier device used in dental emergencies during the COVID-19 pandemic

RESUMEN Introducción: el personal de salud involucrado en la atención odontológica tiene alto riesgo de contagio por exposición constante a aerosoles durante la atención de urgencias. Es necesario incrementar sus medidas de protección personal durante la pandemia por SARSCoV-2. Objetivo: describir la experiencia de odontólogos, auxiliares y pacientes respecto al uso de un dispositivo de barrera para contención de aerosoles en la atención de urgencias odontológicas. Materiales y métodos: estudio descriptivo de corte transversal con 21 pacientes adultos atendidos por urgencias odontológicas en una institución privada durante el mes de junio en la ciudad de Bogotá. Los 21 pacientes, cinco odontólogos tratantes y cinco auxiliares de odontología diligenciaron un cuestionario estructurado sobre la experiencia con el dispositivo, medidas de bioseguridad implementadas y percepción de seguridad respecto al posible contagio del virus. Resultados: la edad promedio de los pacientes fue 41 años (DE±14). La duración de los procedimientos fue de 45 minutos (DE±12) en promedio. No hubo eventos adversos durante los procedimientos con el uso del dispositivo. El 95 % de los pacientes se sintieron más seguros durante la atención con el uso del dispositivo de barrera. Conclusiones: a pesar de la muestra limitada, la alta percepción de seguridad respecto al uso del dispositivo en la atención de urgencias odontológicas reportada aquí, sugiere que pueden llegar a complementar las medidas de bioseguridad y equipos de protección personal establecidos por autoridades sanitarias durante la pandemia.

SUMMARY Introduction: Health personnel involved in dental care are at high risk of contagion from constant exposure to aerosols during emergency care. It is necessary to increase its protection measures during the SARS-CoV-2 pandemic. Objective: Describe the experience of dentists, assistants and patients regarding the use of a barrier device to contain aerosols in dental emergency care. Materials and methods: A descriptive cross-sectional study with 21 adult patients attended by dental emergencies in a private institution during June in the city of Bogotá. The 21 patients, five treating dentists and five dental assistants filled out a structured questionnaire about the experience with the device, the biosafety measures implemented and the perception of safety regarding the possible contagion of the virus. Results: The mean age of the patients was 41 years (SD ± 14). The duration of the procedures was 45 minutes (SD ± 12) on average. There were no adverse events during the procedures with the use of the device. 95% of patients felt safer during care with the use of the barrier device. Conclusions: Despite the limited sample, the high perception of safety regarding the use of the device in dental emergency care reported here suggests that they may complement the biosecurity measures and personal protective equipment established by health authorities during the pandemic.

Sugarcane cellulose utilization by a defined microbial consortium.

Microorganisms isolated from diverse environmental sources were initially screened for carboxymethylcellulase activity. Nine strains that grew at elevated temperatures and which presented the highest activity were characterized further. Culture supernatants were assayed for potentiation of the enzymatic activity and, based on these results, consortia of four or nine microorganisms were tested for their capacity to grow on, and degrade a sugarcane leaf substrate. As predicted by the supernatant mixes, both consortia assayed were capable of degrading the cellulosic substrate provided. The group comprising of four strains was as efficient as the mix of all nine strains.

Highly differentiated human airway epithelial cells: a model to study host cell-parasite interactions in pertussis.

BACKGROUND: Bordetella pertussis colonizes the human respiratory mucosa. Most studies on B. pertussis adherence have relied on cultured mammalian cells that lack key features present in differentiated human airway cells or on animal models that are not natural hosts of B. pertussis. The objectives of this work were to evaluate B. pertussis infection in highly differentiated human airway cells in vitro and to show the role of B. pertussis fimbriae in cell adherence. METHODS: Primary human airway epithelial (PHAE) cells from human bronchi and a human bronchial epithelial (HBE) cell line were grown in vitro under air-liquid interface conditions. RESULTS: PHAE and HBE cells infected with B. pertussis wild-type strain revealed bacterial adherence to the apical surface of cells, bacteria-induced cytoskeleton changes, and cell detachment. Mutations in the major fimbrial subunits Fim2/3 or in the minor fimbrial adhesin subunit FimD affected B. pertussis adherence to predominantly HBE cells. This cell model recapitulates the morphologic features of the human airway infected by B. pertussis and confirms the role of fimbriae in B. pertussis adherence. Furthermore, HBE cells show that fimbrial subunits, and specifically FimD adhesin, are critical in B. pertussis adherence to airway cells. CONCLUSIONS: The relevance of this model to study host-parasite interaction in pertussis lies in the striking physiologic and morphologic similarity between the PHAE and HBE cells and the human airway ciliated and goblet cells in vivo. These cells can proliferate in vitro, differentiate, and express the same genetic profile as human respiratory cells in vivo.

The Discovery and Preclinical Development of ASG-5ME, an Antibody-Drug Conjugate Targeting SLC44A4-Positive Epithelial Tumors Including Pancreatic and Prostate Cancer.

Here, we report the development of an antibody-drug conjugate, ASG-5ME, which targets the solute carrier receptor SLC44A4. SLC44A4 is a member of a family of putative choline transporters that we show to be markedly upregulated in a variety of epithelial tumors, most notably prostate and pancreatic cancer. SLC44A4 is normally expressed on the apical surface of secretory epithelial cells, but in cancer we show expression is not restricted to the luminal surface in advanced and undifferentiated tumors. ASG-5ME consists of a human IgG2 anti-SLC44A4 antibody conjugated through a cleavable linker to the microtubule-disrupting agent monomethylauristatin E. It has potent antitumor activity in both cell line - and patient-derived xenograft models of pancreatic and prostate cancers. Combination studies with ASG-5ME and nab-paclitaxel demonstrated combination effect in both pancreatic and prostate tumor models. Altogether, the data presented here suggest that ASG-5ME may have the potential to offer a new therapeutic option for the treatment of pancreatic and prostate cancers. Mol Cancer Ther; 15(11); 2679-87. ©2016 AACR.

Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models.

The identification of optimal target antigens on tumor cells is central to the advancement of new antibody-based cancer therapies. We performed suppression subtractive hybridization and identified nectin-4 (PVRL4), a type I transmembrane protein and member of a family of related immunoglobulin-like adhesion molecules, as a potential target in epithelial cancers. We conducted immunohistochemical analysis of 2,394 patient specimens from bladder, breast, lung, pancreatic, ovarian, head/neck, and esophageal tumors and found that 69% of all specimens stained positive for nectin-4. Moderate to strong staining was especially observed in 60% of bladder and 53% of breast tumor specimens, whereas the expression of nectin-4 in normal tissue was more limited. We generated a novel antibody-drug conjugate (ADC) enfortumab vedotin comprising the human anti-nectin-4 antibody conjugated to the highly potent microtubule-disrupting agent MMAE. Hybridoma (AGS-22M6E) and CHO (ASG-22CE) versions of enfortumab vedotin (also known as ASG-22ME) ADC were able to bind to cell surface-expressed nectin-4 with high affinity and induced cell death in vitro in a dose-dependent manner. Treatment of mouse xenograft models of human breast, bladder, pancreatic, and lung cancers with enfortumab vedotin significantly inhibited the growth of all four tumor types and resulted in tumor regression of breast and bladder xenografts. Overall, these findings validate nectin-4 as an attractive therapeutic target in multiple solid tumors and support further clinical development, investigation, and application of nectin-4-targeting ADCs. Cancer Res; 76(10); 3003-13. ©2016 AACR.

p14ARF is a component of the p53 response following ionizing irradiation of normal human fibroblasts.

Ionizing radiation leads to rapid stabilization and activation of the p53 tumor suppressor. Previous reports demonstrate that murine p19ARF cooperates with p53 in the cellular response to gamma irradiation. Here, we show that endogenous ARF sequentially interacts with p53 and MDM2 following irradiation of primary human and mouse embryonic fibroblasts. Shortly after irradiation, p14ARF binds p53 independently of MDM2. As nuclear pools of p53 decline, endogenous p14ARF co-immunoprecipitates with MDM2 and is localized within the nucleolus. Interestingly, p14ARF nucleolar localization during this response is abrogated in cells lacking functional p53. Taken together, our data suggest that human and murine ARF contribute to the mammalian DNA damage response.

AGS67E, an Anti-CD37 Monomethyl Auristatin E Antibody-Drug Conjugate as a Potential Therapeutic for B/T-Cell Malignancies and AML: A New Role for CD37 in AML.

CD37 is a tetraspanin expressed on malignant B cells. Recently, CD37 has gained interest as a therapeutic target. We developed AGS67E, an antibody-drug conjugate that targets CD37 for the potential treatment of B/T-cell malignancies. It is a fully human monoclonal IgG2 antibody (AGS67C) conjugated, via a protease-cleavable linker, to the microtubule-disrupting agent monomethyl auristatin E (MMAE). AGS67E induces potent cytotoxicity, apoptosis, and cell-cycle alterations in many non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) cell lines and patient-derived samples in vitro. It also shows potent antitumor activity in NHL and CLL xenografts, including Rituxan-refractory models. During profiling studies to confirm the reported expression of CD37 in normal tissues and B-cell malignancies, we made the novel discovery that the CD37 protein was expressed in T-cell lymphomas and in AML. AGS67E bound to >80% of NHL and T-cell lymphomas, 100% of CLL and 100% of AML patient-derived samples, including CD34(+)CD38(-) leukemic stem cells. It also induced cytotoxicity, apoptosis, and cell-cycle alterations in AML cell lines and antitumor efficacy in orthotopic AML xenografts. Taken together, this study shows not only that AGS67E may serve as a potential therapeutic for B/T-cell malignancies, but it also demonstrates, for the first time, that CD37 is well expressed and a potential drug target in AML.

In vitro and in vivo evaluation of cysteine and site specific conjugated herceptin antibody-drug conjugates.

Antibody drug conjugates (ADCs) are monoclonal antibodies designed to deliver a cytotoxic drug selectively to antigen expressing cells. Several components of an ADC including the selection of the antibody, the linker, the cytotoxic drug payload and the site of attachment used to attach the drug to the antibody are critical to the activity and development of the ADC. The cytotoxic drugs or payloads used to make ADCs are typically conjugated to the antibody through cysteine or lysine residues. This results in ADCs that have a heterogeneous number of drugs per antibody. The number of drugs per antibody commonly referred to as the drug to antibody ratio (DAR), can vary between 0 and 8 drugs for a IgG1 antibody. Antibodies with 0 drugs are ineffective and compete with the ADC for binding to the antigen expressing cells. Antibodies with 8 drugs per antibody have reduced in vivo stability, which may contribute to non target related toxicities. In these studies we incorporated a non-natural amino acid, para acetyl phenylalanine, at two unique sites within an antibody against Her2/neu. We covalently attached a cytotoxic drug to these sites to form an ADC which contains two drugs per antibody. We report the results from the first direct preclinical comparison of a site specific non-natural amino acid anti-Her2 ADC and a cysteine conjugated anti-Her2 ADC. We report that the site specific non-natural amino acid anti-Her2 ADCs have superior in vitro serum stability and preclinical toxicology profile in rats as compared to the cysteine conjugated anti-Her2 ADCs. We also demonstrate that the site specific non-natural amino acid anti-Her2 ADCs maintain their in vitro potency and in vivo efficacy against Her2 expressing human tumor cell lines. Our data suggests that site specific non-natural amino acid ADCs may have a superior therapeutic window than cysteine conjugated ADCs.

Tamoxifen and its new derivatives in cancer research.

A major challenge in cancer research is to discover drugs with high selectivity and minor side-effects. Tamoxifen has been widely used for more than 30 years in breast cancer treatment and prevention. Tamoxifen acts mainly via estrogen receptors (ER), but also displays anti-tumor activity in breast cancer negative to ERs, suggesting other targets. Actually, tamoxifen has effects on several transduction pathways and diverse ion channels. Despite the successful use of tamoxifen, this drug produces some non-desirable side-effects by acting on different targets. However, such non-specificity of tamoxifen might be used to unravel new targets to inhibit tumor cell proliferation, to elucidate new mechanisms of action of tamoxifen and tamoxifen analogs, and finally, to design new more specific and potent drugs on the benefit of cancer patients. This review will briefly describe first the current and general aspects of tamoxifen and then will focus more deeply on various tamoxifen analogues and new uses of tamoxifen described in recent patents. We will describe the biological effects and the therapeutic targets of the new patented analogues, in order to offer an alternative panorama on tamoxifen-based chemotherapy.

Estrogens and human papilloma virus oncogenes regulate human ether-à-go-go-1 potassium channel expression.

Ether-à-go-go-1 (Eag1) potassium channels are potential tools for detection and therapy of numerous cancers. Here, we show human Eag1 (hEag1) regulation by cancer-associated factors. We studied hEag1 gene expression and its regulation by estradiol, antiestrogens, and human papillomavirus (HPV) oncogenes (E6/E7). Primary cultures from normal placentas and cervical cancer tissues; tumor cell lines from cervix, choriocarcinoma, keratinocytes, and lung; and normal cell lines from vascular endothelium, keratinocytes, and lung were used. Reverse transcription-PCR (RT-PCR) experiments and Southern blot analysis showed Eag1 expression in all of the cancer cell types, normal trophoblasts, and vascular endothelium, in contrast to normal keratinocytes and lung cells. Estradiol and antiestrogens regulated Eag1 in a cell type-dependent manner. Real-time RT-PCR experiments in HeLa cells showed that Eag1 estrogenic regulation was strongly associated with the expression of estrogen receptor-alpha. Eag1 protein was detected by monoclonal antibodies in normal placenta and placental blood vessels. Patch-clamp recordings in normal trophoblasts treated with estradiol exhibited potassium currents resembling Eag1 channel activity. Eag1 gene expression in keratinocytes depended either on cellular immortalization or the presence of HPV oncogenes. Eag1 protein was found in keratinocytes transfected with E6/E7 HPV oncogenes. Cell proliferation of E6/E7 keratinocytes was decreased by Eag1 antibodies inhibiting channel activity and by the nonspecific Eag1 inhibitors imipramine and astemizole; the latter also increased apoptosis. Our results propose novel oncogenic mechanisms of estrogen/antiestrogen use and HPV infection. We also suggest Eag1 as an early indicator of cell proliferation leading to malignancies and a therapeutic target at early stages of cellular hyperproliferation.

Tyrosine-phosphorylated SOCS3 interacts with the Nck and Crk-L adapter proteins and regulates Nck activation.

Suppressors of cytokine signaling (SOCS) are negative feedback inhibitors of cytokine and growth factor signal transduction. Although the affect of SOCS proteins on the Jak-STAT pathway has been well characterized, their role in the regulation of other signaling modules is not well understood. In the present study, we demonstrate that SOCS3 physically interacts with the SH2/SH3-containing adapter proteins Nck and Crk-L, which are known to couple activated receptors to multiple downstream signaling pathways and the actin cytoskeleton. Our data show that the SOCS3/Nck and SOCS3/Crk-L interactions depend on tyrosine phosphorylation of SOCS3 Tyr(221) within the conserved SOCS box motif and intact SH2 domains of Nck and Crk-L. Furthermore, SOCS3 Tyr(221) forms a YXXP motif, which is a consensus binding site for the Nck and Crk-L SH2 domains. Expression of SOCS3 in NIH3T3 cells induces constitutive recruitment of a Nck-GFP fusion protein to the plasma membrane and constitutive tyrosine phosphorylation of endogenous Nck. Our findings suggest that SOCS3 regulates multiple cytokine and growth factor-activated signaling pathways by acting as a recruitment factor for adapter proteins.

The product of the candidate prostate cancer susceptibility gene ELAC2 interacts with the gamma-tubulin complex.

ELAC2 is a novel candidate cancer susceptibility gene located on chromosome 17p: Carriers of mutations in ELAC2 display a higher risk of developing prostate cancer. Overexpression of ELAC2 in tumor cells causes a delay in G2-M progression characterized by accumulation of cyclin B levels. Consistent with a function in mitosis, further biochemical analysis revealed that ELAC2 physically interacts with the gamma-tubulin complex. This is the first biologic insight into the function of this new putative cancer susceptibility gene, providing clues of how perturbation of ELAC2 might promote tumorigenesis through irregular cell division.

Hábito de fumar en los estudiantes de primeros semestres de la facultad de salud: características y percepciones: Universidad del Valle, 2003 / Smoking habit in students of first semesters of the faculty of health: characteristics and perceptions: Universidad del Valle, 2003

Introducción: Si se tiene en cuenta que los profesionales de la salud influyen sobre los conocimientos y estilos sanos de vida en la comunidad y que deben ser ejemplo en la promoción de hábitos saludables, es importante identificar las percepciones y prácticas sobre tabaquismo en estudiantes, para generar campañas anti-tabaquismo en la universidad. Materiales y métodos: Mediante muestreo por conveniencia se encuestaron 487 estudiantes de las carreras profesionales de la Facultad de Salud de la Universidad del Valle, Cali. La información se digitó y analizó de forma univariada en Epi-Info 2000. Resultados: Son fumadores activos, 13%; fumadores pasivos, 11%; y ex-fumadores, 4%. Relacionan el tabaquismo con hipertensión, 22%. De los fumadores 26% aumentaron el hábito en la universidad. Antes de los 17 años fumaban 65%; empezaron a fumar por angustia, depresión o nerviosismo, 18%; y 52% consideran que se deben mejorar las campañas masivas de prevención. Discusión: La falta de campañas eficaces trae como consecuencia el aumento del consumo. Algunos estudios muestran que el empleo de mensajes saludables masivos cortos para prevenir el tabaquismo tiene pocos efectos positivos sobre los adolescentes. Sin embargo, cuando se trabajan campañas prolongadas de promoción donde los mensajes se orientan a cambios individuales los resultados son mejores. Conclusiones: La frecuencia de tabaquismo en los estudiantes de salud es alta y se acompaña de un desconocimiento sobre las enfermedades relacionadas. La cantidad de fumadores pasivos es similar a la de fumadores activos. Falta diseñar estudios de seguimiento que permitan no sólo describir, sino comprender las causas intrínsecas del tabaquismo.

Introduction: Taking in a count that health professionals influence in the knowledge and practices of the community and that they must be an example in the promotions of health behaviors, it’s important to identify the perceptions and practices related to smoking cigarettes in students, for developing campaigns against tobacco consumption in the university. Materials and methods: Through a convenience sample, 487 health students from the Universidad of Valle, Cali were inquired. The information was typed and analyzed in Epi-Info 2000. Results: 13% are active smokers, 11% are passive smokers and 4% have stopped smoking; 22% relates tobacco consumption with hypertension; 26% of the smokers increased the habit in the university; 65% smoked before 17 years old, 18% started smoking because of anguish, depression or nervousness; 52% consider that prevention campaigns must be reinforced. Discussion: The lack of massive health messages against tobacco consumption led an increase of smoking. The studies show that short massive campaigns have a low positive effect on adolescents. Although, when messages are directed to individuals in long manners the results are better. Conclusions: The tobacco smoking among health’s students is high and the knowledge of its effects is low. The amount of passive smokers is similar to active smokers. It’s mandatory to design studies that permit not only to describe the behavior of the habit, but also the intrinsic causes of it.