Exploring the Genetic Diversity of Epstein-Barr Virus among Patients with Gastric Cancer in Southern Chile.

The Epstein-Barr virus (EBV) has been associated with gastric cancer (GC), one of the deadliest malignancies in Chile and the world. Little is known about Chilean EBV strains. This study aims to investigate the frequency and genetic diversity of EBV in GC in patients in southern Chile. To evaluate the prevalence of EBV in GC patients from the Chilean population, we studied 54 GC samples using the gold standard detection method of EBV-encoded small RNA (EBER). The EBV-positive samples were subjected to amplification and sequencing of the Epstein-Barr virus nuclear protein 3A (EBNA3A) gene to evaluate the genetic diversity of EBV strains circulating in southern Chile. In total, 22.2% of the GC samples were EBV-positive and significantly associated with diffuse-type histology (p = 0.003). Phylogenetic analyses identified EBV-1 and EBV-2 in the GC samples, showing genetic diversity among Chilean isolates. This work provides important information for an epidemiological follow-up of the different EBV subtypes that may cause GC in southern Chile.

Diferencias en el abordaje de dos premolares inferiores con dens evaginatus: reporte de caso / Diferencas na abordagem de dois pré-molares inferiores com dens evaginatus: relato de caso / Differences in the approach of two lower premolars with dens evaginatus: case report

El dens evaginatus es una anomalía dentaria de forma que consiste en una elevación del esmalte en forma de cúspide o tubérculo que se ubica en el surco central o en la zona bucal de las cúspides de premolares o molares, así como en las superficies palatinas de dientes anteriores. La estructura interna del tubérculo está formada por una capa de esmalte que recubre un núcleo de dentina el cual contiene, en el 90% de los casos una evaginación de tejido pulpar. En este artículo se reporta el caso de un paciente de ascendencia asiática con dos premolares inferiores con dens evaginatus las cuales fueron abordadas de diferente forma: una premolar recibió tratamiento preventivo y mínimamente invasivo mientras que la otra premolar requirió un tratamiento pulpar

Dens evaginatus é uma anormalidade dentaria que consiste em uma elevação do esmalte em forma de cúspide ou tubérculo que se localiza no sulco central ou na zona bucal das cúspides de pré-molares ou molares, bem como nas superficies palatinas dos dentes anteriores. A estructura interna do tubérculo é formada por uma camada de esmalte que recobre um núcleo de dentina que contém, em 90% dos casos, uma evaginação de tecido pulpar. Neste artigo relata o caso de um paciente de ascendência asiática com duas pré-molares inferiores com dens evaginatus, que foram abordados de forma diferente: um pré-molar recebeu tratamento preventivo e minimamente invasivo enquanto a outra pré-molar necessitou de tratamento pulpar

Dens evaginatus is a dental abnormality consisting of a cusp- or tubercle-shaped elevation of the enamel that is in the central groove or in the buccal area of the cusps of premolars or molars, as well as on the palatal surfaces of teeth. The internal structure of the tubercle is formed by a layer of enamel that covers a core of dentin which contains, in 90% of cases, an evagination of pulp tissue. This article reports the case of a patient of Asian descent with two lower premolars with dens evaginatus, which were approached differently: one premolar received preventive and minimally invasive treatment while the other premolar required root canal treatment.

Integrated, Transparent Silicon Carbide Electronics and Sensors for Radio Frequency Biomedical Therapy.

The integration of micro- and nanoelectronics into or onto biomedical devices can facilitate advanced diagnostics and treatments of digestive disorders, cardiovascular diseases, and cancers. Recent developments in gastrointestinal endoscopy and balloon catheter technologies introduce promising paths for minimally invasive surgeries to treat these diseases. However, current therapeutic endoscopy systems fail to meet requirements in multifunctionality, biocompatibility, and safety, particularly when integrated with bioelectronic devices. Here, we report materials, device designs, and assembly schemes for transparent and stable cubic silicon carbide (3C-SiC)-based bioelectronic systems that facilitate tissue ablation, with the capability for integration onto the tips of endoscopes. The excellent optical transparency of SiC-on-glass (SoG) allows for direct observation of areas of interest, with superior electronic functionalities that enable multiple biological sensing and stimulation capabilities to assist in electrical-based ablation procedures. Experimental studies on phantom, vegetable, and animal tissues demonstrated relatively short treatment times and low electric field required for effective lesion removal using our SoG bioelectronic system. In vivo experiments on an animal model were conducted to explore the versatility of SoG electrodes for peripheral nerve stimulation, showing an exciting possibility for the therapy of neural disorders through electrical excitation. The multifunctional features of SoG integrated devices indicate their high potential for minimally invasive, cost-effective, and outcome-enhanced surgical tools, across a wide range of biomedical applications.

The J-IDEA Pandemic Planner: A Framework for Implementing Hospital Provision Interventions During the COVID-19 Pandemic.

BACKGROUND: Planning for extreme surges in demand for hospital care of patients requiring urgent life-saving treatment for coronavirus disease 2019 (COVID-19), while retaining capacity for other emergency conditions, is one of the most challenging tasks faced by health care providers and policymakers during the pandemic. Health systems must be well-prepared to cope with large and sudden changes in demand by implementing interventions to ensure adequate access to care. We developed the first planning tool for the COVID-19 pandemic to account for how hospital provision interventions (such as cancelling elective surgery, setting up field hospitals, or hiring retired staff) will affect the capacity of hospitals to provide life-saving care. METHODS: We conducted a review of interventions implemented or considered in 12 European countries in March to April 2020, an evaluation of their impact on capacity, and a review of key parameters in the care of COVID-19 patients. This information was used to develop a planner capable of estimating the impact of specific interventions on doctors, nurses, beds, and respiratory support equipment. We applied this to a scenario-based case study of 1 intervention, the set-up of field hospitals in England, under varying levels of COVID-19 patients. RESULTS: The Abdul Latif Jameel Institute for Disease and Emergency Analytics pandemic planner is a hospital planning tool that allows hospital administrators, policymakers, and other decision-makers to calculate the amount of capacity in terms of beds, staff, and crucial medical equipment obtained by implementing the interventions. Flexible assumptions on baseline capacity, the number of hospitalizations, staff-to-beds ratios, and staff absences due to COVID-19 make the planner adaptable to multiple settings. The results of the case study show that while field hospitals alleviate the burden on the number of beds available, this intervention is futile unless the deficit of critical care nurses is addressed first. DISCUSSION: The tool supports decision-makers in delivering a fast and effective response to the pandemic. The unique contribution of the planner is that it allows users to compare the impact of interventions that change some or all inputs.

Optimal national prioritization policies for hospital care during the SARS-CoV-2 pandemic.

In response to unprecedented surges in the demand for hospital care during the SARS-CoV-2 pandemic, health systems have prioritized patients with COVID-19 to life-saving hospital care to the detriment of other patients. In contrast to these ad hoc policies, we develop a linear programming framework to optimally schedule elective procedures and allocate hospital beds among all planned and emergency patients to minimize years of life lost. Leveraging a large dataset of administrative patient medical records, we apply our framework to the National Health Service in England and show that an extra 50,750-5,891,608 years of life can be gained compared with prioritization policies that reflect those implemented during the pandemic. Notable health gains are observed for neoplasms, diseases of the digestive system, and injuries and poisoning. Our open-source framework provides a computationally efficient approximation of a large-scale discrete optimization problem that can be applied globally to support national-level care prioritization policies.

Adapting hospital capacity to meet changing demands during the COVID-19 pandemic.

BACKGROUND: To calculate hospital surge capacity, achieved via hospital provision interventions implemented for the emergency treatment of coronavirus disease 2019 (COVID-19) and other patients through March to May 2020; to evaluate the conditions for admitting patients for elective surgery under varying admission levels of COVID-19 patients. METHODS: We analysed National Health Service (NHS) datasets and literature reviews to estimate hospital care capacity before the pandemic (pre-pandemic baseline) and to quantify the impact of interventions (cancellation of elective surgery, field hospitals, use of private hospitals, deployment of former medical staff and deployment of newly qualified medical staff) for treatment of adult COVID-19 patients, focusing on general and acute (G&A) and critical care (CC) beds, staff and ventilators. RESULTS: NHS England would not have had sufficient capacity to treat all COVID-19 and other patients in March and April 2020 without the hospital provision interventions, which alleviated significant shortfalls in CC nurses, CC and G&A beds and CC junior doctors. All elective surgery can be conducted at normal pre-pandemic levels provided the other interventions are sustained, but only if the daily number of COVID-19 patients occupying CC beds is not greater than 1550 in the whole of England. If the other interventions are not maintained, then elective surgery can only be conducted if the number of COVID-19 patients occupying CC beds is not greater than 320. However, there is greater national capacity to treat G&A patients: without interventions, it takes almost 10,000 G&A COVID-19 patients before any G&A elective patients would be unable to be accommodated. CONCLUSIONS: Unless COVID-19 hospitalisations drop to low levels, there is a continued need to enhance critical care capacity in England with field hospitals, use of private hospitals or deployment of former and newly qualified medical staff to allow some or all elective surgery to take place.

Canonical ErbB-2 isoform and ErbB-2 variant c located in the nucleus drive triple negative breast cancer growth.

Triple negative breast cancer (TNBC) refers to tumors that do not express clinically significant levels of estrogen and progesterone receptors, and lack membrane overexpression or gene amplification of ErbB-2/HER2, a receptor tyrosine kinase. Transcriptome and proteome heterogeneity of TNBC poses a major challenge to precision medicine. Clinical biomarkers and targeted therapies for this disease remain elusive, so chemotherapy has been the standard of care for early and metastatic TNBC. Our present findings placed ErbB-2 in an unanticipated scenario: the nucleus of TNBC (NErbB-2). Our study on ErbB-2 alternative splicing events, using a PCR-sequencing approach combined with an RNA interference strategy, revealed that TNBC cells express either the canonical (wild-type) ErbB-2, encoded by transcript variant 1, or the non-canonical ErbB-2 isoform c, encoded by alternative variant 3 (RefSeq), or both. These ErbB-2 isoforms function in the nucleus as transcription factors. Evicting both from the nucleus or silencing isoform c only, blocks TN cell and tumor growth. This reveals not only NErbB-2 canonical and alternative isoforms role as targets of therapy in TNBC, but also isoform c dominant oncogenic potential. Furthermore, we validated our findings in the clinic and observed that NErbB-2 correlates with poor prognosis in primary TN tumors, disclosing NErbB-2 as a novel biomarker for TNBC. Our discoveries challenge the present scenario of drug development for personalized BC medicine that focuses on wild-type RefSeq proteins, which conserve the canonical domains and are located in their classical cellular compartments.

Nuclear PDCD4 Expression Defines a Subset of Luminal B-Like Breast Cancers with Good Prognosis.

The hormone receptor-positive (estrogen and/or progesterone receptor (PR)-positive) and HER2-negative breast cancer (BC) subtype is a biologically heterogeneous entity that includes luminal A-like (LumA-like) and luminal B-like (LumB-like) subtypes. Decreased PR levels is a distinctive biological feature of LumB-like tumors. These tumors also show reduced sensitivity to endocrine therapies and poorer prognosis than LumA-like tumors. Identification of biomarkers to accurately predict disease relapse in these subtypes is crucial in order to select effective therapies. We identified the tumor suppressor PDCD4 (programmed cell death 4), located in the nucleus (NPDCD4), as an independent prognostic factor of good clinical outcome in LumA-like and LumB-like subtypes. NPDCD4-positive LumB-like tumors presented overall and disease-free survival rates comparable to those of NPDCD4-positive LumA-like tumors, indicating that NPDCD4 improves the outcome of LumB-like patients. In contrast, NPDCD4 loss increased the risk of disease recurrence and death in LumB-like compared with LumA-like tumors. This, along with our results showing that LumB-like tumors present lower NPDCD4 positivity than LumA-like tumors, suggests that NPDCD4 loss contributes to endocrine therapy resistance in LumB-like BCs. We also revealed that PR induces PDCD4 transcription in LumB-like BC, providing a mechanistic explanation to the low PDCD4 levels in LumB-like BCs lacking PR. Finally, PDCD4 silencing enhanced BC cell survival in a patient-derived explant model of LumB-like disease. Our discoveries highlight NPDCD4 as a novel biomarker in LumA- and LumB-like subtypes, which could be included in the panel of immunohistochemical markers used in the clinic to accurately predict the prognosis of LumB-like tumors.

The impact of scaling up cervical cancer screening and treatment services among women living with HIV in Kenya: a modelling study.

Introduction: We aimed to quantify health outcomes and programmatic implications of scaling up cervical cancer (CC) screening and treatment options for women living with HIV in care aged 18-65 in Kenya. Methods: Mathematical model comparing from 2020 to 2040: (1) visual inspection with acetic acid (VIA) and cryotherapy (Cryo); (2) VIA and Cryo or loop excision electrical procedure (LEEP), as indicated; (3) human papillomavirus (HPV)-DNA testing and Cryo or LEEP; and (4) enhanced screening technologies (either same-day HPV-DNA testing or digitally enhanced VIA) and Cryo or LEEP. Outcomes measured were annual number of CC cases, deaths, screening and treatment interventions, and engaged in care (numbers screened, treated and cured) and five yearly age-standardised incidence. Results: All options will reduce CC cases and deaths compared with no scale-up. Options 1-3 will perform similarly, averting approximately 28 000 (33%) CC cases and 7700 (27%) deaths. That is, VIA screening would yield minimal losses to follow-up (LTFU). Conversely, LTFU associated with HPV-DNA testing will yield a lower care engagement, despite better diagnostic performance. In contrast, option 4 would maximise health outcomes, averting 43 200 (50%) CC cases and 11 800 (40%) deaths, given greater care engagement. Yearly rescreening with either option will impose a substantial burden on the health system, which could be reduced by spacing out frequency to three yearly without undermining health gains. Conclusions: Beyond the specific choice of technologies to scale up, efficiently using available options will drive programmatic success. Addressing practical constraints around diagnostics' performance and LTFU will be key to effectively avert CC cases and deaths.

Mapping the Current and Future Noncommunicable Disease Burden in Kenya by Human Immunodeficiency Virus Status: A Modeling Study.

BACKGROUND: The noncommunicable disease (NCD) burden in Kenya is not well characterized, despite estimates needed to identify future health priorities. We aimed to quantify current and future NCD burden in Kenya by human immunodeficiency virus (HIV) status. METHODS: Original systematic reviews and meta-analyses of prevalence/incidence of cardiovascular disease (CVD), chronic kidney disease, depression, diabetes, high total cholesterol, hypertension, human papillomavirus infection, and related precancerous stages in Kenya were carried out. An individual-based model was developed, simulating births, deaths, HIV disease and treatment, aforementioned NCDs, and cancers. The model was parameterized using systematic reviews and epidemiological national and regional surveillance data. NCD burden was quantified for 2018-2035 by HIV status among adults. RESULTS: Systematic reviews identified prevalence/incidence data for each NCD except ischemic heart disease. The model estimates that 51% of Kenyan adults currently suffer from ≥1 NCD, with a higher burden in people living with HIV (PLWH) compared to persons not living with HIV (62% vs 51%), driven by their higher age profile and partly by HIV-related risk for NCDs. Hypertension and high total cholesterol are the main NCD drivers (adult prevalence of 20.5% [5.3 million] and 9.0% [2.3 million]), with CVD and cancers the main causes of death. The burden is projected to increase by 2035 (56% in persons not living with HIV; 71% in PLWH), with population growth doubling the number of people needing services (15.4 million to 28.1 million) by 2035. CONCLUSIONS: NCD services will need to be expanded in Kenya. Guidelines in Kenya already support provision of these among both the general and populations living with HIV; however, coverage remains low.

Ectopic pituitary adenoma of the TSH-secreting sphenoidal sinus with excellent response to somatostatin analogs. Theory of the embryogenesis and literature review from a clinical case.

Ectopic thyrotropin-secreting pituitary adenomas are rare, with only 10 published cases. We report the case of a 52-year-old woman who was referred for primary hypothyroidism, who showed clinical signs of hyperthyroidism and had been under treatment with levothyroxine. Her exams revealed high levels of thyroid stimulating hormone (TSH), at odds with free thyroxin (FT4) and raised triiodothyronine (T3), which remained elevated after medication suspension, suggesting possible central hyperthyroidism. Sellar MRI showed normal pituitary gland, with a mass in the sphenoid sinus of 24 mm. A possible ectopic TSH secreting pituitary tumor of sphenoid sinus was hypothesized. After a intramuscularly (IM) single dose of a sustained-relase of a somatostatin analog (octreotide) 20 mg, plasma levels of thyroid hormones were normalized and a significant tumor reduction was demonstrated in MRI control at 7-weeks' follow-up. The tumor was removed by transsphenoidal endoscopy, and the biopsy confirmed an adenoma with positive immunostaining for TSH and GH. Hyperthyroidism recurrence was observed in hormonal controls 4 weeks after surgery. Treatment with sustained-release octreotide was reinitiated, every 60-days for two years, with normalization of the thyroid hormone profile, but with a residual lesion with the appearance of a tumor in the MRI. A second tumor resection was performed, achieving sustained hormonal cure and no residual tumor lesion at 2-years' follow-up. To our knowledge, this is the first report of an ectopic thyrotropin-secreting pituitary adenoma of the sphenoid sinus. Clinical and laboratory aspects relevant to this entity are reviewed, emphasizing the usefulness of octreotide in the management of the reported case.

Telemedicina: acercando la reumatología a la población de la zona sur / Telemedicine: bringing rheumatology to the population of the chilean south zone

La Telemedicina constituye una herramienta que permite proporcionar atención médica especializada usando la tecnología de las telecomunicaciones.Entre mayo del 2015 y julio del 2017 se realizaron 1020 atenciones a través de esta modalidad, entre el Hospital Puerto Montt (HPM) y distintos centros de Atención primaria del SS Reloncaví.Se utilizaron dos modalidades de atención: asincrónica y sincrónica con presencia virtual del paciente.Se realizaron 1020 atenciones con una resolución inmediata en el 61,7% de los casos. Esta modalidad de atención implicó un ahorro de 139.412 Km, y por concepto de pasajes de $ 10.675.200 requeridos para el desplazamiento de los pacientes desde su lugar de origen al HPM.En lugares geográficamente distantes, la Telereumatología se convierte en una herramienta fundamental que permite expandir la cobertura de atenciones de salud por especialista, reducir las listas de espera, disminuir los tiempos de traslado y el costo que estos implican.

Telemedicine constitutes a tool that allows to provide specialized medical attention using telecommunications technology.Between May 2015 and July 2017, 1,020 care were carried out through this modality, between the Puerto Montt Hospital (HPM) and different primary care centers of the SS Reloncavi.Two care modalities were used: asynchronous and synchronous with the virtual presence of the patient.1020 visits were performed with immediate resolution in 61.7% of the cases.This care modality implied a saving of 139,412 km, and for the concept of passages of $ 10,675,200 required for the movement of patients from their place of origin to the HPM.In geographically remote places, Telerheumatology becomes a fundamental tool that allows expanding the coverage of health care by specialist, reducing waiting lists, reducing travel times and the cost that these imply.

[Frequency of cervical cytological alterations and human papilloma virus in a sample of university students in Temuco, Chile]. / Frecuencia de alteraciones citológicas cervicales y virus papiloma humano en una muestra de estudiantes universitarias en Temuco, Chile.

BACKGROUND: The early onset of sexual activity can promote the development of cervical alterations and sexually transmitted infections, especially the human papillomavirus (HPV) very common in adolescents and young people. AIM: The condition of the cervix, HPV and sexual behavior in young women under 25 years of age were analyzed. METHODS: 182 university students, healthy, sexually active, 18-24 years old, without vaccine for HPV participated. Papanicolaou (Pap) test and classification of high and low risk HPV (HR and LR) were performed by real time polymerase chain reaction. The sexual behaviors were consulted in private. RESULTS: The 46.9% of Pap presented cytological alterations, non-specific inflammation/hemorrhagic (29.4%) and atypical smear (10.2%) being de most frequent. The overall frequency of HPV-HR was 24.3%, of these 67.4% presented an altered Pap. There was an association between cytological alterations and HPV (p < 0.0001) and years of sexual activity and atypical smear or cervical intraepithelial neoplasia grade I (CIN I) (p = 0.009). 11.9% of young women (21/177) presented atypical smear or CIN I, with 66.7% of cases HPV-HR. CONCLUSIONS: These findings alert the vulnerability of these young women who would have a potential risk of viral persistence, CIN and eventually cancer. It is important to emphasize counseling and prevention prior to the regular age of admission to the screening program for cervical cancer. This study was financed by the Universidad de La Frontera through Projects DI15-0047 and DI17-0123.

Frecuencia de alteraciones citológicas cervicales y virus papiloma humano en una muestra de estudiantes universitarias en Temuco, Chile / Frequency of cervical cytological alterations and human papilloma virus in a sample of university students in Temuco, Chile

Resumen Introducción: El inicio precoz de actividad sexual puede favorecer el desarrollo de alteraciones cervicales y de infecciones de transmisión sexual, en especial del virus papiloma humano (VPH) muy frecuente en adolescentes y jóvenes. Objetivo: Analizar el estado del cuello uterino, presencia del VPH y conductas sexuales en mujeres menores de 25 años. Material y Métodos: Participaron 182 estudiantes universitarias de 18-24 años, sanas, sexualmente activas y no vacunadas para VPH. Se realizó Papanicolaou (Pap) y clasificación del VPH en alto y bajo riesgo (AR y BR) mediante reacción de polimerasa en cadena en tiempo real. Las conductas sexuales fueron consultadas privadamente. Resultados: El 46,9% de los Pap presentaron alteraciones citológicas (inflamación inespecífica/hemorrágico: 29,4% y frotis atípicos (FA):10,2%). La frecuencia de los VPH-AR fue 24,3%; de éstos, 67,4% presentó un Pap alterado. Hubo asociación entre alteraciones citológicas y presencia de VPH (p < 0,0001) y años de actividad sexual y FA o neoplasia intraepitelial grado I (NIE I) (p = 0,009). El 11,9% de las jóvenes estudiadas (21/177) presentó FA o NIE I, con 66,7% de casos VPH-AR. Conclusiones: Estos hallazgos alertan la vulnerabilidad de estas jóvenes que tendrían un riesgo potencial de persistencia viral, NIE y eventualmente cáncer. Es importante enfatizar consejería y prevención previo a la edad normada de ingreso al programa de cribado para cáncer cérvico uterino en Chile.

Background: The early onset of sexual activity can promote the development of cervical alterations and sexually transmitted infections, especially the human papillomavirus (HPV) very common in adolescents and young people. Aim: The condition of the cervix, HPV and sexual behavior in young women under 25 years of age were analyzed. Methods: 182 university students, healthy, sexually active, 18-24 years old, without vaccine for HPV participated. Papanicolaou (Pap) test and classification of high and low risk HPV (HR and LR) were performed by real time polymerase chain reaction. The sexual behaviors were consulted in private. Results: The 46.9% of Pap presented cytological alterations, non-specific inflammation/hemorrhagic (29.4%) and atypical smear (10.2%) being de most frequent. The overall frequency of HPV-HR was 24.3%, of these 67.4% presented an altered Pap. There was an association between cytological alterations and HPV (p < 0.0001) and years of sexual activity and atypical smear or cervical intraepithelial neoplasia grade I (CIN I) (p = 0.009). 11.9% of young women (21/177) presented atypical smear or CIN I, with 66.7% of cases HPV-HR. Conclusions: These findings alert the vulnerability of these young women who would have a potential risk of viral persistence, CIN and eventually cancer. It is important to emphasize counseling and prevention prior to the regular age of admission to the screening program for cervical cancer. This study was financed by the Universidad de La Frontera through Projects DI15-0047 and DI17-0123.

Invasive micropapillary carcinoma of the breast overexpresses MUC4 and is associated with poor outcome to adjuvant trastuzumab in HER2-positive breast cancer.

BACKGROUND: Invasive micropapillary carcinoma of the breast (IMPC) is a histological tumor variant that occurs with low frequency characterized by an inside-out formation of tumor clusters with a pseudopapillary arrangement. IMPC is an aggressive tumor with poor clinical outcome. In addition, this histological subtype usually expresses human epidermal growth factor receptor 2 (HER2) which also correlates with a more aggressive tumor. In this work we studied the clinical significance of IMPC in HER2-positive breast cancer patients treated with adjuvant trastuzumab. We also analyzed mucin 4 (MUC4) expression as a novel biomarker to identify IMPC. METHODS: We retrospectively studied 86 HER2-positive breast cancer patients treated with trastuzumab and chemotherapy in the adjuvant setting. We explored the association of the IMPC component with clinicopathological parameters at diagnosis and its prognostic value. We compared MUC4 expression in IMPC with respect to other histological breast cancer subtypes by immunohistochemistry. RESULTS: IMPC, either as a pure entity or associated with invasive ductal carcinoma (IDC), was present in 18.6% of HER2-positive cases. It was positively correlated with estrogen receptor expression and tumor size and inversely correlated with patient's age. Disease-free survival was significantly lower in patients with IMPC (hazard ratio = 2.6; 95%, confidence interval 1.1-6.1, P = 0.0340). MUC4, a glycoprotein associated with metastasis, was strongly expressed in all IMPC cases tested. IMPC appeared as the histological breast cancer subtype with the highest MUC4 expression compared to IDC, lobular and mucinous carcinoma. CONCLUSION: In HER2-positive breast cancer, the presence of IMPC should be carefully examined. As it is often not informed, because it is relatively difficult to identify or altogether overlooked, we propose MUC4 expression as a useful biomarker to highlight IMPC presence. Patients with MUC4-positive tumors with IMPC component should be more frequently monitored and/or receive additional therapies.

Frequency of Human papillomavirus in women attending cervical cancer screening program in Chile.

BACKGROUND: Human papillomavirus (HPV) is the etiological factor for cervical cancer and its precursor lesions. The characterization of HPV genotypes in preneoplastic lesions and cervical cancer could establishes the effectiveness of vaccination plan in Chilean population. The aim of this study was to determine HPV frequency in a group of women including in a cervical screening program in the public health care system in Chile. METHODS: We analyzed 985 cervical smears samples from women with different histological diagnosis, attending to public health care in Temuco-Chile between 2004 and 2012, to detect HPV genotypes, through PCR followed by reverse line blotting assay. RESULTS: HPV was found present in 80.8% (n = 796) of samples. Only a 5.6% of 985 samples were infected with a low-risk HPV, considering multiple infections. 10.5% (n = 8/76) of normal cervical epithelia, 83.5% (n = 208/249) and 87.6% (n = 557/636) of low and high grade squamous intraepithelial lesions, respectively, and 95.8% (n = 23/24) of squamous cervical carcinomas tested positive for HPV. HPV 16 was the most frequent genotype found (Overall 44.9%, n = 442/985; SCC: 62.5%, n = 15/24). A high variability of HPV types was also found in preneoplastic lesions, whereas there was a selection of genotypes in neoplasia. Also, there was a higher risk of infection with HPV 16 in women ≤26 years and 34-41 years old (p < 0.05), meanwhile infections with HPV 16 or HPV 18 have related with cancer development (p < 0.01). CONCLUSIONS: These data provide further information about the frequency of HPV genotypes in women with cervical lesions in Chile, and the introduction of new targeted vaccines against a wider spectrum of HPV is suggested.

Efecto de los extractos vegetales de Jatropha curcas y Anonna muricata sobre teleoginas de la garrapata común del ganado Ripichephalus (Boophilus) microplus bajo condiciones de laboratorio / Effect of plant extracts of jatropha curcas and Anonna muricata on engorged females of common cattle tick Ripichephalus (Boophilus) microplus under laboratory conditions / Efeito de extractos de plantas de Jatropha curcas e Anonna muricata em teleogines do carrapato gado comum Ripichephalus (Boophilus) microplus sob condições de laboratório

Resumen La garrapata común (Rhipicephalus (B.) microplus) del ganado es considerada el ectoparásito más importante en la ganadería. El uso repetitivo y tradicional de acaricidas comerciales se ha convertido en un serio problema en cuanto a la resistencia adquirida por esta garrapata. Por esta razón, el control biológico ha surgido como una alternativa prometedora en el control de este ectoparásito. En este estudio se evalúa el efecto de los extractos vegetales de dos plantas, J. curcas y A. muricata, sobre el índice de producción de huevos y la eficiencia reproductiva de R (B.) microplus bajo condiciones de laboratorio. Cada extracto fue evaluado a cinco concentraciones (entre 0.1 y 5%), usando controles negativo y positivo para su comparación. Ambas plantas mostraron actividad biológica, sin embargo, A. muricata tuvo un efecto mayor comparado con J. curcas, inclusive a concentraciones bajas (0,5 y 1 %). Por el contrario, J. curcas mostró solo un efecto moderado en concentraciones altas (5%). En conclusión, los resultados obtenidos en laboratorio indican que los extractos de A. muricata son promisorios para controlar la garrapata común del ganado.

Abstract Rhipicephalus (B.) microplus or common cattle tick is considered the most important ectoparasite of livestock. Traditional and repetitive control of this tick through the use of conventional products has become a serious problem regarding tick's resistance. For this reason, biological control has emerged as a very promising alternative to control this tick. In the present study, an experiment was designed to assess the effect of plant extracts of J. curcas y A. muricata on Production eggs Index (IPH) and estimated reproduction (ER) of R (B) microplus under laboratory conditions. Each plant extract was assessed in five different concentrations (between 0.1 and 5%); a positive and negative control was used for comparison. Both plants showed biological activity, however, A. muricata showed significantly effect on engorged females of the cattle tick compared with J. curcas, even at lower concentrations (0.5, and 1 %). In conclusion, the results obtained indicate that A. muricata's seed extracts are promissory to biocontrol the common cattle tick under laboratory conditions.

Resumo O carrapato comum (Rhipicephalus (B.) microplus) do gado é considerado o ectoparasita mais importante da pecuária. O uso repetitivo e tradicional de inseticidas comerciais se converteu em um sério problema quanto a resisitência adquirida por esse carrapato. Por essa razão, o controle biológico surgiu como uma alternativa promissora no controle deste ectoparasita. Esse estudo avalia o efeito dos extratos vegetais das plantas,J. curcas e A. muricata,sobre o índice de produção de ovos e a eficiência reprodutiva deR (B.) microplussegundo condições de laboratório. Cada extrato foi avaliado em 5 concentrações (entre 0,1 e 5%), usando controles negativo e positivo para sua comparação. Ambas as plantas mostraram atividade biológica, porém,A. muricatateve um efeito maior comparado comJ. curcas,inclusive as concentrações baixas (0,5 y 1 %). Pelo contrário,J. curcasmostrou só um efeito moderado nas concentrações altas (5%). Em conclusão, os resultados obtidos no laboratório indicam que os extratos deA. muricatasão promissores para controlar o carrapato comum do gado.

TNFα-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer.

PURPOSE: Although trastuzumab administration improved the outcome of HER2-positive breast cancer patients, resistance events hamper its clinical benefits. We demonstrated that TNFα stimulation in vitro induces trastuzumab resistance in HER2-positive breast cancer cell lines. Here, we explored the mechanism of TNFα-induced trastuzumab resistance and the therapeutic strategies to overcome it. EXPERIMENTAL DESIGN: Trastuzumab-sensitive breast cancer cells, genetically engineered to stably overexpress TNFα, and de novo trastuzumab-resistant tumors, were used to evaluate trastuzumab response and TNFα-blocking antibodies effectiveness respectively. Immunohistochemistry and antibody-dependent cell cytotoxicity (ADCC), together with siRNA strategy, were used to explore TNFα influence on the expression and function of its downstream target, mucin 4 (MUC4). The clinical relevance of MUC4 expression was studied in a cohort of 78 HER2-positive breast cancer patients treated with adjuvant trastuzumab. RESULTS: TNFα overexpression turned trastuzumab-sensitive cells and tumors into resistant ones. Histopathologic findings revealed mucin foci in TNFα-producing tumors. TNFα induced upregulation of MUC4 that reduced trastuzumab binding to its epitope and impaired ADCC. Silencing MUC4 enhanced trastuzumab binding, increased ADCC, and overcame trastuzumab and trastuzumab-emtansine antiproliferative effects in TNFα-overexpressing cells. Accordingly, administration of TNFα-blocking antibodies downregulated MUC4 and sensitized de novo trastuzumab-resistant breast cancer cells and tumors to trastuzumab. In HER2-positive breast cancer samples, MUC4 expression was found to be an independent predictor of poor disease-free survival (P = 0.008). CONCLUSIONS: We identified TNFα-induced MUC4 expression as a novel trastuzumab resistance mechanism. We propose MUC4 expression as a predictive biomarker of trastuzumab efficacy and a guide to combination therapy of TNFα-blocking antibodies with trastuzumab. Clin Cancer Res; 23(3); 636-48. ©2016 AACR.