Interleukin-2 superkines by computational design.

Affinity maturation of protein­protein interactions is an important approach in the development of therapeutic proteins such as cytokines. Typical experimental strategies involve targeting the cytokine-receptor interface with combinatorial libraries and then selecting for higher-affinity variants. Mutations to the binding scaffold are usually not considered main drivers for improved affinity. Here we demonstrate that computational design can provide affinity-enhanced variants of interleukin-2 (IL-2) "out of the box" without any requirement for interface engineering. Using a strategy of global IL-2 structural stabilization targeting metastable regions of the three-dimensional structure, rather than the receptor binding interfaces, we computationally designed thermostable IL-2 variants with up to 40-fold higher affinity for IL-2Rß without any library-based optimization. These IL-2 analogs exhibited CD25-independent activities on T and natural killer (NK) cells both in vitro and in vivo, mimicking the properties of the IL-2 superkine "super-2" that was engineered through yeast surface display [A. M. Levin et al., Nature, 484, 529­533 (2012)]. Structure-guided stabilization of cytokines is a powerful approach to affinity maturation with applications to many cytokine and protein­protein interactions.

Arterial input function estimation compensating for inflow and partial voluming in dynamic contrast-enhanced MRI.

Both inflow and the partial volume effect (PVE) are sources of error when measuring the arterial input function (AIF) in dynamic contrast-enhanced (DCE) MRI. This is relevant, as errors in the AIF can propagate into pharmacokinetic parameter estimations from the DCE data. A method was introduced for flow correction by estimating and compensating the number of the perceived pulse of spins during inflow. We hypothesized that the PVE has an impact on concentration-time curves similar to inflow. Therefore, we aimed to study the efficiency of this method to compensate for both effects simultaneously. We first simulated an AIF with different levels of inflow and PVE contamination. The peak, full width at half-maximum (FWHM), and area under curve (AUC) of the reconstructed AIFs were compared with the true (simulated) AIF. In clinical data, the PVE was included in AIFs artificially by averaging the signal in voxels surrounding a manually selected point in an artery. Subsequently, the artificial partial volume AIFs were corrected and compared with the AIF from the selected point. Additionally, corrected AIFs from the internal carotid artery (ICA), the middle cerebral artery (MCA), and the venous output function (VOF) estimated from the superior sagittal sinus (SSS) were compared. As such, we aimed to investigate the effectiveness of the correction method with different levels of inflow and PVE in clinical data. The simulation data demonstrated that the corrected AIFs had only marginal bias in peak value, FWHM, and AUC. Also, the algorithm yielded highly correlated reconstructed curves over increasingly larger neighbourhoods surrounding selected arterial points in clinical data. Furthermore, AIFs measured from the ICA and MCA produced similar peak height and FWHM, whereas a significantly larger peak and lower FWHM was found compared with the VOF. Our findings indicate that the proposed method has high potential to compensate for PVE and inflow simultaneously. The corrected AIFs could thereby provide a stable input source for DCE analysis.

Improved reliability of perfusion estimation in dynamic susceptibility contrast MRI by using the arterial input function from dynamic contrast enhanced MRI.

The arterial input function (AIF) plays a crucial role in estimating quantitative perfusion properties from dynamic susceptibility contrast (DSC) MRI. An important issue, however, is that measuring the AIF in absolute contrast-agent concentrations is challenging, due to uncertainty in relation to the measured R 2 ∗ -weighted signal, signal depletion at high concentration, and partial-volume effects. A potential solution could be to derive the AIF from separately acquired dynamic contrast enhanced (DCE) MRI data. We aim to compare the AIF determined from DCE MRI with the AIF from DSC MRI, and estimated perfusion coefficients derived from DSC data using a DCE-driven AIF with perfusion coefficients determined using a DSC-based AIF. AIFs were manually selected in branches of the middle cerebral artery (MCA) in both DCE and DSC data in each patient. In addition, a semi-automatic AIF-selection algorithm was applied to the DSC data. The amplitude and full width at half-maximum of the AIFs were compared statistically using the Wilcoxon rank-sum test, applying a 0.05 significance level. Cerebral blood flow (CBF) was derived with different AIF approaches and compared further. The results showed that the AIFs extracted from DSC scans yielded highly variable peaks across arteries within the same patient. The semi-automatic DSC-AIF had significantly narrower width compared with the manual AIFs, and a significantly larger peak than the manual DSC-AIF. Additionally, the DCE-based AIF provided a more stable measurement of relative CBF and absolute CBF values estimated with DCE-AIFs that were compatible with previously reported values. In conclusion, DCE-based AIFs were reproduced significantly better across vessels, showed more realistic profiles, and delivered more stable and reasonable CBF measurements. The DCE-AIF can, therefore, be considered as an alternative AIF source for quantitative perfusion estimations in DSC MRI.

Anatomical changes in resection cavity during brain radiotherapy.

BACKGROUND AND PURPOSE: Brain tumors are in general treated with a maximal safe resection followed by radiotherapy of remaining tumor including the resection cavity (RC) and chemotherapy. Anatomical changes of the RC during radiotherapy can have impact on the coverage of the target volume. The aim of the current study was to quantify the potential changes of the RC and to identify risk factors for RC changes. MATERIALS AND METHODS: Sixteen patients treated with pencil beam scanning proton therapy between October 2019 and April 2020 were retrospectively analyzed. The RC was delineated on pre-treatment computed tomography (CT) and magnetic resonance imaging, and weekly CT-scans during treatment. Isotropic expansions were applied to the pre-treatment RC (1-5 mm). The percentage of volume of the RC during treatment within the expanded pre-treatment volumes was quantified. Potential risk factors (volume of RC, time interval surgery-radiotherapy and relationship of RC to the ventricles) were evaluated using Spearman's rank correlation coefficient. RESULTS: The average variation in relative RC volume during treatment was 26.1% (SD 34.6%). An expansion of 4 mm was required to cover > 95% of the RC volume in > 90% of patients. There was a significant relationship between the absolute volume of the pre-treatment RC and the volume changes during treatment (Spearman's ρ = - 0.644; p = 0.007). CONCLUSION: RCs are dynamic after surgery. Potentially, an additional margin in brain cancer patients with an RC should be considered, to avoid insufficient target coverage. Future research on local recurrence patterns is recommended.

Prevalence and development of a risk score for oral human papillomavirus infection in men who have sex with men in Mexico.

BACKGROUND: Men who have sex with men (MSM) are at high risk for oral human papillomavirus (HPV infection). There are no specific screening guidelines to facilitate the identification of people at risk for oral HPV infection. We aimed to estimate the prevalence of oral high-risk HPV and create a risk score to identify MSM at higher risk for prevalent oral HPV. METHODS: We collected baseline data from a clinical trial from a subsample of 500 MSM attending sexually transmitted disease treatment clinics; they provided an oral gargle sample for high-risk HPV detection. We calculated oral high-risk HPV prevalence and 95% confidence intervals (CIs), used a logistic regression model to identify factors associated with high-risk HPV infection, and created a risk score. RESULTS: The prevalence of any oral high-risk HPV among MSM was 11.1% (95% CI: 8.6-14.2), with a higher prevalence observed among men living with HIV (14.8%). Factors independently associated with oral high-risk HPV were age ≥40 years (OR = 2.71, 95% CI: 1.28-5.73 compared to <40 years), being HIV-positive with CD4 count 200-499 (OR = 2.76, 95% CI: 1.34-5.65 compared to HIV-negative), and recent recreational use of vasodilators (poppers/sildenafil) (OR = 2.02, 95% CI: 1.02-2.97). The risk score had good discriminatory power (AUC = 0.70, 95% CI: 0.63-0.77). CONCLUSIONS: MSM have specific predictors for prevalent oral high-risk HPV, and a risk score could be used by clinicians to target men with vaccine recommendations and counseling, and identify those who could benefit from primary interventions given the available resources, or for referral to dental services for follow-up when available.

Sintomatología depresiva en adolescentes y adultos mexicanos: Ensanut 2022.

OBJETIVO: Estimar la prevalencia de sintomatología depresiva en adolescentes y adultos mexicanos. Material y métodos. La Encuesta Nacional de Salud y Nutrición 2022 evaluó la prevalencia de sintomatología depresiva mediante la Escala de Depresión del Centro de Estudios Epidemiológicos (CESD-7). En adolescentes se estimó el puntaje promedio y en adultos la prevalencia de sintomatología depresiva. RESULTADOS: En adolescentes el puntaje promedio de la CESD-7 fue 3.2. El 16.7% de los adultos tiene sintomatología depresiva, siendo mayor en adultos mayores (38.3%) que en adultos (11.3%). Se observaron mayores prevalencias en mujeres, adultos con índice de bienestar bajo y en adultos mayores residentes del área rural. Conclusión. A nivel nacional la prevalencia de sintomatología depresiva es similar a lo estimado en 2018-19. Se deben orientar acciones para mejorar la salud mental de la población, particularmente el diagnóstico y tratamiento de personas con mayor sintomatología depresiva como son mujeres, adultos con bajo índice de bienestar y residentes de área rural.

Subclinical systolic dysfunction by speckle tracking echocardiography in patients with systemic lupus erythematosus.

BACKGROUND: We aimed to compare the prevalence of subclinical left ventricular systolic dysfunction in Hispanic systemic lupus erythematosus (SLE) patients versus healthy controls. MATERIAL AND METHODS: This cross-sectional study included 46 SLE patients who fulfilled the 2019 European League Against Rheumatism and American College of Rheumatology (EULAR/ACR) classification criteria for SLE and with age ≥ 18 years. For comparison, we included a control group with 46 non-SLE subjects matched by age (±5 years) and gender. A transthoracic echocardiogram was performed on every participant. The echocardiographic measurements evaluated were left ventricular ejection fraction (LVEF), relative wall thickness (RWT), and tricuspid annular plane systolic excursion (TAPSE). Left ventricular-Global Longitudinal Strain (GLS) was evaluated, and a value higher than -18% was classified as subclinical left ventricular systolic dysfunction. Comparisons between groups were made using the Chi-square test or Fisher's exact test for qualitative variables, and Student's t-test or the Mann-Whitney's U test for quantitative variables. A p-value <.05 was considered significant. RESULTS: We found a significant difference in the presence of subclinical left ventricular systolic dysfunction between SLE-patients and controls (37.0% vs 8.7%, p = .001). We also found that SLE patients had a lower left ventricular GLS (-18.90% vs -20.51%, p = .011), TAPSE (21.63 mm vs 23.60 mm, p = .009), and LVEF (57.17% vs 62.47%, p = <.001) than controls. Systemic lupus erythematosus diagnosis was independently associated with the presence of subclinical left ventricular systolic dysfunction with an OR of 6.068 (CI 95% 1.675-21.987) (p = .006). Subclinical systolic dysfunction was more common in men (29.4% vs 3.4%, p = .020), patients with obesity (17.6% vs 0%, p = .045), or hypertension (47.1% vs 6.9%, p = .001). CONCLUSION: Systemic lupus erythematosus Hispanic patients had a higher prevalence of subclinical left ventricular systolic dysfunction, and worse left ventricular GLS, LVEF, and TAPSE values than matched healthy controls. Additionally, we found that male gender, obesity, and hypertension are associated with the presence of subclinical left ventricular systolic dysfunction in SLE patients. The inclusion of speckle tracking echocardiography as part of the cardiovascular evaluation of SLE patients may help identify high cardiovascular risk patients.

Positive allosteric γ-aminobutyric acid type A receptor modulation prevents lipotoxicity-induced injury in hepatocytes in vitro.

AIM: To determine if a novel positive allosteric modulator of the γ-aminobutyric acid type A (GABAA ) receptor, the thioacrylamide-derivative HK4, which does not penetrate the blood-brain barrier, protects human hepatocytes against lipotoxicity-induced injury. MATERIALS AND METHODS: Allosteric modulation of the GABAA receptor by HK4 was determined by patch clamp in HEK-293 cells, calcium influx in INS-1E cells and by using the specific GABAA channel blockers picrotoxin and tert-butylbicyclophosphorothionate (TBPS) in HepG2 cells. Apoptosis was analysed using caspase 3/7, terminal deoxynucleotidyl transferase-dUTP nick end labelling (TUNEL) and array assays in HepG2 cells and/or human primary hepatocytes. Phosphorylation of STAT3 and the NF-κB subunit p65, protein disulphide isomerase (PDI) and poly-ADP-ribose polymerase-1 (PARP-1) was detected by Western blotting. RESULTS: Patch clamping, calcium influx measurements and apoptosis assays with the non-competitive GABAA channel blockers picrotoxin and TBPS proved HK4 as a selective positive allosteric modulator of the GABAA receptor. In HepG2 cells, which expressed the main GABAA receptor subunits, HK4 prevented palmitate-induced apoptosis. This protective effect was mediated by downregulation of caspase 3/7 activity and was additionally verified by TUNEL assay. HK4 effectively prevented palmitate-induced apoptosis in human primary hepatocytes. HK4 reduced STAT3 and NF-κB phosphorylation, reduced cleaved PARP-1 expression and upregulated the endoplasmic reticulum (ER) chaperone PDI. CONCLUSIONS: HK4 reduced lipotoxic-induced apoptosis by preventing inflammation, DNA damage and ER stress. We propose that the effect of HK4 is mediated by STAT3 and NF-κB. It is suggested that thioacrylamide compounds represent an innovative pharmacological tool to treat or prevent non-alcoholic steatohepatitis as first-in-class drugs.

The potential of advanced MR techniques for precision radiotherapy of glioblastoma.

As microscopic tumour infiltration of glioblastomas is not visible on conventional magnetic resonance (MR) imaging, an isotropic expansion of 1-2 cm around the visible tumour is applied to define the clinical target volume for radiotherapy. An opportunity to visualize microscopic infiltration arises with advanced MR imaging. In this review, various advanced MR biomarkers are explored that could improve target volume delineation for radiotherapy of glioblastomas. Various physiological processes in glioblastomas can be visualized with different advanced MR techniques. Combining maps of oxygen metabolism (CMRO2), relative cerebral blood volume (rCBV), vessel size imaging (VSI), and apparent diffusion coefficient (ADC) or amide proton transfer (APT) can provide early information on tumour infiltration and high-risk regions of future recurrence. Oxygen consumption is increased 6 months prior to tumour progression being visible on conventional MR imaging. However, presence of the Warburg effect, marking a switch from an infiltrative to a proliferative phenotype, could result in CMRO2 to appear unaltered in high-risk regions. Including information on biomarkers representing angiogenesis (rCBV and VSI) and hypercellularity (ADC) or protein concentration (APT) can omit misinterpretation due to the Warburg effect. Future research should evaluate these biomarkers in radiotherapy planning to explore the potential of advanced MR techniques to personalize target volume delineation with the aim to improve local tumour control and/or reduce radiation-induced toxicity.

Conversion of a colorectal cancer guideline into clinical decision trees with assessment of validity.

OBJECTIVE: The interpretation and clinical application of guidelines can be challenging and time-consuming, which may result in noncompliance to guidelines. The aim of this study was to convert the Dutch guideline for colorectal cancer (CRC) into decision trees and subsequently implement decision trees in an online decision support environment to facilitate guideline application. METHODS: The recommendations of the Dutch CRC guidelines (published in 2014) were translated into decision trees consisting of decision nodes, branches and leaves that represent data items, data item values and recommendations, respectively. Decision trees were discussed with experts in the field and published as interactive open access decision support software (available at www.oncoguide.nl). Decision tree validation and a concordance analysis were performed using consecutive reports (January 2016-January 2017) from CRC multidisciplinary tumour boards (MTBs) at Amsterdam University Medical Centers, location AMC. RESULTS: In total, we developed 34 decision trees driven by 101 decision nodes based on the guideline recommendations. Decision trees represented recommendations for diagnostics (n = 1), staging (n = 10), primary treatment (colon: n = 1, rectum: n = 5, colorectal: n = 9), pathology (n = 4) and follow-up (n = 3) and included one overview decision tree for optimal navigation. We identified several guideline information gaps and areas of inconclusive evidence. A total of 158 patients' MTB reports were eligible for decision tree validation and resulted in treatment recommendations in 80% of cases. The concordance rate between decision tree treatment recommendations and MTB advices was 81%. Decision trees reported in 22 out of 24 non-concordant cases (92%) that no guideline recommendation was available. CONCLUSIONS: We successfully converted the Dutch CRC guideline into decision trees and identified several information gaps and areas of inconclusive evidence, the latter being the main cause of the observed disagreement between decision tree recommendations and MTB advices. Decision trees may contribute to future strategies to optimize quality of care for CRC patients.

Chemical Diversity and Antimicrobial Potential of Cultivable Fungi from Deep-Sea Sediments of the Gulf of Mexico.

A collection of 29 cultivable fungal strains isolated from deep-sea sediments of the Gulf of Mexico were cultivated under the "one strain, many compounds" approach to explore their chemical diversity and antimicrobial potential. From the 87 extracts tested, over 50% showed antimicrobial activity, and the most active ones were those from cultures grown at 4 °C in darkness for 60 days (resembling deep-sea temperature). PCA analysis of the LC-MS data of all the extracts confirmed that culture temperature is the primary factor in the variation of the 4462 metabolite features, accounting for 21.3% of the variation. The bioactivity-guided and conventional chemical studies of selected fungal strains allowed the identification of several active and specialized metabolites. Finally, metabolomics analysis by GNPS molecular networking and manual dereplication revealed the biosynthetic potential of these species to produce interesting chemistry. This work uncovers the chemical and biological study of marine-derived fungal strains from deep-sea sediments of the Gulf of Mexico.

Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation.

Oligometastatic disease has been proposed as an intermediate state between localised and systemically metastasised disease. In the absence of randomised phase 3 trials, early clinical studies show improved survival when radical local therapy is added to standard systemic therapy for oligometastatic disease. However, since no biomarker for the identification of patients with true oligometastatic disease is clinically available, the diagnosis of oligometastatic disease is based solely on imaging findings. A small number of metastases on imaging could represent different clinical scenarios, which are associated with different prognoses and might require different treatment strategies. 20 international experts including 19 members of the European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer OligoCare project developed a comprehensive system for characterisation and classification of oligometastatic disease. We first did a systematic review of the literature to identify inclusion and exclusion criteria of prospective interventional oligometastatic disease clinical trials. Next, we used a Delphi consensus process to select a total of 17 oligometastatic disease characterisation factors that should be assessed in all patients treated with radical local therapy for oligometastatic disease, both within and outside of clinical trials. Using a second round of the Delphi method, we established a decision tree for oligometastatic disease classification together with a nomenclature. We agreed oligometastatic disease as the overall umbrella term. A history of polymetastatic disease before diagnosis of oligometastatic disease was used as the criterion to differentiate between induced oligometastatic disease (previous history of polymetastatic disease) and genuine oligometastatic disease (no history of polymetastatic disease). We further subclassified genuine oligometastatic disease into repeat oligometastatic disease (previous history of oligometastatic disease) and de-novo oligometastatic disease (first time diagnosis of oligometastatic disease). In de-novo oligometastatic disease, we differentiated between synchronous and metachronous oligometastatic disease. We did a final subclassification into oligorecurrence, oligoprogression, and oligopersistence, considering whether oligometastatic disease is diagnosed during a treatment-free interval or during active systemic therapy and whether or not an oligometastatic lesion is progressing on current imaging. This oligometastatic disease classification and nomenclature needs to be prospectively evaluated by the OligoCare study.

Sanitizing after fresh-cutting carrots reduces the wound-induced accumulation of phenolic antioxidants compared to sanitizing before fresh-cutting.

BACKGROUND: During the production of fresh-cut products, crops are exposed to wounding stress, and as a stress response, phenolic antioxidants are synthesized. This stress response is elicited by extracellular adenosine triphosphate, released from wounded cells and recognized by receptors of unwounded cells. The phenolic antioxidants produced as a stress response are beneficial for human health. However, a common practice in the fresh-cut industry is the application of washing/sanitizing procedures after cutting. These procedures could be highly detrimental, since they partially remove the wound signal that elicits the biosynthesis of phenolics in plants. In this study, the impact of different washing/sanitizing treatments post-shredding on the wound-induced accumulation of chlorogenic acid (CHA) in carrot was evaluated. Peeled carrots were shredded and dipped in aqueous solutions containing chlorine (100 ppm, 2 min), hydrogen peroxide (1.5%, 2 min) or water (2 min). The content of CHA in treated carrots was evaluated before and after 48 h of storage (19 ± 2 °C). RESULTS: The control carrots sanitized only before peeling and shredding showed 4000% higher content of CHA as compared with time 0 h samples. However, carrots treated with washing/sanitizing procedures post-shredding including water, chlorine and hydrogen peroxide showed a decrease in the accumulation of CHA by 46.9%, 53.6% and 89.9%, respectively. CONCLUSIONS: The results demonstrated that washing/sanitizing procedures applied after fresh-cutting are potentially detrimental to the wound-induced accumulation of health-promoting compounds during storage of fresh produce. Thus, the fresh-cut industry could consider avoiding washing procedures after cutting and implement alternative sanitizing procedures that avoid the partial removal of the wound signal, such as sanitizing only before cutting. © 2020 Society of Chemical Industry.

Expanding the horizons: Uncontrolled donors after circulatory death for lung transplantation-First comparison with brain death donors.

Uncontrolled donation after cardiac death is an appealing source of organs for lung transplantation. We compare early and long-term outcomes of lung transplantation with these donors with a cohort of transplants from brain death donors at our institution. Retrospective analysis of all lung transplantations was performed from 2002 to 2012. We collected variables regarding recipients, donors, recover and transplant procedures, early and late complications, and survival. We included 292 lung transplants from brain death donors and 38 from uncontrolled donors after cardiac death. Both groups were comparable except for sex mismatch (male recipient-female donor was more frequent in the brain death cohort, 17.8% vs 0%, P 0.002), total ischemic time (longer for donors after cardiac death, 657 minutes for the first lung and 822 minutes for the second vs 309 and 425 minutes, P < 0.001), and ex vivo evaluation (more frequent in cardiac death donors, 21.1% vs 1.4%, P < 0.001). Early and late outcomes were not different (ICU stay [9 vs 10.5 days], hospital stay [33.5 vs 35 days], primary graft dysfunction G3 [24 vs 34.2%], and chronic graft dysfunction HR 1.19 [0.61-2.32]), but overall survival was significantly lower for patients transplanted from cardiac death donors [HR 1.67 (1.06-2.64)]. Lung transplantation after uncontrolled cardiac death offers poorer results in terms of survival compared to brain death donation. Refinement of current strategies for graft preservation and evaluation is essential to improve outcomes with this source of grafts.

HPV vaccine acceptance is high among adults in Mexico, particularly in people living with HIV.

OBJECTIVE: To measure HPV vaccine acceptance in diverse Mexican adult popula-tions, taking into account HIV status. MATERIALS AND METHODS: A total of 1 329 men and women, with and without HIV, participated in one of three intervention studies, offering HPV vaccination, carried out in the states of Morelos, Tlaxcala and Mexico City; either the bivalent (Morelos n=103, Tlaxcala n=127) or quadrivalent HPV-vaccine (Mexico City n=1 099) was offered. RESULTS: HPV vaccine was accepted by 80.3% of participants; acceptance was higher in people living with HIV than those without (84.4 vs. 78%, p=0.004). Women had greater HPV infection knowledge (p<0.0001) than men and slightly higher (p=0.4) vaccine acceptance. The main reason for vaccine non-acceptance among HIV-positive participants was their doctor recommended they not get vaccinated. CONCLUSIONS: Acceptance of HPV-vaccine was high in men and women regardless of HIV status. Even higher rates of acceptability may be achieved by educating healthcare providers to recommend HPV vaccine to their patients.

OBJETIVO: Medir la aceptación de la vacuna de VPH en una muestra diversa de población adulta mexicana, teniendo en cuenta su estado de VIH. MATERIAL Y MÉTODOS: 1 329 hombres y mujeres con y sin VIH participaron en tres estudios de intervención, realizados en los estados de Morelos, Tlaxcala y Ciudad de México. Se ofreció la vacuna bivalente (Morelos n=103, Tlaxcala n=127) o la cuadrivalente (Ciudad de México n=1 099) contra VPH. RESULTADOS: La vacuna fue aceptada por 80.3% de los participantes; la aceptación fue mayor en personas que viven con VIH que en aquéllas que no (84.4 vs. 78%, p=0.004). Las mujeres (p<0.0001) tenían mayor conocimientos sobre VPH que los hombres y una aceptación de la vacuna ligeramente mayor (p=0.4). El motivo principal de la no aceptación de la vacuna entre personas con VIH fue que su médico recomendó que no se vacunaran. CONCLUSIONES: La aceptación de la vacuna contra el VPH fue alta en hombres y mujeres,independientemente del estado de VIH. Se pueden lograr mayores tasas de aceptabilidad educando a los proveedores de atención médica para que recomienden la vacuna contra el VPH a sus pacientes.

Prevention and control of neoplasms associated with HPV in high-risk groups in Mexico City: The Condesa Study.

OBJECTIVE: To evaluate the effectiveness of a combined strategy of human papillomavirus virus (HPV) vaccination and high-risk HPV screening to reduce the occurrence of anogenital and oropharyngeal neoplasms among men who have sex with men, people with HIV, homeless people, transgender women, female sex workers and rape victims. MATERIALS AND METHODS: This mixed methods study evaluates the effectiveness of a combined vaccination-screening strategy to reduce HPV prevalence/incidence and occurrence of cervical intraepithelial neoplasms grade 2+ and/or anal intraepithelial neoplasms grade 2+, using Kaplan-Meier. The time-to-event method will evaluate time from positive results for specific anogenital HPV to incidence of anogenital lesions containing that HPV type. RESULTS: People vaccinated against HPV and screened for HPV as a primary test will have lower prevalence and incidence of HPV infection and consequently lower frequency of HPV-related anogenital and oropharyngeal lesions. CONCLUSIONS: Thisstudy will generate scientific evidence on effectiveness of a combined vaccination-screening strategy to reduce the burden of HPV-associated neoplasms.

OBJETIVO: Evaluar la efectividad de una estrategia combinada de vacunación contra el virus de papiloma humano (VPH) y tamizaje de VPH de alto riesgo para reducir neoplasias anogenitales y orofaringeas entre hombres que tienen sexo con hombres, personas con VIH, personas en situación de calle, mujeres transgénero, trabajadoras sexuales y víctimas de violación. MATERIAL Y MÉTODOS: Este estudio evaluará la efectividad de una estrategia combinada de vacunación y tamizaje para reducir la ocurrencia de neoplasias intraepiteliales cervicales grado 2+ o neoplasias intraepiteliales anales grado NIA2+ utilizando Kaplan-Meier. Se evaluará tiempo de resultados positivos para tipos específicos deVPH anogenital a incidencia de lesiones anogenitales con ese tipo de VPH. RESULTADOS: Las personas vacunadas contra VPH y con tamizaje de VPH tendrán menor prevalencia e incidencia de infecciones por VPH y por ende menor frecuencia de lesiones anogenitales y orofaringeas relacionadas con VPH. CONCLUSIONES: Este estudio generará evidencia científica sobre la efectividad de una estrategia combinada de vacunación y tamizaje para reducir la carga de neoplasias asociadas al VPH.

Dual Effects of Resveratrol on Cell Death and Proliferation of Colon Cancer Cells.

Colorectal cancer remains a main cause of deaths worldwide, and novel agents are being searched to treat this disease. Polyphenols have emerged as promising therapeutic tools in cancer. Resveratrol (3,5,4'-trihydoxy-trans-stilbene) induces cell death in different tumor cell lines, and it also stimulates the proliferation of specific breast and prostate cancer cell lines. Here, we studied the impact of resveratrol over a 100-fold concentration range on cell death and proliferation of HT-29 colorectal adenocarcinoma cells. After 96 h of treatment, a biphasic pattern was observed. At lower concentrations (1 and 10 µmol/l), resveratrol increased the cell number, as did the polyphenol quercetin. At 50 or 100 µmol/l, resveratrol reduced the cell number and increased the percentage of apoptotic or necrotic cells, thus indicating cytotoxicity. On HCT116 colon cancer cells, however, no proliferative properties of resveratrol were observed. Resveratrol-induced cytotoxicity on HT-29 cells was associated with NADPH oxidase activation and increased levels of histone γH2AX, a marker of DNA damage, paralleled by enhanced sirtuin 6 levels, likely as a repair mechanism. Overall, resveratrol may be an effective tool in anti-tumor chemotherapy. However, since under some conditions it may favor tumor cell growth, appropriate local concentrations must be achieved to minimize unwanted effects of resveratrol.

Institutional experience in the treatment of colorectal liver metastases with stereotactic body radiation therapy.

AIM: To investigate whether the impact of dose escalation in our patient population represented an improvement in local control without increasing treatment related toxicity. MATERIALS AND METHODS: A cohort of consecutive patients with colorectal liver metastases treated with stereotactic body radiation therapy (SBRT) between December 2002 and December 2013 were eligible for this study. Inclusion criteria were a Karnofsky performance status ≥80% and, according to the multidisciplinary tumor board, ineligibility for surgery or radiofrequency ablation. Exclusion criteria were a lesion size >6 cm, more than 3 metastases, and treatment delivered with other fractionation scheme than 3 times 12.5 Gy or 16.75 Gy prescribed at the 65-67% isodose. To analyze local control, CT or MRI scans were acquired during follow-up. Toxicity was scored using the Common Toxicity Criteria Adverse Events v4.0. RESULTS: A total of 40 patients with 55 colorectal liver metastases were included in this study. We delivered 37.5 Gy to 32 lesions, and 50.25 Gy to 23 lesions. Median follow-up was 26 and 25 months for these two groups. Local control at 2 and 3 years was 74 and 66% in the low dose group while 90 and 81% was reached in the high dose group. No significant difference in local control between the two dose fractionation schemes could be found. Grade 3 toxicity was limited and was not increased in the high dose group. CONCLUSIONS: SBRT for colorectal liver metastases offers a high chance of local control at long term. High irradiation doses may contribute to enhance this effect without increasing toxicity.

C-SPAM: an open-source time-resolved specimen vitrification device with light-activated molecules.

Molecular structures can be determined in vitro and in situ with cryo-electron microscopy (cryo-EM). Specimen preparation is a major obstacle in cryo-EM. Typical sample preparation is orders of magnitude slower than biological processes. Time-resolved cryo-EM (TR-cryo-EM) can capture short-lived states. Here, Cryo-EM sample preparation with light-activated molecules (C-SPAM) is presented, an open-source, photochemistry-coupled device for TR-cryo-EM that enables millisecond resolution and tunable timescales across broad biological applications.