Paradoxical activation of oncogenic signaling as a cancer treatment strategy.

Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress-response programs that counteract the inherent toxicity of such aberrant signaling. While inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause lethality. We show here that inhibition of Protein Phosphatase 2A (PP2A) hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells. Genetic and compound screens identify combined inhibition of PP2A and WEE1 as synergistic in multiple cancer models by collapsing DNA replication and triggering premature mitosis followed by cell death. This combination also suppressed the growth of patient-derived tumors in vivo. Remarkably, acquired resistance to this drug combination suppressed the ability of colon cancer cells to form tumors in vivo. Our data suggest that paradoxical activation of oncogenic signaling can result in tumor suppressive resistance.

Potential predictors for surgical delay in patients with intertrochanteric fractures and their impact on hospitalization length, in a Latin American trauma center.

INTRODUCTION: The incidence of intertrochanteric fractures is increasing, and health institutions must know the profile of their patients. This paper describes the relationship between clinical characteristics and attention process with surgical delay and prolonged hospitalization length in patients with intertrochanteric fractures admitted to a Latin-American trauma center. MATERIALS AND METHODS: Retrospective, comparative, cross-sectional study. The medical records of patients admitted for intertrochanteric fracture between August 1st 2019 and May 31st 2021 were reviewed to extract data regarding clinical characteristics, causes of surgery delay, and hospitalization length. Regression models were used to distinguish potential predictor variables on surgical delay and hospitalization length. RESULTS: 362 cases with intertrochanteric fractures were surgically treated during the study period. The mean time from admission to surgery was 4.2 ± 3.8 days. in 33,1% of the cases the surgery was performed within the first 48 h. A history of coronary heart disease (CHD) and chronic kidney disease were potential predictors of surgery delay (p<0.005). Only CHD was independently associated with surgery delay (OR 5.267 [95%CI 1.201-23.100); p = 0.028). Hospitalization was extended in cases where surgery was performed after 48 h (10,1 ± 6,2 days vs 5,9 ± 3,0 days; p<0.001). The regression model showed that for each day passed from fracture to admission and each day from admission to surgery, the hospitalization duration increased by 3,7 and 4,4 days, respectively. DISCUSSION: Patients with intertrochanteric fractures have comorbidities that potentially delay their surgical treatment and prolong hospitalization duration. The efficient use of hospital resources and the proper early evaluation of cardiac pathologies conducted during admission, could positively impact the achievement of surgical treatment within the first 48 h after the fracture, reducing hospitalization duration.

IκB kinase-α coordinates BRD4 and JAK/STAT signaling to subvert DNA damage-based anticancer therapy.

Activation of the IκB kinase (IKK) complex has recurrently been linked to colorectal cancer (CRC) initiation and progression. However, identification of downstream effectors other than NF-κB has remained elusive. Here, analysis of IKK-dependent substrates in CRC cells after UV treatment revealed that phosphorylation of BRD4 by IKK-α is required for its chromatin-binding at target genes upon DNA damage. Moreover, IKK-α induces the NF-κB-dependent transcription of the cytokine LIF, leading to STAT3 activation, association with BRD4 and recruitment to specific target genes. IKK-α abrogation results in defective BRD4 and STAT3 functions and consequently irreparable DNA damage and apoptotic cell death upon different stimuli. Simultaneous inhibition of BRAF-dependent IKK-α activity, BRD4, and the JAK/STAT pathway enhanced the therapeutic potential of 5-fluorouracil combined with irinotecan in CRC cells and is curative in a chemotherapy-resistant xenograft model. Finally, coordinated expression of LIF and IKK-α is a poor prognosis marker for CRC patients. Our data uncover a functional link between IKK-α, BRD4, and JAK/STAT signaling with clinical relevance.

p53 wild-type colorectal cancer cells that express a fetal gene signature are associated with metastasis and poor prognosis.

Current therapy against colorectal cancer (CRC) is based on DNA-damaging agents that remain ineffective in a proportion of patients. Whether and how non-curative DNA damage-based treatment affects tumor cell behavior and patient outcome is primarily unstudied. Using CRC patient-derived organoids (PDO)s, we show that sublethal doses of chemotherapy (CT) does not select previously resistant tumor populations but induces a quiescent state specifically to TP53 wildtype (WT) cancer cells, which is linked to the acquisition of a YAP1-dependent fetal phenotype. Cells displaying this phenotype exhibit high tumor-initiating and metastatic activity. Nuclear YAP1 and fetal traits are present in a proportion of tumors at diagnosis and predict poor prognosis in patients carrying TP53 WT CRC tumors. We provide data indicating the higher efficacy of CT together with YAP1 inhibitors for eradication of therapy resistant TP53 WT cancer cells. Together these results identify fetal conversion as a useful biomarker for patient prognosis and therapy prescription.

Bacteria in (vermi)composted organic wastes mostly survive when applied to an arable soil cultivated with wheat (Triticum sp. L.).

Composting and vermicomposting are an environmentally friendly way to reduce pathogens in organic wastes and generate a valuable product that provides nutrients for crops. However, how the bacterial community structure changes during these different processes and if the bacteria applied with the (vermi)composted products survive in an arable cultivated soil is still largely unknown. In this study, we monitored how the bacterial community structure changed during conditioning, composting with and without Eisenia fetida, and when the end-product was applied to arable soil cultivated with wheat Triticum sp. L. The organic wastes used were biosolid, cow manure, and a mixture of both. Large changes occurred in the relative abundance of some of the most abundant bacterial genera during conditioning, but the changes were much smaller during composting or vermicomposting. The bacterial community structure was significantly different in the organic wastes during conditioning and (vermi)composting but adding E. fetida had no significant effect on it. Changes in the relative abundance of the bacterial groups in the (vermi)composted waste applied to the arable soil cultivated with wheat were small, suggesting that most survived even after 140 days. As such, applying (vermi)composted organic wastes not only adds nutrients to a crop but also contributes to the survival of plant growth-promoting bacteria found in the (vermi)compost. However, putative human pathogens found in the biosolid also survived in the arable soil, and their relative abundance remained high but mixing the biosolid with cow manure reduced that risk. It was found that applying (vermi)composted organic wastes to an arable soil not only provides plant nutrients and adds bacteria with plant growth-promoting capacities, but some putative pathogens also survived.

Greenhouse gas emissions of biosolid and cow manure during composting and vermicomposting and when applied to soil cultivated with wheat (Triticum sp. L.).

Biosolids are a by-product of wastewater treatment, and their nutritional composition makes them ideal for fertilizing crops. However, pre-treatments, such as conditioning and/or (vermi)composting, are often required to stabilize the product and remove pathogens. Biosolids, cow manure, and a 50-50% mixture were conditioned for 21 days, composted or vermicomposted with Eisenia fetida (Savigny 1826) for 28 days, and applied to soil cultivated with wheat (Triticum sp. L.), while emissions of nitrous oxide (N2O), methane (CH4), and carbon dioxide (CO2) were monitored. Emissions of CH4 were large from the biosolid and N2O from the cow manure during conditioning. Emissions of CH4 remained high during (vermi)composting of the biosolids, while the emissions of N2O from the cow manure dropped. The addition of E. fetida did not affect the emissions of greenhouse gases during (vermi)composting. The emission of N2O was higher when (vermi)composted biosolid was applied to soil cultivated with wheat than when (vermi)composted cow manure was applied. The global warming potential (GWP) of the sum of the emitted greenhouse gases (GHG) during conditioning, (vermi)composting, and when the final product was applied to soil was 3 times larger from the cow manure than from the biosolid, but mixing biosolid with cow manure eliminated that difference. It was concluded that mixing biosolid with cow manure might be a simple way to reduce the GWP of the emitted GHG during storage, (vermi)composting, and when applied to soil.

Dynamic chromatin association of IκBα is regulated by acetylation and cleavage of histone H4.

IκBs exert principal functions as cytoplasmic inhibitors of NF-kB transcription factors. Additional roles for IκB homologues have been described, including chromatin association and transcriptional regulation. Phosphorylated and SUMOylated IκBα (pS-IκBα) binds to histones H2A and H4 in the stem cell and progenitor cell compartment of skin and intestine, but the mechanisms controlling its recruitment to chromatin are largely unknown. Here, we show that serine 32-36 phosphorylation of IκBα favors its binding to nucleosomes and demonstrate that p-IκBα association with H4 depends on the acetylation of specific H4 lysine residues. The N-terminal tail of H4 is removed during intestinal cell differentiation by proteolytic cleavage by trypsin or chymotrypsin at residues 17-19, which reduces p-IκBα binding. Inhibition of trypsin and chymotrypsin activity in HT29 cells increases p-IκBα chromatin binding but, paradoxically, impaired goblet cell differentiation, comparable to IκBα deletion. Taken together, our results indicate that dynamic binding of IκBα to chromatin is a requirement for intestinal cell differentiation and provide a molecular basis for the understanding of the restricted nuclear distribution of p-IκBα in specific stem cell compartments.

Case Report: COVID-19 with cytokine storm in a 16-year-old patient: if heart failures comes think about levosimendan.

Introduction: Our case is unique because the differential diagnosis was a challenge. At first, the patient presented with septic shock and multi-organ failure in the context of a suspected lymphoproliferative syndrome. Once the lymphoproliferative process had been ruled out, hemophagocytic syndrome due to COVID-19 infection was suspected, so he is probably one of the few patients with such an exhaustive study that could contribute to our understanding of COVID-19. We followed therapeutic guidelines that differ from the usual, using adrenalin and levosimendan. Corticosteroids helped to modulate the cytokine storm. Case report: A 16-year-old adolescent was admitted to the intensive care unit with fever, diarrhea, multiorgan failure and septic shock. He was IgG positive for COVID-19 and IgM negative. Thoraco-abdominal computed tomography demonstrated multiple para-aortic and peri-pancreatic lymphadenopathy and acute respiratory distress syndrome. The first suspected diagnosis was a lymphoproliferative syndrome and bacterial infection. The second possibility was a hemophagocytic syndrome in a patient recovering from COVID-19. He was treated with broad spectrum antibiotics because the differential diagnosis was difficult, and we removed them when the microbiological screening was negative. During the course of the disease he presented with severe biventricular dysfunction, probably due to the cytokine storm, so we used inotropic drugs (adrenaline, levosimendan). Infection with Salmonella species group B was diagnosed later, when the patient was in the Internal Medicine ward, although he was asymptomatic. Conclusion: The severity of COVID-19 infection ranges from mild to severe, causing serious disease in some people. Although the pathophysiology is not well known, it seems that in some cases an immune storm is triggered, and it is related to more serious and prolonged disease. In our case, heart failure was important, because it could have worsened the prognosis. Fortunately, the response to levosimendan and corticosteroids was adequate and he recovered favorably until discharge.

Renal and Neurologic Benefit of Levosimendan vs Dobutamine in Patients With Low Cardiac Output Syndrome After Cardiac Surgery: Clinical Trial FIM-BGC-2014-01.

BACKGROUND: Low-cardiac output syndrome (LCOS) after cardiac surgery secondary to systemic hypoperfusion is associated with a higher incidence of renal and neurological damage. A range of effective therapies are available for LCOS. The beneficial systemic effects of levosimendan persist even after cardiac output is restored, which suggests an independent cardioprotective effect. METHODS: A double-blind clinical trial was conducted in patients with a confirmed diagnosis of LCOS randomized into two treatment groups (levosimendan vs. dobutamine). Monitoring of hemodynamic (cardiac index, systolic volume index, heart rate, mean arterial pressure, central venous pressure, central venous saturation); biochemical (e.g. creatinine, S100B protein, NT-proBNP, troponin I); and renal parameters was performed using acute kidney injury scale (AKI scale) and renal and brain ultrasound measurements [vascular resistance index (VRI)] at diagnosis and during the first 48 h. RESULTS: Significant differences were observed between groups in terms of cardiac index, systolic volume index, NT-proBNP, and kidney injury stage at diagnosis. In the levosimendan group, there were significant variations in AKI stage after 24 and 48 h. No significant differences were observed in the other parameters studied. CONCLUSION: Levosimendan showed a beneficial effect on renal function in LCOS patients after cardiac surgery that was independent from cardiac output and vascular tone. This effect is probably achieved by pharmacological postconditioning. CLINICAL TRIAL REGISTRATION: EUDRA CT, identifier 2014-001461-27. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001461-27.

A case report of tuberculous chylothorax. / Reporte de un caso de quilotórax tuberculoso.

Tuberculous chylothorax is a rare infectious disease that occurs when the thoracic duct is obstructed. Treatment is directed to the tuberculosis infection. A 55-year-old male, driver, born in Trujillo (Peru) is admitted to the emergency department with increasing dyspnea and a 5-day dry cough. The physical examination revealed vocal fremitus, dullness to percussion, and a vesicular murmur that was decreased on the lower 2/3 of the left hemithorax. The X-ray and the thoracic ultrasound revealed significant left pleural effusion. The thoracocentesis drained fluid identified as chylothorax. Subsequently, a thoracic tube was placed, with a decrease in pleural fluid volume and later normalization of the cytochemical changes. Diagnostic video bronchoscopy was performed with a bronchoalveolar aspirate, revealing acid-fast bacilli. The patient received antituberculosis treatment with a favorable outcome. Tuberculous chylothorax is an important cause of chylothorax to be considered in endemic areas of tuberculosis. Proper treatment of the infection leads to resolution of the disease.

El quilotórax tuberculoso es una patología infecciosa infrecuente, que se produce como consecuencia del bloqueo del conducto torácico. Su tratamiento está dirigido a combatir la infección tuberculosa. Se presenta el caso de un varón de 55 años de edad, chofer, natural de Trujillo-Perú, que acudió a emergencia por disnea progresiva y tos seca de cinco días de evolución. El examen físico reveló frémito vocal, matidez y murmullo vesicular disminuido en 2/3 inferiores del hemitórax izquierdo. La radiografía y ecografía torácica evidenciaron derrame pleural significativo, y la toracocentesis reveló quilotórax. Posteriormente, se colocó un tubo de drenaje torácico, con disminución progresiva del volumen del líquido pleural y cambios citoquímicos. Se realizó videobroncoscopía diagnóstica con aspirado broncoalveolar, revelando bacilos ácido-alcohol resistentes. El paciente recibió tratamiento antituberculoso, con evolución favorable. El quilotórax tuberculoso constituye una causa importante de quilotórax a considerar en zonas endémicas de tuberculosis. El tratamiento adecuado de la infección, conlleva a resolución de la enfermedad.

Factores de riesgo y displasia broncopulmonar en recién nacidos prematuros de muy bajo peso al nacer / Risk factors and bronchopulmonary dysplasia in very low weight premature infants

Introducción: La displasia broncopulmonar es la secuela más común relacionada con los recién nacidos prematuros de muy bajo peso al nacer, derivada de la inmadurez pulmonar y en algunos casos del tratamiento. Objetivo: Identificar los factores de riesgo maternos y neonatales asociados a displasia broncopulmonar en recién nacidos prematuros de muy bajo peso al nacer. Métodos: La muestra estuvo conformada por 205 recién nacidos prematuros de muy bajo peso al nacer en el Hospital Belén de Trujillo, durante el período 2008-2015. El grupo de casos y el de controles fueron 41 pacientes con diagnóstico de displasia broncopulmonar y 164 pacientes sin diagnóstico de este trastorno respiratorio y que se ajustaran a los criterios de exclusión. Resultados: Los factores de riesgo asociados a displasia broncopulmonar fueron dos o más episodios de sepsis tardía (OR= 5,12; IC95 por ciento: 1,87-14,06), la prematuridad extrema (OR= 4,86; IC95 por ciento: 1,71-13,80), el peso extremadamente bajo al nacer (OR= 2,72; IC95 por ciento: 0,93- 7,94) y la reanimación neonatal (OR= 2,28; IC95 por ciento: 0,89-5,87). Conclusiones: La prematuridad extrema y dos episodios o más de sepsis tardía fueron los factores de riesgo que más se relacionan con la aparición de displasia broncopulmonar en recién nacidos prematuros de muy bajo peso al nacer(AU)

Introduction: Bronchopulmonary dysplasia is the most common sequelae related to very low birth weight premature infants, and it is derived from pulmonary immaturity and in some cases from treatment. Objective: To identify maternal and neonatal risk factors associated with bronchopulmonary dysplasia in very low birth weight premature infants. Methods: The sample was composed of 205 very low birth weight premature infants at Belén of Trujillo Hospital during the period 2008-2015. The group of cases and controls were 41 patients with diagnosis of bronchopulmonary dysplasia and 164 patients with no diagnosis of this respiratory disorder, respectively, and that both groups adjusted with exclusion criteria. Results: Risk factors associated with bronchopulmonary dysplasia were 2 or more episodes of late onset sepsis (OR=5.12; IC95 percent: 1,87-14,06), extreme prematurity (OR= 4.86; IC95 percent: 1.7-13.80), extremely low birth weight (OR= 2.72; IC95 percent: 0.9-7.94) and neonatal resuscitation (OR= 2.28; IC95 percent: 0.89-5.87). Conclusions: Extreme prematurity and 2 or more episodes of late onset sepsis were the most associated risk factors to the onset of bronchopulmonary dysplasia in very low birth weight premature infants(AU)

Factores de riesgo y displasia broncopulmonar en recién nacidos prematuros de muy bajo peso al nacer / Risk factors and bronchopulmonary dysplasia in very low weight premature infants

Introducción: La displasia broncopulmonar es la secuela más común relacionada con los recién nacidos prematuros de muy bajo peso al nacer, derivada de la inmadurez pulmonar y en algunos casos del tratamiento. Objetivo: Identificar los factores de riesgo maternos y neonatales asociados a displasia broncopulmonar en recién nacidos prematuros de muy bajo peso al nacer. Métodos: La muestra estuvo conformada por 205 recién nacidos prematuros de muy bajo peso al nacer en el Hospital Belén de Trujillo, durante el período 2008-2015. El grupo de casos y el de controles fueron 41 pacientes con diagnóstico de displasia broncopulmonar y 164 pacientes sin diagnóstico de este trastorno respiratorio y que se ajustaran a los criterios de exclusión. Resultados: Los factores de riesgo asociados a displasia broncopulmonar fueron dos o más episodios de sepsis tardía (OR= 5,12; IC95 por ciento: 1,87-14,06), la prematuridad extrema (OR= 4,86; IC95 por ciento: 1,71-13,80), el peso extremadamente bajo al nacer (OR= 2,72; IC95 por ciento: 0,93- 7,94) y la reanimación neonatal (OR= 2,28; IC95 por ciento: 0,89-5,87). Conclusiones: La prematuridad extrema y dos episodios o más de sepsis tardía fueron los factores de riesgo que más se relacionan con la aparición de displasia broncopulmonar en recién nacidos prematuros de muy bajo peso al nacer(AU)

Introduction: Bronchopulmonary dysplasia is the most common sequelae related to very low birth weight premature infants, and it is derived from pulmonary immaturity and in some cases from treatment. Objective: To identify maternal and neonatal risk factors associated with bronchopulmonary dysplasia in very low birth weight premature infants. Methods: The sample was composed of 205 very low birth weight premature infants at Belén of Trujillo Hospital during the period 2008-2015. The group of cases and controls were 41 patients with diagnosis of bronchopulmonary dysplasia and 164 patients with no diagnosis of this respiratory disorder, respectively, and that both groups adjusted with exclusion criteria. Results: Risk factors associated with bronchopulmonary dysplasia were 2 or more episodes of late onset sepsis (OR=5.12; IC95 percent: 1,87-14,06), extreme prematurity (OR= 4.86; IC95 percent: 1.7-13.80), extremely low birth weight (OR= 2.72; IC95 percent: 0.9-7.94) and neonatal resuscitation (OR= 2.28; IC95 percent: 0.89-5.87). Conclusions: Extreme prematurity and 2 or more episodes of late onset sepsis were the most associated risk factors to the onset of bronchopulmonary dysplasia in very low birth weight premature infants(AU)

C/EBPδ links IL-6 and HIF-1 signaling to promote breast cancer stem cell-associated phenotypes.

To improve cancer patient outcome significantly, we must understand the mechanisms regulating stem-like cancer cells, which have been implicated as a cause of metastasis and treatment resistance. The transcription factor C/EBPδ can exhibit pro- and anti-tumorigenic activities, but the mechanisms underlying the complexity of its functions are poorly understood. Here we identify a role for breast cancer cell intrinsic C/EBPδ in promoting phenotypes that have been associated with cancer stem cells (CSCs). While C/EBPδ expression is not abundant in most metastatic breast cancers, our data support a pro-tumorigenic role of C/EBPδ when expressed in subsets of tumor cells and/or through transient activation by the tumor microenvironment or loss of substrate adhesion. Using genetic mouse models and human breast cancer cell lines, we show that deletion or depletion of C/EBPδ reduced expression of stem cell factors and stemnness markers, sphere formation and self-renewal, along with growth of tumors and established experimental metastases in vivo. C/EBPδ is also known as a mediator of the innate immune response, which is enhanced by hypoxia and interleukin-6 (IL-6) signaling, two conditions that also play important roles in cancer progression. Our mechanistic data reveal C/EBPδ as a link that engages two positive feedback loops, in part by directly targeting the IL-6 receptor (IL6RA) gene, and, thus, amplifying IL-6 and HIF-1 signaling. This study provides a molecular mechanism for the synergism of tumor microenvironmental conditions in cancer progression with potential implications for the targeting of CSCs.

Organoid Modeling of the Tumor Immune Microenvironment.

In vitro cancer cultures, including three-dimensional organoids, typically contain exclusively neoplastic epithelium but require artificial reconstitution to recapitulate the tumor microenvironment (TME). The co-culture of primary tumor epithelia with endogenous, syngeneic tumor-infiltrating lymphocytes (TILs) as a cohesive unit has been particularly elusive. Here, an air-liquid interface (ALI) method propagated patient-derived organoids (PDOs) from >100 human biopsies or mouse tumors in syngeneic immunocompetent hosts as tumor epithelia with native embedded immune cells (T, B, NK, macrophages). Robust droplet-based, single-cell simultaneous determination of gene expression and immune repertoire indicated that PDO TILs accurately preserved the original tumor T cell receptor (TCR) spectrum. Crucially, human and murine PDOs successfully modeled immune checkpoint blockade (ICB) with anti-PD-1- and/or anti-PD-L1 expanding and activating tumor antigen-specific TILs and eliciting tumor cytotoxicity. Organoid-based propagation of primary tumor epithelium en bloc with endogenous immune stroma should enable immuno-oncology investigations within the TME and facilitate personalized immunotherapy testing.

The Bacterial Community Structure and Microbial Activity in a Traditional Organic Milpa Farming System Under Different Soil Moisture Conditions.

Agricultural practices affect the bacterial community structure, but how they determine the response of the bacterial community to drought, is still largely unknown. Conventional cultivated soil, i.e., inorganic fertilization, tillage, crop residue removal and maize (Zea mays L.) monoculture, and traditional organic farmed soil "milpa," i.e., minimum tillage, rotation of maize, pumpkin (Cucurbita sp.) and beans (Phaseolus vulgaris L.) and organic fertilization were sampled. Both soils from the central highlands of Mexico were characterized and incubated aerobically at 5% field capacity (5%FC) and 100% field capacity (FC) for 45 days, while the C and N mineralization, enzyme activity and the bacterial community structure were monitored. After applying the different agricultural practices 3 years, the organic C content was 1.8-times larger in the milpa than in the conventional cultivated soil, the microbial biomass C 1.3-times, and C and N mineralization 2.0-times (mean for soil incubated at 5%FC and FC). The dehydrogenase, activity was significantly higher in the conventional cultivated soil than in the milpa soil when incubated at 5%FC, but not when incubated at FC. The relative abundance of Gemmatimonadetes was larger in the conventional cultivated soil than in the milpa soil in soil both at 5%FC and FC, while that of Bacteroidetes showed an opposite trend. The relative abundance of other groups, such as Nitrospirae and Proteobacteria, was affected by cultivation technique, but controlled by soil water content. The relative abundance of other groups, e.g., FBP, Gemmatimonadetes and Proteobacteria, was affected by water content, but the effect depended on agricultural practice. For soil incubated at FC, the xenobiotics biodegradation and metabolism related functions were higher in the milpa soil than in the conventional cultivated soil, and carbohydrate metabolism showed an opposite trend. It was found that agricultural practices and soil water content had a strong effect on soil characteristics, C and N mineralization, enzyme activity, and the bacterial community structure and its functionality. Decreases or increases in the relative abundance of bacterial groups when the soil water content decreased, i.e., from FC to 5%FC, was defined often by the cultivation technique, and the larger organic matter content in the milpa soil did not prevent large changes in the bacterial community structure when the soil was dried.

Early synergistic interactions between the HPV16­E7 oncoprotein and 17ß-oestradiol for repressing the expression of Granzyme B in a cervical cancer model.

Although high-risk human papillomavirus (HR­HPV) infection has a prominent role in the aetiology of cervical cancer (CC), sex steroid hormones may also be involved in this process; however, the cooperation between oestrogen and HR­HPV in the early stages of cervical carcinogenesis is poorly understood. Since 17ß-oestradiol (E2) and the HPV type 16­E7 oncoprotein induce CC in transgenic mice, a microarray analysis was performed in the present study to generate global gene expression profiles from 2­month­old FVB (non­transgenic) and K14E7 (transgenic) mice who were left untreated or were treated for 1 month with E2. Upregulation of cancer-related genes that have not been previously reported in the context of CC, including glycerophosphodiester phosphodiesterase domain containing 3, interleukin 1 receptor type II, natriuretic peptide type C, MGAT4 family member C, lecithin-retinol acyltransferase (phosphatidylcholine-retinol-O-acyltransferase) and glucoside xylosyltransferase 2, was observed. Notably, upregulation of the serine (or cysteine) peptidase inhibitor clade B member 9 gene and downregulation of the Granzyme gene family were observed; the repression of the Granzyme B pathway may be a novel mechanism of immune evasion by cancer cells. The present results provide the basis for further studies on early biomarkers of CC risk and synergistic interactions between HR­HPV and oestrogen.

The PDZ-Binding Motif of HPV16-E6 Oncoprotein Modulates the Keratinization and Stemness Transcriptional Profile In Vivo.

OBJECTIVE: The aim of this work was to compare the early gene expression profiles in the skin of HPV16-E6 transgenic mice regulated by the E6 PDZ-binding motif. MATERIALS AND METHODS: The global transcriptional profiles in dorsal skin biopsies from K14E6 and K14E6Δ146-151 transgenic mice were compared using microarrays. Relevant genes obtained from the most differentially expressed processes were further examined by RT-qPCR, in situ RT-PCR, Western blot, or immunofluorescence. RESULTS: The transcriptomic landscape of K14E6 versus K14E6Δ146-151 shows that the most affected expression profiles were those related to keratinocyte differentiation, stem cell maintenance, and keratinization. Additionally, downregulation of epidermal stemness markers such as K15 and CD34, as well as the upregulation of cytokeratin 6b, appeared to be dependent on the E6 PDZ-binding motif. Finally, wound healing, a physiological process linked to stemness, is impaired in the K14E6 mice compared to K14E6Δ146-151. CONCLUSION: The E6 PDZ-binding motif appears to affect stemness and keratinization during early stages of skin carcinogenesis. As E6 plays a significant role in HPV-induced skin carcinogenesis, the K14E6 versus K14E6Δ146-151 transcriptional profile provides a source of valuable data to uncover novel E6 functions in the skin.

Pulmonary alveolar proteinosis: a case report. / Proteinosis alveolar pulmonar: a propósito de un caso.

INTRODUCTION: Pulmonary alveolar proteinosis is a rare, diffuse interstitial lung disease, characterized by alveolar obstruction due to the accumulation of pulmonary surfactant. CLINICAL PRESENTATION: A 30-year-old male with progressively worsening dyspnea and non-productive cough for one year. He was a sugar cane plantation worker and had prior recurrent respiratory infections. Physical exam revealed cyanosis, and bilateral coarse and fine rales. Chest computed tomography showed diffuse crazy paving pattern. Bronchoscopy with bronchoalveolar lavage yielded a foamy, thick whitish material. Cytology revealed lymphocytes and acellular proteinaceous eosinophilic material. Transbronchial biopsy confirmed the diagnosis of pulmonary alveolar proteinosis. Patient met criteria for whole lung lavage, responding favorably to this therapy. CONCLUSION: Pulmonary alveolar proteinosis is a rare lung disease and important to consider due to the diagnostic and therapeutic challenge it represents.

INTRODUCCIÓN: La proteinosis alveolar pulmonar es una enfermedad intersticial difusa poco frecuente, en la cual se produce obstrucción alveolar, debido al acúmulo de surfactante pulmonar. REPORTE DEL CASO: Varón de 30 años de edad, presentó disnea progresiva y tos seca de un año de evolución. Antecedente personal: estibador de caña de azúcar. Presentó infecciones respiratorias recurrentes. Al examen físico se encontró cianosis, crepitantes difusos bilaterales y subcrepitantes en bases pulmonares. En la tomografía torácica con contraste se encontró un patrón de "empedrado loco". Se realizó videobroncoscopia con lavado broncoalveolar, aspirando material lechoso, espumoso y mucoso. Por citología se encontró linfocitos y material eosinofílico proteináceo acelular. El estudio anatomopatológico de la biopsia transbronquial reveló proteinosis alveolar pulmonar. El paciente reunió los criterios para tratamiento con lavado broncoalveolar total. Luego de este procedimiento, evolucionó favorablemente. CONCLUSIÓN: La proteinosis alveolar pulmonar constituye una enfermedad importante a considerar, por el desafío diagnóstico y terapéutico que representa.

Efecto del extracto etanólico de Tropaeolum majus "mastuerzo" sobre la micosis inducida por Trichophyton mentagrophytes en Rattus norvegicus / Effect of the ethanol extract of Tropaeolum majus (cress) upon Trichophyton mentagrophites-induced mycosis in Rattus norvegicus

Objetivo: Determinar el efecto del extracto etanólico de Tropaeolum majus "mastuerzo" sobre la micosis inducida por Trichophyton mentagrophytes (TM) en Rattus norvegicus (RN). Materiales y métodos: Experimental aleatorizado, incluyó 21 especímenes RN machos, a los cuales se les indujo una infección micótica mediante modelo de infección superficial en piel; posteriormente al desarrollo de esta, se dividieron aleatoriamente en tres grupos de 7 especímenes cada uno; siendo tratados con placebo (Grupo I), ungüento preparado con el extracto etanólico de Tropaeolum majus "mastuerzo" al 0,4% (grupo II) y Terbinafina al 1% (grupo III), durante 30 días consecutivos, respectivamente. Se realizó un examen clínico de signos y síntomas presentes en las micosis de piel, evaluados a través de una escala arbitraria cualitativa ordinal adaptada para este estudio, asimismo, de estudio micológico con KOH al 20% y por cultivo en Agar Dextrosa Sabouraud para confirmar la dermatofitosis antes y después del tratamiento. Resultados: El Grupo II presentó disminución significativa de los signos clínicos omparado con el Grupo I (p =0,001), mientras que al compararlo con el Grupo III se obtuvo una evolución clínica positiva para ambos grupos (p =0,05). Conclusión: El extracto etanólico de Tropaeolum majus "mastuerzo" posee un efecto antimicótico sobre la micosis inducidapor TM en RN (p <0,05), pudiendo ser una alternativa segura para tratamiento tópico de tiña

Objective: To determine the effect of the ethanol extract of Tropaeolum majus (cress) upon Trichophyton mentagrophites (TM) - induced tinea in Rattus norvegicus (RN). Materials and methods: This is an experimental randomized trial which included 21 male RN specimens, who were induced a superficial fungal infection; after the infection had developed, the animals were randomly divided in three 7-individual groups; Group I received placebo, Group II received an ointment prepared with a 0.4% ethanol extract of Tropaeolum majus (cress), and Group III received 1% terbinafine during 30 consecutive days, respectively. A clinical exam looking for signs and symptoms present in skin fungal infections was performed, using an arbitrary qualitative ordinal scale that was adapted for this trial. Also, laboratory exams were performed: direct examination of skin samples with 20% KOH, and dextrose-Sabouraud agar cultures in order to confirm the presence of superficial fungal infections before and after therapy. Results: Group II showed a significant reduction of clinical findings compared with Group I (p=0.001), while when compared with Group III, a positive clinical outcome was found in both groups (p=0.05). Conclusion: The ethanol extract of Tropaeolum majus (cress) has antifungal action upon TM-induced tinea in RN (p<0.05), and it may be considered as a safe option for the therapy of tinea

Runx Genes in Breast Cancer and the Mammary Lineage.

A full understanding of RUNX gene function in different epithelial lineages has been thwarted by the lethal phenotypes observed when constitutively knocking out these mammalian genes. However temporal expression of the Runx genes throughout the different phases of mammary gland development is indicative of a functional role in this tissue. A few studies have emerged describing how these genes impact on the fate of mammary epithelial cells by regulating lineage differentiation and stem/progenitor cell potential, with implications for the transformed state. The importance of the RUNX/CBFß core factor binding complex in breast cancer has very recently been highlighted with both RUNX1 and CBFß appearing in a comprehensive gene list of predicted breast cancer driver mutations. Nonetheless, the evidence to date shows that the RUNX genes can have dualistic outputs with respect to promoting or constraining breast cancer phenotypes, and that this may be aligned to individual subtypes of the clinical disease. We take this opportunity to review the current literature on RUNX and CBFß in the normal and neoplastic mammary lineage while appreciating that this is likely to be the tip of the iceberg in our knowledge.