C-terminus of serine–arginine protein kinase-like protein, SrpkF, is involved in conidiophore formation and hyphal growth under salt stress in Aspergillus aculeatus / El extremo C de la proteína similar a la serina-arginina proteína quinasa, SrpkF, participa en la formación de conidióforos y el crecimiento de hifas bajo estrés salino en Aspergillus aculeatus

The serine–arginine protein kinase–like protein, SrpkF, was identified as a regulator for the cellulose-responsive induction of cellulase genes in Aspergillus aculeatus. To analyze various aspects of SrpkF function, we examined the growth of the control strain (MR12); C-terminus deletion mutant, which produced SrpkF1–327 (ΔCsrpkF); whole gene-deletion mutant of srpkF (ΔsrpkF), srpkF overexpressing strain (OEsprkF); and the complemented strain (srpkF+) under various stress conditions. All test strains grew normally on minimal medium under control, high salt (1.5 M KCl), and high osmolality (2.0 M sorbitol and 1.0 M sucrose). However, only ΔCsrpkF showed reduced conidiation on 1.0 M NaCl media. Conidiation of ΔCsrpkF on 1.0 M NaCl media was reduced to 12% compared with that of srpkF+. Further, when OEsprkF and ΔCsrpkF were pre-cultured under salt stress conditions, germination under salt stress conditions was enhanced in both strains. By contrast, deletion of srpkF did not affect hyphal growth and conidiation under the same conditions. We then quantified the transcripts of the regulators involved in the central asexual conidiation pathway in A. aculeatus. The findings revealed that the expression of brlA, abaA, wetA, and vosA was reduced in ΔCsrpkF under salt stress. These data suggest that in A. aculeatus, SrpkF regulates conidiophore development. The C-terminus of SrpkF seems to be important for regulating SrpkF function in response to culture conditions such as salt stress.(AU)

PSTPIP2 is associated with disease severity in patients with pressure ulcer sepsis and has anti-inflammatory effects

Background: One of the common adverse reactions in patients with pressure ulcers (PU) is sepsis, which is mainly related to microbial infections caused by pathogenic organisms. The activation of nuclear factor kappa-B (NF-κB) frequently occurs in conjunction with pathogenic microbial infections. Proline-serine-threonine-phosphatase-interacting protein 2 (PSTPIP2) is closely related to inflammatory disorders. The role and mechanism of PSTPIP2 in sepsis because of pressure ulcers is unclear. In this study, we discovered that PSTPIP2 was lowly expressed in peripheral blood of patients with sepsis induced by pressure ulcers. Methods: Peripheral blood was collected from 20 patients with sepsis due to pressure ulcers and 10 healthy controls, and the expression of PSTPIP2 in peripheral blood was discovered by polymerase chain reaction and Western blot analysis. Information on the clinical characteristics of patients was summarized, and the expression data of PSTPIP2 were correlated with the patients’ acute physiology and chronic health evaluation (APACHE) II score, sequential organ failure assessment (SOFA) score, and C-reactive protein (CRP) and procalcitonin (PCT) scores by Spearman’s correlation analysis. One of the main mediators of Gram-negative sepsis is lipopolysaccharide (LPS). In order to establish an in vitro sepsis model, THP-1 cells were treated with LPS, and the cells were transfected with PSTPIP2. Contents of interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor-α (TNF-α) in each group of cells were detected by enzyme-linked--immunosorbent serologic assay, and NF-κB-related proteins were detected by Western blot analysis (AU)

Glutamine inhibits inflammation, oxidative stress, and apoptosis and ameliorates hyperoxic lung injury

Glutamine (Gln) is the most widely acting and abundant amino acid in the body and has anti-inflammatory properties, regulates body metabolism, and improves immune function. However, the mechanism of Gln’s effect on hyperoxic lung injury in neonatal rats is unclear. Therefore, this work focused on examining Gln’s function in lung injury of newborn rats mediated by hyperoxia and the underlying mechanism. We examined body mass and ratio of wet-to-dry lung tissue weights of neonatal rats. Hematoxylin and eosin (HE) staining was performed to examine histopathological alterations of lung tissues. In addition, enzyme-linked immunoassay (ELISA) was conducted to measure pro-inflammatory cytokine levels within bronchoalveolar lavage fluid (BALF). Apoptosis of lung tissues was observed using TUNEL assay. Western blotting was performed for detecting endoplasmic reticulum stress (ERS)-associated protein levels. The results showed that Gln promoted body weight gain, significantly reduced pathological damage and oxidative stress in lung tissue, and improved lung function in neonatal rats. Gln reduced pro-inflammatory cytokine release as well as inflammatory cell production in BALF and inhibited apoptosis in lung tissue cells. Furthermore, we found that Gln could downregulate ERS-associated protein levels (GRP78, Caspase-12, CHOP) and inhibit c-Jun N-terminal kinase (JNK) and inositol-requiring enzyme 1 alpha (IRE1α) phosphorylation. These results in an animal model of bronchopulmonary dysplasia (BPD) suggest that Gln may have a therapeutic effect on BPD by reducing lung inflammation, oxidative stress, and apoptosis and improving lung function; its mechanism of action may be related to the inhibition of the IRE1α/JNK pathway. (AU)

Hypoxia promotes epithelial mesenchymal transition in lung cancer cells via regulating the MIR271 BUB1 pathway

Purpose Lung cancer (LC) is the most common malignancy in the world. It is well that hypoxia is common in lung cancer, which contributes to lung cancer progression and metastasis [1]. miRNA-27a as a repressor factor is a lowly expression within non-small cell lung cancer (NSCLC). However, the molecular mechanism between miR-27a and hypoxia in lung cancer progression remains poorly understood. This study aims to explore hypoxia promotes epithelial-mesenchymal transition in lung cancer cells via regulating the NRF2/miR‑27a/BUB1 pathway. Methods We detect the expression of miR-27a after exposure to hypoxia conditions in lung cancer cells via qPCR. Using MTT assay and colony assay to assess the ability of proliferation in lung cancer cells under hypoxia or transfect miR-27a mimics. The capability of migration and invasion was evaluated by wound healing assay and Boyden-chamber assay. The mRNA and protein expression of EMT markers was respectively detected by qPCR and western blot. We detected NRF2 occupancy at the miR-27a promoter by ChIP-Seq analysis. Meanwhile, the luciferase assay verified BUB1 as a direct target of miR-27a. Results We found hypoxia promotes lung cancer cell proliferation, migration, invasion, and the epithelial-mesenchymal transition (EMT) process by inhibiting the miR-27a expression. miR-27a mimics significantly reduced the promotion effect of hypoxia on the invasion and proliferation of lung cancer cells. NRF2 as regulating the oxidation/anti-oxidation factor was activated under hypoxia conditions. The activation of NRF2 repressed miR-27a expression. On the contrary, the inhibitory effect of hypoxia on miR-27a was reversed when the NFE2L2 gene was silenced. Ectopic expression of NRF2 inhibited miR-27a expression under normoxia. We further validated BUB1 as a direct target of the miR-27a by luciferase assay. Conclusion Hypoxia promotes invasion and epithelial-mesenchymal transition of Lung cancer cells by regulating the NRF2/miR-27a/BUB1 axis (AU)

NIMA-related kinase-6 (NEK6) as an executable target in cancer

Cancer is a disease that develops when cells begin to divide uncontrollably and spreads to other parts of the body. Proliferation and invasion of cancerous cells are generally known to be influenced by cell cycle-related proteins in human malignancies. Therefore, in this review, we have emphasized on the serine/threonine kinase named NEK6. NEK6 is been deliberated to play a critical role in mitosis progression that includes mitotic spindle formation, metaphase to anaphase transition, and centrosome separation. Moreover, it has a mechanistic role in DNA repair and can cause apoptosis when inhibited. Past studies have connected NEK6 protein expression to cancer cell senescence. Besides, there are reports relating NEK6 to a range of malignancies including breast, lung, ovarian, prostate, kidney, liver, and others. Given its significance, this review attempts to describe the structural and functional aspects of NEK6 in various cellular processes, as well as how it is linked to different forms of cancer. Lastly, we have accentuated, on some of the plausible inhibitors that have been explored against NEK6 overexpression (AU)

Resveratrol inhibits TGF-B1-induced EMT in gastric cancer cells through Hippo-YAP signaling pathway

To investigate the effects of resveratrol (RSVL) on epithelial-mesenchymal transition (EMT) and biological behaviors of gastric cancer cells.MethodsSGC-7901 cells were treated with RSVL, followed by TGF-β1 treatment for induction of EMT. Cell proliferation was tested by MTT assay, migration and invasion by Transwell and scratch assays, and Hippo-YAP signaling pathway activation by immunofluorescence. The RNA and protein expressions of E-cadherin, Vimentin, N-cadherin, and Snail were detected by qPCR and Western blot. A tumor model was constructed to examine the effect of RSVL on gastric tumor growth.ResultsRSVL inhibited the migration, invasion, and growth of gastric cancer cells in concentration- and time-dependent manners. RSVL inhibited TGF-β1-induced EMT of gastric cancer cells, which might relate to inactivation of the Hippo-YAP pathway. In the mouse tumor model, RSVL inhibited the EMT process by suppressing the Hippo-YAP pathway.ConclusionRSVL inhibited EMT of gastric cancer cells probably by weakening the Hippo-YAP signaling pathway. (AU)

CDC7 as a novel biomarker and druggable target in cancer

Due to the bottlenecks encountered in traditional treatment for tumor, more effective drug targets need to be developed. Cell division cycle 7 kinase plays an important role in DNA replication, DNA repair and recombination signaling pathways. In this review, we first describe recent studies on the role of CDC7 in DNA replication in normal human tissues, and then we integrate new evidence focusing on the important role of CDC7 in replication stress tolerance of tumor cells and its impact on the prognosis of clinical oncology patients. Finally, we comb through the CDC7 inhibitors identified in recent studies as a reference for further research in clinical practice. (AU)

MiR-92 overexpression suppresses immune cell function in ovarian cancer via LATS2/YAP1/PD-L1 pathway

Purpose Increasing evidence suggested that microRNA plays an important role in ovarian cancer. In this study, the role of miR-92 in ovarian cancer was investigated. Methods In this study, miR-92 expression in clinical sample was evaluated, role of miR-92 was investigated in vitro, and underlying mechanism was investigated using Chip, co-IP, and western blot. Results In this study, we show that miR-92 is overexpressed in ovarian cancer tissue compared with normal cancer tissue. Transfection of miR-92 increased proliferation of ovarian cancer cell, and increased migration capacity and colony formation were observed after miR-92 transfection; we found that expression of LATS2 was decreased by miR-92, and this was further confirmed by luciferase assay, which proved that miR-92 is targeting 3′ of the endogenous LATS2 gene. Downregulation of LATS2 resulted in increased translocation of YAP1 and upregulation of PD-L1, which subsequently suppressed NK cell function and promoted T cell apoptosis. Moreover, co-transfection of YAP1-targeted shRNA could relieve miR-92-induced immune suppression effect. Mechanically, immunoprecipitation (IP) was used to show that LATS2 interacted with YAP1 and subsequently limited nuclear translocation of YAP1; chromatin immunoprecipitation (ChIP) was used to confirm that YAP1 could bind to enhancer region of PD-L1 to enhance transcription activity of PD-L1. Conclusions Our data revealed a novel mechanism which finally resulted in immune suppression in ovarian cancer (AU)

Characteristics of adverse drug reactions in a vemurafenib early post-marketing phase vigilance study in Japan

Background. Post-approval research or monitoring is important to determine real-world safety of new products; however, evidence is scant for vemurafenib in Japanese patients. In Japan, a unique system is officially obligated to investigate post-approval safety. Here we report the first adverse drug reaction (ADR) data from vemurafenib-treated Japanese patients with metastatic melanoma. Data were collected in an early post-marketing phase vigilance (EPPV) study. Methods. ADRs were events for which a causal relationship with vemurafenib could not be ruled out or was unknown. ADR data were collected for patients treated with vemurafenib (960 mg bid) between 26 February and 25 August 2015. Results. Among 95 patients, 46 patients had 118 ADRs (24 serious ADRs in 13 patients). The most common serious ADRs were hypersensitivity (n = 1; 3 events), arthralgia (n = 2; 2 events), pyrexia (n = 2; 2 events) and drug eruption (n = 2; 2 events). Seven patients had serious skin disorders or hypersensitivity, six of whom had prior anti-programmed cell death-1 (PD-1) antibodies 5-35 days before starting vemurafenib. ADR reports of serious skin disorders appeared to be collected more rapidly than previously reported. Cutaneous squamous cell carcinoma developed in only one patient. Conclusions. EPPV in Japanese vemurafenib-treated patients identified no new safety signals. The most serious skin and hypersensitivity ADRs occurred in patients with prior anti-PD-1 exposure. Cutaneous squamous cell carcinoma appeared to be rare in Japanese patients. Further research is needed to clarify whether prior treatment with anti-PD-1 agents or racial differences affect the characteristic profile of cutaneous ADRs in Japanese patients (AU)

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Síndrome de genes contiguos TSC2/PKD1 / TSC2/PKD1 contiguous gene síndrome

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Leucine supplementation at the onset of high-fat feeding does not prevent weight gain or improve glycemic regulation in male Sprague-Dawley rats

Obesity is a major public health concern and it is essential to identify effective treatments and preventative strategies to stop continued increases in obesity rates. The potential functional roles of the branched chain amino acid leucine make this amino acid an attractive candidate for the treatment and/or prevention of obesity. The objective of this study was to determine if long-term leucine supplementation could prevent the development of obesity and reduce the risk factors for chronic disease in rats fed a high-fat (60 % fat) diet. Male Sprague-Dawley rats (n = 30 per dietary treatment) were meal-fed (3 meals/day) either a control, low-fat diet (LF), control + leucine (LFL), high-fat (HF), or high-fat + leucine (HFL) for 42 days. On day 42, rats were sacrificed at 0, 30, or 90 min postprandial. Animals fed the HF and HFL diets had higher (P < 0.05) final body weights and weight gain compared to animals fed the LF and LFL diets. Leucine supplementation increased epididymal fat mass (P < 0.05) and decreased muscle mass (P < 0.05). There was no effect of leucine supplementation on postprandial glucose or insulin response. However, there was a significant effect (P < 0.05) of diet and time on free fatty acid concentrations. There was no effect of leucine on muscle markers of protein synthesis (4E-BP1, p70S6K) or energy metabolism (Akt, AMPK). Leucine supplementation decreased (P < 0.05) PGC1α expression and increased (P < 0.05) PPARγ expression in skeletal muscle. In conclusion, long-term leucine supplementation does not prevent weight gain, improve body composition, or improve glycemic control in rats fed a high-fat diet (AU)

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Methylation of the DCLK1 promoter region in circulating free DNA and its prognostic value in lung cancer patients

Introduction: The possibility of detection of suppressor genes methylation in circulating free DNA (cf-DNA) of cancer patients and the lack of methylation in healthy individuals makes this epigenetic alternation an ideal diagnostic marker of neoplastic processes. Moreover, hypermethylation in several genes promoter was described as a biomarker of lung cancer. Methylation in the gene encoding doublecortin-like kinase 1 (DCLK1) is observed in patients with colorectal cancer and cholangiocarcinoma. However, there are no studies concerning DCLK1 methylation in lung cancer patients. The aims of the study was to evaluate the frequency of DCLK1 promoter methylation in cf-DNA of lung cancer patients and of healthy persons as well as the usefulness of this test for predicting the lung cancer course. Materials and methods: DCLK1 methylation status was evaluated in DNA isolated from peripheral blood plasma from 65 lung cancer patients and 95 healthy individuals. After DNA bisulfitation, DCLK1 methylation was determined using the qMSP-PCR technique. Moreover, the presence of DCLK1 methylation was correlated with the overall survival (OS) probability of lung cancer patients. Results: DCLK1 promoter methylation was detected in 32 lung cancer patients (49.2 %) and 8 healthy individuals (8.4 %). The methylation of the region before transcription start site (TSS) and the region after TSS of DCLK1 gene was detected in 28 and 11 patients, respectively. In seven cases (10.8 %), the DCLK1 promoter methylation in both regions was reported simultaneously. The methylation was observed slightly frequently in patients with small cell lung cancer (75 % of SCLC patients). The median overall survival of patients with DCLK1 promoter methylation was lower than that of patients without DCLK1 gene modification (p = < 0.001, HR = 4.235). Conclusions: The evaluation of DCLK1 promoter region methylation may be useful in both early diagnosis and prediction of the course of lung cancer (AU)

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Association between TGFBR2 gene polymorphisms and congenital heart defects in Han Chinese population / Asociación entre polimorfismos del gen TGFBR2 y defectos congénitos del corazón en la población China Han

Background: Transforming growth factor-β receptor II (TGFBR2) is a key component of TGF-β signaling pathway. TGFBR2 can be detected in the generation of heart. The mouse embryos of TGFBR2 gene knockout exhibited congenital heart defects. Methods: We conducted a case-control study to investigate the association between TGFBR2 gene polymorphisms and congenital heart defects in Han Chinese population. 125 patients with congenital heart defects and 615 unrelated controls were recruited. Two tagging single nucleotide polymorphisms (tagSNPs) in 5' upstream of TGFBR2 gene (rs6785358, -3779A/G; rs764522, -1444C/ G) were selected and genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assay. Results: A significant difference was seen in the distribution of genotypes between patients with congenital heart defects and controls for SNP rs6785358 (P=0.043). For SNP rs6785358 the carrier of the G allele (AG/GG genotype) showed a significantly higher risk of congenital heart defects compared with AA homozygotes (OR=1.545, 95% CI: 1.013-2.356). Further analysis by sex stratification indicated that individuals carrying G allele (AG/GG genotype) for SNP rs6785358 have a higher susceptibility to congenital heart defects (OR=2.088, 95%CI: 1.123-3.883, P=0.019) in males, but not females (OR=1.195, 95%CI: 0.666-2.146, P=0.55). No statistical significance was detected in the distribution of genotypes and allele frequencies for SNP rs764522 between patients and controls. Conclusion: Our result suggested that SNP rs6785358 of TGFBR2 gene was associated with increased risk of congenital heart defects in Han Chinese men and further research would be warranted (AU)

Antecedentes: Factor de crecimiento transformante β receptor II (TGFBR2) es un componente clave de la via de señalización de TGF - β.TGFBR2 puede ser detectado en la generación de corazón. Los embriones de ratón de TGFBR2 gene knockout mostraron defectos congénitos del corazon. Métodos: Hemos realizado un estudio de casos y controles para investigar la asociación entre polimorfismos del gen TGFBR2 y defectos congénitos del corazón en la población china han. 125 pacientes con defectos congénitos del corazón y 615 unrelated controles fueron reclutados. Marcado de dos polimorfismos de nucleótido único (tagsnps) en 5 'aguas arriba del gen TGFBR2 (rs6785358, - 3779a / g; rs764522, - 1444c / g) fueron seleccionados y genotipados por reacción en cadena de la polimerasa (PCR) - polimorfismos de longitud de fragmentos de restricción (RFLP) de ensayo. Resultados: Se observó una diferencia significativa en la distribución de genotipos entre pacientes con defectos congénitos del corazón y controles para SNP rs6785358 (P = 0043). La SNP rs6785358 el porteador del alelo G (AG / GG genotipo) mostraron un importante crecimiento y mayor riesgo de defectos congénitos del corazón en comparación con AA homocigotos (OR = 1.545, IC del 95%:1.013-2.356). Más análisis por sexo estratificación indicó que los individuos con alelo G (AG / GG genotipo) para SNP rs6785358 tienen una mayor susceptibilidad a defectos congénitos del corazón (OR = 2.088, IC del 95%: 1.123-3.883, p = 0.019) en machos, pero no en las mujeres (OR = 1.195, IC del 95%: 0.666-2.146, p = 0.55). No hay significación estadística fue detectado en la distribución de los genotipos y frecuencias de alelos de SNP rs764522 entre pacientes y controles. Conclusión: Nuestros resultados sugieren que el SNP rs6785358 de gen TGFBR2 se asoció con un mayor riesgo de defectos congénitos del corazón en los chinos han hombres y más investigación estaría justificada (AU)

The expression of Nek7, FoxM11, and Plk1 in gallbladder cancer and their relationships to clinicopathologic features and survival

PURPOSE: Gallbladder carcinoma (GC) is generally considered as a relatively rare malignancy with poor prognosis. In order to guide clinicians in selecting suitable treatment for GC patients, reliable markers predictive of poor clinical outcome are desirable. This study analyzed the expression of Polo-like kinase 1 (Plk1), Nima related kinases 7 (Nek7) and Forkhead box M1 (FoxM1) in GC tissues and their relationship to clinicopathologic features and survival. METHODS: We immunohistochemically investigated the 76 specimens of gallbladder carcinoma, pericarcinoma and normal tissues using Nek7, FoxM1 and Plk1 antibodies and analyzed the overall survival time of these 76 patients. RESULTS: There were significant correlations between the high level expression of Nek7, FoxM1 and Plk1 and the tumor differentiation, Nevin staging and metastasis. The high level expression of Nek7, FoxM1 and Plk1 was significantly associated with shorter overall survival time in univariate analysis (log-rank test), also identified as an independent prognostic factor in multivariate analysis. CONCLUSION: Nek7, FoxM1 and Plk1 were significantly associated with certain clinicopathologic indices in GC. Evaluation of Nek7, FoxM1 and Plk1 expression may be an important factor in identifying a group of poor GC prognosis (AU)

CHECK2 c.1100delC mutation among non-BRCA ½ Spanish hereditary breast cancer families

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Presencia de la mutación BRAF T1799A en el tumor primario como indicador de riesgo, recidiva o persistencia de carcinoma papilar de tiroides / BRAF T1799. A mutation in the primary tumor as a marker of risk, recurrence, or persistence of papillary thyroid carcinoma

Antecedentes y objetivo. La mutación BRAFT1799A se ha relacionado con características tumorales de más agresividad, recidiva tumoral y persistencia de carcinoma papilar de tiroides (CPT), aunque no todos los estudios apoyan esta asociación. En éste, se analiza la asociación entre la presencia de la mutación BRAFT1799A en el tumor primario de pacientes con CPT y las características clinicopatológicas de riesgo, recidiva y persistencia tumoral. Pacientes, material y método. Hemos seguido a 97 pacientes intervenidos de CPT durante una mediana de 64,1 meses. La mutación BRAFT1799A se determinó en ácido desoxirribonucleico procedente de muestras de la tiroidectomía inicial mediante amplificación por PCR del exón 15 del gen braf y análisis de los fragmentos de restricción con la enzima TspRI. Los casos positivos fueron confirmados por secuenciación. La asociación estadística entre la mutación BRAFT1799A y las diferentes variables se estudió mediante los correspondientes tests de contraste de hipótesis más regresión logística. Resultados. El 46,4% de los pacientes eran positivos para la mutación BRAFT1799A. Tras análisis bivariante y multivariante, la mutación BRAFT1799A sólo se asociaba con edad superior a 60 años (odds ratio [OR] = 5,5; intervalo de confianza [IC] del 95%, 1,4-21,9; p=0,019) y tamaño de 1cm o superior (OR=3,6; IC del 95%, 1,2-10,3; p=0,016). No se asociaba con subtipos histológicos, metástasis, recidiva, necesidad de nuevos tratamientos ablativos con I131 o de otras intervenciones quirúrgicas debidas a la aparición de metástasis o persistencia de enfermedad al final del seguimiento. Conclusiones. La mutación BRAFT1799A está asociada a edad superior a 60 años y tamaño tumoral de 1cm o mayor, pero no con otras características clinicopatológicas, recidiva tumoral o persistencia de enfermedad (AU)

Background and objective. The BRAFT1799A mutation is reported to be associated to aggressive, persistent, and recurrent tumor in papillary thyroid carcinoma (PTC) patients. Association of the BRAFT1799A mutation in the primary tumor with the clinicopathological characteristics of PTC patients was analyzed. Patients, material and methods. Ninety-seven PTC patients were followed up for a median of 64.1 months. The BRAFT1799A mutation was analyzed in DNA from initial thyroidectomy biopsies by PCR amplification and restriction fragment length polymorphism using TspRI enzyme. Positive cases were confirmed by DNA sequencing. Statistical association between BRAFT1799A mutation and clinicopathological characteristics was analyzed by the relevant hypothesis tests and logistic regression. Results. 46.4% of patients were positive for the BRAFT1799A mutation. Bivariate and multivariate analysis showed the BRAFT1799A mutation to be only associated to age over 60 years (odds ratio [OR] = 5.5; 95% confidence interval [CI],1.4-21.9; p=0.019) and to tumor size of 1cm or greater (OR=3.6, 95% CI, 1.2-10.3; p=0.016). The BRAFT1799A mutation was not associated to histological subtype, metastasis, recurrence, more aggressive treatments (ablative I131 therapy or surgery), or PTC persistence at the end of follow-up. Conclusions. The BRAFT1799A mutation is associated to age over 60 and a tumor size of 1cm or greater, but not to other clinicopathological characteristics, tumor recurrence or PTC persistence (AU)

Cot/Tpl2 regulates IL-23 p19 expression in LPS-stimulated macrophages through ERK activation

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We have previously reported that a serine/threonine protein kinase, Cot/Tpl2, is a negative regulatorof Th1-type immunity through inhibiting IL-12 expression in antigen presenting cells (APCs)stimulated by Toll-like receptor (TLR) ligands. We here show that Cot/Tpl2-/- macrophages produce significantly less IL-23, an important regulator of Th17-type response, than the wild-type counterparts in response to lipopolysaccharide (LPS), which is a ligand for TLR4. The decreased IL-23 production in Cot/Tpl2-/- macrophages is, at least partly, regulated at the transcriptional level, as the LPS-mediated IL-23 p19 mRNA induction was significantly less in Cot/Tpl2-/- macrophages. Chemical inhibition of extracellular signal-regulated kinase (ERK) activity similarly inhibited IL-23 expression inLPS-stimulated wild-type macrophages. As Cot/Tpl2 is an essential upstream component of theERK activation pathway of LPS, it is suggested that Cot/Tpl2 positively regulates IL-23 expression through ERK activation. These results indicate that Cot/Tpl2 may be involved in balancing Th1/Th17 differentiation by regulating the expression ratio of IL-12 and IL-23 in APCs (AU)

Molecular basis for the treatment of renal cell carcinoma

Renal cell carcinoma (RCC) is a heterogeneous malignancy whose incidence rate has notably increased in recent years without any evident reason. Traditionally, RCC has been resistant to classic treatments (chemotherapy, radiotherapy and hormonal therapy), with only a small percentage of patients benefiting from cytokine therapy. Different hereditary syndromes have been associated with RCC, Von Hippel Lindau (VHL) being the most important syndrome. Understanding key molecular pathways implicated in the tumorigenesis of RCC has crystallised in the development of more effective therapies. Specifically, drugs targeting VEGF (bevacizumab, sunitinib, sorafenib, axitinib, pazopanib) and PI3K-mTOR (temsirolimus and everolimus) have become the cornerstone of renal cancer treatment (AU)

Aurora kinase inhibitors: a new class of drugs targeting the regulatory mitotic system

The present review gives a perspective on the Aurora kinase family members, their function in normal cells, their role in cancer progression as well as their potential as target for anticancer treatment. Mitosis has been an important target for anticancer therapy development, leading to some specific drugs mainly addressing Tubulines, as a key structure of the mitotic spindle. Vinca alkaloids, taxanes or epotilones are good examples of conventionally developed antimitotic agents. However, novel classes of antineoplastic drugs are being studied, targeting the regulatory system that controls functional aspects of mitosis, such as Aurora or Polo-like kinases or Kinespondin inhibitors. The specific role of the different Aurora kinase proteins as regulator enzymes of the mitotic process in normal cells is discussed. Some of the mechanisms that link Aurora overexpression with cancer are also considered. Thereafter, the clinical and preclinical development of the different Aurora kinase inhibitors is presented. This is nowadays a very active area of therapeutic research and at least, sixteen new compounds are being studied as potential antineoplastic drugs. Most of them are in a very early phase of clinical development. However, we summarized the most recently published findings related with these drugs: main characteristics, way of administration, dose limiting toxicities and recommended doses for further studies. Another important aspect in Aurora kinase inhibition is the study and validation of potential biomarkers to optimize the clinical development. Several studies included pharmacodynamic assessments in normal blood cells, skin or/and tumor biopsies. Several proposals included a higher mitotic index, a decreased number of mitosis with bipolar spindles or normal alignment of chromosomes and inhibition of histone H3 phosphorylation. Future strategies and challenges for trials with Aurora kinase inhibitors are also discussed (AU)

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