X Chromosome Inactivation during Grasshopper Spermatogenesis.

Regulation of transcriptional activity during meiosis depends on the interrelated processes of recombination and synapsis. In eutherian mammal spermatocytes, transcription levels change during prophase-I, being low at the onset of meiosis but highly increased from pachytene up to the end of diplotene. However, X and Y chromosomes, which usually present unsynapsed regions throughout prophase-I in male meiosis, undergo a specific pattern of transcriptional inactivation. The interdependence of synapsis and transcription has mainly been studied in mammals, basically in mouse, but our knowledge in other unrelated phylogenetically species is more limited. To gain new insights on this issue, here we analyzed the relationship between synapsis and transcription in spermatocytes of the grasshopper Eyprepocnemis plorans. Autosomal chromosomes of this species achieve complete synapsis; however, the single X sex chromosome remains always unsynapsed and behaves as a univalent. We studied transcription in meiosis by immunolabeling with RNA polymerase II phosphorylated at serine 2 and found that whereas autosomes are active from leptotene up to diakinesis, the X chromosome is inactive throughout meiosis. This inactivation is accompanied by the accumulation of, at least, two repressive epigenetic modifications: H3 methylated at lysine 9 and H2AX phosphorylated at serine 139. Furthermore, we identified that X chromosome inactivation occurs in premeiotic spermatogonia. Overall, our results indicate: (i) transcription regulation in E. plorans spermatogenesis differs from the canonical pattern found in mammals and (ii) X chromosome inactivation is likely preceded by a process of heterochromatinization before the initiation of meiosis.

Omics Approaches in Pancreatic Adenocarcinoma.

Pancreatic ductal adenocarcinoma, which represents 80% of pancreatic cancers, is mainly diagnosed when treatment with curative intent is not possible. Consequently, the overall five-year survival rate is extremely dismal-around 5% to 7%. In addition, pancreatic cancer is expected to become the second leading cause of cancer-related death by 2030. Therefore, advances in screening, prevention and treatment are urgently needed. Fortunately, a wide range of approaches could help shed light in this area. Beyond the use of cytological or histological samples focusing in diagnosis, a plethora of new approaches are currently being used for a deeper characterization of pancreatic ductal adenocarcinoma, including genetic, epigenetic, and/or proteo-transcriptomic techniques. Accordingly, the development of new analytical technologies using body fluids (blood, bile, urine, etc.) to analyze tumor derived molecules has become a priority in pancreatic ductal adenocarcinoma due to the hard accessibility to tumor samples. These types of technologies will lead us to improve the outcome of pancreatic ductal adenocarcinoma patients.

Therapeutic relevance of SOX9 stem cell factor in gastric cancer.

INTRODUCTION: Recent comprehensive genetic and molecular profiling has identified molecular subtypes of gastric cancer (GC) and has linked them to clinical information. Moreover, SOX9 has been recently described as a relevant regulator of the population of GC stem cells (gCSCs), which are responsible for GC initiation and progression. Areas covered: Through public data from The Cancer Genome Atlas (TCGA) project, the Asian Cancer Research Group (ACRG) and published studies, we link SOX9 expression to GC clinical information and molecular subtypes. We also discuss the role of deregulated SOX9 activity in critical aspects of GC progression, as well as therapy resistance. Finally, we provide information of the molecular mechanisms associated with its oncogenic activity. Expert opinion: This review presents the clinical impact of SOX9 in GC and underscores the molecular mechanisms associated with its oncogenic activity. Current evidence highlights the key function of SOX9 in GC and postulates it as a prognostic factor, novel biomarker for patient stratification and a promising target. gCSCs are critical targets for GC eradication and SOX9 is a regulator of gCSCs; hence, the inhibition of SOX9 is a potential therapeutic strategy for GC, particularly for the MSS/TP53+ subgroup of patients in whom SOX9 expression correlates with poor outcome.

Towards precision medicine: linking genetic and cellular heterogeneity in gastric cancer.

Molecular and cellular heterogeneity are phenomena that are revolutionizing oncology research and becoming critical to the idea of personalized medicine. Recent comprehensive molecular profiling has identified molecular subtypes of gastric cancer (GC) and linked them to clinical information. Moreover, GC stem cells (gCSCs) have been identified and found to be responsible for GC initiation and progression, Helicobacter pylori oncogenic action and therapy resistance. Addressing molecular heterogeneity is critical for achieving an optimal therapeutic approach against GC as well as targeting gCSCs. In this review, we outline the implications of molecular and cellular heterogeneity in the treatment of GC and we summarize the clinical impact of the most important regulators of gCSCs.

Gemcitabine-erlotinib versus gemcitabine-erlotinib-capecitabine in the first-line treatment of patients with metastatic pancreatic cancer: Efficacy and safety results of a phase IIb randomised study from the Spanish TTD Collaborative Group.

BACKGROUND: Gemcitabine and erlotinib have shown a survival benefit in the first-line setting in metastatic pancreatic cancer (mPC). The aim of this study was to assess whether combining capecitabine (C) with gemcitabine + erlotinib (GE) was safe and effective versus GE in patients with mPC. PATIENTS AND METHODS: Previously untreated mPC patients were randomised to receive G (1000 mg/m2, days 1, 8, 15) + E (100 mg/day, days 1-28) + C (1660 mg/m2, days 1-21) or GE, q4 weeks, until progression or unacceptable toxicity. Primary end-point: progression-free survival (PFS); secondary end-points: overall survival (OS), response rate, relationship of rash with PFS/OS and safety. RESULTS: 120 patients were randomised, median age 63 years, ECOG status 0/1/2 33%/58%/8%; median follow-up 16.5 months. Median PFS in the gemcitabine-erlotinib-capecitabine (GEC) and GE arms was 4.3 and 3.8 months, respectively (hazard ratio [HR]: 0.88, 95% confidence interval [CI]: 0.58-1.31; p = 0.52). Median OS in the GEC and GE arms was 6.8 and 7.7 months, respectively (HR: 1.09, 95% CI: 0.72-1.63; p = 0.69). Grade 3/4 neutropenia (GEC 43% versus GE 15%; p = 0.0008) and mucositis (GEC 9% versus GE 0%; p = 0.03) were the only statistically significant differences in grade 3/4 adverse events. PFS and OS were significantly longer in patients with rash (grade ≥1) versus no rash (grade = 0): PFS 5.5 versus 2.0 months (HR = 0.39, 95% CI: 0.26-0.6; p < 0.0001) and OS: 9.5 versus 4.0 months (HR = 0.51, 95% CI: 0.33-0.77; p = 0.0014). CONCLUSION: PFS with GEC was not significantly different to that with GE in patients with mPC. Skin rash strongly predicted erlotinib efficacy. The study was registered with ClinicalTrials.gov: NCT01303029.

SOX9-regulated cell plasticity in colorectal metastasis is attenuated by rapamycin.

The cancer stem cell (CSC) hypothesis proposes a hierarchical organization of tumors, in which stem-like cells sustain tumors and drive metastasis. The molecular mechanisms underlying the acquisition of CSCs and metastatic traits are not well understood. SOX9 is a transcription factor linked to stem cell maintenance and commonly overexpressed in solid cancers including colorectal cancer. In this study, we show that SOX9 levels are higher in metastatic (SW620) than in primary colorectal cancer cells (SW480) derived from the same patient. This elevated expression correlated with enhanced self-renewal activity. By gain and loss-of-function studies in SW480 and SW620 cells respectively, we reveal that SOX9 levels modulate tumorsphere formation and self-renewal ability in vitro and tumor initiation in vivo. Moreover, SOX9 regulates migration and invasion and triggers the transition between epithelial and mesenchymal states. These activities are partially dependent on SOX9 post-transcriptional modifications. Importantly, treatment with rapamycin inhibits self-renewal and tumor growth in a SOX9-dependent manner. These results identify a functional role for SOX9 in regulating colorectal cancer cell plasticity and metastasis, and provide a strong rationale for a rapamycin-based therapeutic strategy.

Características clinicopatológicas y supervivencia de los pacientes con cáncer de esófago. Resultados de 200 casos consecutivos / Clinicopathological characteristics and survival outcome of esophageal cancer. Results from a series of 200 patients

Fundamento y objetivo: El cáncer de esófago (CE) es una enfermedad poco frecuente pero grave. El objetivo del presente trabajo es describir las características clinicopatológicas y la supervivencia de los pacientes con CE en nuestro hospital. Pacientes y método: Se estudió a 200 pacientes consecutivos diagnosticados o tratados de CE o de la unión gastroesofágica en el Hospital Donostia entre enero del año 2003 y diciembre del año 2007. Se analizó la localización del tumor, el tipo histológico, las pruebas realizadas para establecer el estadio tumoral, los tratamientos utilizados, la supervivencia y la morbimortalidad de la cirugía. Resultados: La ultrasonografía endoscópica (USE) modificó la estrategia terapéutica en un 12% de los pacientes. Un 32% (74) de los pacientes se operaron; de éstos, un 65% (48) recibió radioquimioterapia (RT-QM) neoadyuvante. La supervivencia al año, a los 3 años y a los 5 años fue del 48, el 25 y el 21%, respectivamente. La mortalidad postoperatoria fue del 8% (6 pacientes) y la morbilidad, del 57% (42 pacientes). Los pacientes en estadio III a los que se realizó RT-QM neoadyuvante y cirugía tuvieron un mejor pronóstico que aquéllos a los que sólo se hizo RT-QM (20 meses de supervivencia frente a 9 meses). En el análisis multivariante, los factores de mal pronóstico fueron la localización en el tercio medio (HR [hazard ratio ‘razón de riesgo’]=2,3; intervalo de confianza [IC] del 95%: 1,3–4,1) y la no realización de cirugía tras la RT-QM (HR=1,9; IC del 95%: 1,15–3) (AU)

Background and objective: The esophageal cancer (EC) is a slightly frequent but serious disease. Our aim is to describe the characteristics of the patients with EC in our Hospital. Patients and method: We included 200 patients consecutively diagnosed and/or treated for CE between between January, 2003 and December, 2007. The location of the tumor was analyzed, the histological type, the proofs realized for to establish the classification, the treatments, the survival and the morbi-mortality of the surgery. Results: The endoscopic ultrasonography (EUS) modified the therapeutic strategy in 12% of the patients. The survival to the year, 3 years and 5 years was 48%, 25% and 21%, respectively. 74 (32%) patients were operated, 48 (65%) of them was treated with neoadyuvant chemoradiotherapy. The postsurgical mortality was 8% (6 patients) and the morbidity was 57% (114 patients). In multivariate analysis, after adjustment for traditional risk factors, were the location in the average third ( [HR, hazard ratio]=2.3; confidence interval [IC] of 95%, 1.3–4.1) and not accomplishment of surgery after the chemotherapy and radiotherapy (HR=1.9; IC to 95%, 1.15–3). Conclusions: The diagnosis is realized very later. The EUS has contributed a better therapeutic strategy to our patients. The mortality continues being high (AU)

[Clinicopathological characteristics and survival outcome of esophageal cancer. Results from a series of 200 patients]. / Características clinicopatológicas y supervivencia de los pacientes con cáncer de esófago. Resultados de 200 casos consecutivos.

BACKGROUND AND OBJECTIVE: The esophageal cancer (EC) is a slightly frequent but serious disease. Our aim is to describe the characteristics of the patients with EC in our Hospital. PATIENTS AND METHOD: We included 200 patients consecutively diagnosed and/or treated for CE between between January, 2003 and December, 2007. The location of the tumor was analyzed, the histological type, the proofs realized for to establish the classification, the treatments, the survival and the morbi-mortality of the surgery. RESULTS: The endoscopic ultrasonography (EUS) modified the therapeutic strategy in 12% of the patients. The survival to the year, 3 years and 5 years was 48%, 25% and 21%, respectively. 74 (32%) patients were operated, 48 (65%) of them was treated with neoadjuvant chemoradiotherapy. The postsurgical mortality was 8% (6 patients) and the morbidity was 57% (114 patients). In multivariate analysis, after adjustment for traditional risk factors, were the location in the average third ( [HR, hazard ratio]=2.3; confidence interval [IC] of 95%, 1.3-4.1) and not accomplishment of surgery after the chemotherapy and radiotherapy (HR=1.9; IC to 95%, 1.15-3). CONCLUSIONS: The diagnosis is realized very later. The EUS has contributed a better therapeutic strategy to our patients. The mortality continues being high.

Neumonía necrosante comunitaria asociada a bacteriemiay focos sépticos metastásicos / Necrotizing community pneumonia associated with bacteriemia and metastatic septic foci

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