Epigenetic Deregulation of Protocadherin PCDHGC3 in Pheochromocytomas/Paragangliomas Associated With SDHB Mutations.

CONTEXT: SDHB mutations are found in an increasing number of neoplasms, most notably in paragangliomas and pheochromocytomas (PPGLs). SDHB-PPGLs are slow-growing tumors, but ∼50% of them may develop metastasis. The molecular basis of metastasis in these tumors is a long-standing and unresolved problem. Thus, a better understanding of the biology of metastasis is needed. OBJECTIVE: This study aimed to identify gene methylation changes relevant for metastatic SDHB-PPGLs. DESIGN: We performed genome-wide profiling of DNA methylation in diverse clinical and genetic PPGL subtypes, and validated protocadherin γ-C3 (PCDHGC3) gene promoter methylation in metastatic SDHB-PPGLs. RESULTS: We define an epigenetic landscape specific for metastatic SDHB-PPGLs. DNA methylation levels were found significantly higher in metastatic SDHB-PPGLs than in SDHB-PPGLs without metastases. One such change included long-range de novo methylation of the PCDHA, PCDHB, and PCDHG gene clusters. High levels of PCDHGC3 promoter methylation were validated in primary metastatic SDHB-PPGLs, it was found amplified in the corresponding metastases, and it was significantly correlated with PCDHGC3 reduced expression. Interestingly, this epigenetic alteration could be detected in primary tumors that developed metastasis several years later. We also show that PCDHGC3 down regulation engages metastasis-initiating capabilities by promoting cell proliferation, migration, and invasion. CONCLUSIONS: Our data provide a map of the DNA methylome episignature specific to an SDHB-mutated cancer and establish PCDHGC3 as a putative suppressor gene and a potential biomarker to identify patients with SDHB-mutated cancer at high risk of metastasis who might benefit from future targeted therapies.

Interplay between surface chemistry and performance of rutile-type catalysts for halogen production.

Catalytic HBr oxidation is an integral step in the bromine-mediated functionalisation of alkanes to valuable chemicals. This study establishes the relationships between the mechanism of HBr oxidation over rutile-type oxides (RuO2, IrO2, TiO2) and their apparent catalytic performance. Comparison with the well-studied HCl oxidation revealed distinct differences in surface chemistry between HBr and HCl oxidation that impact the stability and activity of the catalysts. The kinetic fingerprints of both oxidation reactions over the three rutile-type oxides investigated are compared using temporal analysis of products, which substantiates the energy profiles derived from density functional theory. The quantitative determination of the halogen uptake under operando conditions using prompt gamma activation analysis demonstrates that RuO2 suffers from extensive subsurface bromination upon contact with hydrogen bromide, particularly at low temperature and low O2 : HBr ratios, which negatively affects the stability of the catalyst. TiO2 exhibits intrinsically low halogen coverage (30-50%) under all the conditions investigated, due to its unique defect-driven mechanism that renders it active and stable for Br2 production. On the contrary, for HCl oxidation TiO2 is inactive, and the chlorination of the highly active RuO2 is limited to the surface. Differences in the extent of surface halogenation of the materials were also confirmed by high-resolution transmission electron microscopy and explained by the DFT calculations. These insights into the molecular-level processes taking place under working conditions pave the way for the design of the next generation catalysts for bromine production.

Metal-Organic Framework (MOF) Defects under Control: Insights into the Missing Linker Sites and Their Implication in the Reactivity of Zirconium-Based Frameworks.

For three-dimensional (3D) metal-organic frameworks (MOFs), the presence and nature of structural defects has been recognized as a key factor shaping the material's physical and chemical behavior. In this work, the formation of the "missing linker" defects has been addressed in the model biphenyl-4,4'-dicarboxylate (bpdc)-based Zr MOF, UiO-67. The defect showed strong dependence on the nature of the modulator acid used in the MOF synthesis; the defects, in turn, were found to correlate with the MOF physical and chemical properties. The dynamic nature of the Zr6 (node)-monocarboxylate bond showed promise in defect functionalization and "healing", including the formation of X-ray-quality "defect-free" UiO-67 single crystals. Chemical transformations at defect sites have also been explored. The study was also extended to the isoreticular UiO-66 and UiO-68' systems.

Combined radical prostatectomy and abdominoperineal resection for locally invasive rectal cancer.

INTRODUCTION: An infiltration of urological organs is found in 5-10% of patients with colorectal carcinoma. Total pelvic exenteration is the standard procedure for locally advanced rectal cancer. In selected patients with rectal cancer involving the prostate or seminal vesicles, the bladder can be preserved and en bloc radical prostatectomy with abdominoperineal rectal resection can be performed. We report two patients who treated with this combined approach. PRESENTATION OF CASE: Two patients with symptoms of rectal bleeding and pelvic pain were investigated. Colonoscopy demonstrated a tumor in the lower rectum. Biopsies revealed adenocarcinoma. Both pelvic MRI and endorectal ultrasound showed tumors that invaded the prostate and the seminal vesicles directly but without invasion of the bladder. After neoadjuvant chemoradiation, combined radical prostatectomy and abdominoperineal amputation was performed. None has developed local recurrence, but one of them was operated on for a single lung metastasis. After a follow-up of 28 and 20 months, respectively, the patients are alive without evidence of local recurrence or distant disease. DISCUSSION: This procedure obviates the need for urinary diversion without compromising the local tumor control. Intraoperative and postoperative diagnostic difficulties, and clinical aspects in relation to postoperative anastomotic leak and survival of patients are discussed. CONCLUSION: En bloc radical prostatectomy and proctosigmoidectomy is feasible in selected patients with rectal cancer and invasion limited to the prostate or seminal vesicles because it provides good local tumor control and significantly improves the patient's quality of life in comparison to total pelvic exenteration.

In situ surface coverage analysis of RuO2-catalysed HCl oxidation reveals the entropic origin of compensation in heterogeneous catalysis.

In heterogeneous catalysis, rates with Arrhenius-like temperature dependence are ubiquitous. Compensation phenomena, which arise from the linear correlation between the apparent activation energy and the logarithm of the apparent pre-exponential factor, are also common. Here, we study the origin of compensation and find a similar dependence on the rate-limiting surface coverage term for each Arrhenius parameter. This result is derived from an experimental determination of the surface coverage of oxygen and chlorine species using temporal analysis of products and prompt gamma activation analysis during HCl oxidation to Cl(2) on a RuO(2) catalyst. It is also substantiated by theory. We find that compensation phenomena appear when the effect on the apparent activation energy caused by changes in surface coverage is balanced out by the entropic configuration contributions of the surface. This result sets a new paradigm in understanding the interplay of compensation effects with the kinetics of heterogeneously catalysed processes.

SO2-promoted catalytic N2O removal over iron zeolites.

SO(2) promotes the rate of N(2)O removal over Fe-zeolites more efficiently than other reducing agents (NH(3)) and promoters (NO); the effect of SO(2) as selective reductant is independent of the framework type and composition, preparation method, and iron content, suggesting that its occurrence is not determined by a highly specific iron speciation.

Optimal hydrocarbon selection for catalytic N2O reduction over iron-containing ZSM-5 zeolite.

The selective catalytic reduction of N2O over steam-activated FeZSM-5 zeolite has been investigated at 473-823 K using C1-C3 hydrocarbons (methane, ethane, ethene, ethyne, propane, and propyne). The assessment of the hydrocarbons for nitrous oxide abatement is discussed according to different criteria: (i) de-N2O activity and operation temperature, (ii) hydrocarbon utilization, that is, the selectivity to react with N2O in 02 excess, (iii) emission of CO and CO2, (iv) sensitivity to NO and NH3, and (v) cost. Alkanes are generally more effective reducing agents than unsaturated hydrocarbons. In particular, alkynes require higher temperature to activate N2O and are unselective because of their proneness to react with O2. Ethane is an optimal reductant, featuring a high de-N2O activity, high selectivity, and compared to methane, a lower degree of inhibition by NO.

[I125 low dose rate brachytherapy in localized prostate cancer. Preliminary results after 5 years]. / Braquiterapia de baja tasa (I125) en el cáncer de próstata localizado. Resultados preliminares a 5 años.

OBJECTIVES: Prostatic brachytherapy by permanent implant of I125 or Pd103 is a therapeutic option in the treatment of organ confined prostate cancer We analyze preliminary results and complications after five years in the group of patients who received I125 low dose rate brachytherapy as the only intention-to-cure treatment and evaluate the differences with the standard treatment (surgery). METHODS: From a case series of more than 400 patients treated with brachytherapy as radical intention-to-cure monotherapy for organ-confined prostate cancer we excluded patients with less than 12 months of follow-up for statistical analysis; the study group includes 275 patients enrolled between april 1999 and December 2003. Mean follow-up is 31 months (12-68). Biochemical failure was defined in accordance to the ASTRO criteria. Statistical survival analysis was carried out with the SPSS statistical software using the Kaplan Meyer method. Urinary and gastrointestinal complications were evaluated in accordance to the RTOG criteria. RESULTS: Mean age was 68 years (range 49-83 years). 93% of the patients presented a clinical stage < or ='3dT2a and 7% T2b, with 60 8% of the cases having a PSA < or ='3d 10 ng/ml. Gleason score was < or ='3d 6 in 94% of the cases. 9% of the cases had a prostate volume > 50 cc. Overall 5 year survival was 96%, with a 97% disease-free survival and a 99% biochemical failure-free survival. Figure 3 and tables II-VI summarize the complications in various series including this. CONCLUSIONS: Multiple published series seem to show similar results on biochemical control of the disease when comparing surgery and low dose rate brachytherapy in organ-confined disease. In comparison to surgery, brachytherapy has the advantage of having a lower percentage of immediate postoperative complications, lower incontinence rate, and a higher number of patients preserving erectile function.

Braquiterapia de baja tasa (I125) en el cáncer de próstata localizado. Resultados preliminares a 5 años / I125 low dose rate brachytherapy in localized prostate cancer. Preliminary results after 5 years

OBJETIVO: La braquiterapia prostáticacon implantes permanentes de semillas de I125 ó 103Pdes una opción terapéutica en el tratamiento del cáncerprostático organoconfinado. Analizamos los resultadospreliminares y las complicaciones a cinco años en elgrupo de pacientes tratados con braquiterapia de bajatasa (I125) como tratamiento único de intención curativay evaluamos las diferencias existentes con el tratamientoestándar (cirugía).MÉTODOS: Sobre una casuística que supera los 400pacientes tratados con braquiterapia como monoterapiay con intención curativa radical por adenocarcinomade próstata organoconfinado, hemos excluido elgrupo de pacientes con un seguimiento menor a 12meses para el análisis estadístico de resultados y com-plicaciones, por lo tanto el grupo a estudio consta de275 pacientes reclutados desde abril de 1999 adiciembre del 2003. El seguimiento medio de la seriees de 31 meses (12-68 m). Se consideró fallo bioquímicocuando los pacientes cumplieron los criterios marcadospor la ASTRO. El análisis estadístico de supervivenciase realizó con el paquete estadístico SPSS y elmétodo de Kaplan-Meyer. Las complicaciones urinariasy digestivas fueron evaluadas de acuerdo con los criteriosde la RTOG RESULTADOS: La edad media del grupo fue de 68años con un rango (49-83 años). El 93% de los pacientespresentaron un estadio clínico 50cc. la supervivencia global a los 5 años esdel 96%, con una supervivencia libre de enfermedadde 97% y una con una supervivencia libre de fallo bioquímicodel 99% al mismo tiempo. Las complicacionesde las diferentes series incluida la nuestra están recogidasen la Figura3 y Tablas II-VI.CONCLUSIÓN: Las múltiples series publicadas en laliteratura parecen poner de manifiesto los mismos resultadosde control bioquímico de la enfermedad cuandose compara la cirugía con la braquiterapia de bajatasa en enfermedad organoconfinada. La braquiterapiapresenta frente a la cirugía la ventaja de tener menorporcentaje de complicaciones en el postoperatorioinmediato, menor índice de incontinencias y una preservaciónde la función eréctil en mayor número depacientes

OBJECTIVES: Prostatic brachytherapy bypermanent implant of I125 or Pd103 is a therapeuticoption in the treatment of organ confined prostate cancer.We analyze preliminary results and complications afterfive years in the group of patients who received I125low dose rate brachytherapy as the only intention-tocuretreatment and evaluate the differences with thestandard treatment (surgery).METHODS: From a case series of more than 400patients treated with brachytherapy as radical intentionto-cure monotherapy for organ-confined prostate cancerwe excluded patients with less than 12 months offollow-up for statistical analysis; the study group includes275 patients enrolled between april 1999 andDecember 2003. Mean follow-up is 31 months (12-68). Biochemical failure was defined in accordance tothe ASTRO criteria. Statistical survival analysis wascarried out with the SPSS statistical software using theKaplan Meyer method. Urinary and gastrointestinalcomplications were evaluated in accordance to theRTOG criteria.RESULTS: Mean age was 68 years (range 49-83years). 93% of the patients presented a clinical stage 50 cc. Overall 5 year survival was 96%, with a 97%disease-free survival and a 99% biochemical failure-freesurvival. Figure 3 and tables II-VI summarize thecomplications in various series including this.CONCLUSIONS: Multiple published series seem toshow similar results on biochemical control of the diseasewhen comparing surgery and low dose rate brachytherapyin organ-confined disease. In comparison to surgery,brachytherapy has the advantage of having a lowerpercentage of immediate postoperative complications,lower incontinence rate, and a higher number ofpatients preserving erectile function