A Case Report of Germline Compound Heterozygous Mutations in the BRCA1 Gene of an Ovarian and Breast Cancer Patient

The germline carrier of the BRCA1 pathogenic mutation has been well proven to confer an increased risk of breast and ovarian cancer. Despite BRCA1 biallelic pathogenic mutations being extremely rare, they have been reported to be embryonically lethal or to cause Fanconi anemia (FA). Here we describe a patient who was a 48-year-old female identified with biallelic pathogenic mutations of the BRCA1 gene, with no or very subtle FA-features. She was diagnosed with ovarian cancer and breast cancer at the ages of 43 and 44 and had a strong family history of breast and gynecological cancers.     

Sensitization of MCF7 Cells with High Notch1 Activity by Cisplatin and Histone Deacetylase Inhibitors Applied Together

Histone deacetylase inhibitors (HDIs) are promising anti-cancer agents that inhibit proliferation of many types of cancer cells including breast carcinoma (BC) cells. In the present study, we investigated the influence of the Notch1 activity level on the pharmacological interaction between cisplatin (CDDP) and two HDIs, valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA, vorinostat), in luminal-like BC cells. The type of drug–drug interaction between CDDP and HDIs was determined by isobolographic analysis. MCF7 cells were genetically modified to express differential levels of Notch1 activity. The cytotoxic effect of SAHA or VPA was higher on cells with decreased Notch1 activity and lower for cells with increased Notch1 activity than native BC cells. The isobolographic analysis demonstrated that combinations of CDDP with SAHA or VPA at a fixed ratio of 1:1 exerted additive or additive with tendency toward synergism interactions. Therefore, treatment of CDDP with HDIs could be used to optimize a combined therapy based on CDDP against Notch1-altered luminal BC. In conclusion, the combined therapy of HDIs and CDDP may be a promising therapeutic tool in the treatment of luminal-type BC with altered Notch1 activity.     

GOLPH3 Regulates EGFR in T98G Glioblastoma Cells by Modulating Its Glycosylation and Ubiquitylation

Protein trafficking is altered when normal cells acquire a tumor phenotype. A key subcellular compartment in regulating protein trafficking is the Golgi apparatus, but its role in carcinogenesis is still not well defined. Golgi phosphoprotein 3 (GOLPH3), a peripheral membrane protein mostly localized at the trans-Golgi network, is overexpressed in several tumor types including glioblastoma multiforme (GBM), the most lethal primary brain tumor. Moreover, GOLPH3 is currently considered an oncoprotein, however its precise function in GBM is not fully understood. Here, we analyzed in T98G cells of GBM, which express high levels of epidermal growth factor receptor (EGFR), the effect of stable RNAi-mediated knockdown of GOLPH3. We found that silencing GOLPH3 caused a significant reduction in the proliferation of T98G cells and an unexpected increase in total EGFR levels, even at the cell surface, which was however less prone to ligand-induced autophosphorylation. Furthermore, silencing GOLPH3 decreased EGFR sialylation and fucosylation, which correlated with delayed ligand-induced EGFR downregulation and its accumulation at endo-lysosomal compartments. Finally, we found that EGF failed at promoting EGFR ubiquitylation when the levels of GOLPH3 were reduced. Altogether, our results show that GOLPH3 in T98G cells regulates the endocytic trafficking and activation of EGFR likely by affecting its extent of glycosylation and ubiquitylation.     

An assessment of the Spanish national hydrological plan

The paper is a comprehensive review of the Spanish National Hydrological Plan, which proposes to transfer water from the lower part of the Ebro River up to the Levante basins, around 912 km away. The National Hydrological Plan is a conventional, static plan, which focuses primarily on supply management. The plan is based on the explicit assumption that the world will change only incrementally during its entire economic life of 100-200 years. The analysis indicates that much of the increased water demands forecasted are unlikely to materialize due to increasing emphasis on demand management practices, major structural changes in the agricultural sector that will occur by 2020 and the requirements of the Water Directive of the European Union, which must be fulfilled by 2010. Even now, the cost per cubic metre of water delivered at the end of the transfer is nearly twice the cost of desalinated water. The National Hydrological Plan in its present form cannot be justified for economic, environmental and social reasons. In addition, the plan will not be necessary if demand management practices are implemented.     

Crosslinking reactions and swelling behavior of matrices based on N-acryloyl-TRIS(hydroxymethyl)aminomethane

Summary In this study, new hydrogels in rod shape were prepared from N-acryloyl-TRIS(hydroxymethyl)aminomethane (NAT) using ethylene glycol dimethacrylate (EGDMA) or N,N’methylenebisacrylamide (BIS) as crosslinking agent, dimethylformamide (DMF) as solvent and benzoyl peroxide (BPO) as initiator. In most cases, 2-hydroxyethyl methacrylate (HEMA), acrylamide (Aam) or acrylic acid (Aac) were used as co-monomers. The polymeric matrices obtained by free radical polymerization exhibited different properties by changing crosslinker, crosslinker concentration, co-monomer and initial NAT/co-monomer mole ratio. Besides, hydrogels from HEMA, Aam and Aac with BIS in absence of NAT were prepared under the same experimental reaction conditions in order to compare the properties of these products with those synthesized from NAT and the respective co-monomers. Some of the final products were selected to perform urea release assays, conducted through swelling-controlled release. Urea was chosen as “model” plant fertilizer agent.     

Electron Thermalization in Metallic Islands Probed by Coulomb Blockade Thermometry

We describe a systematic series of experiments on thermalization of electrons in lithographic metallic thin films at millikelvin temperatures using Coulomb blockade thermometry (CBT). Joule dissipation due to biasing of the CBT sensor tends to drive the electron system into non-equilibrium. Under all experimental conditions tested, the electron-electron relaxation is fast enough to ensure thermal electron distribution, which is also in agreement with the theoretical arguments we present. On the other hand, poor electron-phonon relaxation plays a dominant role in lifting the electron temperature above that of the bath. From a comparison of the results with the theoretical current-voltage characteristics of the thermometers we precisely determine the electron-phonon coupling constant for the common metals used. Our experiments show that it is a formidable task to attain thermal equilibrium with the bath using single-electron devices under non-zero bias conditions at 20–50 mK temperatures that are typically encountered in experiments. The conclusion concerning Coulomb blockade thermometry is more optimistic and two-fold: (1) One can now correct the errors due to bias heating in a satisfactory manner based on known material properties and the size of the metal films in the sensor. (2) Reliable thermometry down to 20 mK requires islands whose volumes are >10^?15 m³, which is still acceptable both from the parameter (capacitance) and fabrication points of view.     

Lithiasis of the prostatic loge

Lithiasis may develop in the prostate loge following prostate surgery. Calculus formation in the prostate can be ascribed basically to foreign bodies, residual adenomatous spheroids and clots or fragments of sphacelous mucosa in the presence of a stenotic area after surgery and/or infection. The diagnosis is based on the physical examination and particularly on the radiological findings. Treatment is by open surgery or endoscopic or extracorporeal lithotripsy.     

Reproductive senescence predicts cognitive decline in aged female monkeys

The present investigation provide evidences from a non-human primate model that naturally occurring menopause predicts a prominent signature of age-related cognitive decline. Young and aged rhesus monkeys were tested on a delayed response (DR) task known to the sensitive to aging, and reproductive status was evaluated according to menstrual cyclicity and urinary hormone profiles. Peri-/postmenopausal monkeys exhibited significant DR impairments relative to either age-matched premenopausal females, or young control subjects. In addition, markers of endocrine decline in the aged animals were selectively correlated with behavioral performance measures that distinguished premenopausal and peri-/postmenopausal monkeys. These results document that menopause is coupled to cognitive decline in the monkey, and they establish a valuable primate model for defining the effects of endocrine aging on brain and behavioral function.     

Bibliometric analysis of publications in experimental particle physics on cosmic rays and with accelerators

In the first part, the present paper presents a quantitative analysis of physics publications in the domain of experimental particle physics, before the Second World War in the field of cosmic rays physics and for the modern times in the field of accelerator and collision rings experiments. In the second part, a more general study is made on publications in the various fields of physics separating contributions from experiment, theory and techniques. Three aspects of physics are enlightened: physics of exploration, physics of applications, and forefront physics.