Fluoxetine selectively induces p53-independent apoptosis in human colorectal cancer cells

Fluoxetine has been shown to induce anti-tumour activity. The aim of this study was to determine the effect of fluoxetine on HCT116+/+ and p53 gene-depleted HCT116-/- human colorectal cancer cells and the mechanisms, including potential p53-dependence, of its action. Fluoxetine-induced apoptosis was investigated by mitochondrial membrane potential assay, Annexin V assay, two-step cell cycle analysis using NC-3000™ system and pharmacological inhibition assays. Fluoxetine induced very selectively concentration-dependent apoptosis in human colorectal cancer cells by altering mitochondrial membrane potential and inducing translocation of phosphatidylserine to the outer membrane layer. Further evidence of the preponderance of apoptosis in fluoxetine-induced cell death is provided by the finding that the cell death was not blocked by inhibitors of parthanatos, a form of cell death that results from overactivation of the enzyme poly (ADP-ribose) polymerase (PARP) but is different from apoptosis. Data obtained indicate fluoxetine caused cell cycle event at Sub-G1 and G0/G1 phases in both cell lines. In terms of apoptosis, there is no significant difference between the responses of the two cell lines to fluoxetine. In conclusion, fluoxetine's cytotoxicity induces mainly apoptosis and causes DNA fragmentation in human colorectal cancer cells, which seemed to be independent of the p53 protein, as no significant difference in death profiles in response to fluoxetine treatment was observed in both the p53-intact and the p53-deleted cell lines. Fluoxetine, therefore, has potential for being repurposed as a drug for the treatment of colon cancer and thus deserves further investigations in this context

Investigation of the field-induced ferromagnetic phase transition in spin polarized neutron matter: a lowest order constrained variational approach

In this paper, the lowest order constrained variational (LOCV) method has been used to investigate the magnetic properties of spin polarized neutron matter in the presence of strong magnetic field at zero temperature employing $AV_{18}$ potential. Our results indicate that a ferromagnetic phase transition is induced by a strong magnetic field with strength greater than $10^{18}\ G$, leading to a partial spin polarization of the neutron matter. It is also shown that the equation of state of neutron matter in the presence of magnetic field is stiffer than the case in absence of magnetic field.Comment: 23 pages, 9 figures Phys. Rev. C (2011) in pres

Association between bilirubin and cardiovascular disease risk factors: using Mendelian randomization to assess causal inference

Background: Elevated serum bilirubin has been associated with reduced risk of cardiovascular disease (CVD). However, serum bilirubin is also related with several potential confounders related to CVD, such as obesity. Mendelian randomization has been proposed as a method to address challenges to validity from confounding and reverse causality. It utilizes genotype to estimate causal relationships between a gene product and physiological outcomes. In this report, we demonstrate its use in assessing direct causal relations between serum bilirubin levels and CVD risk factors, including obesity, cholesterol, measures of vascular function and blood pressure. Methods: Study subjects included 868 asymptomatic individuals. Study subjects were genotyped at the UGT1A1*28 locus, which is strongly associated with bilirubin levels. Results: Serum bilirubin levels were inversely associated with levels of several cardiovascular disease risk factors, including body mass index (p = 0.003), LDL (p = 0.0005) and total cholesterol (p = 0.0002). In contrast, UGT1A1*28 genotype, a known cause of elevated bilirubin levels, was not significantly associated with any of these traditional CVD risk factors. We did observe an association between genotype and brachial artery diameter (p = 0.003) and cold pressor reactivity (p = 0.01). Conclusions: Our findings imply that the observed association of serum bilirubin levels with body mass index and cholesterol are likely due to confounding and suggest that previously established CVD benefits of increased bilirubin may in part be mediated by the early regulation of vascular structure and reactivity

Physical Activity and Risk of Breast Cancer, Colon Cancer, Diabetes, Ischemic Heart Disease, and Ischemic Stroke Events: Systematic Review and Dose-Response Meta-Analysis for the Global Burden of Disease Study 2013

Objective: To quantify the dose-response associations between total physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events

PETROLOGY AND THE ORIGIN OF THE INTRUSIVE MASSES OF THE EAST OF JIROFT

The study area with an area of 55 km2 is located south east of Kerman province and in the area of Jiroft city. This area is structurally and geological division in the Urmia-Dokhtar zone. The Urmia- Dokhtar volcanic belt part of the Alpine-Himalayan is a volcanic belt. Several intrusive bodies are in the east of Jiroft, which is part of Jebalbarez Batolite andigneous actives of JabalBarez area have occurred in four stages. The third magma activity of the region occurred in Oligomiocene and occurred during three phases. its lithological composition includes synogranite and Monzogranite, granodiorite, diorite, quartz monzonite. Quartz, Plagioclase and Potassium feldspar are the major minerals in granites. Biotite, Amphibole, espen, opac minerals are other manufactores of these rocks. Various types of granular, myrmekitic, Graphic and perthite textures are observed in them. Regarding field studies, petrographic, and geochemical studies, granite rocks of meta-aluminum and granitoid components of Iseries are volcanic arc of the continental margin of orogenic region that originate from melting of shell-shaped igneous rocks. granitoid specimens are normalized to the original mantle, chondrite, upper and lower crust. The samples show enrichment LREE and less enrichment of HREE. The composition of the samples in terms of these incompatible elements is similar to the medium composition of the crust. Samples in tectonic environment diagrams are located wothing the VAG range. igneous rocks are associated with the subduction zone neotethys. The magma subtraction in the magmatic room in the first stage leads to the formation of quartz- diorite to granodiorite composition, and in the second phase, with the continuation of magmatic subtraction, the magma composition is more acidified than before and the rocks with granodiorite to granite composition composed. In the third stage, with the continuation of the subtraction process, the composition of magma is highly acidic consists of granite and alkali granite stones

МАТЕМАТИЧЕСКОЕ МОДЕЛИРОВАНИЕ СВАРОЧНЫХ ДЕФОРМАЦИЙ В ТОНКИХ ПЛАСТИНАХ

Welding is a crucial manufacturing process and widely used for manufacturing various products including ships, automobiles, trains and bridges. Welding distortions often occur in welded structures of thin plates due to relatively low stiffness and result in their warpage during assembly process and high manufacturing cost. Therefore, prediction and reduction of welding distortions are important in order to improve quality of welded structures. Welding distortion during the assembly process is caused not only by local shrinkage due to rapid heating and cooling. 3-D thermo-elastic-plastic finite element method (FEM) has been used to simulate single-bead-on-plate welding with 1 mm thickness. Experiments have been carried out to prove the simulated results. Comparison of the experimental results and FEM simulation results has confirmed that the proposed method efficiently  predicts level of  welding distortions while making single-bead-on-plate welding with 1 mm thickness.Сварка является ключевым процессом промышленного производства и широко используется для изготовления различных  изделий, включая корабли, автомобили, поезда и мосты. Сварочные деформации часто возникают в сварочных структурах тонких пластин из-за относительно небольшой жесткости. Это приводит к их короблению в процессе монтажа и возрастанию стоимости изготовления. Поэтому прогнозирование и уменьшение сварочных деформаций является ключевым для улучшения качества сварных конструкций. Сварочная деформация при сборке вызвана не только локальной (местной) усадкой из-за быстрого нагрева и охлаждения. В ходе данного исследования для моделирования сварки единичного шва тонким валиком на пластине толщиной1 ммиспользовали метод трехмерных термоупругопластичных конечных элементов (МКЭ). Для подтверждения результатов моделирования провели эксперименты. Сравнение экспериментальных данных и результатов моделирования с помощью МКЭ подтвердили, что предложенный метод эффективно прогнозирует уровень сварочных деформаций при сварке единичного шва тонким валиком на пластинах толщиной 1 мм

Dorsal Scapular Artery Variations And Relationship To The Brachial Plexus, And A Related Thoracic Outlet Syndrome Case

Knowledge of the relationship of the dorsal scapular artery (DSA) with the brachial plexus is limited. We report a case of a variant DSA path, and revisit DSA origins and underinvestigated relationship with the plexus in cadavers. The DSA was examined in a male patient and 106 cadavers. In the case, we observed an unusual DSA compressing the lower plexus trunk, that resulted in intermittent radiating pain and paresthesia. In the cadavers, the DSA originated most commonly from the subclavian artery (71%), with 35% from the thyrocervical trunk. Nine sides of eight cadavers (seven females) had two DSA branches per side, with one branch from each origin. The most typical DSA path was a subclavian artery origin before passing between upper and middle brachial plexus trunks (40% of DSAs), versus between middle and lower trunks (23%), or inferior (4%) or superior to the plexus (1%). Following a thyrocervical trunk origin, the DSA passed most frequently superior to the plexus (23%), versus between middle and lower trunks (6%) or upper and middle trunks (4%). Bilateral symmetry in origin and path through the brachial plexus was observed in 13 of 35 females (37%) and 6 of 17males (35%), with the most common bilateral finding of a subclavian artery origin and a path between upper and middle trunks (17%). Variability in the relationship between DSA and trunks of the brachial plexus has surgical and clinical implications, such as diagnosis of thoracic outlet syndrome

A phase 1 study evaluating rovalpituzumab tesirine in frontline treatment of patients with extensive-stage SCLC

INTRODUCTION: Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, a Notch pathway ligand highly expressed on SCLC cells. Rova-T was evaluated alone or in combination with platinum-based chemotherapy (cisplatin or carboplatin combined with etoposide [CE]) in frontline treatment of extensive-stage SCLC. METHODS: One cycle of CE pre-enrollment was permitted (later mandated). The following four cohorts were enrolled: Rova-T monotherapy (0.3 mg/kg, every 6 [q6] wk × 2; cohort 1; n = 4); Rova-T induction (0.3 mg/kg, q6 wk × 2) followed by CE every 21 days (q21) × 4 (cohort 2; n = 5); Rova-T (0.1 or 0.2 mg/kg, q6 wk × 2) overlapping with CE q21 × 4 (cohort 3; n = 14); and Rova-T maintenance (0.3 mg/kg, q6 wk × 2) after CE q21 × 4 (cohort 4; n = 3). RESULTS: A total of 26 patients were dosed (cohort 3: 14; cohorts 1, 2, and 4 combined: 12). Median age was 66 years, and 73% had Eastern Cooperative Oncology Group performance status of 1. In cohort 3, seven patients (50%) had confirmed objective responses, with a median progression-free survival of 5.2 months and median overall survival of 10.3 months. Compared with cohorts 1, 2, and 4 combined, cohort 3 had lower frequency of some Rova-T-related adverse events of special interest, such as pleural effusion (0 versus 33%), pericardial effusion (0 versus 17%), ascites (0 versus 8%), peripheral edema (36% versus 42%), generalized edema (0 versus 8%), pneumonia (7% versus 25%), and hypoalbuminemia (0 versus 17%). CONCLUSIONS: Lower Rova-T doses may be associated with lower incidence of some Rova-T-related adverse events of special interest. Rova-T 0.2 mg/kg plus CE (cohort 3) was tolerable; however, there was no clear efficacy benefit of adding Rova-T to CE