Clinical relevance of thymidylate syntetase expression in the signet ring cell histotype component of colorectal carcinoma

Thymidylate Synthase (TS) is the key enzyme for DNA synthesis pathways and is inhibited by 5-fluorouracil (5FU). The aim of this work was to study TS expression and the proliferation rate in the different histological types of colorectal carcinoma (CRC). 50 patients with CRC were included in this study and evaluated immunohistochemically using the monoclonal antibodies, TS106 and Ki67. 20 tumours were of the intestinal type, 15 cases were signet ring cell carcinoma (SRCCs) and 15 cases were "mixed-type", with at least two different histological components. Intestinal and mucinous histotypes were positive for TS and Ki67, while "signet ring cell" samples were negative or showed only weak and focal positivity for both the TS and Ki67 antibodies. Our results show that signet ring cells (that are also often present in intestinal and mucinous carcinomas), are in the post-mitotic phase of the cell cycle and show a low proliferation index and TS expression. As TS is the key enzyme for DNA synthesis pathways and is inhibited by 5-fluorouracil (5FU), we can hypothesise that TS expression levels in the different histotypes of CRC could affect the potential responsiveness of these tumours to fluoropyrimidine chemotherapy, with a low efficacy being expected in signet ring cell areas

Clinical and Experimental Projects on Chemotherapy of Bladder Tumours

Our clinical and experimental experience with chemotherapy of bladder tumours is reviewed. The routes of drug administrations, drug dosages and combinations, are presented. Adjuvant radiotherapy and chemoprophylaxis of certain tumours are discussed.S. Afr. Med. J., 48, 631 (1974

Clinical and experimental projects on chemotherapy of bladder tumours

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Role of CBP and SATB-1 in Aging, Dietary Restriction, and Insulin-Like Signaling

Increased transcriptional complex activity, or pharmacological mimics of increased complex activity, predict lifespan in mice and mediate the protective effects of dietary restriction during aging

Incidence of traumatic brain injuries in head‐injured children with seizures

Objective: Incidence and short‐term outcomes of clinically important traumatic brain injury (ciTBI) in head‐injured children presenting to ED with post‐traumatic seizure (PTS) is not described in current literature. Methods: Planned secondary analysis of a prospective observational study undertaken in 10 Australasian Paediatric Research in Emergency Department International Collaborative (PREDICT) network EDs between 2011 and 2014 of head‐injured children 24 h (9 [2.7%] AR 2.5 [95% CI 0.8–4.2]) and neurosurgery (8 [2.4%] AR 2.0 [95% CI 0.4–3.7]), were higher than those without PTS. Children with PTS and GCS 15 or 14 had no neurosurgery, intubations or death, with two deaths in children with PTS and GCS ≤13. Conclusions: PTS was uncommon in head‐injured children presenting to the ED but associated with an increased risk of ciTBI in those with reduced GCS on arrival

FGF4 and Retinoic Acid Direct Differentiation of hESCs into PDX1-Expressing Foregut Endoderm in a Time- and Concentration-Dependent Manner

BACKGROUND: Retinoic acid (RA) and fibroblast growth factor 4 (FGF4) signaling control endoderm patterning and pancreas induction/expansion. Based on these findings, RA and FGFs, excluding FGF4, have frequently been used in differentiation protocols to direct differentiation of hESCs into endodermal and pancreatic cell types. In vivo, these signaling pathways act in a temporal and concentration-dependent manner. However, in vitro, the underlying basis for the time of addition of growth and differentiation factors (GDFs), including RA and FGFs, as well as the concentration is lacking. Thus, in order to develop robust and reliable differentiation protocols of ESCs into mature pancreatic cell types, including insulin-producing beta cells, it will be important to mechanistically understand each specification step. This includes differentiation of mesendoderm/definitive endoderm into foregut endoderm--the origin of pancreatic endoderm. METHODOLOGY/PRINCIPAL FINDINGS: Here, we provide data on the individual and combinatorial role of RA and FGF4 in directing differentiation of ActivinA (AA)-induced hESCs into PDX1-expressing cells. FGF4's ability to affect endoderm patterning and specification in vitro has so far not been tested. By testing out the optimal concentration and timing of addition of FGF4 and RA, we present a robust differentiation protocol that on average generates 32% PDX1(+) cells. Furthermore, we show that RA is required for converting AA-induced hESCs into PDX1(+) cells, and that part of the underlying mechanism involves FGF receptor signaling. Finally, further characterization of the PDX1(+) cells suggests that they represent foregut endoderm not yet committed to pancreatic, posterior stomach, or duodenal endoderm. CONCLUSION/SIGNIFICANCE: In conclusion, we show that RA and FGF4 jointly direct differentiation of PDX1(+) foregut endoderm in a robust and efficient manner. RA signaling mediated by the early induction of RARbeta through AA/Wnt3a is required for PDX1 expression. Part of RA's activity is mediated by FGF signaling

Foxa1 Reduces Lipid Accumulation in Human Hepatocytes and Is Down-Regulated in Nonalcoholic Fatty Liver

Triglyceride accumulation in nonalcoholic fatty liver (NAFL) results from unbalanced lipid metabolism which, in the liver, is controlled by several transcription factors. The Foxa subfamily of winged helix/forkhead box (Fox) transcription factors comprises three members which play important roles in controlling both metabolism and homeostasis through the regulation of multiple target genes in the liver, pancreas and adipose tissue. In the mouse liver, Foxa2 is repressed by insulin and mediates fasting responses. Unlike Foxa2 however, the role of Foxa1 in the liver has not yet been investigated in detail. In this study, we evaluate the role of Foxa1 in two human liver cell models, primary cultured hepatocytes and HepG2 cells, by adenoviral infection. Moreover, human and rat livers were analyzed to determine Foxa1 regulation in NAFL. Results demonstrate that Foxa1 is a potent inhibitor of hepatic triglyceride synthesis, accumulation and secretion by repressing the expression of multiple target genes of these pathways (e.g., GPAM, DGAT2, MTP, APOB). Moreover, Foxa1 represses the fatty acid transporter protein FATP2 and lowers fatty acid uptake. Foxa1 also increases the breakdown of fatty acids by inducing peroxisomal fatty acid β-oxidation and ketone body synthesis. Finally, Foxa1 is able to largely up-regulate UCP1, thereby dissipating energy and consistently decreasing the mitochondria membrane potential. We also report that human and rat NAFL have a reduced Foxa1 expression, possibly through a protein kinase C-dependent pathway. We conclude that Foxa1 is an antisteatotic factor that coordinately tunes several lipid metabolic pathways to block triglyceride accumulation in hepatocytes. However, Foxa1 is down-regulated in human and rat NAFL and, therefore, increasing Foxa1 levels could protect from steatosis. Altogether, we suggest that Foxa1 could be a novel therapeutic target for NAFL disease and insulin resistance

GREENPEG – exploration for pegmatite minerals to feed the energy transition: first steps towards the Green Stone Age

This is the final version. Available on open access from the Geological Society via the DOI in this recordData availability: All data generated or analysed during this study are included in this published article.The GREENPEG project, which is funded by the European Commission Horizon 2020 ‘Climate action, environment, resource efficiency and raw materials’ programme, aims to develop multimethod exploration toolsets for the identification of European, buried, small-scale (0.01–5 million m3) pegmatite ore deposits of the Nb–Y–F (NYF) and Li–Cs–Ta (LCT) chemical types. The project is being coordinated by the Natural History Museum of the University of Oslo and involves four exploration services/mining operators, one geological survey, one non-profit helix association of administration, industry and academia, two consulting companies and five academic institutions from eight European countries. The target raw materials are Li, high-purity quartz for silica and metallic Si, ceramic feldspar, rare earth elements, Ta, Be and Cs, which are naturally concentrated in granitic pegmatites. Silicon and Li are two of the most sought-after green technology metals as they are essential for photovoltaics and Li-ion batteries for electric cars, respectively. GREENPEG will change the focus of exploration strategies from large-volume towards small-volume, high-quality ores and overcome the lack of exploration technologies for pegmatite ore deposits by developing toolsets tailored to these ore types. This contribution focuses on the methods applied in the GREENPEG project and as such provides a potential pathway towards the ‘Green Stone Age’ from the perspective of pegmatite-sourced minerals.European Union Horizon 2020FCT – Fundação para a Ciência e a TecnologiaScience Foundation IrelandEuropean Regional Development Fund (ERDF)Society of the Friendly Sons of St. Patrick for the Relief of Emigrants from Irelan

Contemporary Management of Locally Advanced and Recurrent Rectal Cancer: Views from the PelvEx Collaborative

Pelvic exenteration is a complex operation performed for locally advanced and recurrent pelvic cancers. The goal of surgery is to achieve clear margins, therefore identifying adjacent or involved organs, bone, muscle, nerves and/or vascular structures that may need resection. While these extensive resections are potentially curative, they can be associated with substantial morbidity. Recently, there has been a move to centralize care to specialized units, as this facilitates better multi-disciplinary care input. Advancements in pelvic oncology and surgical innovation have redefined the boundaries of pelvic exenterative surgery. Combined with improved neoadjuvant therapies, advances in diagnostics, and better reconstructive techniques have provided quicker recovery and better quality of life outcomes, with improved survival This article provides highlights of the current management of advanced pelvic cancers in terms of surgical strategy and potential future developments