Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D

Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRASG13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRASG13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.This work was supported by European Union FP7 Grant No. 278568 “PRIMES” and Science Foundation Ireland Investigator Program Grant 14/IA/2395 to W.K. B.K. is supported by SmartNanoTox (Grant no. 686098), NanoCommons (Grant no. 731032), O.R. by MSCA-IF-2016 SAMNets (Grant no. 750688). D.M. is supported by Science Foundation Ireland Career Development award 15-CDA-3495. I.J. is supported by the Canada Research Chair Program (CRC #225404), Krembil Foundation, Ontario Research Fund (GL2-01-030 and #34876), Natural Sciences Research Council (NSERC #203475), Canada Foundation for Innovation (CFI #225404, #30865), and IBM. O.S. is supported by ERC investigator Award ColonCan 311301 and CRUK. I.S. is supported by the Canadian Cancer Society Research Institute (#703889), Genome Canada via Ontario Genomics (#9427 & #9428), Ontario Research fund (ORF/ DIG-501411 & RE08-009), Consortium Québécois sur la Découverte du Médicament (CQDM Quantum Leap) & Brain Canada (Quantum Leap), and CQDM Explore and OCE (#23929). T.C. was supported by a Teagasc Walsh Fellowshi

Diagnostics of chronic small intestinal obstruction in patient with ectopic pancreas in the Meckel's diverticulum (case report)

Aim of the case report presentation. To draw attention of general practitioners to the rare case of intestinal obstruction - intussusception of Meckel's diverticulum in small intestinal lumen. Key points. The present case is characterized by development of chronic small-intestinal obstruction due to repeating intussusception of Meckel's diverticulum in the small intestinal lumen. Episodes of intussusception manifested clinically by attacks of severe right iliac pain that made patient to take «embryonic posture». Deep palpation revealed «spastic bowel» sign in the area of intussusception. A specific type of intussusception was detected by transabdominal ultrasound: thickening and «lamination of intestinal wall» due to «diverticulum interposition» into the lumen of ileum and «overlaying» of wall layers. The evacuation delay at the small intestine was followed by dilation of overlying loops of the small intestine containing bulky liquid content; pendular movement of liquid observed at ultrasonography with visible «air-fluid levels» at plain radiograph. The patient at the same time had frequent liquid stool that indicated presence of incomplete obstruction. Surgical intervention for intussusception and resection of diverticulum-containing portion of the small intestine resulted in improvement of the patient state, relief of pain attacks and signs of intestinal obstruction. Histological examination of resected specimen revealed the presence of ectopic pancreatic tissue in the Meckel's diverticulum wall. Conclusion. Carrying out differential diagnosis in colicky abdominal pain should encompass existence of Meckel's diverticulum with recurrent small intestinal intussusception that can result in chronic intestinal obstruction. In diverticulum wall ectopic pancreas can be detected. Key words: ileus, Meckel's diverticulum, ectopic pancreas

The orphan GPR50 receptor promotes constitutive TGFβ receptor signaling and protects against cancer development

Transforming growth factor-β (TGFβ) regulates many cellular processes. Here the authors show that the orphan G-protein coupled receptor GPR50 can activate the TGFβ receptor I, in the absence of TGFβ, by stabilizing its active conformation and show antitumor activity in a mouse model of breast cancer

Novel etiopathophysiological aspects of thyrotoxic periodic paralysis

Thyrotoxicosis can lead to thyrotoxic periodic paralysis (TPP), an endocrine channelopathy, and is the most common cause of acquired periodic paralysis. Typically, paralytic attacks cease when hyperthyroidism is abolished, and recur if hyperthyroidism returns. TPP is often underdiagnosed, as it has diverse periodicity, duration and intensity. the age at which patients develop TPP closely follows the age at which thyrotoxicosis occurs. All ethnicities can be affected, but TPP is most prevalent in people of Asian and, secondly, Latin American descent. TPP is characterized by hypokalemia, suppressed TSH levels and increased levels of thyroid hormones. Nonselective beta adrenergic blockers, such as propranolol, are an efficient adjuvant to antithyroid drugs to prevent paralysis; however, an early and definitive treatment should always be pursued. Evidence indicates that TPP results from the combination of genetic susceptibility, thyrotoxicosis and environmental factors (such as a high-carbohydrate diet). We believe that excess T-3 modifies the insulin sensitivity of skeletal muscle and pancreatic beta cells and thus alters potassium homeostasis, but only leads to a depolarization-induced acute loss of muscle excitability in patients with inherited ion channel mutations. An integrated etiopathophysiological model is proposed based on molecular findings and knowledge gained from long-term follow-up of patients with TPP.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fleury GroupUniversidade Federal de São Paulo, Escola Paulista Med, Dept Biochem, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Med, Lab Mol & Translat Endocrinol, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Biochem, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Med, Lab Mol & Translat Endocrinol, BR-04039032 São Paulo, BrazilWeb of Scienc