Sugar and chromosome stability: Clastogenic effects of sugars in vitamin B6-deficient cells

Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, has been implicated in preventing human pathologies, such as diabetes and cancer. However, the mechanisms underlying the beneficial effects of PLP are still unclear. Using Drosophila as a model system, we show that PLP deficiency caused either by mutations in the pyridoxal kinase-coding gene (dPdxk) or by vitamin B6 antagonists results in chromosome aberrations (CABs). The CAB frequency in PLP-depleted cells was strongly enhanced by sucrose, glucose or fructose treatments, and dPdxk mutant cells consistently displayed higher glucose contents than their wild type counterparts, an effect that is at least in part a consequence of an acquired insulin resistance. Together, our results indicate that a high intracellular level of glucose has a dramatic clastogenic effect if combined with PLP deficiency. This is likely due to an elevated level of Advanced Glycation End-products (AGE) formation. Treatment of dPdxk mutant cells with alpha lipoic acid (ALA) lowered both AGE formation and CAB frequency, suggesting a possible AGE-CAB cause-effect relationship. The clastogenic effect of glucose in PLP-depleted cells is evolutionarily conserved. RNAi-mediated silencing of PDXK in human cells or treatments with PLP inhibitors resulted in chromosome breakage, which was potentiated by glucose and reduced by ALA. These results suggest that patients with concomitant hyperglycemia and vitamin B6 deficiency may suffer chromosome damage. This might impact on cancer risk, as CABs are a well-known tumorigenic factor

Protein phosphatase 2A (PP2A) is required for the maintenance of Drosophila chromosome integrity

Cellular responses to DNA damage are based on signal-transduction pathways involving phosphorylation-dephosphorylation events. Recent literature has demonstrated that protein serine/threonine phosphatases have important functions in DNA damage response (DDR). In particular growing evidence indicate that the protein phosphatase 2A (PP2A) plays a crucial role in genome stability maintenance, acts as tumor suppressor and is mutated in some cancer types. However current knowledge on the mechanisms and the pathways linking PP2A to DDR is still rudimentary. Although most of the roles of PP2A are evolutionarily conserved, there are at present very few data suggesting an involvement of Drosophila PP2A in DNA repair. In the course of a screening aimed at identifying new Drosophila genes involved in the maintenance of genome stability we found an allele of twins (tws) gene, encoding the regulatory PP2A B subunit, that caused frequent chromosome aberrations (CABs), suggesting that also in Drosophila this phosphatase is involved in DNA repair. We observed that all previously identified alleles at the tws locus also caused CABs and high frequency of spontaneous γ-H2Av foci. Moreover tws mutations determined γ-H2Av foci persistence in irradiated brain cells, indicating that Tws promotes foci regression by dephosphorylating γ-H2Av. We also demonstrated that mutants in the Pp4-19C gene, that encodes the PP4 catalytic subunit, affected γ-H2Av foci dissolution but not exhibited CABs suggesting that impaired foci regression is not sufficient to cause CABs. PP2A and PP4 are also involved in the G2/M checkpoint. In irradiated tws mutant brains the mitotic index (MI) did not drop at 15 minutes (min) as in control cells, but remained similar to that of non-irradiated controls without significant variations over time. In contrast in Pp4-19C mutant cells MI dropped at 15 min after irradiation but the recovery was significantly delayed. These data indicate that PP2A and PP4 are both implicated in the G2/M checkpoint although with different roles. To better understand the origin of CABs in tws mutants we tried to individuate Tws substrates by cytological examination of double mutants carrying tws mutation and mutations in genes involved in DDR pathway. This analysis revealed that mutations in the ATM-coding gene tefu and mutations in ku70 gene, encoding a component of NHEJ system, are both perfectly epistatic to tws mutations. From these data we deduced that Tws controls genome integrity through a pathway in which Ku70 is first phosphorylated by ATM and then dephosphorylated by Tws (that perhaps dephosphorylates also ATM itself) to allow DNA repair. Therefore, in tws mutants CABs are induced by the hyperphosphorylation status of Ku70

Genomic instability and DNA replication defects in progeroid syndromes

Progeroid syndromes induced by mutations in lamin A or in its interactors – named progeroid laminopathies – are model systems for the dissection of the molecular pathways causing physio- logical and premature aging. A large amount of data, based mainly on the Hutchinson Gilford Progeria syndrome (HGPS), one of the best characterized progeroid laminopathy, has highlighted the role of lamins in multiple DNA activities, including replication, repair, chromatin organization and telomere function. On the other hand, the phenotypes generated by mutations affecting genes directly acting on DNA function, as mutations in the helicases WRN and BLM or in the polymerase polδ, share many of the traits of progeroid laminopathies. These evidences support the hypothesis of a concerted implication of DNA function and lamins in aging. We focus here on these aspects to contribute to the comprehension of the driving forces acting in progeroid syndromes and premature aging

Mesenteric-Portal Vein Resection during Pancreatectomy for Pancreatic Cancer

The aim of the present study was to determine the outcome of patients undergoing pancreatic resection with (VR+) or without (VR 12) mesenteric-portal vein resection for pancreatic carcinoma. Between January 1998 and December 2012, 241 patients with pancreatic cancer underwent pancreatic resection: in 64 patients, surgery included venous resection for macroscopic invasion of mesenteric-portal vein axis. Morbidity and mortality did not differ between the two groups (VR+: 29% and 3%; VR 12: 30% and 4.0%, resp.). Radical resection was achieved in 55/64 (78%) in the VR+ group and in 126/177 (71%) in the VR 12 group. Vascular invasion was histologically proven in 44 (69%) of the VR+ group. Survival curves were not statistically different between the two groups. Mean and median survival time were 26 and 15 months, respectively, in VR 12 versus 20 and 14 months, respectively, in VR+ group . In the VR+ group, only histologically proven vascular invasion significantly impacted survival , while, in the VR 12 group, R0 resection and tumor\u2019s grading significantly influenced long-term survival. Vascular resection during pancreatectomy can be performed safely, with acceptable morbidity and mortality. Long-term survival was the same, with or without venous resection. Survival was worse for patients with histologically confirmed vascular infiltration

Knowledge e Management: sono compatibili?

Knowledge e Management: sono compatibili

Collision of ductal adenocarcinoma and neuroendocrine tumor of the pancreas: a case report and review of the literature

Background: Simultaneous occurrence of exocrine and neuroendocrine tumors of the pancreas is very infrequent. We report a patient with an endocrine tumor in the pancreatic-duodenal area and extensive exocrine carcinoma involving the whole pancreas. Case presentation: A 69-year-old woman was hospitalized in May 2016 for epigastric pain and weight loss. Her past medical history revealed an undefined main pancreatic duct dilation that was subsequently confirmed at CT scan (23 mm) and endoscopic ultrasound. There was no evidence of pancreatic masses, but the cephalic portion of the main pancreatic duct presented hypoechoic nodules. A diagnosis of the main-duct intraductal papillary mucinous neoplasm was made, and the patient underwent total pancreatectomy. Pathological examination showed a collision tumor constituted by a ductal adenocarcinoma involving the whole pancreas and a neuroendocrine tumor located in the duodenal peripancreatic wall and the head of the pancreas. There was one peripancreatic lymph node metastasis from the ductal adenocarcinoma and eight node metastases from the neuroendocrine tumor. These findings suggested a diagnosis of collision of neuroendocrine and ductal adenocarcinomas of the pancreas. The postoperative course was uneventful. Conclusions: The coexistence of pancreatic endocrine and exocrine tumors is very uncommon. When present, problems in differential diagnosis may arise between mixed exocrine-endocrine carcinoma or the collision of separate tumors

Subclinical myopathy in patients with colorectal cancer: clinical-pathological characterization and search for tissue markers

Skeletal muscle in patients with cancer undergoes many morphological changes due to immuno-inflammatory factors of tumor origin or treatment.T he latest event of these changes is cancer cachexia. Aim of the study is to identify myopathic features in skeletal muscle biopsies from weight stable patients with colorectal cancer and without cachexia or asthenia / weakness, that could possibly provide new diagnostic and prognostic cancer biomarkers. Morphometric analyses and immunohistochemical studies were performed on intraoperative muscle biopsies from patients with colorectal cancer and from weight stable patients undergoing surgery for benign non-inflammatory conditions. A rectus abdominis biopsy was taken in all patients and controls.A correlation between histopathologic findings and clinical characteristics, circulating inflammatory biomarkers and markers of muscle necrosis,surgery data and cancer phenotype were investigated.. Forty four patients (21male/23 female) and 17 controls (6 male/11 female) (p=NS) were studied. In cancer patients’biopsies we observed asubclinical myopathy characterized by an abnormal distribution of myonuclei, which are localized inside the myofiber rather than at the periphery, and by the presence of regenerating muscle fibers. The percentage of myofibers with internalized nuclei is significantly higher in patients (median= 9%, IQR= 3.7-18.8) than in controls (median= 2.7%, IQR= 1.7-3.2) ( p=0.0002). In patients we observed an inverse correlation between the number of centronucleated fibers and the presence of node metastasis (N+)(ρ)=-0.64 (p=0.002). Patients affected with colorectal cancer display early sign of a myopathy, characterized by centronucleated and regenerating myofibers. This myopathy appears to be associated with an early stage of neoplasia and it could be an adaptive response of muscle to cancer. We hope a future application of these findings as a possible early diagnostic and prognostic biomarker of neoplasia

Cine y psicología: lectura postracionalista de las películas: el laberinto del fauno y el espinazo del diablo de guillermo del toro

In this article the author takes a constructivist postracionalistic point of view regarding two films of Guillermo del Toro “El laberinto del fauno” and “El espinazo del diablo”. Both film discusses the use of imaginative activities of the young protagonists to deal with issues of grief and loss. The study aims to shed light on the meaning which emerges from two painful life experiences of the actors, which is the leit motif around which takes shape a narrative identity. Postracionalistic Guidano’s model demonstrates once more applicable and very effective, even in the study of human functioning of the harmonic individuals, in the absence of psychopathological disorders.En este trabajo la autora lleva a cabo una lectura constructivista postracionalista de dos películas cinematográficas del director Guillermo del Toro “El laberinto del fauno” y “El espinazo del diablo”

Przetrwała hipoglikemia hiperinsulinemiczna współistniejąca z nieaktywnym wyspiakiem trzustki

The most common cause of hyperinsulinaemic hypoglycaemia in adult is insulinoma. Although nesidioblastosis is a rare but well-recognised disorder of persistent hypoglycaemia in infants, it is extremely rare in adults. We present a case of a 59-year-old woman with small neuroendocrine tumour of the tail of the pancreas, diagnosed by CT scans and MRI, and hypoglycaemic syndrome. Laparoscopic distal pancreatectomy was performed, and pathologic examination showed a well-differentiated, non-functioning endocrine tumour of the pancreas and diffuse nesidioblastosis in the remnant gland. In the early postoperative period, recurrent hypoglycaemia occurred in spite of oral diazoxide therapy. Plasma proinsulin levels were extremely high. 18F-DOPA positron emission tomography showed a pathologic uptake of tracer in the head and the uncinate process of the pancreas. Subtotal pancreatectomy was suggested but the patient refused operation: she is taking diazoxide 100 mg three times daily. Coexistence of nesidioblastosis with a neuroendocrine tumour makes preoperative diagnosis and management of severe hypoglycaemia more difficult. Nesidioblastosis should be considered in differential diagnosis of hypoglycaemic syndrome, but histological examination is necessary for a definitive tissue diagnosis. (Endokrynol Pol 2015; 66 (4): 356–360)    Najczęstszą przyczyną hipoglikemii hiperinsulinemicznej u osób dorosłych jest insulinoma. Chociaż przetrwała hipoglikemia hiperinsulinemiczna to rzadkie, lecz łatwo rozpoznawalne zaburzenie przetrwałej hipoglikemii u noworodków, bardzo rzadko występuje u osób dorosłych. Autorzy badania przedstawiają przypadek 59-letniej kobiety z niewielkim guzem neuroendokrynnym ogona trzustki, zdiagnozowanym dzięki tomografii komputerowej oraz rezonansowi magnetycznemu, oraz zespołem hipoglikemicznym. Wykonano laparoskopową dystalną pankreatektomię, a badanie patologiczne wykazało wysoko zróżnicowanego, nieaktywnego, endokrynnego wyspiaka trzustki oraz rozlaną przetrwałą hipoglikemię hiperinsulinemiczną w pozostałej części gruczołu. We wczesnym okresie pooperacyjnym wystąpiła nawracająca hipoglikemia, mimo stosowania doustnego leczenia diazoksydem. Stężenie proinsuliny w osoczu był bardzo wysoki. Pozytonowa tomografia emisyjna z 18F-DOPA wykazała patologiczną absorpcję znacznika w głowie i wyrostku haczykowatym trzustki. Sugerowano subtotalną pankreatektomię, lecz pacjentka nie zgodziła się na operację: przyjmowała dawkę 100 mg diazoksydu trzy razy dziennie. Współistnienie przetrwałej hipoglikemii hiperinsulinemicznej z nowotworem neuroendokrynnym utrudnia diagnostykę przedoperacyjną i leczenie ciężkiej hipoglikemii. Przetrwała hipoglikemia hiperinsulinemiczna powinna być brana pod uwagę w diagnozie różnicującej zespół hipoglikemiczny, lecz badanie histologiczne jest niezbędne do definitywnej diagnozy tkanek. (Endokrynol Pol 2015; 66 (4): 356–360)