The Glucose Transporter 2 regulates CD8+ T cell function via environment sensing

T cell activation is associated with a profound and rapid metabolic response to meet increased energy demands for cell division, differentiation and development of effector function. Glucose uptake and engagement of the glycolytic pathway are major checkpoints for this event. Here we show that the low-affinity, concentration-dependent glucose transporter 2 (Glut2) regulates the development of CD8+ T cell effector responses in mice by promoting glucose uptake, glycolysis and glucose storage. Expression of Glut2 is modulated by environmental factors including glucose and oxygen availability and extracellular acidification. Glut2 is highly expressed by circulating, recently primed T cells, allowing efficient glucose uptake and storage. In glucose-deprived inflammatory environments, Glut2 becomes downregulated, thus preventing passive loss of intracellular glucose. Mechanistically, Glut2 expression is regulated by a combination of molecular interactions involving hypoxia-inducible factor-1 alpha, galectin-9 and stomatin. Finally, we show that human T cells also rely on this glucose transporter, thus providing a potential target for therapeutic immunomodulation

Guidelines for autopsy investigation of sudden cardiac death: 2017 update from the Association for European Cardiovascular Pathology.

Although sudden cardiac death (SCD) is one of the most important modes of death in Western countries, pathologists and public health physicians have not given this problem the attention it deserves. New methods of preventing potentially fatal arrhythmias have been developed and the accurate diagnosis of the causes of SCD is now of particular importance. Pathologists are responsible for determining the precise cause and mechanism of sudden death but there is still considerable variation in the way in which they approach this increasingly complex task. The Association for European Cardiovascular Pathology has developed these guidelines, which represent the minimum standard that is required in the routine autopsy practice for the adequate investigation of SCD. The present version is an update of our original article, published 10 years ago. This is necessary because of our increased understanding of the genetics of cardiovascular diseases, the availability of new diagnostic methods, and the experience we have gained from the routine use of the original guidelines. The updated guidelines include a detailed protocol for the examination of the heart and recommendations for the selection of histological blocks and appropriate material for toxicology, microbiology, biochemistry, and molecular investigation. Our recommendations apply to university medical centers, regionals hospitals, and all healthcare professionals practicing pathology and forensic medicine. We believe that their adoption throughout Europe will improve the standards of autopsy practice, allow meaningful comparisons between different communities and regions, and permit the identification of emerging patterns of diseases causing SCD. Finally, we recommend the development of regional multidisciplinary networks of cardiologists, geneticists, and pathologists. Their role will be to facilitate the identification of index cases with a genetic basis, to screen appropriate family members, and ensure that appropriate preventive strategies are implemented

Idiopathic noncirrhotic portal hypertension: current perspectives

Oliviero Riggio,1 Stefania Gioia,1 Ilaria Pentassuglio,1 Valeria Nicoletti,1 Michele Valente,2 Giulia d’Amati2 1Department of Clinical Medicine, Center for the Diagnosis and Treatment of Portal Hypertension, 2Department of Radiological, Oncological, and Pathological Sciences, Sapienza University of Rome, Rome, Italy Abstract: The term idiopathic noncirrhotic portal hypertension (INCPH) has been recently proposed to replace terms, such as hepatoportal sclerosis, idiopathic portal hypertension, incomplete septal cirrhosis, and nodular regenerative hyperplasia, used to describe patients with a hepatic presinusoidal cause of portal hypertension of unknown etiology, characterized by features of portal hypertension (esophageal varices, nonmalignant ascites, porto-venous collaterals), splenomegaly, patent portal, and hepatic veins and no clinical and histological signs of cirrhosis. Physicians should learn to look for this condition in a number of clinical settings, including cryptogenic cirrhosis, a disease known to be associated with INCPH, drug administration, and even chronic alterations in liver function tests. Once INCPH is clinically suspected, liver histology becomes mandatory for the correct diagnosis. However, pathologists should be familiar with the histological features of INCPH, especially in cases in which histology is not only requested to exclude liver cirrhosis. Keywords: idiopathic portal hypertension, obliterative portal venopathy, esophageal varices, splenomegal

Idiopathic noncirrhotic portal hypertension: current perspectives

Oliviero Riggio,1 Stefania Gioia,1 Ilaria Pentassuglio,1 Valeria Nicoletti,1 Michele Valente,2 Giulia d’Amati2 1Department of Clinical Medicine, Center for the Diagnosis and Treatment of Portal Hypertension, 2Department of Radiological, Oncological, and Pathological Sciences, Sapienza University of Rome, Rome, Italy Abstract: The term idiopathic noncirrhotic portal hypertension (INCPH) has been recently proposed to replace terms, such as hepatoportal sclerosis, idiopathic portal hypertension, incomplete septal cirrhosis, and nodular regenerative hyperplasia, used to describe patients with a hepatic presinusoidal cause of portal hypertension of unknown etiology, characterized by features of portal hypertension (esophageal varices, nonmalignant ascites, porto-venous collaterals), splenomegaly, patent portal, and hepatic veins and no clinical and histological signs of cirrhosis. Physicians should learn to look for this condition in a number of clinical settings, including cryptogenic cirrhosis, a disease known to be associated with INCPH, drug administration, and even chronic alterations in liver function tests. Once INCPH is clinically suspected, liver histology becomes mandatory for the correct diagnosis. However, pathologists should be familiar with the histological features of INCPH, especially in cases in which histology is not only requested to exclude liver cirrhosis. Keywords: idiopathic portal hypertension, obliterative portal venopathy, esophageal varices, splenomegal

Systemic administration of the PARP-1 inhibitor GPI 15427 increases the antitumor activity of temozolomide against metastatic melanoma.

We previously demonstrated that the antitumor activity of temozolomide (TMZ) can be enhanced at the CNS site by intracerebral injection of a PARP-1 inhibitor that does not permeate the blood-brain barrier [1]. TMA is an anticancer agent with promising activity against metastatic melanoma [2,3]. Here we tested whether systemic administration of GPI 15427, a novel PARP inhibitor capable of crossing the blood-brain barrier, could enhance the anti-tumor efficacy of TMZ against melanoma involving the CNS site. The efficacy of the drug treatment was also tetsed against lung metastases.ùMurine B16 melanoma cells were injected intracranially in syngeneic mice. Animals were treated for three days with TMZ (100 mg/kg, i.p.) +/- GPI 15427 (1mg/mouse, i.v.) when neoplastin infiltration of the brain tissue was evident in histological sections. Administration of shortly before TMZ significantly increased life-span of tumor-bearing mice with respect to untreated controls, or to group treated with either GPI 15427 or TMZ only (P<0.0001). The increase in survival detected in the group treated with the drug combination was accompanied by a marked reduction of tumor ingiltration in the brain, as evidenced by histological studies. GPI 15427 aslo enhanced the anti-metastatic acitivity of TMZ. In fact, the number of pulmonary metastases obtained after iv injection of B16 cells was significantly lower in mice treated with GPI 15427+TMZ than in those receiving TMZ only (P=0.004). In conclusion, these data indicate that systemic administration of GPI 15427 induces significant enhancement of TMZ anti-tumor activity against melanoma, even at the CNS site

Systemic administration of the PARP-1 inhibitor GPI 15427 increases the antitumor activity of temozolomide against metastatic melanoma.

We previously demonstrated that the antitumor activity of temozolomide (TMZ) can be enhanced at the CNS site by intracerebral injection of a PARP-1 inhibitor that does not permeate the blood-brain barrier [1]. TMA is an anticancer agent with promising activity against metastatic melanoma [2,3]. Here we tested whether systemic administration of GPI 15427, a novel PARP inhibitor capable of crossing the blood-brain barrier, could enhance the anti-tumor efficacy of TMZ against melanoma involving the CNS site. The efficacy of the drug treatment was also tetsed against lung metastases.ùMurine B16 melanoma cells were injected intracranially in syngeneic mice. Animals were treated for three days with TMZ (100 mg/kg, i.p.) +/- GPI 15427 (1mg/mouse, i.v.) when neoplastin infiltration of the brain tissue was evident in histological sections. Administration of shortly before TMZ significantly increased life-span of tumor-bearing mice with respect to untreated controls, or to group treated with either GPI 15427 or TMZ only (P<0.0001). The increase in survival detected in the group treated with the drug combination was accompanied by a marked reduction of tumor ingiltration in the brain, as evidenced by histological studies. GPI 15427 aslo enhanced the anti-metastatic acitivity of TMZ. In fact, the number of pulmonary metastases obtained after iv injection of B16 cells was significantly lower in mice treated with GPI 15427+TMZ than in those receiving TMZ only (P=0.004). In conclusion, these data indicate that systemic administration of GPI 15427 induces significant enhancement of TMZ anti-tumor activity against melanoma, even at the CNS site

Systemic administration of the PARP inhibitor GPI 15427 increases the anti-tumor activity of temozolomide in melanoma, glioma and lymphoma preclinical models in vivo

Temozolomide (TMZ) is a DNA methylating agent that in recent clinical trials has shown promising antitumor activity against high grade gliomas, metastatic melanoma and brain lymphoma. We previously demonstrated that the anti-tumor activity of TMZ against L5178Y lymphoma cells growing in the brain can be enhanced by intra-cerebral injection of a poly(ADP-ribose) polymerase (PARP) inhibitor. In this study we tested whether systemic administration of GPI 15427, a novel PARP inhibitor capable of crossing the blood-brain barrier, could enhance the anti-tumor efficacy of TMZ against CNS lymphoma or against an orthotopic xenograft of human glioblastoma multiforme. Animals were treated for three consecutive days with TMZ (100 mg/Kg, ip) +/- GPI 15427 (1 mg/mouse, iv) when neoplastic infiltration of the brain tissue was evident in histological sections. This schedule was chosen on the basis of preliminary toxicological studies that showed drug-related death only after 4 consecutive daily doses of the drug combination. In both lymphoma and glioma models systemic administration of GPI 15427 shortly before TMZ significantly increased life span of tumor bearing mice with respect to untreated controls, or to groups treated with GPI 15427 or TZM used as single agents (P< 0.01). The GPI 15427 + TMZ combination was also tested against B16 melanoma inoculated in BDF1 syngeneic mice. In this case, treatment of mice was started when the tumor was palpable. Combined treatment with GPI 15427 + TMZ significantly reduced tumor growth with respect to TMZ only (P< 0.01). In conclusion, these data indicate that systemic administration of the PARP inhibitor GPI 15427, at a tolerable dose, induces significant enhancement of TMZ anti-tumor efficacy against hematological or solid neoplasias

Systemic administration of the PARP inhibitor GPI 15427 increases the anti-tumor activity of temozolomide in melanoma, glioma and lymphoma preclinical models in vivo

Temozolomide (TMZ) is a DNA methylating agent that in recent clinical trials has shown promising antitumor activity against high grade gliomas, metastatic melanoma and brain lymphoma. We previously demonstrated that the anti-tumor activity of TMZ against L5178Y lymphoma cells growing in the brain can be enhanced by intra-cerebral injection of a poly(ADP-ribose) polymerase (PARP) inhibitor. In this study we tested whether systemic administration of GPI 15427, a novel PARP inhibitor capable of crossing the blood-brain barrier, could enhance the anti-tumor efficacy of TMZ against CNS lymphoma or against an orthotopic xenograft of human glioblastoma multiforme. Animals were treated for three consecutive days with TMZ (100 mg/Kg, ip) +/- GPI 15427 (1 mg/mouse, iv) when neoplastic infiltration of the brain tissue was evident in histological sections. This schedule was chosen on the basis of preliminary toxicological studies that showed drug-related death only after 4 consecutive daily doses of the drug combination. In both lymphoma and glioma models systemic administration of GPI 15427 shortly before TMZ significantly increased life span of tumor bearing mice with respect to untreated controls, or to groups treated with GPI 15427 or TZM used as single agents (P< 0.01). The GPI 15427 + TMZ combination was also tested against B16 melanoma inoculated in BDF1 syngeneic mice. In this case, treatment of mice was started when the tumor was palpable. Combined treatment with GPI 15427 + TMZ significantly reduced tumor growth with respect to TMZ only (P< 0.01). In conclusion, these data indicate that systemic administration of the PARP inhibitor GPI 15427, at a tolerable dose, induces significant enhancement of TMZ anti-tumor efficacy against hematological or solid neoplasias