Is porto sinusoidal vascular disease to be actively searched in patients with portal vein thrombosis?

Porto sinusoidal vascular liver disease (PSVD) and portal vein thrombosis (PVT) are distinct vascular liver diseases characterized, respectively, by an intrahepatic and a prehepatic obstacle to the flow in the liver portal system. PVT may also occur as a complication of the natural history of PSVD, especially if a prothrombotic condition coexists. In other cases, it is associated to local and systemic pro-thrombotic conditions, even if its cause remains unknown in up to 25% despite an active search. In our opinion, the presence of PSVD should be suspected in patients with PVT especially in those with PVT "sine causa" and the active search of this condition should be included in their diagnostic work-out. However, sometimes the diagnosis of pre-existing PSVD is very hard. Biopsy cannot be fully discriminant as similar histological data have been described in both conditions. Liver stiffness may help as it has been shown to be higher in PSVD than in "pure" PVT, due to the presence of sclerosis in the portal venous radicles observable in PSVD patients. Nevertheless, comparing liver stiffness between PVT and PSVD has until now been restricted to very limited series of patients. In conclusion, even if it is still totally hypothetical, our point of view may have clinical consequences, especially when deciding to perform a liver biopsy in patients with a higher liver stiffness and suspending the anticoagulation in patients with PVT and no detectable prothrombotic factors

Idiopathic noncirrhotic portal hypertension: current perspectives

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

Chloroquine supplementation increases the cytotoxic effect of curcumin against Her2/neu overexpressing breast cancer cells in vitro and in vivo in nude mice while counteracts it in immune competent mice

Autophagy is usually a pro-survival mechanism in cancer cells, especially in the course of chemotherapy, thus autophagy inhibition may enhance the chemotherapy-mediated anti-cancer effect. However, since autophagy is strongly involved in the immunogenicity of cell death by promoting ATP release, its inhibition may reduce the immune response against tumors, negatively influencing the overall outcome of chemotherapy. In this study, we evaluated the in vitro and in vivo anti-cancer effect of curcumin (CUR) against Her2/neu overexpressing breast cancer cells (TUBO) in the presence or in the absence of the autophagy inhibitor chloroquine (CQ). We found that TUBO cell death induced by CUR was increased in vitro by CQ and slightly in vivo in nude mice. Conversely, CQ counteracted the Cur cytotoxic effect in immune competent mice, as demonstrated by the lack of in vivo tumor regression and the reduction of overall mice survival as compared with CUR-treated mice. Immunohistochemistry analysis revealed the presence of a remarkable FoxP3 T cell infiltrate within the tumors in CUR/CQ treated mice and a reduction of T cytotoxic cells, as compared with single CUR treatment. These findings suggest that autophagy is important to elicit anti-tumor immune response and that autophagy inhibition by CQ reduces such response also by recruiting T regulatory (Treg) cells in the tumor microenvironment that may be pro-tumorigenic and might counteract CUR-mediated anti-cancer effects

Nonischemic left ventricular scar and cardiac sudden death in the young

Nonischemic Left Ventricular Scar (NLVS) is a pattern of myocardial injury characterized by midventricular and/or subepicardial gadolinium hyper enhancement at cardiac magnetic resonance, in absence of significant coronary artery disease. We aimed to evaluate the prevalence of NLVS in juvenile sudden cardiac death and to ascertain its aetiology at autopsy. We examined 281 consecutive cases of sudden death of subjects aged 1 to 35 years of age. NLVS was defined as a thin, grey rim of subepicardial and/or midmyocardial scar in the left ventricular free wall and/or the septum, in absence of significant stenosis of coronary arteries. NLVS was the most frequent finding (25%) in sudden deaths occurring during sports. Myocardial scar was localized most frequently within the left ventricular posterior wall, and affected the subepicardial myocardium, often extending to the midventricular layer. On histology it consisted of fibrous or fibro-adipose tissue. Right ventricular involvement was always present. Patchy lymphocytic infiltrates were frequent. Genetic and molecular analyses clarified the aetiology of NLVS in a subset of cases. ECG recordings were available in over half of subjects. The most frequent abnormality was the presence of low QRS voltages (< 0,5 mV) in limb leads. In serial ECG tracings, the decrease in QRS voltages appeared, in some way progressive. NLVS is the most frequent morphologic substrate of juvenile cardiac sudden death in sports. It can be suspected based on ECG findings. Autopsy study and clinical screening of family members are required to differentiate between Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia and chronic acquired myocarditis

Platelet-derived growth factor C and calpain-3 are modulators of human melanoma cell invasiveness.

The molecular mechanisms responsible for the elevated metastatic potential of malignant melanoma are still not fully understood. In order to shed light on the molecules involved in the acquisition by melanoma of a highly aggressive phenotype, we compared the gene expression profiles of two cell clones derived from the human cutaneous metastatic melanoma cell line M14: a highly invasive clone (M14C2/MK18) and a clone (M14C2/C4) with low ability to invade the extracellular matrix (ECM). The highly invasive phenotype of M14C2/MK18 cells was correlated with overexpression of neuropilin-1, activation of a vascular endothelial growth factor (VEGF)-A/VEGFR-2 autocrine loop and secretion of matrix metalloprotease-2. Moreover, in an in vivo murine model, M14C2/MK18 cells displayed a higher growth rate as compared with M14C2/C4 cells, even though in vitro both clones possessed comparable proliferative potential. Microarray analysis in M14C2/MK18 cells showed a strong upregulation of platelet-derived growth factor (PDGF)-C, a cytokine that contributes to angiogenesis, and downregulation of calpain-3, a calcium-dependent thiol-protease that regulates specific signalling cascade components. Inhibition of PDGF-C with a specific antibody resulted in a significant decrease in ECM invasion by M14C2/MK18 cells, confirming the involvement of PDGF-C in melanoma cell invasiveness. Moreover, the PDGF-C transcript was found to be upregulated in a high percentage of human melanoma cell lines (17/20), whereas only low PDGF-C levels were detected in a few melanocytic cultures (2/6). By contrast, inhibition of calpain-3 activity in M14C2/C4 control cells, using a specific chemical inhibitor, markedly increased ECM invasion, strongly suggesting that downregulation of calpain-3 plays a role in the acquisition of a highly invasive phenotype. The results indicate that PDGF-C upregulation and calpain-3 downregulation are involved in the aggressiveness of malignant melanoma and suggest that modulators of these proteins or their downstream effectors may synergise with VEGF‑A therapies in combating tumour-associated angiogenesis and melanoma spread

NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest.

Notch dysregulation has been implicated in numerous tumors, including triple-negative breast cancer (TNBC), which is the breast cancer subtype with the worst clinical outcome. However, the importance of individual receptors in TNBC and their specific mechanism of action remain to be elucidated, even if recent findings suggested a specific role of activated-Notch3 in a subset of TNBCs. Epidermal growth factor receptor (EGFR) is overexpressed in TNBCs but the use of anti-EGFR agents (including tyrosine kinase inhibitors, TKIs) has not been approved for the treatment of these patients, as clinical trials have shown disappointing results. Resistance to EGFR blockers is commonly reported. Here we show that Notch3-specific inhibition increases TNBC sensitivity to the TKI-gefitinib in TNBC-resistant cells. Mechanistically, we demonstrate that Notch3 is able to regulate the activated EGFR membrane localization into lipid rafts microdomains, as Notch3 inhibition, such as rafts depletion, induces the EGFR internalization and its intracellular arrest, without involving receptor degradation. Interestingly, these events are associated with the EGFR tyrosine dephosphorylation at Y1173 residue (but not at Y1068) by the protein tyrosine phosphatase H1 (PTPH1), thus suggesting its possible involvement in the observed Notch3-dependent TNBC sensitivity response to gefitinib. Consistent with this notion, a nuclear localization defect of phospho-EGFR is observed after combined blockade of EGFR and Notch3, which results in a decreased TNBC cell survival. Notably, we observed a significant correlation between EGFR and NOTCH3 expression levels by in silico gene expression and immunohistochemical analysis of human TNBC primary samples. Our findings strongly suggest that combined therapies of TKI-gefitinib with Notch3-specific suppression may be exploited as a drug combination advantage in TNBC treatment

Novel compound mutations in the mitochondrial translation elongation factor (TSFM) gene cause severe cardiomyopathy with myocardial fibro-adipose replacement

Primary mitochondrial dysfunction is an under-appreciated cause of cardiomyopathy, especially when cardiac symptoms are the unique or prevalent manifestation of disease. Here, we report an unusual presentation of mitochondrial cardiomyopathy, with dilated phenotype and pathologic evidence of biventricular fibro-adipose replacement, in a 33-year old woman who underwent cardiac transplant. Whole exome sequencing revealed two novel compound heterozygous variants in the TSFM gene, coding for the mitochondrial translation elongation factor EF-Ts. This protein participates in the elongation step of mitochondrial translation by binding and stabilizing the translation elongation factor Tu (EF-Tu). Bioinformatics analysis predicted a destabilization of the EF-Ts variants complex with EF-Tu, in agreement with the dramatic steady-state level reduction of both proteins in the clinically affected myocardium, which demonstrated a combined respiratory chain enzyme deficiency. In patient fibroblasts, the decrease of EF-Ts was paralleled by up-regulation of EF-Tu and induction of genes involved in mitochondrial biogenesis, along with increased expression of respiratory chain subunits and normal oxygen consumption rate. Our report extends the current picture of morphologic phenotypes associated with mitochondrial cardiomyopathies and confirms the heart as a main target of TSFM dysfunction. The compensatory response detected in patient fibroblasts might explain the tissue-specific expression of TSFM-associated disease

Vasculitis and organ pathology: a practical approach to histological diagnosis and clinical-pathologic correlations

Vasculitides are a complex and pleomorphic group of diseases, involving all types of vessels and, potentially, all organs, with heterogeneous clinical manifestations. The clinical diagnosis can be challenging due to the diverse clinical manifestations, variable disease course, and overlapping features with other conditions. Overall, the histopathologic diagnosis is a crucial component in the clinical workup and plays a central role in guiding treatment decisions and prognosis estimation. However, reaching a diagnosis can be challenging, due to the complexity of the disease, and the variability in histological findings of these disorders, often caused by the development of secondary changes that may obscure the diagnostic features. Moreover, vasculitides are relatively rare, and many pathologists are unfamiliar with the disease and their diagnostic criteria, both in the biopsy and autopsy setting. This monographic issue collects papers focused on the updated classification of vasculitis, recommendations for sample histologic processing, and clues to the histopathologic diagnosis in diverse organs and systems, providing a practical approach to this complex disease. We also want to take this opportunity to honor the memory of our friend and colleague G. Rossi with the editorial written by some of his best friends. His great commitment as a pathologist and as a researcher, his personality, full of generous outbursts, and his ability to put himself completely at the service of the institutions in which he served professionally, are a legacy that helps all of us in our daily lives and professions

Matrimonium e Postliminium: brief consideration

Neste trabalho encontra-se breve reflexão do matrimônio, enfatizando o cidadão romano, a permanência da mulher na casa do marido, além de circustâncias e efeitos do ordenamento jurídico da Roma antiga; o divórcio e a condição da viúva são também comentados a partir de fontes greco-romanas.In this write takes place a brief reflection of matrimony, enphasing the Roman citizen, the permanence of woman in husband's house, besides the circunstances and effects of the juridical order; the divorce and the widow's condition are boarded from Greek-Roman fonts