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Proteins of the BCL2 family are key regulators of apoptosis. Their expression levels are frequently altered in cancers, enabling tumor cells to survive. To gain insight into the pathogenesis of hepatocellular carcinoma (HCC), we performed a comprehensive survey of the expression of the members of the BCL2 family in samples obtained from surgically resected HCCs. Here, we report the occurrence of a new molecular anomaly, consisting of a strong reduction in the expression of the proapoptotic protein BAD in HCC compared with surrounding nontumoral tissue. We investigate the function of BAD in a panel of HCC cell lines. Using gene overexpression and RNA interference, we show that BAD is involved in the cytotoxic effects of sorafenib, a multikinase blocker, which is currently the sole therapeutic drug effective for the treatment of HCC. Finally, we report that ABT-737, a compound that interacts with proteins of the BCL2 family and exhibits a BAD-like reactivity, sensitizes HCC cells toward sorafenib-induced apoptosis. Collectively, our findings indicate that BAD is a key regulator of apoptosis in HCC and an important determinant of HCC cell response to sorafenib. Mol Cancer Res; 8(8); 1116–25. ©2010 AACR.

Supplementary Figures S1-S6; Supplementary Materials and Methods; Supplementary Table S1.

OBJECTIVES: To assess the usefulness of histopathologic examination in forensic autopsies. MATERIAL AND METHODS: All consecutive pathological reports and slides from forensic autopsies performed in our department since 2006 have been reviewed. RESULTS: Four hundred forensic necropsies were reviewed. In only 150 cases (38%), pathologists had data about manner of death and gross autopsy findings. Major diagnoses, related to death, and unsuspected by forensic pathologists, were discovered in 83 cases (21%): in 48 cases (12%) gross examination of the heart, lungs and liver showed gross diagnoses missed by the forensic pathologists, and in only 35 cases (9%) microscopic examination revealed a major unsuspected diagnosis (in brain, heart, lungs, liver, kidney and pancreas specimens). In 213 cases (53%), histopathologic examination confirmed gross autopsy findings and allowed to date some wounds. In 104 cases (26%), microscopic examination was not contributory. CONCLUSION: Microscopic examination revealed major diagnoses in less than 10% of forensic autopsies. Its effectiveness is limited for homicides and suicides. Systematic microscopic examination of numerous organs is often useless and should be limited to cases with no anatomic causes of death. Our study emphasizes the need for a better communication between forensic pathologists and histopathologists, and for a better training of some forensic pathologists for gross examination. Language: fr

It is not known whether local factors within the airway wall or parenchyma may influence the emergence and spatial distribution of ventilation defects (VDs), thereby modulating the dynamic system behavior of the lung during bronchoconstriction. We assessed the relationship between the distribution of cellular effectors and the emergence of defects in regional ventilation distribution following allergen challenge. We performed high-resolution K-edge subtraction (KES) synchrotron imaging during xenon inhalation and measured the forced oscillatory input impedance in ovalbumin (OVA)-sensitized Brown-Norway rats ( n = 12) at baseline and repeatedly following OVA challenge. Histological slices with best anatomic matching to the computed tomographic images were stained with a modified May-Grunwald Giemsa and immunohistochemical staining with monoclonal anti-rat CD68, in six rats. Slides were digitized and total cells and eosinophils were counted in the walls of bronchi and vessels randomly selected within and outside of VDs on the basis of xenon-KES images. Ventilated alveolar area decreased and ventilation heterogeneity, Newtonian resistance, tissue damping, and elastance increased following OVA challenge. Eosinophil, total cell, and CD68+ counts were significantly higher in the bronchial and vascular walls within vs. outside of the VDs. The minimal central airway diameters during OVA-induced bronchoconstriction were correlated with eosinophil ( R = −0.85; P = 0.031) and total cell densities ( R = −0.82; P = 0.046) in the airway walls within the poorly ventilated zones. Our findings suggest that allergic airway inflammation is locally heterogeneous and is topographically associated with the local emergence of VDs following allergen challenge.

In a recent propensity score study, we established that overall- and disease-free survival were worse after use of a colonic stent (CS) than after emergency surgery for colonic obstruction. The present study sought to explain the association between CS use and poor survival by analyzing pathological specimens. From January 1998 to December 2011, all patients with left obstructive colon cancer and having been operated on with curative intent were included in the study. The primary end point involved a comparison of pathological data from the CS- and the surgery-only groups in a case-matched analysis (with the groups matched for the T stage). In a series of secondary analyses, we studied a range of factors known to be associated with adverse outcomes (microscopic perforation, vascular embolism, perineural invasion, and lymph node invasion) in the study population as a whole (in order to evaluate stenting as an adverse factor) and in the CS group alone (in order to identify factors associated with a poor prognosis in this specific group of patients). A total of 84 patients were included in the study (50 in the CS group). Stenting was mentioned in only 70 % of the pathology lab reports (n = 35/50). Twenty-five patients in the CS group were matched with 25 patients of the surgery-only group. Tumor ulceration (p

Background & Aims To assess the accuracy of pathology reports in patients operated on for hilar cholangiocarcinoma. Methods Pathology reports for 263 patients operated on in 22 tertiary hepatobiliary centers were reviewed. The report format, turnaround time, tissue specimens, intraoperative consultations, macroscopic and microscopic descriptions, and conclusions were assessed. Results Surgeons provided pathologists with pertinent clinical and imaging data in only 14% of cases and gave information on specimen orientation in only 24% of cases. The reports frequently failed to give information on prognostic histological factors: tumor differentiation (missing in 27% of cases), vascular invasion (45%), tumor thickness (99%), and infiltration of the bile duct surgical margins (4%). Distances between the tumor and the vessel margin, liver margin and the periductal soft tissue circumferential margin were not specified in 87%, 79%, and 89% of cases, respectively. Only 21% of the reports gave the pTNM stage in the conclusion section. A lack of information prevented retrospective pTNM staging in 48% of cases. Three percent of the reports had discrepancies in their conclusion section. Conclusions Our French, nationwide study revealed that pathology reports on hilar cholangiocarcinoma frequently lack important information on the main prognostic histological factors and pTNM staging. We recommend the use of a standardized pathology report in this context.

Proteins of the BCL2 family are key regulators of apoptosis. Their expression levels are frequently altered in cancers, enabling tumor cells to survive. To gain insight into the pathogenesis of hepatocellular carcinoma (HCC), we performed a comprehensive survey of the expression of the members of the BCL2 family in samples obtained from surgically resected HCCs. Here, we report the occurrence of a new molecular anomaly, consisting of a strong reduction in the expression of the proapoptotic protein BAD in HCC compared with surrounding nontumoral tissue. We investigate the function of BAD in a panel of HCC cell lines. Using gene overexpression and RNA interference, we show that BAD is involved in the cytotoxic effects of sorafenib, a multikinase blocker, which is currently the sole therapeutic drug effective for the treatment of HCC. Finally, we report that ABT-737, a compound that interacts with proteins of the BCL2 family and exhibits a BAD-like reactivity, sensitizes HCC cells toward sorafenib-induced apoptosis. Collectively, our findings indicate that BAD is a key regulator of apoptosis in HCC and an important determinant of HCC cell response to sorafenib. Mol Cancer Res; 8(8); 1116–25. ©2010 AACR.

To assess the usefulness of histopathologic examination in forensic autopsies.All consecutive pathological reports and slides from forensic autopsies performed in our department since 2006 have been reviewed.Four hundred forensic necropsies were reviewed. In only 150 cases (38%), pathologists had data about manner of death and gross autopsy findings. Major diagnoses, related to death, and unsuspected by forensic pathologists, were discovered in 83 cases (21%): in 48 cases (12%) gross examination of the heart, lungs and liver showed gross diagnoses missed by the forensic pathologists, and in only 35 cases (9%) microscopic examination revealed a major unsuspected diagnosis (in brain, heart, lungs, liver, kidney and pancreas specimens). In 213 cases (53%), histopathologic examination confirmed gross autopsy findings and allowed to date some wounds. In 104 cases (26%), microscopic examination was not contributory.Microscopic examination revealed major diagnoses in less than 10% of forensic autopsies. Its effectiveness is limited for homicides and suicides. Systematic microscopic examination of numerous organs is often useless and should be limited to cases with no anatomic causes of death. Our study emphasizes the need for a better communication between forensic pathologists and histopathologists, and for a better training of some forensic pathologists for gross examination.