We have developed an innovative system, AI QM Docking Net (AQDnet), which utilizes the three-dimensional structure of protein–ligand complexes to predict binding affinity. This system is novel in two ...respects: first, it significantly expands the training dataset by generating thousands of diverse ligand configurations for each protein–ligand complex and subsequently determining the binding energy of each configuration through quantum computation. Second, we have devised a method that incorporates the atom-centered symmetry function (ACSF), highly effective in describing molecular energies, for the prediction of protein–ligand interactions. These advancements have enabled us to effectively train a neural network to learn the protein–ligand quantum energy landscape (P–L QEL). Consequently, we have achieved a 92.6% top 1 success rate in the CASF-2016 docking power, placing first among all models assessed in the CASF-2016, thus demonstrating the exceptional docking performance of our model.
Fatty change is frequently observed in small hepatocellular carcinoma (HCC) of the early stage. However, the mechanism of fatty change and its pathomorphological features in small HCC are not yet ...fully understood. These issues are addressed here.
Histological examinations were conducted on 260 HCC nodules (< or =3 cm in diameter) which were surgically obtained from 249 patients. According to the distribution pattern, fatty changes were classified into two types: 'diffuse type' when the change was found throughout the cancerous nodule; and 'focal type' when the change was localized in part of the nodule. To study the pathogenesis of fatty change in HCC in relation to angioarchitecture, the number of arterial tumor vessels and intratumoral portal tracts in 104 of the 260 nodules was counted.
Fatty change was found in 51 of the 260 nodules (19.6%), the frequency was highest (36.4%) in the nodules whose diameter was 1.1 to approximately 1.5 cm, and the frequency decreased with the increase in tumor diameter. Small well-differentiated HCCs were often associated with a diffuse type fatty change. With the increase in tumor diameter, moderately differentiated cancerous tissues without associated fatty change appeared, and the focal type was found more frequently. According to the angioarchitecture, in HCCs < or =1.5 cm, the number of intratumoral arteries was significantly smaller in HCCs with fatty change (p<0.05), though the number of intratumoral portal tracts was not significantly different compared with HCCs without fatty change.
These findings suggest that fatty change of small HCC is closely related to the tumor size, the histological grade and insufficient development of the arterial tumor vessels.
Abstract
Motivation
Extended connectivity interaction features (ECIF) is a method developed to predict protein–ligand binding affinity, allowing for detailed atomic representation. It performed very ...well in terms of Comparative Assessment of Scoring Functions 2016 (CASF-2016) scoring power. However, ECIF has the limitation of not being able to adequately account for interatomic distances.
Results
To investigate what kind of distance representation is effective for P-L binding affinity prediction, we have developed two algorithms that improved ECIF’s feature extraction method to take distance into account. One is multi-shelled ECIF, which takes into account the distance between atoms by dividing the distance between atoms into multiple layers. The other is weighted ECIF, which weights the importance of interactions according to the distance between atoms. A comparison of these two methods shows that multi-shelled ECIF outperforms weighted ECIF and the original ECIF, achieving a CASF-2016 scoring power Pearson correlation coefficient of 0.877.
Availability and implementation
All the codes and data are available on GitHub (https://github.com/koji11235/MSECIFv2).
Ramipril-associated hepatotoxicity Yeung, Elaine; Wong, Florence S; Wanless, Ian R ...
Archives of pathology & laboratory medicine (1976)
127, Številka:
11
Journal Article
Recenzirano
Angiotensin-converting enzyme inhibitors are prescribed for many cardiovascular and renal diseases. Adverse hepatic events, especially cholestasis, have rarely been reported with captopril, ...enalapril, lisinopril, and fosinopril. To date, hepatic injury associated with ramipril has not been reported.
To describe 3 patients who developed hepatitis, with or without jaundice, after receiving ramipril.
Medical records and liver biopsies of the 3 patients were reviewed. Clinical, laboratory, and histologic findings were compared with findings in other cases of angiotensin-converting enzyme inhibitor-induced liver injury reported in the literature.
The 3 patients were middle-aged men. In 2 patients, jaundice appeared 4 and 8 weeks after starting ramipril. Bilirubin levels peaked at 15.5 and 5 mg/dL, and alkaline phosphatase values peaked at 957 and 507 U/L. Aminotransferase levels were mildly elevated. Endoscopic retrograde cholangiopancreatography and ultrasonography showed no bile duct obstruction. Liver biopsies from the jaundiced patients were similar, with cholestasis, duct necrosis, and extravasation of bile, ductular proliferation, and portal inflammation. Cholestasis improved in 1 patient 6 weeks after stopping ramipril and was prolonged for 14 months in the other, in whom biliary cirrhosis was present on biopsy. The third patient developed hepatitis without jaundice 3 weeks after starting ramipril; symptoms resolved after stopping the drug. Ramipril-associated liver injury is similar to that seen with other angiotensin-converting enzyme inhibitors, but liver biopsy findings of duct necrosis and extravasation of bile have not been reported previously.
Prolonged cholestatic hepatitis and biliary cirrhosis may result from the use of ramipril. Monitoring of liver enzymes is advisable for patients starting on ramipril.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Acinar cell carcinoma (ACC) of the pancreas is relatively rare, accounting for only approximately 1% of all exocrine pancreatic tumors. A 69‐year‐old man was found to have a mass lesion measuring ...approximately 4 cm in diameter in the pancreatic head on ultrasound, abdominal dynamic CT, and percutaneous transhepatic cholangiography. Magnetic resonance cholangiopancreatography showed defect of the lower common bile duct (CBD) due to obstruction by the tumor cast. Histopathologically, the pancreatic head tumor invaded the main pancreatic duct (MPD) and CBD with extension into the CBD in a form of tumor cast. The tumor cells consisted of a solid proliferation with abundant eosinophilic cytoplasm and round nuclei in an acinar and trabecular fashion. A 55‐year‐old man with upper abdominal pain and nausea, had a cystic lesion approximately 3 cm in size in the pancreatic tail on CT. Histopathologically, the tumor was encapsulated by fibrous capsule and had extensive central necrosis with solid areas in the tumor periphery, and invaded with extension into the MPD in a form of tumor cast. The tumor cells resembled acinar cells in solid growths. Two resected cases of ACC with unusual tumor extension into the CBD and the MPD, respectively, are reported.
We clinicopathologically studied 6 resected cases of cholangiolocarcinoma (CLC) including 2 referred cases from other hospitals. The frequency of CLC was 0.56% of the 708 consecutively resected cases ...of primary liver cancer and the mean age of CLC cases was 66 years. Three of the 6 cases (50%) were hepatitis C virus antibody (HCVab) positive, one (17%) was hepatitis B virus surface antigen (HBsAg) positive, and 2 (33%) were negative to both HCVAb and HBsAg. Serum levels of alpha-fetoprotein were slightly elavated only in 1 case. Clinically, 4 cases were diagnosed as hepatocellular carcinoma (HCC) and 2 cases as cholangiocellular carcinoma (CCC). Grossly, CLCs were whitish in color and solid, not encapsulated, and resembled CCC. Histologically, the tumor cells had eosinophilic cytoplasm with ovoid nuclei, and mild atypia. The tumor proliferated in an anastomosing pattern of Hering's canal-like small glands with an abundant fibrous stroma. Four of the 6 tumors (83%) consisted of only CLC and other 2 tumors contained CCC-like area and HCC-like area in a part of the nodules, respectively. Immunohistochemically, all tumors were positive to cytokeratin (CK) 7. CK8 were also positive in all of 6 cases. These results revealed that CLC had the clinical features resembling HCC but the morphologic features resembling CCC. It is suggested that CLC cells might be derived from Hering's canal or stem cells which have the intermediate features between hepatocytes and bile duct epithelium.
In order to clarify angiogenic mechanism in biliary tract carcinoma, expressions and functions of basic fibroblast growth factor (bFGF) and its receptors (FGFR-1–4), and vascular endothelial growth ...factor (VEGF) and its receptors were investigated by using human biliary tract carcinoma cell lines (KMC-1, KMC-2, KMBC and KMG-C). Expression of bFGF was confirmed in KMC-1 and KMC-2, and that of FGFR-1–4 in all the cell lines except no FGFR-2 in KMC-2. Expression of VEGF was detected in all the cell lines, whereas the cell lines did not express VEGF receptors. Addition of anti-bFGF neutralizing antibody to the medium did not suppress cell proliferation, whereas exogenous bFGF with or without heparin accelerated cell proliferation in all cell lines. Addition of anti-bFGF neutralizing antibody or anti-VEGF neutralizing antibody to the co-culture of human umbilical vascular endothelial cells (HUVEC) and KMC-2 suppressed the proliferation of HUVEC. Surgically obtained cholangiocarcinoma tissues (
n=7) were immunohistochemically negative to bFGF, while six of the seven were positive to VEGF. These findings suggested that human biliary tract carcinoma cells express both bFGF and VEGF not as autocrine growth factors but as angiogenic factors. On the other hand, expression of VEGF was found at a higher frequency than bFGF both in the cell lines and tissues.
Fatty liver disease involves the accumulation of triglycerides in hepatocytes, necrosis of hepatocytes, inflammation, and often fibrosis with progression to cirrhosis. The two-hit model summarizes ...the important early metabolic events leading to hepatocellular necrosis in nonalcoholic steatohepatitis (NASH). In this article, we provide evidence of lipid release from hepatocytes in posttransplant fat necrosis and in NASH and quantify vascular obliteration in a series of biopsies with NASH. Obliteration of small hepatic veins (<30 microm) in small numbers is compensated by collateral flow. Obliteration of larger hepatic veins (>30 microm) is associated with fibrotic collapse lesions that are not easily resorbed. Based on these observations, we propose a new four-step model that includes the later events that lead to cirrhosis after necrosis has occurred. This model is applicable to nonalcoholic fatty liver disease (NAFLD), alcoholic disease, postjejunoileal bypass disease, and posttransplant fat necrosis. The first step is steatosis facilitated by insulin, and the second is necrosis induced by intracellular lipid toxicity or lipid peroxidation, or both, modified by alcohol, drugs, and ischemia. The third step is release of bulk lipid from hepatocytes into the interstitium leading to direct and inflammatory injury to hepatic veins. The fourth step is venous obstruction with secondary collapse and ultimately fibrous septation and cirrhosis.
Carcinoid tumors are common in the duodenum except for in the Vater's papilla 1-9. We report here a case of carcinoid tumor arising in the Vater's papilla with repeated episods of pancreatitis. The ...patient is a 28 year-old-woman who had repeated abdominal pain with elevated serum amylase and had been treated as chronic pancreatitis. Computed tomography (CT) revealed a slight dilatation of the main pancreatic duct from the pancreatic head to the tail, and mild swelling of the pancreas. A submucosal tumor measuring 1.3 cm in diameter was detected in the ampulla of Vater by esophagogastroduodenscopy (EGD), and total papillectomy was performed under the suspicious of carcinoid tumor. The tumor was not encapsulated, 1.0 cm in diameter, undefined, and whitish in color. Histologically monomorphic tumor cells with lightly eosinophlic cytoplasm and round nuclei proliferate in trabecular and solid patterns. Immunohistochemically tumor cells were positive for neuron - specific enolase, chromogranin A and synaptophysin, and the tumor was diagnosed as carcinoid tumor. It should be noted that carcinoid tumor in the ampulla may occur with initial signs of acute or chronic pancreatitis.
This paper presents verification of capacity for generation control system of central load dispatching center. A dynamic power system model considering a central load dispatching center, load model, ...power system model and generator model for verification of generation control system is developed. The dynamic power system model is evaluation of validity and consider of optimal LFC system. The application scope of a dynamic power system model is verified.
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