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Introduction: To determine if treatment and clinical outcomes of adrenocortical carcinoma (ACC) vary by race and insurance status., Methods: ACC patients from the National Cancer Database (2004-2017) were reviewed. Race was defined as White versus minority (Black and Hispanic). Insurance types were private (PI) versus other (Medicaid/uninsured/unknown). Metastatic ACC (M-ACC) was defined as distant metastases at the time of diagnosis; nonmetastatic ACC (NM-ACC) patient had no distant disease., Results: Of 2351 NM-ACC patients, 83.6% were White and 16.4% minority. There were 1216 M-ACC patients, with 80.3% White and 19.8% minority. Both White NM-ACC and M-ACC patients had more PI (each P < 0.001). PI NM-ACC was associated with a shorter duration from diagnosis to first treatment (14 versus 18 d, P = 0.005). Both NM-ACC and M-ACC with PI were more likely to receive surgery (92.6% versus 86.9%, P = 0.001 and 35.4% versus 27%, P = 0.02) and to receive surgery sooner (13 versus 16 d, P = 0.03). M-ACC with PI were more likely to receive chemotherapy (63.6% versus 54.3%, P = 0.01) and to have lymph nodes examined (14.8% versus 8.6%, P = 0.02). Length of stay postoperatively was shorter for White NM-ACC (6 versus 7 d, P = 0.04) and M-ACC (8 versus 17 d, P = 0.02). For NM-ACC and M-ACC, the 30-d readmission, 90-d mortality, and overall survival were similar by race. A multivariable analysis showed minorities (OR 0.69, 95% confidence interval 0.54-0.88, P = 0.003) and patients without PI (OR 0.75, 95% confidence interval 0.58-0.97, P = 0.03) were less likely to have surgery. However, a multivariable analysis showed survival was similar for White versus minority patients and PI versus other., Conclusions: White NM-ACC or M-ACC and PI were more likely to receive surgery and timely multimodality care. These disparities were not associated with differences in 90-d mortality or overall survival., (Copyright © 2022. Published by Elsevier Inc.)

Porcine epidemic diarrhea (PED) virus (PEDV) is a coronavirus that primarily infects porcine intestinal epithelial cells and causes severe diarrhea and high fatality in piglets. A77 1726 is the active metabolite of leflunomide, a clinically approved anti-rheumatoid arthritis (RA) drug. A77 1726 inhibits the activity of protein tyrosine kinases (PTKs), p70 S6 kinase (S6K1), and dihydroorotate dehydrogenase (DHO-DHase). Whether A77 1726 can control coronavirus infections has not been investigated. Here we report that A77 1726 effectively restricted PEDV replication by inhibiting Janus kinases (JAKs) and Src kinase activities but not by inhibiting DHO-DHase and S6K1 activities. Overexpression of Src, JAK2 or its substrate STAT3 enhanced PEDV replication and attenuated the antiviral activity of A77 1726. Our study demonstrates for the first time the ability of A77 1726 to control coronavirus replication by inhibiting PTK activities. Leflunomide has potential therapeutic value for the control of PEDV and other coronavirus infections., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Activation of c-Jun terminal kinase (JNK) by the nonstructural protein 1 (NS1) of the H5N1 subtype of influenza A virus (IAV) plays an important role in inducing autophagy and virus replication. However, the mechanisms of NS1-induced JNK activation remain elusive. Here we first confirmed the ability of H5N1 (A/mallard/Huadong/S/2005) to activate JNK and to induce autophagy in 293T cells, a human embryonic kidney cell line. We further showed that TAK1, MAP kinase kinase 4 (MKK4), and JNK were activated in 293T cells transfected with the NS1 gene of the H5N1 virus. JNK activation by the NS1 protein or by H5N1 virus was blocked by 5Z-7-Oxozeaenol (5Z), a TAK1-specific inhibitor, and by TAK1 siRNA. Further study showed that 5Z and TAK1 siRNA suppressed H5N1 virus-induced autophagy and inhibited virus replication. Our study unveiled a previously unrecognized role of TAK1 in IAV replication, IAV-induced JNK activation, and autophagy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The non-structural protein 1 (NS1) of different influenza A virus (IAV) strains can differentially regulate the activity of c-Jun terminal kinase (JNK) and PI-3 kinase (PI3K). Whether varying JNK and PI3K activation impacts autophagy and IAV replication differently remains uncertain. Here we report that H5N1 (A/mallard/Huadong/S/2005) influenza A virus induced functional autophagy, as evidenced by increased LC3 lipidation and decreased p62 levels, and the presence of autolysosomes in chicken fibroblast cells. H9N2 (A/chicken/Shanghai/F/98) virus weakly induced autophagy, whereas H1N1 virus (A/PR/8/34, PR8) blocked autophagic flux. H5N1 virus activated JNK but inhibited the PI-3 kinase pathway. In contrast, N9N2 virus infection led to modest JNK activation and strong PI-3 kinase activation; whereas H1N1 virus activated the PI-3 kinase pathway but did not activate JNK. SP600125, a JNK inhibitor, inhibited H5N1 virus-induced autophagy and virus replication in a DF-1 chicken fibroblast cell line. Our study uncovered a previously unrecognized role of JNK in IAV replication and autophagy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: 25-OH Vitamin D (VitD) plays a role in serum calcium (Ca) and parathyroid hormone (PTH) homeostasis. VitD insufficiency in patients with primary hyperparathyroidism (HPT) may be associated with greater disease severity and a higher incidence of multi-gland disease and postoperative normocalcemic PTH elevation., Materials and Methods: One hundred ten patients with HPT undergoing parathyroidectomy had preoperative VitD levels as follows: levels were insufficient (< or =20 ng/mL) in 55 patients (group 1) and sufficient (>20 ng/mL) in 55 patients (group 2). All patients had preoperative localizing sestamibi scans and/or ultrasounds and postoperative serum Ca and PTH levels. A focused approach was performed when possible, and intraoperative PTH monitoring (IPM) was used in all patients., Results: Patients with VitD insufficiency had significantly higher preoperative Ca (11.3 +/- 1.2 versus 10.8 +/- 0.9 mg/dL, P = 0.012) and PTH levels (204 +/- 138 versus 156 +/- 179 pg/mL; P = 0.006) as well as higher bone specific alkaline phosphatase (P = 0.006). Localization studies were similar. IPM levels were significantly higher in group 1 at all time intervals. Both groups were similar in operative time, conversions to bilateral explorations, number of glands removed, and number of frozen sections. The glands in group 1 were larger (1757 versus 524 g; P = 0.005). Postoperative Ca levels, PTH levels, rates of eucalcemia, and rates of eucalcemic PTH elevation were all similar., Conclusion: Patients with HPT and VitD insufficiency may have significantly more severe disease based on preoperative serum Ca and PTH levels, bone markers, and gland size. IPM levels in these patients are higher but can be used to predict postoperative eucalcemia, an outcome which appears be independent of VitD status.

Background: Intraoperative intact parathyroid hormone (iPTH) monitoring is useful in the operative management of hyperparathyroidism. Recent studies suggest that measurement of intraoperative total serum calcium (TSC) levels may be a more cost effective and readily available method of intraoperative guidance during neck dissection than iPTH levels, the gold standard. We compared the accuracy of intraoperative TSC to iPTH in predicting surgical cure during parathyroidectomy., Patients and Methods: From September 1, 2001 to October 31, 2002, 88 parathyroidectomies were performed. iPTH and TSC were measured at the start of the operation, and at 5 and 10 min after gland removal. Data were compared, and trends were analyzed with respect to removal of abnormal parathyroid tissue as confirmed by pathology. One-way analysis of variance was used to determine if decreases in TSC were significant., Results: The mean baseline iPTH level (418 +/- 610 pg/ml) dropped by 70% 5 min after removal of the abnormal glands (86 +/- 102 pg/ml) and by 85% at 10 min (39 +/- 39 pg/ml). The mean baseline TSC level (10.0 +/- 0.8 mg/dl) dropped by 4% at 5 min after removal of the abnormal glands (9.6 +/- 0.9 mg/dl) and remained at 4% at 10 min (9.6 +/- 0.8 mg/dl). iPTH dropped by > or =50% in 73 patients (83%) at 5 min and in 87 patients (99%) at 10 min after gland resection. TSC decreased below baseline at 5 min and remained below baseline at 10 min in only 47 patients (54%). In the remaining patients, intraoperative TSC changes were less predictable and did not respond consistently to resection of abnormal glands., Conclusions: The decreases in TSC during parathyroidectomy, if present, are minimal. Unlike iPTH levels, TSC levels do not consistently decrease at 5 and 10 min after gland resection. While attractive in terms of cost and availability, intraoperative TSC levels are not clinically reliable in confirming removal of abnormal parathyroid tissue.

Introduction: Extracellular matrix (ECM) degradation is an essential step that allows tumor cells to penetrate a tissue barrier and become metastatic. Heparanase-1 (HPR) is an endoglycosidase that specifically degrades heparan sulfate proteoglycans, a chief component of the ECM. Previous studies have demonstrated HPR expression in various malignancies and that there is differential HPR expression between benign and malignant tumors. Currently, there is no technique that can reliably predict the malignant behavior of some pheochromocytomas. This study tests whether HPR is differentially expressed in malignant and benign pheochromocytomas., Methods: Paraffin-embedded specimens from 29 pheochromocytomas were evaluated. The tissues were collected from surgical specimens over a 10-year period from 26 patients (8 males, 18 females) with a mean age of 47 years (range 19-78 years, median 47 years). One female patient underwent 3 separate operations for malignant pheochromocytoma and thus provided 3 specimens. Another female patient had both the primary tumor and a liver metastasis processed, and therefore provided 2 specimens. Patient charts and pathology reports were reviewed to classify the pheochromocytomas as either benign or malignant. Based on clinical behavior and/or pathological evidence of metastasis or invasion into surrounding tissues, 10 specimens were malignant and 19 had benign behavior. As a control, normal adrenal tissue from 3 nephrectomy specimens was included in the study, as was tissue from 1 adrenocortical adenoma. All 33 specimens were tested for HPR gene expression by in situ hybridization (ISH) with an antisense RNA probe and immunohistochemistry (IHC) with an anti-HPR antibody. Statistical analysis was done using the chi(2) test of proportions to determine if HPR expression correlated with malignancy using ISH, IHC, or both tests together., Results: Using ISH, the percentage of HPR expression in the malignant pheochromocytomas was 50% while HPR expression in the benign tumors was 21% (P = 0.11). Using IHC, the percentage of HPR expression in the malignant pheochromocytomas was 80% while HPR expression in the benign tumors was 32% (P = 0.01). Considering both tests cumulatively, all 10 malignant pheochromocytomas stained positive for HPR by ISH and IHC, while only 37% of the benign tumors were positive for HPR expression (P = 0.001). The one adrenal adenoma and the 3 normal adrenal glands processed stained negative for HPR expression by both ISH and IHC., Conclusions: HPR expression is higher in malignant pheochromocytomas than in benign pheochromocytomas or normal tissue. HPR may contribute to the invasive characteristics of malignant pheochromocytomas and might be used as a marker to distinguish malignant from benign pheochromocytomas. HPR expression might also be used as a prognostic tool in guiding long-term patient follow-up.

Bacterial translocation (BT) from the gastrointestinal tract to mesenteric lymph nodes (MLN) and other extraintestinal organs is an important source of infection in acute pancreatitis (AP). Epidermal growth factor (EGF), a peptide hormone with trophic effects on gut mucosa, has decreased intestinal mucosal injury in septic rats and decreased burn-induced BT in mice. The purpose of this study is to examine whether EGF could affect BT in acute necrotizing pancreatitis. Forty-eight male Sprague-Dawley rats (250-350 g) were studied. AP was induced in Group I and Group II by pressure injection of 3% taurocholate and trypsin into the biliopancreatic duct (1 ml/kg of body weight). Group III and Group IV underwent laparotomy without induction of acute pancreatitis. Group I rats received human recombinant EGF (100 micrograms/kg, subcutaneously twice daily) and Group II rats received a similar volume of 0.1% bovine serum albumin as a placebo postoperatively. Group III and Group IV received EGF and placebo, respectively. At 48 hr postoperatively, blood was drawn for culture and amylase determinations. Jejunum and ileum were obtained to measure mucosal protein content, mucosal thickness, villus height, and crypt depth. Specimens from MLN, spleen, liver, pancreas, and cecum were harvested for pathology and culture of gram positive (G+), gram negative (G-), and anaerobic bacteria. Ileal mucosal protein levels were increased significantly in Group I (1.96 +/- 0.14 mg/cm) compared to Group II (0.95 +/- 0.15 mg/cm intestinal segment) (P < 0.01). Jejunal and ileal mucosal thickness, villus height, and crypt depth in Group I were significantly increased when compared to Group II (P < 0.05). All 12 rats in Group II had BT to MLN compared to 58% (7 of 12 rats) in Group I (P < 0.05). Thirty-three percent (4 of 12 rats) had BT to distant sites such as pancreas, spleen, liver, and/or blood in Group I vs 83% (10 of 12 rats) in Group II (P < 0.05). EGF treatment minimizes intestinal damage, decreases BT to MLN and bacterial spread to distant sites, and may be beneficial in preventing septic complications in AP.

Calcitonin gene-related peptide (CGRP) is a potent vasodilator, but its effects on in situ ventricular function are unknown. We studied effects of intracoronary CGRP (100, 200, and 600 pmole/min, for 10 min) in 21 open-chest chloralose-anesthetized dogs. Systemic, pulmonary, left ventricular (LVP), central venous, and pulmonary capillary wedge pressures were continuously monitored. Left ventricular wall thickness (WT) and circumflex coronary blood flow were also measured. CGRP was infused into the proximal circumflex artery. During CGRP infusion there were no changes in heart rate, cardiac index, pulmonary artery pressure, or systemic vascular resistance, no percentage change in ventricular WT, and no changes in dWT/dt, peak dP/dt, or the slope of end-systolic points on WT/LVP loops. But there were significant changes in coronary flow (CQ), coronary resistance (CRES) and mean arterial blood pressure (MAP) from control (C)* (P less than 0.05). (table; see text) CGRP is a potent coronary artery vasodilator causing notable dose-dependent decreases in coronary resistance and a rise in myocardial flow, despite a decreased MAP (all P less than 0.05). CGRP does not affect ventricular contractility in vivo.

The effects of human pancreatic fluid (HPF) on platelet aggregation and activation were studied. HPF, obtained at operation from nine patients with chronic pancreatitis and two with pancreas cancer, was pooled, lyophilized, and adjusted to a concentration of 1 mg protein/cc of 0.9% saline after dialysis. Platelet aggregation was evaluated by measuring platelet count after iv administration of HPF to five rabbits in concentrations ranging from 0.2 to 2.0 mg/kg. Platelet activation was evaluated by adding 0.1-ml aliquots of pooled HPF in various concentrations to 0.9 ml of human platelet-rich plasma. After a 15-min incubation at 37 degrees C, the platelets were removed by centrifugation and the supernatant examined for platelet-release products. Serotonin was measured by high-performance liquid chromatography (HPLC) and platelet factor 4 and thromboxane B2 were measured by radioimmunoassay. A significant decrease in rabbit platelet count signifying platelet aggregation was seen after iv administration of 1.0 mg/kg (P less than 0.05) and 2.0 mg/kg (P less than 0.001) HPF. Platelet activation was confirmed by a significant increase (P less than 0.05) in serotonin, platelet factor 4, and thromboxane B2 at almost all concentrations of HPF. This study indicates that HPF induces platelet aggregation and activation and suggests that platelet contact with pancreatic exocrine fluid may have both local and systemic effects that are important in the pathophysiology of acute pancreatitis.

Coagulation abnormalities induced by pancreatitis were studied in 36 dogs. The 12 dogs in group I underwent a duodenotomy alone. The six dogs in groups II, III, IV, and V had pancreatitis induced by bile injection (1 cc/kg) into the pancreatic duct. Twenty minutes after bile-induced pancreatitis, group III was given 1.0 mg/kg aprotinin (trasylol), group IV was given 10 mg/kg S-2441, a new synthetic protease inhibitor, and group V was given 0.5 mg/kg alpha 2-antitrypsin by intravenous infusion over 10 min. Blood was drawn for amylase, protime (PT), partial thromboplastin time (PTT), fibrinogen, and platelets, in addition to markers of hypercoagulation, fibrinopeptide A, and antithrombin III, and markers of fibrinolysis, B beta 15-42 immunoreactive peptide (IP), and alpha 2-antiplasmin at baseline, 1/2, 1, 3, 6, 24, 48, and 72 hr after duodenotomy or bile injection. There was no significant difference in PT, platelets, antithrombin III, and fibrinopeptide A among the five groups. With the induction of pancreatitis (group II), serum amylase was significantly elevated but fibrinogen only became elevated at 24 hr and PTT at 48 hr. The increase in B beta 15-42 IP seen 30 min after induction of pancreatitis and the decrease in alpha 2-antiplasmin were blunted by aprotinin, alpha 1-antitrypsin, and S-2441, but inhibition of the rise in amylase and B beta 15-42 IP only reached significance with S-2441 (P less than 0.05). Pancreatitis-induced fibrinolysis was inhibited by S-2441 suggesting that synthetic protease inhibitors may play a therapeutic role in pancreatitis.