Biomedical subjects

Jason K Sicklick

Publications and source records attributed to Jason K Sicklick.

10 recordsLinked to original sources

PubMed2025

CD40 transcriptomic expression patterns across malignancies: implications for clinical trials of CD40 agonists.

BACKGROUND: CD40 is a T-cell co-stimulatory receptor targeted by next-generation immunotherapies. We conducted a pan-cancer transcriptome analysis of CD40, its ligand, and related immune markers to evaluate co-expression patterns and clinical outcomes. METHODS: We analyzed transcriptome data for CD40, its ligand, and other common checkpoints and co-stimulators (PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, ICOS, CD27, CD28, OX40, and GITR). RNA expression was classified as high (75-100th percentile), moderate (25-74th), or low (0-24th) against a reference population of 735 previously tested solid tumors. RESULTS: Of 514 patients, 114 (22%) showed high, 247 (48%) moderate, and 153 (30%) low CD40 RNA expression. High CD40 expression was most frequent in liver and bile duct (42%), pancreatic (42%), and ovarian (40%) cancers. Both high CD40 and low-moderate CD40 ligand expression-potentially conducive to CD40 agonist therapy-was most frequent in ovarian (33%) and pancreatic (24%) cancer. In both UCSD (N = 514) and TCGA (N = 10,953) cohorts, high CD40 expression significantly correlated with high CD28 and GITR. High CD40 RNA levels were not prognostic for overall survival (OS) from metastatic disease (P = 0.2) (n = 272 immune checkpoint inhibitor (ICI)-naïve patients). High CD40 expression correlated with longer OS from immunotherapy initiation (n = 217 ICI-treated patients; P = 0.04, univariable analysis), but not multivariable analysis, suggesting it may not be an independent predictive biomarker. CONCLUSION: High CD40 expression correlated with liver and bile duct, pancreatic, and ovarian cancers, as well as with CD28 and GITR transcripts. Immune marker co-expression in individual patients merits further exploration for the development of CD40-based and other immunotherapy interventions.

Humans↗

PubMed2006

Interleukin-15 increases hepatic regenerative activity.

BACKGROUND/AIMS: Interleukin-15 (IL-15) is expressed in many organs. It generally inhibits apoptosis and increases cellular proliferation and differentiation. However, IL-15's roles in liver are unknown. We aimed to determine if IL-15 influences hepatic integrity and regenerative activity. METHODS: Expression of IL-15 and its receptors was evaluated in several liver injury models, primary hepatocytes, and two liver cell lines. Effects of IL-15 on viability, proliferation, and apoptosis were assessed in cultured liver cells, and also in the livers of healthy mice. RESULTS: IL-15 and its receptors are expressed constitutively in healthy livers, and ligand expression is induced in injured livers. Cultured primary hepatocytes and liver cell lines express IL-15 and its receptors. Administration of IL-15 has minimal effects on cultured liver cells, but significantly up-regulates oval cell accumulation, cyclin mRNA expression, and mature hepatocyte replication in healthy mice. These effects are associated with focal hepatic inflammation and increased expression of TNF-alpha and IFN-gamma, but not with increased cell death or aminotransferase release. CONCLUSIONS: IL-15 expression increases during liver injury and IL-15 treatment induces a wound healing-type response in healthy adult mice. These findings suggest that IL-15 may contribute to regenerative activity in damaged liver.

Animals↗

PubMed2006

Evidence for epithelial-mesenchymal transitions in adult liver cells.

Both myofibroblastic hepatic stellate cells (HSC) and hepatic epithelial progenitors accumulate in damaged livers. In some injured organs, the ability to distinguish between fibroblastic and epithelial cells is sometimes difficult because cells undergo epithelial-mesenchymal transitions (EMT). During EMT, cells coexpress epithelial and mesenchymal cell markers. To determine whether EMT occurs in adult liver cells, we analyzed the expression profile of primary HSC, two HSC lines, and hepatic epithelial progenitors. As expected, all HSC expressed HSC markers. Surprisingly, these markers were also expressed by epithelial progenitors. In addition, one HSC line expressed typical epithelial progenitor mRNAs, and these epithelial markers were inducible in the second HSC line. In normal and damaged livers, small ductular-type cells stained positive for an HSC marker. In conclusion, HSC and hepatic epithelial progenitors both coexpress epithelial and mesenchymal markers, providing evidence that EMT occurs in adult liver cells.

Animals↗

PubMed2006

Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and fibrosis in mice.

Rac, a small, GTP-binding protein in the Rho family, regulates several cellular functions, including the activation of NADPH oxidase, a major intracellular producer of reactive oxygen species (ROS). Hepatic stellate cells (HSCs) isolated from mice that are genetically deficient in NADPH oxidase produce less ROS, and their activation during chronic liver injury is abrogated, resulting in decreased liver fibrosis. Therefore, we hypothesized that HSC ROS production and activation would be enhanced, and fibrosis worsened, by increasing Rac expression in HSCs. To achieve this, we used transgenic mice that express constitutively active human Rac1 under the control of the alpha-smooth muscle actin (alpha-sma) promoter, because alpha-sma expression is induced spontaneously during HSC activation. Transgene expression was upregulated progressively during culture of primary Rac-transgenic HSCs, and this increased HSC ROS production as well as expression of activation markers and collagen. Similarly, Rac mice treated with carbon tetrachloride (CCl(4)) accumulated greater numbers of activated HSCs and had more liver damage, hepatocyte apoptosis, and liver fibrosis-as well as higher mortality-than CCl(4)-treated wild-type mice. In conclusion, sustained activation of Rac in HSCs perpetuates their activation and exacerbates toxin-induced liver injury and fibrosis, prompting speculation that Rac may be a therapeutic target in patients with cirrhosis.

Actins↗

PubMed2005

Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis.

Hedgehog (Hh) pathway activation promotes tumors in several endodermally derived tissues, but its role in the pathogenesis of hepatocellular carcinoma (HCC) is unknown. Although normal hepatocytes lack Hh signaling, activation of the Hh pathway in endodermal progenitors is required for liver development. Thus, we hypothesized that hepatocarcinogenesis may involve regulation of Hh signaling. This pathway is activated when Hh ligand binds to its receptor, Patched (PTC). In an unoccupied state, PTC normally functions as a tumor suppressor that inhibits Smoothened (SMO), a proto-oncoprotein, from activating downstream components and transcription of target genes. Here we show that in HCCs, overexpression of the Smo proto-oncogene, as well as an increase in the stoichiometric ratio of Smo to Ptc mRNA levels, correlated with tumor size, a prognostic indicator in HCC biology. In one tumor we identified a novel Smo mutation in an evolutionarily conserved residue. We also demonstrated that HCC cell lines (HepG2 and Hep3B) expressed Hh pathway components and activated Hh transcriptional targets. In Hep3B cells, cyclopamine, an inhibitor of wild-type SMO, had no effect, but KAAD-cyclopamine, a blocker of oncogenic SMO, inhibited Hh signaling activity by 50%, decreased expression of the hepatocarcinogenic oncogene, c-myc, by 8-fold, and inhibited the growth rate of Hep3B cells by 94%. These data support our hypothesis that Hh signaling is dysregulated in human hepatocarcinogenesis. We demonstrate that overexpression and/or tumorigenic activation of the Smo proto-oncogene mediates c-myc overexpression which plays a critical role in hepatocarcinogenesis and suggests that Smo is a prognostic factor in HCC tumorigenesis.

Animals↗

PubMed2005

Hedgehog signaling maintains resident hepatic progenitors throughout life.

Hedgehog signaling through its receptor, Patched, activates transcription of genes, including Patched, that regulate the fate of various progenitors. Although Hedgehog signaling is required for endodermal commitment and hepatogenesis, the possibility that it regulates liver turnover in adults had not been considered because mature liver epithelial cells lack Hedgehog signaling. Herein, we show that this pathway is essential throughout life for maintaining hepatic progenitors. Patched-expressing cells have been identified among endodermally lineage-restricted, murine embryonic stem cells as well as in livers of fetal and adult Ptc-lacZ mice. An adult-derived, murine hepatic progenitor cell line expresses Patched, and Hedgehog-responsive cells exist in stem cell compartments of fetal and adult human livers. In both species, manipulation of Hedgehog activity influences hepatic progenitor cell survival. Therefore, Hedgehog signaling is conserved in hepatic progenitors from fetal development through adulthood and may be a new therapeutic target in patients with liver damage.

Animals↗

PubMed2005

Role for hedgehog signaling in hepatic stellate cell activation and viability.

Hepatic stellate cells (HSC) have a complex phenotype that includes both neural and myofibroblastic features. The Hedgehog (Hh) pathway has been shown to direct the fate of neural and myofibroblastic cells during embryogenesis and during tissue remodeling in adults. Therefore, we hypothesized that Hh signaling may regulate the fate of HSC in adults. In this study, we find that freshly isolated stellate cells from adult Patched-lacZ transgenic mice exhibit beta-galactosidase activity, indicating Hh pathway activity. Transcripts of Hh ligands, the Hh pathway receptor, and Hh-regulated transcription factors are expressed by stellate cells from mice, rats, and humans. Transfection experiments in a cell line using a Hh-inducible luciferase reporter demonstrate constitutive Hh pathway activity. Moreover, neutralizing antibodies to Hh increase apoptosis, while viability is restored by treatment with Hh ligand. In vitro treatment of primary stellate cells with cyclopamine (Cyc), a pharmacologic inhibitor of the Hh pathway, inhibits activation and slightly decreases cell survival, while a single injection of Cyc into healthy adult mice reduces activation of HSC by more than 50% without producing obvious liver damage. Our findings reveal a novel mechanism, namely the Hh pathway, that regulates the activation and viability of HSC.

Animals↗

PubMed2005

Controversies in the surgical management of cholangiocarcinoma and gallbladder cancer.

Cholangiocarcinoma and gallbladder cancer are relatively rare malignancies with poor prognoses. Surgery is the primary form of treatment, with few data being available on the use of adjuvant therapies. Even with regard to surgery, there are few definitive data supporting various approaches that nevertheless are widely used and have become recognized as traditional. This review examines available information and controversies in the areas of preoperative evaluation and surgical treatment of cholangiocarcinoma and gallbladder cancer.

Bile Duct Neoplasms↗

PubMed2005

Surgical management of bile duct injuries sustained during laparoscopic cholecystectomy: perioperative results in 200 patients.

OBJECTIVE: A single institution retrospective analysis of 200 patients with major bile duct injuries was completed. Three patients died without surgery due to uncontrolled sepsis. One hundred seventy-five patients underwent surgical repair, with a 1.7% postoperative mortality and a complication rate of 42.9%. SUMMARY BACKGROUND DATA: The widespread application of laparoscopic cholecystectomy (LC) has led to a rise in the incidence of major bile duct injuries (BDI). Despite the frequency of these injuries and their complex management, the published literature contains few substantial reports regarding the perioperative management of BDI. METHODS: From January 1990 to April 2003, a prospective database of all patients with a BDI following LC was maintained. Patients' charts were retrospectively reviewed to analyze perioperative surgical management. RESULTS: Over 13 years, 200 patients were treated for a major BDI following LC. Patient demographics were notable for 150 women (75%) with a mean age of 45.5 years (median 44 years). One hundred eighty-eight sustained their BDI at an outside hospital. The mean interval from the time of BDI to referral was 29.1 weeks (median 3 weeks). One hundred nine patients (58%) were referred within 1 month of their injury for acute complications including bile leak, biloma, or jaundice. Twenty-five patients did not undergo a surgical repair at our institution. Three patients (1.5%) died after delayed referral before an attempt at repair due to uncontrolled sepsis. Twenty-two patients, having intact biliary-enteric continuity, underwent successful balloon dilatation of an anastomotic stricture. A total of 175 patients underwent definitive biliary reconstruction, including 172 hepaticojejunostomies (98%) and 3 end-to-end repairs. There were 3 deaths in the postoperative period (1.7%). Seventy-five patients (42.9%) sustained at least 1 postoperative complication. The most common complications were wound infection (8%), cholangitis (5.7%), and intraabdominal abscess/biloma (2.9%). Minor biliary stent complications occurred in 5.7% of patients. Early postoperative cholangiography revealed an anastomotic leak in 4.6% of patients and extravasation at the liver dome-stent exit site in 10.3% of patients. Postoperative interventions included percutaneous abscess drainage in 9 patients (5.1%) and new percutaneous transhepatic cholangiography and stent placement in 4 patients (2.3%). No patient required reoperation in the postoperative period. The mean postoperative length of stay was 9.5 days (median 9 days). The timing of operation (early, intermediate, delayed), presenting symptoms, and history of prior repair did not affect the incidence of the most common perioperative complications or length of postoperative hospital stay. CONCLUSIONS: This series represents the largest single institution experience reporting the perioperative management of BDI following LC. Although perioperative complications are frequent, nearly all can be managed nonoperatively. Early referral to a tertiary care center with experienced hepatobiliary surgeons and skilled interventional radiologists would appear to be necessary to assure optimal results.

Adult↗

PubMed2002

Azygous vein to right atrium bypass graft in a patient with idiopathic fibrosing mediastinitis and symptomatic superior and inferior vena cava obstructions.

We report an unusual case of a patient with diminished cardiac output caused by systemic venous occlusions of unclear etiology with a history of idiopathic fibrosing mediastinitis and retroperitoneal fibrosis. On thoracic, abdominal, and pelvic venograms, the patient was previously known to have superior vena caval and infrarenal inferior vena caval occlusions. Subsequent studies revealed retrograde flow through the azygous and hemiazygous veins and numerous caval-portal anastomoses providing venous return from the upper and lower extremities. After an extensive hypercoagulable state work-up, no abnormalities were found. To relieve the symptoms, the patient underwent an elective right thoracotomy with azygous vein to right atrial bypass graft. The patient has had complete amelioration of the disabling symptoms and participates in many activities that he could not tolerate previously. Because this condition and procedure are unreported, we present a novel surgical treatment option to palliate symptoms caused by concurrent superior and inferior caval obstructions by improving venous return to the heart.

Adult↗