Sigma-2 receptor agonist derivatives of 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) induce cell death via mitochondrial superoxide production and caspase activation in pancreatic cancer.

Background: Despite considerable efforts by scientific research, pancreatic cancer is the fourth leading cause of cancer related mortalities. Sigma-2 receptors, which are overexpressed in several tumors, represent promising targets for triggering selective pancreatic cancer cells death.

Methods: We selected five differently structured high-affinity sigma-2 ligands (PB28, PB183, PB221, F281 and PB282) to study how they affect the viability of diverse pancreatic cancer cells (human cell lines BxPC3, AsPC1, Mia PaCa-2, and Panc1 and mouse Panc-02, KCKO and KP-02) and how this is reflected in vivo in a tumor model.

A telephone call 1 week after hospitalization can identify risk factors for vascular surgery readmission.

Objective: Compared with other populations, patients who undergo vascular surgery have higher 30-day hospital readmission rates of up to 25%. Postdischarge telephone call assessments have demonstrated utility in patients with significant medical comorbidities and traditionally high readmission rates. Therefore, we hypothesized that a 1-week postdischarge telephone call evaluation can identify risk factors for readmission among vascular surgery patients.

Targeted pancreatic cancer therapy with the small molecule drug conjugate SW IV-134.

Pancreatic adenocarcinoma is highly resistant to conventional therapeutics and has been shown to evade apoptosis by deregulation of the X-linked and cellular inhibitors of apoptosis proteins (XIAP and cIAP). Second mitochondria-derived activator of caspases (Smac) induces and amplifies cell death by reversing the anti-apoptotic activity of IAPs. Thus, Smac-derived peptide analogues (peptidomimetics) have been developed and shown to represent promising cancer therapeutics.

A phase I study of IMP321 and gemcitabine as the front-line therapy in patients with advanced pancreatic adenocarcinoma.

Purpose: This phase I study was conducted to determine the safety profile and maximum tolerated dose (MTD) of IMP321, a soluble lymphocyte activation gene-3 (LAG-3) Ig fusion protein and MHC Class II agonist, combined with gemcitabine in patients with advanced pancreatic adenocarcinoma.

Patients And Methods: Patients with advanced pancreatic adenocarcinoma were treated with gemcitabine (1,000 mg/m(2))(level 1), gemcitabine (1,000 mg/m(2)) plus IMP 321 at 0.5 mg (level 2) and 2.

Therapeutic targeting of pancreatic cancer utilizing sigma-2 ligands.

One major barrier in the development of pancreas cancer therapeutics is the selective delivery of the drugs to their cellular targets. We have previously developed several sigma-2 ligands and reported the discovery of a component of the receptor for these ligands. Several sigma-2 ligands have been shown to trigger apoptosis in pancreas cancer cells.

Lysosomal membrane permeabilization is an early event in Sigma-2 receptor ligand mediated cell death in pancreatic cancer.

Background: Sigma-2 receptor ligands have been studied for treatment of pancreatic cancer because they are preferentially internalized by proliferating cells and induce apoptosis. This mechanism of apoptosis is poorly understood, with varying reports of caspase-3 dependence. We evaluated multiple sigma-2 receptor ligands in this study, each shown to decrease tumor burden in preclinical models of human pancreatic cancer.

Use of multifunctional sigma-2 receptor ligand conjugates to trigger cancer-selective cell death signaling.

One major challenge in the development of cancer therapeutics is the selective delivery of the drugs to their cellular targets. In the case of pancreatic cancer, the σ-2 receptor is a unique target that triggers apoptosis upon activation. We have previously developed a series of chemical compounds with high affinity for the σ-2 receptor and showed rapid internalization of the ligands.

A single-institution review of 157 patients presenting with benign and malignant tumors of the ampulla of Vater: management and outcomes.

Background: Although benign ampullary tumors are removed endoscopically, due to their potential to progress to malignant disease, the favored treatment for adenocarcinoma is pancreaticoduodenectomy. We reviewed our institution's experience in order to identify which patients were at highest risk of disease progression following surgical resection, as well as evaluate whether localized T1 tumors are best treated by pancreaticoduodenectomy.

Methods: We retrospectively reviewed 157 patients who presented with an ampullary mass, from 2001 to 2010, and identified 51 with benign adenoma and 106 with adenocarcinoma.

Fluorescent derivatives of σ receptor ligand 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) as a tool for uptake and cellular localization studies in pancreatic tumor cells.

Fluorescent derivatives of σ(2) high affinity ligand 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine 1 (PB28) were synthesized. NBD or dansyl fluorescent tags were connected through a 5- or 6-atom linker in two diverse positions of 1 structure. Good σ(2) affinities were obtained when the fluorescent tag was linked to 5-methoxytetralin nucleus replacing the methyl function.

The novel sigma-2 receptor ligand SW43 stabilizes pancreas cancer progression in combination with gemcitabine.

Background: Sigma-2 receptors are over-expressed in proliferating cancer cells, making an attractive target for the targeted treatment of pancreatic cancer. In this study, we investigated the role of the novel sigma-2 receptor ligand SW43 to induce apoptosis and augment standard chemotherapy.

Results: The binding affinity for sigma-2 ligands is high in pancreas cancer, and they induce apoptosis with a rank order of SV119 < SW43 < SRM in vitro.