Neoadjuvant management of locally advanced pancreatic ductal adenocarcinoma - Heading towards a promising change in treatment paradigm.

Traditional chemotherapy-based adjuvant therapies for locally advanced pancreatic ductal adenocarcinoma (PDAC) have been associated with poor clinical outcomes driven partly by its complex anatomy and molecular heterogeneity. Treatment for PDAC is challenged by presence of a dense tumour microenvironment involving an interplay of multiple tumoural and stromal components which promote metastatic oncogenic behaviour. PDAC also involves aberrations in multiple signalling pathways with paucity of treatment options against the most common mutations including KRAS, TP53, CDKN2A andSMAD4.

Pamrevlumab, a Fully Human Monoclonal Antibody Targeting Connective Tissue Growth Factor, for Non-Ambulatory Patients with Duchenne Muscular Dystrophy.

Background: Duchenne muscular dystrophy (DMD) is a neuromuscular disease stemming from dystrophin gene mutations. Lack of dystrophin leads to progressive muscle damage and replacement of muscle with fibrotic and adipose tissue. Pamrevlumab (FG-3019), a fully human monoclonal antibody that binds to connective tissue growth factor (CTGF), is in Phase III development for treatment of DMD and other diseases.

A novel event-free survival endpoint in locally advanced pancreatic cancer.

The treatment paradigm for locally advanced pancreatic cancer (LAPC) is evolving rapidly. The development of neoadjuvant therapies composed of combination therapies and the evaluation of their impact on conversion to borderline resectable (BR) status, resection, and ultimately overall survival (OS) are presently being pursued. These efforts justify re-visiting study endpoints in order to better predict therapeutic effects on OS, by capturing not only the achievement of R0 resection at the end of induction therapy but also the long-term reductions in the rate of local and distal recurrence.

Gemcitabine/nab-paclitaxel with pamrevlumab: a novel drug combination and trial design for the treatment of locally advanced pancreatic cancer.

Purpose: Pancreatic ductal adenocarcinomas exhibit a high degree of desmoplasia due to extensive extracellular matrix deposition. Encasement of mesenteric vessels by stroma in locally advanced pancreatic cancer (LAPC) prevents surgical resection. This study sought to determine if the addition of a monoclonal antibody to connective tissue growth factor, pamrevlumab, to neoadjuvant chemotherapy would be safe and lead to improved resectability in this surgically adverse patient population.

Molecular integrity and global gene expression of breast and lung cancer stem cells under long-term storage and recovery.

Cryopreservation is a common procedure widely used in biological and clinical sciences. Similar protocols are also applied in preserving cancer stem cells, a field with high promises and challenges. Specific cell surface membrane proteins are considered to be biomarkers of cancer stem cells and they may play a critical role in differentiating stem cells from non stem cells.

Expression of the epigenetic factor BORIS (CTCFL) in the human genome.

BORIS, or CTCFL, the so called Brother of the Regulator of Imprinted Sites because of the extensive homology in the central DNA binding region of the protein to the related regulator, CTCF, is expressed in early gametogenesis and in multiple cancers but not in differentiated somatic cells. Thus it is a member of the cancer testes antigen group (CTAs). Since BORIS and CTCF target common DNA binding sites, these proteins function on two levels, the first level is their regulation via the methylation context of the DNA target site and the second level is their distinct and different epigenetic associations due to differences in the non-homologous termini of the proteins.

Enhanced presentation of MHC class Ia, Ib and class II-restricted peptides encapsulated in biodegradable nanoparticles: a promising strategy for tumor immunotherapy.

Background: Many peptide-based cancer vaccines have been tested in clinical trials with a limited success, mostly due to difficulties associated with peptide stability and delivery, resulting in inefficient antigen presentation. Therefore, the development of suitable and efficient vaccine carrier systems remains a major challenge.

Methods: To address this issue, we have engineered polylactic-co-glycolic acid (PLGA) nanoparticles incorporating: (i) two MHC class I-restricted clinically-relevant peptides, (ii) a MHC class II-binding peptide, and (iii) a non-classical MHC class I-binding peptide.

Artificial hematopoietic stem cell niche: bioscaffolds to microfluidics to mathematical simulations.

Due to the recent advancements in stem cell biology and engineering, scientists have been increasingly interested in creating in vitro niches for embryonic and adult stem cells, and, following induction and differentiation with the appropriate media, the production of large scale blood production. This artificially created niche for hematopoietic cells will be composed of three materials: the stem cells themselves, the scaffold surrounding the stem cell, and the media used to expand and differentiate the stem cells. This paper will examine the recent advancements in technology for each of these relating to the development of an artificial stem cell niche.

Effect of eszopiclone on sleep, fatigue, and pain in patients with mucositis associated with hematologic malignancies.

Purpose: Patients with malignancy sometimes develop painful mucositis and require patient-controlled analgesia (PCA) to treat their pain. Pain disrupts sleep and there is some evidence that analgesic medications also disrupt sleep. This study examined whether treatment with the sedative hypnotic eszopiclone could improve self-reports of sleep, fatigue, and pain as well as decrease opioid self-administered via PCA.

Tumor vaccines in 2010: need for integration.

Induction of tumor-specific immunity is an attractive approach to cancer therapy, however to date every major pivotal trial has resulted in failure. While the phenomena of tumor-mediated immune suppression has been known for decades, only recently have specific molecular pathways been elucidated, and for the first time, rationale means of intervening and observing results of intervention have been developed. In this review we describe major advances in our understanding of tumor escape from immunological pressure and provide some possible therapeutic scenarios for enhancement of efficacy in future cancer vaccine trials.

Lasers, stem cells, and COPD.

The medical use of low level laser (LLL) irradiation has been occurring for decades, primarily in the area of tissue healing and inflammatory conditions. Despite little mechanistic knowledge, the concept of a non-invasive, non-thermal intervention that has the potential to modulate regenerative processes is worthy of attention when searching for novel methods of augmenting stem cell-based therapies. Here we discuss the use of LLL irradiation as a "photoceutical" for enhancing production of stem cell growth/chemoattractant factors, stimulation of angiogenesis, and directly augmenting proliferation of stem cells.

The search for multiple myeloma stem cells: the long and winding road.

Recent years have brought significant breakthroughs in the understanding of tumor biology, related to discovery of cancer stem cells (CSCs) in acute myelogenous leukemia as well as in a number of solid tumors. This finding revealed that not all tumor cells are able to divide indefinitely, and that the bulk of tumor cells are expanded because of divisions and differentiation of CSC fraction. Although the CSCs identified in acute leukemia have a phenotype of early hematopoietic progenitors, it seems that CSCs in multiple myeloma (MM) may resemble the memory B cell fraction.

Autologous hematopoietic stem cell transplantation as an intensive consolidation therapy for adult patients in remission from acute myelogenous leukemia.

Autologous peripheral blood stem/progenitor cell transplantation (APBSCT) has been investigated as a potential therapeutic option to improve outcome in patients with acute myelogenous leukemia (AML). However, its optimal role in treatment for adults in remission has not been clearly established. We performed a retrospective analysis on 45 patients aged 21 to 73 years (median 51 years) with de novo AML who underwent APBSCT stratified by age, complete remission status, and cytogenetic risk.

Human embryonic stem cells hemangioblast express HLA-antigens.

Background: It has been suggested that the initial differentiation of endothelial and hematopoietic cells during embryogenesis occurs from a common progenitor, called hemangioblast (hB). We hypothesized that these cells with dual hematopoietic/endothelial potential could be used in future regenerative medicine.

Methods: We used the two-step differentiation technology to generate bipotential blast cells from human embryonic stem cells (hES).

Multiple myeloma bone marrow niche.

"Niche" is defined as a specialized regulatory microenvironment, consisting of components which control the fate specification of stem and progenitor cells, as well as maintaining their development by supplying the requisite factors. Bone marrow (BM) niche has a well-organized architecture and is composed of osteoblasts, osteoclasts, bone marrow endothelial cells, stromal cells, adipocytes and extracellular matrix proteins (ECM). These elements play an essential role in the survival, growth and differentiation of diverse lineages of blood cells, but also provide optimal growth environment for multiple hematological malignancies including multiple myeloma (MM).

Inhibition of intracranial glioma growth by endometrial regenerative cells.

Animal studies have demonstrated that selective tropism of mesenchymal stem cells (MSC) for glioma may be used as a means of selective delivery of cytotoxic payloads. Endometrial Regenerative Cells (ERC) are a population of mesenchymal-like cells which possesse pluripotent differentiation capacity and is characterized by unique surface markers and growth factor production. In this study we sought to determine whether unmanipulated ERC would alter the growth of glioma using the aggressive C6/LacZ7 (C6) into Sprague Dawley rat model.

A novel in vivo siRNA delivery system specifically targeting dendritic cells and silencing CD40 genes for immunomodulation.

Translation of small interfering RNA (siRNA)-based approaches into practical therapeutics is limited because of lack of an effective and cell-specific delivery system. Herein, we present a new method of selectively delivering siRNA to dendritic cells (DCs) in vivo using CD40 siRNA-containing immunoliposomes (siILs) that were decorated with DC-specific DEC-205 mAb. Administration of CD40 siILs resulted in DC-specific cell targeting in vitro and in vivo.

CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation.

Relapse of malignancy after allogeneic hematopoietic cell transplantation (allo-HCT) remains a therapeutic challenge. Blockade of the CTLA4 molecule can effectively augment antitumor immunity mediated by autologous effector T cells. We have assessed the safety and preliminary efficacy of a neutralizing, human anti-CTLA4 monoclonal antibody, ipilimumab, in stimulating the graft-versus-malignancy (GVM) effect after allo-HCT.

Allogeneic endometrial regenerative cells: an "Off the shelf solution" for critical limb ischemia?

Critical limb ischemia (CLI) is an advanced form of peripheral artery disease which is responsible for approximately 100,000 amputations per year in the US. Trials to date have reported clinical improvement and reduced need for amputation in CLI patients receiving autologous bone marrow or mobilized peripheral blood stem cells for stimulation of angiogenesis. While such treatments are currently entering Phase III trials, practical and scientific pitfalls will limit widespread implementation if efficacy is proven.

Prospects of embryonic stem cells in treatment of hematopoietic disorders.

Cellular therapies derived from embryonic stem (ES) cells have gained a renewed interest with the experimental demonstration that an embryonic stem cell lines can be established from human blastocyst-stage embryos and prompted to differentiate into almost all types of cells present in the body including hematopoietic cells. Hematopoiesis is a series of cellular processes whereby short-lived mature blood cells are continuously replenished from a pool of rare pluripotential hematopoietic stem cells, in a highly orchestrated process. Aberrances in this intricate process may lead to a malignancy of essential blood-forming organs, causing diseases such as leukemia, aplastic anemia, lymphoma, myelodysplasia and myeloproliferative disorders.

Peripheral blood progenitor cell mobilization with intermediate-dose cyclophosphamide, sequential granulocyte-macrophage-colony-stimulating factor and granulocyte-colony-stimulating factor, and scheduled commencement of leukapheresis in 225 patients undergoing autologous transplantation.

Background: Interpatient variability in the kinetics of peripheral blood progenitor cell (PBPC) mobilization is commonly seen with conventional chemotherapy-based mobilization regimens. This necessitates the availability of leukapheresis (LP) facilities 7 days a week.

Study Design And Methods: The efficacy of an approach where LP was invariably commenced on Day 11 after intermediate-dose cyclophosphamide followed by sequential administration of granulocyte-macrophage-colony-stimulating factor (CSF) and granulocyte-CSF (Cy/GM/G) was retrospectively analyzed in 225 consecutive, unselected patients undergoing autologous hematopoietic stem cell transplantation for all diagnoses other than acute leukemia at our center.

Embryonic stem cells ameliorate piroxicam-induced colitis in IL10-/- KO mice.

The primary objective of this work is to determine the repairing potential of murine embryonic stem cells (ES) in murine model of Crohn's disease (CD). Colitis, induced in IL10-/- KO mice using piroxicam, was associated with the increased levels of IL-12. Enhanced yellow fluorescent protein (EYFP) marked murine ES cells (R1/129) and control non-fluorescent ES cells were subjected to in vitro differentiation into intestinal epithelial cells.

Thrombopoietin enhances generation of CD34+ cells from human embryonic stem cells.

The role of thrombopoietin (TPO) in adult hematopoiesis is well-established. A recent report suggests that TPO and vascular endothelial growth factor (VEGF) play a role in promoting formation of early erythropoietic progenitors in a nonhuman primate embryonic stem cell (ES) model. No such report exists for human ES cells as yet.

Dexamethasone facilitates erythropoiesis in murine embryonic stem cells differentiating into hematopoietic cells in vitro.

Differentiating embryonic stem (ES) cells are increasingly emerging as an important source of hematopoietic progenitors with a potential to be useful for both basic and clinical research applications. It has been suggested that dexamethasone facilitates differentiation of ES cells towards erythrocytes but the mechanism responsible for sequential expression of genes regulating this process are not well-understood. Therefore, we in vitro induced differentiation of murine ES cells towards erythropoiesis and studied the sequential expression of a set of genes during the process.

Transplanted embryonic stem cells successfully survive, proliferate, and migrate to damaged regions of the mouse brain.

An understanding of feasibility of implanting embryonic stem cells (ESCs), their behavior of migration in response to lesions induced in brain tissues, and the mechanism of their in vivo differentiation into neighboring neural cells is essential for developing and refining ESC transplantation strategies for repairing damages in the nervous system, as well as for understanding the molecular mechanism underlying neurogenesis. We hypothesized that damaged neural tissues offer a niche to which injected ESCs can migrate and differentiate into the neural cells. We inflicted damage in the murine (C57BL/6) brain by injecting phosphate-buffered saline into the left frontal and right caudal regions and confirmed neural damage by histochemistry.