Effects of Body Weight Support in Running on Achilles Tendon Loading.

Achilles tendon (AT) tendinopathy is common in runners. Repetitive AT loading may play a role in etiology. Interventions such as body weight support (BWS) may reduce loading on the AT in running.

Examination of a social-learning program implemented in a maximum-security state hospital setting.

The present study examines the extent to which clients with serious mental illnesses (SMI) enrolled in a social-learning program (SLP) within a maximum-security state hospital were able to achieve discharge to less restrictive settings without requiring a return to maximum security. Retrospective analyses were undertaken to examine several time periods of the SLP's operation within maximum security. From 1988 to 2019, 248 clients were discharged from the SLP.

Two controls of cell proliferation underlie cancer relapse.

Much progress has been made in understanding the basis of cancer. Current therapies can effectively shrink tumors. But they frequently relapse, metastasize to other locations, and are lethal.

Tumor-Derived α-Fetoprotein Directly Drives Human Natural Killer-Cell Activation and Subsequent Cell Death.

Hepatocellular carcinoma (HCC) patients with reduced natural killer (NK)-cell numbers and function have been shown to have a poor disease outcome. Mechanisms underlying NK-cell deficiency and dysfunction in HCC patients remain largely unresolved. α-Fetoprotein (AFP) is an oncofetal antigen produced by HCC.

Highly Aggressive Women in a Forensic Psychiatric Hospital.

In this study, we compared three groups of women admitted to a public forensic inpatient facility over the course of a two-year period. Detailed and systematic examination of social and psychiatric histories revealed that the group with the most persistent levels of aggression differed from the other two groups with respect to frequency of self-harming behavior, intellectual impairment, hypothyroidism, a childhood diagnosis of attention deficit-hyperactivity disorder (ADHD), and age of onset of psychiatric and behavioral symptoms. The high-aggression group also had the highest rate of childhood physical and sexual abuse, but the difference between that group and the two lower aggression groups did not achieve statistical significance.

Route of antigen delivery impacts the immunostimulatory activity of dendritic cell-based vaccines for hepatocellular carcinoma.

Background: Dendritic cells (DC) are uniquely equipped to capture, process, and present antigens from their environment. The context in which an antigen is acquired by DC helps to dictate the subsequent immune response. Cancer vaccination promotes antitumor immunity by directing an immune response to antigens expressed by tumors.

Bioregulation.

During the 20th century great progress was made in genetics and biochemistry, and these were combined into a molecular biological understanding of functions of macromolecules. Further great discoveries will be made about bioregulations, applicable to scientific problems such as cell development and evolution, and to illnesses including heart disease through defective control of cholesterol production, and to neurological cell-based diseases. The "War Against Cancer" is still far from won.

Suppression of cancer relapse and metastasis by inhibiting cancer stemness.

Partial or even complete cancer regression can be achieved in some patients with current cancer treatments. However, such initial responses are almost always followed by relapse, with the recurrent cancer being resistant to further treatments. The discovery of therapeutic approaches that counteract relapse is, therefore, essential for advancing cancer medicine.

Tumor-derived α-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells.

Several tumor-derived factors have been implicated in dendritic cell (DC) dysfunction in cancer patients. α-fetoprotein (AFP) is an oncofetal Ag that is highly expressed in abnormalities of prenatal development and several epithelial cancers, including hepatocellular carcinoma (HCC). In HCC patients exhibiting high levels of serum AFP, we observed a lower ratio of myeloid/plasmacytoid circulating DCs compared with patients with low serum AFP levels and healthy donors.

Human dendritic cells adenovirally-engineered to express three defined tumor antigens promote broad adaptive and innate immunity.

Dendritic cell (DC) immunotherapy has shown a promising ability to promote anti-tumor immunity in vitro and in vivo. Many trials have tested single epitopes and single antigens to activate single T cell specificities, and often CD8(+) T cells only. We previously found that determinant spreading and breadth of antitumor immunity correlates with improved clinical response.

Immunotherapy of hepatocellular carcinoma: Unique challenges and clinical opportunities.

Current therapies for advanced hepatocellular carcinoma (HCC) are marginally effective and exacerbate underlying liver disease. The ability of immunotherapy to elicit nontoxic, systemic, long-lived anti-tumor activity makes it particularly well-suited for use in the setting of HCC. While therapeutic benefit has been achieved in early clinical trials, the efficacy of immune-based therapies is limited by several unique properties of HCC, most notably the inherently tolerogenic character of the liver in both healthy and diseased (chronically-infected or tumor-bearing) states.

The abbreviated pluripotent cell cycle.

Human embryonic stem cells (hESCs) and induced pluripotent stem cells proliferate rapidly and divide symmetrically producing equivalent progeny cells. In contrast, lineage committed cells acquire an extended symmetrical cell cycle. Self-renewal of tissue-specific stem cells is sustained by asymmetric cell division where one progeny cell remains a progenitor while the partner progeny cell exits the cell cycle and differentiates.

The pursuit of oncotargets through understanding defective cell regulation.

More effective anticancer agents are essential, as has too often been demonstrated by the paucity of therapeutics which preserve life. Their discovery is very difficult. Many approaches are being applied, from testing folk medicines to automated high throughput screening of large chemical libraries.

A therapeutic OX40 agonist dynamically alters dendritic, endothelial, and T cell subsets within the established tumor microenvironment.

Little preclinical modeling currently exists to support the use of OX40 agonists as therapeutic agents in the setting of advanced cancers, as well as the mechanisms through which therapeutic efficacy is achieved. We show that treatment of mice bearing well-established day 17 sarcomas with a novel OX40 ligand-Fc fusion protein (OX40L-Fc) resulted in tumor regression or dormancy in the majority of treated animals. Unexpectedly, dendritic cells (DC) in the progressive tumor microenvironment (TME) acquire OX40 expression and bind fluorescently labeled OX40L-Fc.

Intralesional delivery of dendritic cells engineered to express T-bet promotes protective type 1 immunity and the normalization of the tumor microenvironment.

T-bet (Tbx21), a T-box transcription factor, has been previously identified as a master regulator of type 1 T cell polarization. We have also recently shown that the genetic engineering of human dendritic cells (DCs) to express human T-bet cDNA yields type 1-polarizing APCs in vitro (1). In the present study, murine CD11c(+) DCs were transduced with a recombinant adenovirus encoding full-length murine T-bets (DC.

A need for basic research on fluid-based early detection biomarkers.

Cancer continues to be a major cause of mortality despite decades of effort and expense. The problem reviewed here is that before many cancers are discovered they have already progressed to become drug resistant or metastatic. Biomarkers found in blood or other body fluids could supplement current clinical indicators to permit earlier detection and thereby reduce cancer mortality.

Mst1 is an interacting protein that mediates PHLPPs' induced apoptosis.

PHLPP1 and PHLPP2 phosphatases exert their tumor-suppressing functions by dephosphorylation and inactivation of Akt in several breast cancer and glioblastoma cells. However, Akt, or other known targets of PHLPPs that include PKC and ERK, may not fully elucidate the physiological role of the multifunctional phosphatases, especially their powerful apoptosis induction function. Here, we show that PHLPPs induce apoptosis in cancer cells independent of the known targets of PHLPPs.

Integrating costimulatory agonists to optimize immune-based cancer therapies.

While immunotherapy for cancer has become increasingly popular, clinical benefits for such approaches remain limited. This is likely due to tumor-associated immune suppression, particularly in the advanced-disease setting. Thus, a major goal of novel immunotherapeutic design has become the coordinate reversal of existing immune dysfunction and promotion of specific tumoricidal T-cell function.

The role of nucleus accumbens adenosine-opioid interaction in mediating palatable food intake.

Nucleus accumbens micro-opioid stimulation leads to robust increases in the intake of highly palatable foods, such as a high-fat diet. While interactions between opioids and certain striatal neurotransmitters underlying this phenomenon have been explored, many potential interactions have not. Striatal adenosine has been shown to have a significant influence on striatal neurotransmission and locomotor activity behavior, however the interaction between opioids and adenosine on feeding behaviors has received less attention.

IL-4 suppresses very late antigen-4 expression which is required for therapeutic Th1 T-cell trafficking into tumors.

Murine CD4 T cells cultured under type 1 polarizing conditions selectively express significantly higher levels of the very late antigen (VLA)-4 and VLA-6 integrins when compared with T cells cultured under type 2 or nonpolarizing (type 0) conditions. This difference appears due to the action of interleukin (IL)-4, as loss of VLA-4/-6 expression on Th cells was prevented by inclusion of neutralizing anti-IL-4 mAb during the initial culture period. We also observed that CD4 T cells deficient in Stat6, a critical component of the IL-4R signaling cascade, retained high levels of VLA-4 and VLA-6 expression, regardless of IL-4 status in the culture conditions.

Metastasis and AKT activation.

Metastasis, responsible for 90% of cancer patient deaths, is an inefficient process because many tumor cells die. The survival of metastatic tumor cells should be considered as a critical therapeutic target. This review provides a new perspective regarding the role of AKT in tumor survival, and the rationale to target AKT in anti-metastasis therapies.

IL-4 inhibits VLA-4 expression on Tc1 cells resulting in poor tumor infiltration and reduced therapy benefit.

We and others have previously demonstrated that IL-4-dependent Tc2 are inferior to Tc1-effector CD8+ T cells in regulating tumor progression in vivo. This functional disparity relates, in part, to the comparatively poor ability of Tc2 to migrate into diseased tissues. We now show that IL-4 treatment of committed Tc1 cells promotes the selective loss in the expression of very-late antigen (VLA)-4, without impacting the Tc1 cytokine production profile, cytotoxic activity, or expression of alternate cell surface markers.

CD8+ T-cell responses against hemoglobin-beta prevent solid tumor growth.

Bone marrow-derived dendritic cells engineered using recombinant adenovirus to secrete high levels of IL-12p70 dramatically inhibited the growth of established CMS4 sarcomas in BALB/c mice after intratumoral administration. An analysis of splenic CD8(+) T cells in regressor mice revealed a strong, complex reactivity pattern against high-performance liquid chromatography (HPLC)-resolved peptides isolated by acid elution from single-cell suspensions of surgically resected CMS4 lesions. Mass spectrometry analyses defined two major overlapping peptide species that derive from the murine hemoglobin-beta (HBB) protein within the most stimulatory HPLC fractions.

Metastasis and AKT activation.

Metastasis is responsible for 90% of cancer patient deaths. More information is needed about the molecular basis for its potential detection and treatment. The activated AKT kinase is necessary for many events of the metastatic pathway including escape of cells from the tumor's environment, into and then out of the circulation, activation of proliferation, blockage of apoptosis, and activation of angiogenesis.

Stat6 signaling suppresses VLA-4 expression by CD8+ T cells and limits their ability to infiltrate tumor lesions in vivo.

VLA-4 plays a critical role in T cell trafficking into inflammatory sites. Our recent studies have suggested that VLA-4 expression on CD8+ T cells is negatively controlled by IL-4 and serves as a functionally distinguishing variable for why Type-1, but not Type-2, CD8+ T cells are able to traffic into tumors. In this study, using in vitro culture of murine CD8+ T cells under Type-1 and Type-2 cytokine conditions, we show that IL-4-mediated down-regulation of VLA-4 expression is completely abrogated in Stat6-deficient CD8+ T cells.