IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy.

Background: Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1-specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression.

Greater Somatosensory Afference With Acupuncture Increases Primary Somatosensory Connectivity and Alleviates Fibromyalgia Pain via Insular γ-Aminobutyric Acid: A Randomized Neuroimaging Trial.

Objective: Acupuncture is a complex multicomponent treatment that has shown promise in the treatment of fibromyalgia (FM). However, clinical trials have shown mixed results, possibly due to heterogeneous methodology and lack of understanding of the underlying mechanism of action. The present study was undertaken to understand the specific contribution of somatosensory afference to improvements in clinical pain, and the specific brain circuits involved.

Phase Ib with expansion study of olaparib plus weekly (Metronomic) carboplatin and paclitaxel in relapsed ovarian cancer patients.

Objective: Our goals were to: establish the maximum-tolerated dose of olaparib tablets combined with metronomic carboplatin and paclitaxel in patients with relapsed high-grade serous ovarian cancer; evaluate dose-limiting toxicities; and evaluate efficacy at the maximum tolerated dose.

Methods: In this open-label, single-arm, investigator-initiated trial (ClinicalTrials.gov NCT01650376), patients with high-grade serous ovarian cancer who failed primary platinum and taxane therapy received oral olaparib tablets twice daily days 1-3 each week combined with fixed-dose metronomic carboplatin AUC2 and paclitaxel 60 mg/m weekly for 3 out of 4 weeks.

Medical students developing confidence and patient centredness in diverse clinical settings: a longitudinal survey study.

Background: Medical student clinical confidence and positive attitudes to patient centredness are important outcomes of medical education. The clinical placement setting is regarded as a critical support to these outcomes, so understanding how the setting is influential is important. The aim of this study was to compare students' attitudes towards patient-centredness and clinical confidence as they progressed through their medical course, and understand the influence of diverse clinical placement zones.

T-Cell Therapy Using Interleukin-21-Primed Cytotoxic T-Cell Lymphocytes Combined With Cytotoxic T-Cell Lymphocyte Antigen-4 Blockade Results in Long-Term Cell Persistence and Durable Tumor Regression.

Purpose Peripheral blood-derived antigen-specific cytotoxic T cells (CTLs) provide a readily available source of effector cells that can be administered with minimal toxicity in an outpatient setting. In metastatic melanoma, this approach results in measurable albeit modest clinical responses in patients resistant to conventional therapy. We reasoned that concurrent cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) checkpoint blockade might enhance the antitumor activity of adoptively transferred CTLs.

Combined IL-21-primed polyclonal CTL plus CTLA4 blockade controls refractory metastatic melanoma in a patient.

Adoptive transfer of peripheral blood-derived, melanoma-reactive CD8(+) cytotoxic T lymphocytes (CTLs) alone is generally insufficient to eliminate bulky tumors. Similarly, monotherapy with anti-CTLA4 infrequently yields sustained remissions in patients with metastatic melanoma. We postulated that a bolus of enhanced IL-21-primed polyclonal antigen-specific CTL combined with CTLA4 blockade might boost antitumor efficacy.

Mating and Memory : Can Mating Cues Enhance Cognitive Performance?

The literature on sexual selection and the social brain hypothesis suggest that human cognition and communication evolved, in part, for the purpose of displaying desirable cognitive abilities to potential mates. An evolutionary approach to social cognition implies that proximate mating motives may lead people to display desirable mental traits. In signaling such traits, one can increase the likelihood of attracting a potential mate.

Identification of ATR-Chk1 pathway inhibitors that selectively target p53-deficient cells without directly suppressing ATR catalytic activity.

Resistance to DNA-damaging chemotherapy is a barrier to effective treatment that appears to be augmented by p53 functional deficiency in many cancers. In p53-deficient cells in which the G1-S checkpoint is compromised, cell viability after DNA damage relies upon intact intra-S and G2-M checkpoints mediated by the ATR (ataxia telangiectasia and Rad3 related) and Chk1 kinases. Thus, a logical rationale to sensitize p53-deficient cancers to DNA-damaging chemotherapy is through the use of ATP-competitive inhibitors of ATR or Chk1.

Regression of metastatic Merkel cell carcinoma following transfer of polyomavirus-specific T cells and therapies capable of re-inducing HLA class-I.

Merkel cell carcinoma (MCC) is an aggressive skin cancer that typically requires the persistent expression of Merkel cell polyomavirus (MCPyV) oncoproteins that can serve as ideal immunotherapeutic targets. Several immune evasion mechanisms are active in MCC including down-regulation of HLA class-I expression on tumor cells and dysfunctional endogenous MCPyV-specific CD8 T cell responses. To overcome these obstacles, we combined local and systemic immune therapies in a 67-year-old man, who developed metastatic MCPyV-expressing MCC.

Optimisation of pharmacokinetic properties to afford an orally bioavailable and selective V1A receptor antagonist.

The previously described lead compound 5 is a potent and selective V(1A) antagonist with affinity at both the rat and human receptor, but displays poor oral bioavailability and moderate clearance. We report herein the successful optimisation of the pharmacokinetic (PK) properties to afford the potent, selective, orally bioavailable and CNS penetrant compound 15f. A custom optimisation approach was required which demonstrated the value of using early, rapid in vivo PK studies to show improvements in oral exposure.

The selective phosphodiesterase 9 (PDE9) inhibitor PF-04447943 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) enhances synaptic plasticity and cognitive function in rodents.

Inhibition of phosphodiesterase 9 (PDE9) has been reported to enhance rodent cognitive function and may represent a potential novel approach to improving cognitive dysfunction in Alzheimer's disease. PF-04447943, (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one), a recently described PDE9 inhibitor, was found to have high affinity (Ki of 2.8, 4.

The discovery of novel 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamides as vasopressin V1A receptor antagonists.

The discovery of a novel series of 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamide antagonists of the vasopressin V(1A) receptor is disclosed.

Regional differences in neurovascular coupling in rat brain as determined by fMRI and electrophysiology.

Increases in neuronal activity induce local increases in cerebral perfusion. However, our understanding of the processes underlying this neurovascular coupling remains incomplete and, particularly, how these vary across the brain. Recent work supports an important role for astrocytes in neurovascular coupling, in large part via activation of their metabotropic glutamate receptors (mGluR).

Overcoming barriers to engaging socio-economically disadvantaged populations in CHD primary prevention: a qualitative study.

Background: Preventative medicine has become increasingly important in efforts to reduce the burden of chronic disease in industrialised countries. However, interventions that fail to recruit socio-economically representative samples may widen existing health inequalities. This paper explores the barriers and facilitators to engaging a socio-economically disadvantaged (SED) population in primary prevention for coronary heart disease (CHD).

Nitrous oxide and isoflurane are synergistic with respect to amplitude and latency effects on sensory evoked potentials.

Objective: Combinations of anesthetic agents are frequently employed to produce the desired clinical effect. No systematic study has been conducted on the effect of the combination of nitrous oxide with a potent inhalational agent such as isoflurane on sensory evoked responses.

Methods: Median nerve somatosensory evoked responses from the cervical and cortical regions (SSEP), auditory brainstem responses (ABR) and flash visual evoked responses (VEP) were tested in baboons.

Hippocampal lesions impair performance on a conditional delayed matching and non-matching to position task in the rat.

The hippocampus is thought to be involved in a range of cognitive processes, from the ability to acquire new memories, to the ability to learn about spatial relationships. Humans and monkeys with damage to the hippocampus are typically impaired on delayed matching to sample tasks, of which the operant delayed matching to position task (DMTP) is a rat analogue. The reported effects of hippocampal damage on DMTP vary, ranging from delay-dependent deficits to no deficit whatsoever.

Double dissociation between hippocampal and prefrontal lesions on an operant delayed matching task and a water maze reference memory task.

The hippocampus and prefrontal cortex have both been implicated in various aspects of the acquisition, retention and performance of delayed matching to position (DMTP) tasks in the rat, although their precise respective contributions remain unclear. In the present study, rats were trained preoperatively on DMTP before receiving excitotoxic bilateral lesions of either the entire hippocampus or the medial prefrontal cortex. Rats with lesions of the prefrontal cortex exhibited a significant delay-dependent impairment on retention of the DMTP task, whereas hippocampal lesions were without effect.

Developing and testing of the Foot Care Confidence Scale.

This study developed and tested the Foot Care Confidence Scale (FCCS), an instrument designed to measure the confidence (self-efficacy) diabetics have in performing foot self care. Content validity was assessed using Lynn's (1986) Content Validity Index (CVI) with a total of 100% content validity (Sloan, 1993). The FCCS was administered to four persons with diabetes (Sloan, 1994) and pilot tested with 41 healthy older adults (Wills & Sloan, 1995).

Clinical application of the Omaha system with the Nightingale Tracker: a community health nursing student home visit program.

The application of computer use in the clinical and educational arena needs to be emphasized for both the improved management of patient data and nursing knowledge. Faculty commitment to automation of home visit documentation records was essential to sustain the trial of implementing the Nightingale Trackers in the clinical area. The Nightingale Tracker is a software program that automates the Omaha system, a community-friendly nursing language that encourages a focus on health promotion.

Teaching the use of walkers and canes.

Home care and hospice nurses frequently encounter patients who use assistive devices to safely remain mobile in their homes. Incorrectly used, these devices may contribute to falls. This article provides a review on the use and teaching of these devices to patients and caregivers.

The antilipidemic effects of plain and extended-release niacin.

The extensive antihyperlipidemic effects of niacin are well known. Cardiac doses of niacin are effective in lowering low density lipoprotein, triglyceride, and lipoprotein(a) levels and in elevating high density lipoprotein levels. Adverse reactions to niacin range from annoying cutaneous flushing to hepatic toxicity.