TFP5, a Peptide Inhibitor of Aberrant and Hyperactive Cdk5/p25, Attenuates Pathological Phenotypes and Restores Synaptic Function in CK-p25Tg Mice.

It has been reported that cyclin-dependent kinase 5 (cdk5), a critical neuronal kinase, is hyperactivated in Alzheimer's disease (AD) and may be, in part, responsible for the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs). It has been proposed by several laboratories that hyperactive cdk5 results from the overexpression of p25 (a truncated fragment of p35, the normal cdk5 regulator), which, when complexed to cdk5, induces hyperactivity, hyperphosphorylated tau/NFTs, amyloid-β plaques, and neuronal death. It has previously been shown that intraperitoneal (i.

Educational Needs Assessment Highlights Several Areas of Emphasis in Teaching Evidence-Based Medicine Skills to Physician Assistant Students.

Purpose: An assessment of educational needs is essential for curricular reform in medical education. Using the conceptual framework of needs assessment, this study aimed to determine which content should be emphasized in teaching evidence-based medicine (EBM) skills to physician assistant (PA) students.

Methods: Key content areas were identified from the published literature and objectives for previous courses.

Lipoprotein abnormalities in patients with type 2 diabetes and metabolic syndrome.

Cardiovascular disease remains the leading cause of death in men and women in the United States. Aggressive treatment of insulin resistance and its associated lipid abnormalities remains a top priority for preventing cardiovascular morbidity and mortality.

Treatment of restless legs syndrome with iron infusion therapy.

Initially, the patient in this case received CPAP for sleep apnea and pramipexole for RLS. Her symptoms failed to resolve, which led to consultation with a sleep specialist who recommended diagnostic studies that identified an underlying iron/ferritin deficiency. After receiving IV iron therapy, the patient's RLS symptoms resolved.

Development and evaluation of BioScore: a biomarker panel to enhance prognostic algorithms for clear cell renal cell carcinoma.

Background: The authors previously showed that increased tumor expression levels of B7-H1, survivin, and Ki-67 are independent predictors of poor outcome for patients with clear cell renal cell carcinoma (ccRCC). In the current study, they described the creation of a scoring system based on this panel of biomarkers that can be used in tandem with existing clinicopathologic features and algorithms to improve ccRCC outcome prediction.

Methods: The authors used immunohistochemistry to determine tumor expression levels of B7-H1, survivin, and Ki-67 for 634 consecutive ccRCC patients.

Tumor cell and tumor vasculature expression of B7-H3 predict survival in clear cell renal cell carcinoma.

Purpose: Although the prognostic value of B7-H1 and B7-H4 expression by tumor cells in clear cell renal cell carcinoma (ccRCC) has been established, the role of B7-H3 is unknown. As such, we evaluated the association of B7-H3 expression with clinicopathologic outcomes in patients treated for ccRCC.

Experimental Design: Nephrectomy specimens from 743 consecutive patients treated for ccRCC at our institution from 1990 to 1999 were evaluated for B7-H3 expression by immunohistochemical staining.

T-cell coregulatory molecule expression in urothelial cell carcinoma: clinicopathologic correlations and association with survival.

Purpose: Aberrant expression of T-cell coregulatory molecules has been investigated as a mechanism by which certain cancers may evade host immune surveillance. We evaluated expression of the T-cell coregulators B7-H1, B7-H3, and PD-1 in urothelial cell carcinoma (UCC) of the bladder.

Experimental Design: Immunohistochemistry for B7-H1, B7-H3, and PD-1 was done on paraffin-embedded sections from 318 consecutive patients with UCC who underwent radical cystectomy.

Questionable relevance of gamma delta T lymphocytes in renal cell carcinoma.

Adoptive gammadelta T cell immunotherapy has moved briskly into clinical trials prompted by several small studies suggesting abundant accumulation of gammadelta T cells within renal cell carcinoma (RCC). In this study, we re-examined levels of gammadelta T cells within RCC tumors and correlated levels of these cells with pathologic features and outcome associated with this form of cancer. Tissues from 248 consecutive clear cell RCC tumors obtained from 2000 to 2003 were stained and quantified for total CD3+ and gammadelta T cells per mm2.

Targeting molecular and cellular inhibitory mechanisms for improvement of antitumor memory responses reactivated by tumor cell vaccine.

Development of effective vaccination approaches to treat established tumors represents a focus of intensive research because such approaches offer the promise of enhancing immune system priming against tumor Ags via restimulation of pre-existing (memory) antitumoral helper and effector immune cells. However, inhibitory mechanisms, which function to limit the recall responses of tumor-specific immunity, remain poorly understood and interfere with therapies anticipated to induce protective immunity. The mouse renal cell carcinoma (RENCA) tumor model was used to investigate variables affecting vaccination outcomes.

B7-H3 ligand expression by prostate cancer: a novel marker of prognosis and potential target for therapy.

B7 coregulatory ligands can be aberrantly expressed in human disease. In the context of cancer, these ligands may act as antigen-specific inhibitors of T-cell-mediated antitumoral immunity. We recently reported that B7-H1 expression by carcinomas of the kidney and bladder portends aggressive disease and diminished survival.

Tumor-infiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma.

Purpose: Regulatory T cells (Tregs) have been implicated as inhibitors of antitumoral immunity, and evidence suggests that elimination of Tregs may augment natural and pharmacologic immunity. We tested for the presence of putative Tregs within renal cell carcinoma (RCC) tumors.

Experimental Design: We identified 170 patients who underwent radical or partial nephrectomy for clear cell RCC between 2000 and 2002.

Survivin and b7-h1 are collaborative predictors of survival and represent potential therapeutic targets for patients with renal cell carcinoma.

Purpose: Clear cell renal cell carcinoma (ccRCC) is an immunogenic tumor that can progress in the presence of an intact host immune system. We previously reported that survivin and B7-H1 are independently associated with disease progression and death when expressed by ccRCC tumors. Herein, we examine the clinical effect of ccRCC combined expression of both survivin and B7-H1.

B7-H4 expression in renal cell carcinoma and tumor vasculature: associations with cancer progression and survival.

B7-H4 is a recently described B7 family coregulatory ligand that has been implicated as an inhibitor of T cell-mediated immunity. Although expression of B7-H4 is typically limited to lymphoid cells, aberrant B7-H4 expression has also been reported in several human malignancies. To date, associations of B7-H4 with clinical outcomes for cancer patients are lacking.

Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up.

B7-H1 participates in T-cell costimulation functioning as a negative regulator of immunity. Recent observations suggest that B7-H1 is expressed by renal cell carcinoma (RCC) tumor cells and is associated with poor prognosis. However, outcome analyses have been restricted to patients with fresh-frozen tissue and limited follow-up.

B7-H1 glycoprotein blockade: a novel strategy to enhance immunotherapy in patients with renal cell carcinoma.

Cancer cell expression of the B7-H1 glycoprotein has been implicated as a potent inhibitor of T cell-mediated antitumoral immunity. We recently reported that B7-H1 is aberrantly expressed in renal cell carcinoma (RCC) and suggested that blockade of B7-H1, as demonstrated in several murine cancer models, represents a promising therapeutic target in RCC. Herein, we update our results with tumor-associated B7-H1 and discuss future clinical applications.

Augmentation of T cell levels and responses induced by androgen deprivation.

Androgen has been implicated as a negative regulator of host immune function and a factor contributing to the gender dimorphism of autoimmunity. Conversely, androgen deprivation has been suggested to potentiate male host immunity. Studies have shown that removal of androgen in postpubertal male mice produces an increase in size and cellularity of primary and peripheral lymphoid organs, and enhances a variety of immune responses.

Silencing of secretin receptor function by dimerization with a misspliced variant secretin receptor in ductal pancreatic adenocarcinoma.

Secretin receptors that are key for regulation of healthy pancreatic ductal epithelial cells have been reported to be functionally absent on ductal pancreatic adenocarcinomas. Here, we examine the possible presence and function of molecular forms of the secretin receptor in pancreatic cancer cell lines and in primary tumors. Surprisingly, reverse transcription-PCR and sequencing demonstrated wild-type secretin receptor mRNA in each of four cell lines and three primary tumors.

Dominant negative action of an abnormal secretin receptor arising from mRNA missplicing in a gastrinoma.

Background & Aims: The provocative secretin-stimulation test has an important role in the diagnosis and management of gastrin-secreting neuroendocrine tumors. The aim of the present study was to explore the molecular basis for positive and false-negative secretin-stimulation test results in patients with these tumors.

Methods: One of the rare patients with this histologically proven tumor who had a normal serum gastrin level and a negative secretin-stimulation test result, and 2 more typical patients with this syndrome were investigated using immunohistochemistry, reverse-transcription polymerase chain reaction, receptor binding, and signaling assays.

A misspliced form of the cholecystokinin-B/gastrin receptor in pancreatic carcinoma: role of reduced sellular U2AF35 and a suboptimal 3'-splicing site leading to retention of the fourth intron.

Abnormal splicing of primary RNA transcripts of normal genes is a recognized mechanism for the production of some abnormal proteins found in cancer cells. A misspliced form of the cholecystokinin-B/gastrin (CCK-B) receptor recently was reported to be present in colon carcinoma, where it was postulated to play a role in stimulating tumor growth (M. R.