T-Cell Infiltration and Adaptive Treg Resistance in Response to Androgen Deprivation With or Without Vaccination in Localized Prostate Cancer

Purpose: Previous studies suggest that androgen deprivation therapy (ADT) promotes antitumor immunity in prostate cancer. Whether a vaccine-based approach can augment this effect remains unknown. Experimental Design: Therefore, we conducted a neoadjuvant, randomized study to quantify the immunologic effects of a granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting allogeneic cellular vaccine in combination with low-dose cyclophosphamide (Cy/GVAX) followed by degarelix versus degarelix alone in patients with high-risk localized prostate adenocarcinoma who were planned for radical prostatectomy. Results: Both Cy/GVAX plus degarelix and degarelix alone led to significant increases in intratumoral CD8+ T cell infiltration and PD-L1 expression as compared to a cohort of untreated, matched controls. However, the CD8+ T cell infiltrate was accompanied by a proportional increase in regulatory T cells (Treg), suggesting that adaptive Treg resistance may dampen the immunogenicity of ADT. Although Cy/GVAX followed by degarelix was associated with a modest improvement in time-to-PSA progression and time-to-next treatment as well as an increase in PD-L1, there was no difference in the CD8 T-cell infiltrate as compared to degarelix alone. Gene expression profiling demonstrated that CHIT1, a macrophage marker, was differentially upregulated with Cy/GVAX plus degarelix compared to degarelix alone. Conclusions: Our results highlight that ADT with or without Cy/GVAX induces a complex immune response within the prostate tumor microenvironment. These data have important implications for combining ADT with immunotherapy. In particular, our finding that ADT increases both CD8+ T cells and Tregs, supports the development of regimens combining ADT with Treg-depleting agents in the treatment of prostate cancer

The Movember Global Action Plan 1 (GAP1) : Unique Prostate Cancer Tissue Microarray Resource

BACKGROUND: The need to better understand the molecular underpinnings of the heterogeneous outcomes of patients with prostate cancer is a pressing global problem and a key research priority for Movember. To address this, the Movember Global Action Plan 1 Unique tissue microarray (GAP1-UTMA) project constructed a set of unique and richly annotated tissue microarrays (TMA) from prostate cancer samples obtained from multiple institutions across several global locations. METHODS: Three separate TMA sets were built that differ by purpose and disease state. RESULTS: The intended use of TMA1 (Primary Matched LN) is to validate biomarkers that help determine which clinically localized prostate cancers with associated lymph node metastasis have a high risk of progression to lethal castration-resistant metastatic disease, and to compare molecular properties of high-risk index lesions within the prostate to regional lymph node metastases resected at the time of prostatectomy. TMA2 (Pre vs. Post ADT) was designed to address questions regarding risk of castration-resistant prostate cancer (CRPC) and response to suppression of the androgen receptor/androgen axis, and characterization of the castration-resistant phenotype. TMA3 (CRPC Met Heterogeneity)'s intended use is to assess the heterogeneity of molecular markers across different anatomic sites in lethal prostate cancer metastases. CONCLUSIONS: The GAP1-UTMA project has succeeded in combining a large set of tissue specimens from 501 patients with prostate cancer with rich clinical annotation. IMPACT: This resource is now available to the prostate cancer community as a tool for biomarker validation to address important unanswered clinical questions around disease progression and response to treatment.publishedVersionPeer reviewe

The effects of pentoxifylline on skeletal muscle contractility and neuromuscular transmission during hypoxia

Objectives: The objective of this study was to investigate the effects of pentoxifylline (PTX), a drug that is mainly used for indications related to tissue hypoxia, on hypoxia-induced inhibition of skeletal muscle contractility and neuromuscular transmission in mice. We hypothesized that chronic PTX treatment alters skeletal muscle contractility and hypoxia-induced dysfunction. Materials and Methods: Mice were treated with 50 mg/kg PTX or saline intraperitoneally for a week. Following ether anesthesia, diaphragm muscles were removed; isometric muscle contractions and action potentials were recorded. Time to reach neuromuscular blockade and the rate of recovery of muscle contractility were assessed during hypoxia and re-oxygenation. Results: The PTX group displayed 90% greater twitch amplitudes (P < 0.01). Hypoxia depressed twitch contractions and caused neuromuscular blockade in both groups. However, neuromuscular blockade occurred earlier in PTX-treated animals (P < 0.05). Muscle contractures developed during hypoxia were more pronounced in the PTX group (P < 0.05). Re-oxygenation reduced contracture and indirect muscle contractions resumed. The rate of recovery of contractions was faster (P < 0.05) and the amplitude of contractions was greater (P < 0.01) in the PTX group. PTX treatment increased amplitude (P < 0.05) and shortened action potential (P < 0.05) without altering resting membrane potential, excitation threshold, and neurotransmitter release. Conclusion: Chronic PTX treatment increases diaphragm contractility, but amplifies hypoxia-induced contractile dysfunction in mice. These results may implicate important clinical consequences for clinical usage of PTX in hypoxia-related conditions.PubMedWo

Exercise and suspension hypokinesia-induced alterations in mechanical properties of rat fast and slow-twitch skeletal muscles

Physical activity has a modulatory role on regulatory steps of excitation-contraction coupling (ECC) determining skeletal muscle contractility. We evaluated and compared the contractile responsiveness and caffeine-induced contractures of fast (extensor digitorum longus; EDL) and slow-twitch (soleus; SOL) muscles in suspension hypokinesia (SH) and exercised rats. After SH or low intensity exercise, EDL and SOL were isolated, twitch and tetanic contractions and caffeine (10 mM) contractures were recorded. Twitch and tetanic contractions of EDL increased by 60% in exercised rats ( p <0.05) while no alteration was observed after SH. Exercise did not alter twitch and tetanic contractions of SOL, while SH depressed contractions ( p <0.05). Caffeine contractures were diminished in exercised rat EDL ( P <0.05). In SH-rat EDL, contractures increased in amplitude ( p <0.01) with a rapid time course ( p <0.05). Contractures did not change in SOL after exercise or SH. We concluded that SH and exercise exerted diverse modulatory effects on skeletal muscle contractility. Contractile improvement due to exercise was prominent in EDL. Our results suggest that the muscle-type specific adaptations are related to a change in ECC due to the differences in the regulatory steps, particularly in the intracellular Ca2+ handling mechanisms

Intraosseous Angiolipoma of the Rib.

Angiolipomas are a subgroup of lipomas and are rarely observed benign tumours in which mature fat tissue and angiomatous elements exist jointly. Costa-induced angiolipomas are rarer. A male patient aged 46 years consulted our clinic due to severe pain in his left side. The patient's X-ray showed a lobulated area with increased density (bone mass) in the left upper zone of the lung. A lesion in the fourth rib was excised with a left thoracotomy. Pathological diagnosis was reported as angiolipoma

Intraosseous Angiolipoma of the Rib

Angiolipomas are a subgroup of lipomas and are rarely observed benign tumours in which mature fat tissue and angiomatous elements exist jointly. Costa-induced angiolipomas are rarer. A male patient aged 46 years consulted our clinic due to severe pain in his left side. The patient's Xray showed a lobulated area with increased density (bone mass) in the left upper zone of the lung. A lesion in the fourth rib was excised with a left thoracotomy. Pathological diagnosis was reported as angiolipoma

Salt-Sparing Diuretic Action of a Water-Soluble Urea Analog Inhibitor of Urea Transporters Ut-A and Ut-B In Rats

Inhibitors of kidney urea transporter (UT) proteins have potential use as salt-sparing diuretics (‘urearetics’) with a different mechanism of action than diuretics that target salt transporters. To study UT inhibition in rats, we screened about 10,000 drugs, natural products and urea analogs for inhibition of rat UT-A1. Drug and natural product screening found nicotine, sanguinarine and an indolcarbonylchromenone with IC50 of 10–20 μM. Urea analog screening found methylacetamide and dimethylthiourea (DMTU). DMTU fully and reversibly inhibited rat UT-A1 and UT-B by a noncompetitive mechanism with IC50 of 2–3 mM. Homology modeling and docking computations suggested DMTU binding sites on rat UT-A1. Following a single intraperitoneal injection of 500 mg/kg DMTU, peak plasma concentration was 9 mM with t1/2 of about 10 hours, and a urine concentration of 20–40 mM. Rats chronically treated with DMTU had a sustained, reversible reduction in urine osmolality from 1800 to 600 mOsm, a 3-fold increase in urine output, and mild hypokalemia. DMTU did not impair urinary concentrating function in rats on a low protein diet. Compared to furosemide-treated rats, the DMTU-treated rats had greater diuresis and reduced urinary salt loss. In a model of Syndrome of Inappropriate Antidiuretic Hormone secretion, DMTU treatment prevented hyponatremia and water retention produced by water-loading in dDAVP-treated rats. Thus, our results establish a rat model of UT inhibition and demonstrate the diuretic efficacy of UT inhibition.PubMedWoSScopu

A Nobel-Winning Scientist: Aziz Sancar and the Impact of his Work on the Molecular Pathology of Neoplastic Diseases

Aziz Sancar, Nobel Prize winning Turkish scientist, made several discoveries which had a major impact on molecular sciences, particularly disciplines that focus on carcinogenesis and cancer treatment, including molecular pathology. Cloning the photolyase gene, which was the initial step of his work on DNA repair mechanisms, discovery of the "Maxicell" method, explanation of the mechanism of nucleotide excision repair and transcription-coupled repair, discovery of "molecular matchmakers", and mapping human excision repair genes at single nucleotide resolution constitute his major research topics. Moreover, Sancar discovered the cryptochromes, the clock genes in humans, in 1998, and this discovery led to substantial progress in the understanding of the circadian clock and the introduction of the concept of "chrono-chemoterapy" for more effective therapy in cancer patients. This review focuses on Aziz Sancar's scientific studies and their reflections on molecular pathology of neoplastic diseases. While providing a new perspective for researchers working in the field of pathology and molecular pathology, this review is also an evidence of how basic sciences and clinical sciences complete each other