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Reports that a member of the protein inhibitor of activated STAT family, PIASy, is a transcriptional corepressor of signal transducer and activator of transcription (Stat1). Presence of an LXXLL coregulator signature motif near the NH2 terminus of PIASy; Proposed mechanism of how PIAS proteins repress STAT-mediated gene activation.

Background: Prostate cancer patients on androgen deprivation therapy (ADT) experience adverse effects such as lean mass loss, known as sarcopenia, fat gain, and changes in cardiometabolic factors that increase risk of metabolic syndrome (MetS). Resistance training can increase lean mass, reduce body fat, and improve physical function and quality of life, but no exercise interventions in prostate cancer patients on ADT have concomitantly improved body composition and MetS. This pilot trial investigated 12 weeks of resistance training on body composition and MetS changes in prostate cancer patients on ADT. An exploratory aim examined if a combined approach of training and protein supplementation would elicit greater changes in body composition.Methods: Prostate cancer patients on ADT were randomized to resistance training and protein supplementation (TRAINPRO), resistance training (TRAIN), protein supplementation (PRO), or control stretching (STRETCH). Exercise groups (EXE = TRAINPRO, TRAIN) performed supervised exercise 3 days per week for 12 weeks, while non-exercise groups (NoEXE = PRO, STRETCH) performed a home-based stretching program. TRAINPRO and PRO received 50 g⋅day- 1 of whey protein. The primary outcome was change in lean mass assessed through dual energy x-ray absorptiometry. Secondary outcomes examined changes in sarcopenia, assessed through appendicular skeletal mass (ASM) index (kg/m2), body fat %, strength, physical function, quality of life, MetS score and the MetS components of waist circumference, blood pressure, glucose, high-density lipoprotein-cholesterol, and triglyceride levels.Results: A total of 37 participants were randomized; 32 participated in the intervention (EXE n = 13; NoEXE n = 19). At baseline, 43.8% of participants were sarcopenic and 40.6% met the criteria for MetS. Post-intervention, EXE significantly improved lean mass (d = 0.9), sarcopenia prevalence (d = 0.8), body fat % (d = 1.1), strength (d = 0.8-3.0), and prostate cancer-specific quality of life (d = 0.9) compared to NoEXE (p < 0.05). No significant differences were observed between groups for physical function or MetS-related variables except waist circumference (d = 0.8).Conclusions: A 12-week resistance training intervention effectively improved sarcopenia, body fat %, strength and quality of life in hypogonadal prostate cancer patients, but did not change MetS or physical function. PRO did not offer additional benefit in improving body composition.Trial Registration: ClinicalTrials.gov: NCT01909440 . Registered 24 July 2013. [ABSTRACT FROM AUTHOR]

Simple Summary: In addition to millions of normal red and white blood cells, the blood of cancer patients contains a variety of very rare cell types associated with the tumor. A simple blood draw or 'liquid biopsy' can, thus, provide important information about the state of the disease no matter where it exists in the body. In this paper, we describe a method for imaging all rare cells in a blood draw and the means to define each cell type using a combination of genomic, proteomic, and morphological measurements to distinguish tumor cells from mesenchymal and endothelial cells that are present in the tumor microenvironment. We compare the results of this assay among multiple prostate and breast cancer patients and show that this cellular profiling method is valid across patients and cancer types and may provide important biomarkers for assessing disease in real time. Bi-directional crosstalk between the tumor and the tumor microenvironment (TME) has been shown to increase the rate of tumor evolution and to play a key role in neoplastic progression, therapeutic resistance, and a patient's overall survival. Here, we set out to use a comprehensive liquid-biopsy analysis to study cancer and specific TME cells in circulation and their association with disease status. Cytokeratin+, CD45- circulating rare cells (CRCs) from nine breast and four prostate cancer patients were characterized through morphometrics, single-cell copy number analysis, and targeted multiplexed proteomics to delineate cancer cell lineage from other rare cells originating in the TME. We show that we can detect epithelial circulating tumor cells (EPI.CTC), CTCs undergoing epithelial-to-mesenchymal transition (EMT.CTC) and circulating endothelial cells (CECs) using a universal rare event detection platform (HDSCA). Longitudinal analysis of an index patient finds that CTCs are present at the time of disease progression, while CECs are predominately present at the time of stable disease. In a small cohort of prostate and breast cancer patients, we find high inter-patient and temporal intra-patient variability in the expression of tissue specific markers such as ER, HER2, AR, PSA and PSMA and EpCAM. Our study stresses the importance of the multi-omic characterization of circulating rare cells in patients with breast and prostate carcinomas, specifically highlighting overlapping and cell type defining proteo-genomic characteristics of CTCs and CECs. [ABSTRACT FROM AUTHOR]

The circumsporozoite (CS) protein of the human malaria parasite Plasmodium falciparum may be the most promising target for the development of a malaria vaccine. In this study, proteins composed of 16, 32, or 48 tandem copies of a tetrapeptide repeating sequencefound in the, CS protein were efficiently expressed in the bacterium Escherichia coli. When injected into mice, these recombinant products resulted in the production of high titers of antibodies that reacted with the authentic CS protein on live sporozoites and blocked sporozoite invasion of human hepatoma cells in vitro. These CS protein derivatives are therefore candidates for a human malaria vaccine. [ABSTRACT FROM AUTHOR]

Signaling between the C C chemokine receptor 2 (CCR2) with its ligand, monocyte chemoattractant protein-1 (MCP-1) promotes cancer progression by directly stimulating tumor cell proliferation and downregulating the expression of apoptotic proteins. Additionally, the MCP-1/CCR2 signaling axis drives the migration of circulating monocytes into the tumor microenvironment, where they mature into tumor-associated macrophages (TAMs) that promote disease progression through induction of angiogenesis, tissue remodeling, and suppression of the cytotoxic T lymphocyte (CTL) response. In order to simultaneously disrupt MCP-1/CCR2 signaling and target CCR2-expressing cancer cells for drug delivery, KLAK-MCP-1 micelles consisting of a CCR2-targeting peptide sequence (MCP-1 peptide) and the apoptotic KLAKLAK peptide were synthesized. In vitro , KLAK-MCP-1 micelles were observed to bind and induce cytotoxicity to cancer cells through interaction with CCR2. In vivo, KLAK-MCP-1 micelles inhibited tumor growth (34 ± 11%) in a subcutaneous B16F10 murine melanoma model despite minimal tumor accumulation upon intravenous injection. Tumors treated with KLAK-MCP1 demonstrated reduced intratumor CCR2 expression and altered infiltration of TAMs and CTLs as evidenced by immunohistochemical and flow cytometric analysis. These studies highlight the potential application of CCR2-targeted nanotherapeutic micelles in cancer treatment. Unlabelled Image • KLAK-MCP-1 micelles combine apoptotic peptides (KLAK) with CCR2-binding ligands (MCP-1) for targeted therapy of CCR2+ cancer. • KLAK-MCP-1 micelles exhibited CCR2-dependent binding and toxicity to cancer cells and monocytes in vitro. • KLAK-MCP-1 micelles inhibited tumor growth and altered tumor-infiltrating macrophage and cytotoxic T lymphocyte populations. [ABSTRACT FROM AUTHOR]

[Display omitted] • Clorgyline is an irreversible monoamine oxidase A inhibitor used clinically as an antidepressant. • Previous studies show that clorgyline and other monoamine oxidase inhibitors exhibit anti-cancer activity in a variety of cancer model systems. • The clinical utility of clorgyline and other monoamine oxidase inhibitors may be limited by central nervous system toxicity. • A series of clorgyline analogues designed to minimize blood brain permeability were synthesized and evaluated for biologic activity. Monoamine oxidases (MAOA/MAOB) are enzymes known for their role in neurotransmitter regulation in the central nervous system (CNS). Irreversible and non-selective MAO inhibitors (MAOi's) were the first class of antidepressants, thus subsequent work on drugs such as the selective MAOA inhibitor clorgyline has focussed on selectivity and increased CNS penetration. MAOA is highly expressed in high grade and metastatic prostate cancer with a proposed effect on prostate cancer growth, recurrence, and drug resistance. A Phase II Clinical Trial has demonstrated the therapeutic effects of the irreversible nonselective MAOi phenelzine for prostate cancer. However, neurologic adverse effects led to early withdrawal in 25% of the enrolled patient-population. In this work, we revised the clorgyline scaffold with the goal of de creasing CNS penetration to minimize CNS-related side effects while retaining or enhancing MAOA inhibition potency and selectivity. Using the known co-crystal structure of clorgyline bound with FAD co-factor in the hMAOA active site as a reference, we designed and synthesized a series of compounds predicted to have lower CNS penetration (logBB). All synthesized derivatives displayed favorable drug-like characteristics such as predicted Caco-2 permeability and human oral absorption, and exhibited highly selective hMAOA binding interactions. Introduction of an HBD group (NH 2 or OH) at position 5 of the phenyl ring clorgyline resulted in 3x more potent hMAOA inhibition with equivalent or better hMAOB selectivity, and similar prostate cancer cell cytotoxicity. In contrast, introduction of larger substituents at this position or at the terminal amine significantly reduced the hMAOA inhibition potency, attributed in part to a steric clash within the binding pocket of the MAOA active site. Replacement of the N -methyl group by a more polar, but larger 2-hydroxyethyl group did not enhance potency. However, introduction of a polar 2-hydroxy in the propyl chain retained the highly selective MAOA inhibition and cancer cell cytotoxicity of clorgyline while reducing its CNS score from 2 to 0. We believe that these results identify a new class of peripherally directed MAOIs that may allow safer therapeutic targeting of MAOA for a variety of anti-cancer and anti-inflammatory indications. [ABSTRACT FROM AUTHOR]

Purpose: To compare the diagnostic yield of targeted prostate biopsy using image-fusion of multi-parametric magnetic resonance (mp-MR) with real-time trans-rectal ultrasound (TRUS) for clinically significant lesions that are suspicious only on mp-MR versus lesions that are suspicious on both mp-MR and TRUS. Methods: Pre-biopsy MRI and TRUS were each scaled on a 3-point score: highly suspicious, likely, and unlikely for clinically significant cancer (sPCa). Using an MR-TRUS elastic image-fusion system (Koelis), a 127 consecutive patients with a suspicious clinically significant index lesion on pre-biopsy mp-MR underwent systematic biopsies and MR/US-fusion targeted biopsies (01/2010-09/2013). Biopsy histological outcomes were retrospectively compared with MR suspicion level and TRUS-visibility of the MR-suspicious lesion. sPCa was defined as biopsy Gleason score ≥7 and/or maximum cancer core length ≥5 mm. Results: Targeted biopsies outperformed systematic biopsies in overall cancer detection rate (61 vs. 41 %; p = 0.007), sPCa detection rate (43 vs. 23 %; p = 0.0013), cancer core length (7.5 vs. 3.9 mm; p = 0.0002), and cancer rate per core (56 vs. 12 %; p < 0.0001), respectively. Highly suspicious lesions on mp-MR correlated with higher positive biopsy rate ( p < 0.0001), higher Gleason score ( p = 0.018), and greater cancer core length ( p < 0.0001). Highly suspicious lesions on TRUS in corresponding to MR-suspicious lesion had a higher biopsy yield ( p < 0.0001) and higher sPCa detection rate ( p < 0.0001). Since majority of MR-suspicious lesions were also suspicious on TRUS, TRUS-visibility allowed selection of the specific MR-visible lesion which should be targeted from among the multiple TRUS suspicious lesions in each prostate. Conclusions: MR-TRUS fusion-image-guided biopsies outperformed systematic biopsies. TRUS-visibility of a MR-suspicious lesion facilitates image-guided biopsies, resulting in higher detection of significant cancer. [ABSTRACT FROM AUTHOR]

Objective Prostate cancer survivors have reported cognitive complaints following treatment, and these difficulties may be associated with survivors' ongoing cancer-related distress. Intolerance of uncertainty may exacerbate this hypothesized relationship by predisposing individuals to approach uncertain situations such as cancer survivorship in an inflexible and negative manner. We investigated whether greater cognitive complaints and higher intolerance of uncertainty would interact in their relation to more cancer-related distress symptoms. Methods This cross-sectional, questionnaire-based study included 67 prostate cancer survivors who were 3 to 5 years post treatment. Hierarchical multiple regression analyses tested the extent to which intolerance of uncertainty, cognitive complaints, and their interaction were associated with cancer-related distress (measured with the Impact of Event Scale-Revised; IES-R) after adjusting for age, education, physical symptoms, and fear of cancer recurrence. Results Intolerance of uncertainty was positively associated with the IES-R avoidance and hyperarousal subscales. More cognitive complaints were associated with higher scores on the IES-R hyperarousal subscale. The interaction of intolerance of uncertainty and cognitive complaints was significantly associated with IES-R intrusion, such that greater cognitive complaints were associated with greater intrusive thoughts in survivors high in intolerance of uncertainty but not those low in it. Conclusions Prostate cancer survivors who report cognitive difficulties or who find uncertainty uncomfortable and unacceptable may be at greater risk for cancer-related distress, even 3 to 5 years after completing treatment. It may be beneficial to address both cognitive complaints and intolerance of uncertainty in psychosocial interventions. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective Most men diagnosed with prostate cancer in the USA will survive. Of the many aspects of survivorship affected by prostate cancer, body image receives limited attention despite some indication that it may be important to men with the disease. The present study investigated how body image changes over time and the relations between changes in body image and quality of life (QOL) in men with prostate cancer. Methods In a longitudinal design, patients ( N = 74) completed questionnaires before treatment (T1) and at 1 month (T2) and 2 years (T3) following treatment completion. Results Growth curve modeling indicated that there was no significant change over time in group-level body image scores. However, hormone treatment was associated with a negative trajectory of change over 2 years. Also, analysis of individual difference scores indicated that ≥50% of patients demonstrated change of at least 0.5 standard deviation between time points. Hierarchical regression indicated that change in body image between T1 and T2 was significantly associated with change in QOL between T1 and T3, while controlling for demographic variables, treatment, treatment-related functioning, and general and treatment-specific positive expectations. In predicting change in body image between T1 and T2, treatment-specific positive expectation was the only significant predictor. Conclusions The present study demonstrates that body image is an important component of the prostate cancer experience. Findings suggest that body image has a meaningful association with QOL among prostate cancer survivors.Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective: Research suggests that cancer patients who are more involved in treatment decision-making (TDM) report better quality of life following treatment. This study examines the association and possible mechanisms between prostate cancer patient's discussions about TDM and affect following treatment. We predicted that the length of time patients spent discussing treatment options with social networks and physicians prior to treatment would predict emotional adjustment after treatment. We further predicted that cognitive processing, coping, and patient understanding of treatment options would mediate this association. Methods: Fifty-seven patients completed questionnaires prior to treatment and at 1 and 6 months following treatment completion. Results: Findings from the present study suggest that discussing treatment options with others, prior to beginning treatment for prostate cancer, significantly contributed to improvements in affect 1 and 6 months following treatment. Residualized regression analyses indicated that discussing treatment options with patient's social networks predicted a decrease in negative affect 1 and 6 months following treatment, while discussions with physicians predicted an increase in positive affect 1 month following treatment. Patients who spent more time discussing treatment options with family and friends also reported greater pre-treatment social support and emotional expression. Mediation analyses indicated that these coping strategies facilitated cognitive processing (as measured by a decrease in intrusive thoughts) and that cognitive processing predicted improvement in affect. Conclusions: Greater time spent talking with family and friends about treatment options may provide opportunities for patients to cope with their cancer diagnosis and facilitate cognitive processing, which may improve patient distress over time. Copyright © 2008 John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

The article provides information on a study that evaluated ixabepilone or mitoxantrone/prednisone (MP) as second-line chemotherapy for taxane-refractory, hormone-refractory, prostate cancer (HRPC). It describes the methodology used in the study. It concludes that ixabepilone and MP had modest activity as second-line chemotherapy for docetaxel-refractory HRPC.

Abstract: Lipid kinase PIK3CA mutations have been described in several cancers. They clustered in two ‘hot spots’ located in helical (exon 9) and kinase (exon 20) domains associated with increased kinase activity strongly suggesting oncogenic potential. Mutational analysis of previously unexamined tumors showed an amino acid change from threonine to alanine (T1025A) in exon 20 in one of 28 endometrial cancer samples and 6 endometrial cell lines. Additionally, a silent polymorphism (T1025T) was found in two of 20 MDS samples, one of 43 NHL samples, two of 40 osteosarcoma samples and Ishikawa. The polymorphism was established by identifying two of 92 normal samples with the same change. No PIK3CA mutations were found in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and non-Hodgkin lymphomas (NHL) as well as in osteosarcomas, prostate and ovarian cancer samples. Additionally, a previously unidentified PIK3CA pseudogene spanning exons 9–13 on chromosome 22 was discovered. [Copyright &y& Elsevier]

OBJECTIVES To determine, in preclinical in vivo animal and in clinical studies, whether raloxifene (a selective oestrogen-receptor (ER) modulator that targets ER-β and induces apoptosis in vitro in androgen-independent prostate cancer, AIPC cells) affects prostate cell differentiation, proliferation and carcinogenesis, and in the pilot phase II clinical trial, the response rate and duration of patients with AIPC treated with a daily oral dose of raloxifene. PATIENTS, MATERIALS AND METHODS Tumour proliferation rate in response to raloxifene treatment, and molecular markers of cell cycle and apoptosis, were evaluated in established ER-β-positive androgen-dependent (AD) CWR22 and AI CWRSA9 human xenograft prostate cancer models. Twenty-one patients with AIPC and evidence of disease progression were enrolled into the clinical trial and given daily oral raloxifene. RESULTS There was significant growth inhibition by raloxifene in the ADPC and AIPC xenograft models (CWR22 68%, P < 0.010; CWRSA9 64%, P < 0.001), with no tumour regression. There was evidence of G1 arrest by increased p27kip1 expression in the raloxifene-treated group. Eighteen patients comprised the efficacy analysis, as three withdrew before the first evaluation. At the first evaluation, five men had stable disease and continued on the study for a median of five cycles. The longest response was 17 cycles. Drug related toxicity was minimal. CONCLUSION Raloxifene has activity in xenograft models, slowing disease progression. This translated to possible disease stabilization in patients with AIPC. Further studies are warranted. [ABSTRACT FROM AUTHOR]

Objective: Cell-free DNA (cfDNA) is an attractive cancer biomarker, as it is thought to reflect a component of the underlying genetic makeup of the tumor and is readily accessible in serial fashion. Because chemotherapy regimens are expected to act rapidly on cancer and cfDNA is cleared from the blood within minutes, we hypothesized that cfDNA would reflect immediate effects of treatment. Here, we developed a method for monitoring long cfDNA fragments, and report dynamic changes in response to cytotoxic chemotherapy. Results: Peripheral blood was obtained from 15 patients with metastatic castration-resistant prostate cancer (CRPC) immediately before and after cytotoxic chemotherapy infusion. cfDNA was extracted and quantified for long interspersed nuclear elements (LINE1; 297 bp) using qPCR. Targeted deep sequencing was performed to quantify the frequency of mutations in exon 8 of the androgen receptor (AR), a mutational hotspot region in CRPC. Single nucleotide mutations in AR exon 8 were found in 6 subjects (6/15 = 40%). Analytical variability was minimized by pooling independent PCR reactions for each library. In 5 patients, tumor-derived long cfDNA levels were found to change immediately after infusion. Detailed analysis of one subject suggests that cytotoxic chemotherapy can produce rapidly observable effects on cfDNA. [ABSTRACT FROM AUTHOR]

Objective: Quantitative parameter mapping conventionally relies on curve fitting techniques to estimate parameters from magnetic resonance image series. This study compares conventional curve fitting techniques to methods using neural networks (NN) for measuring T 2 in the prostate., Materials and Methods: Large physics-based synthetic datasets simulating T 2 mapping acquisitions were generated for training NNs and for quantitative performance comparisons. Four combinations of different NN architectures and training corpora were implemented and compared with four different curve fitting strategies. All methods were compared quantitatively using synthetic data with known ground truth, and further compared on in vivo test data, with and without noise augmentation, to evaluate feasibility and noise robustness., Results: In the evaluation on synthetic data, a convolutional neural network (CNN), trained in a supervised fashion using synthetic data generated from naturalistic images, showed the highest overall accuracy and precision amongst the methods. On in vivo data, this best performing method produced low-noise T 2 maps and showed the least deterioration with increasing input noise levels., Discussion: This study showed that a CNN, trained with synthetic data in a supervised manner, may provide superior T 2 estimation performance compared to conventional curve fitting, especially in low signal-to-noise regions., (© 2024. The Author(s).)

Biopsy is the clinical standard for diagnosing lymph node (LN) metastasis, but it is invasive and poses significant risk to patient health. Magnetic resonance imaging (MRI) has been utilized as a noninvasive alternative but is limited by low sensitivity, with only ∼35% of LN metastases detected, as clinical contrast agents cannot discriminate between healthy and metastatic LNs due to nonspecific accumulation. Nanoparticles targeted to the C-C chemokine receptor 2 (CCR2), a biomarker highly expressed in metastatic LNs, have the potential to guide the delivery of contrast agents, improving the sensitivity of MRI. Additionally, cancer cells in metastatic LNs produce monocyte chemotactic protein 1 (MCP1), which binds to CCR2 + inflammatory monocytes and stimulates their migration. Thus, the molecular targeting of CCR2 may enable nanoparticle hitchhiking onto monocytes, providing an additional mechanism for metastatic LN targeting and early detection. Hence, we developed micelles incorporating gadolinium (Gd) and peptides derived from the CCR2-binding motif of MCP1 (MCP1-Gd) and evaluated the potential of MCP1-Gd to detect LN metastasis. When incubated with migrating monocytes in vitro , MCP1-Gd transport across lymphatic endothelium increased 2-fold relative to nontargeting controls. After administration into mouse models with initial LN metastasis and recurrent LN metastasis, MCP1-Gd detected metastatic LNs by increasing MRI signal by 30-50% relative to healthy LNs. Furthermore, LN targeting was dependent on monocyte hitchhiking, as monocyte depletion decreased accumulation by >70%. Herein, we present a nanoparticle contrast agent for MRI detection of LN metastasis mediated by CCR2-targeting and demonstrate the potential of monocyte hitchhiking for enhanced nanoparticle delivery.

Objectives: We sought to identify immune biomarkers associated with severe Coronavirus disease 2019 (COVID-19) in patients admitted to a large urban hospital during the early phase of the SARS-CoV-2 pandemic., Design: The study population consisted of SARS-CoV-2 positive subjects admitted for COVID-19 (n = 58) or controls (n = 14) at the Los Angeles County University of Southern California Medical Center between April 2020 through December 2020. Immunologic markers including chemokine/cytokines (IL-6, IL-8, IL-10, IP-10, MCP-1, TNF-α) and serologic markers against SARS-CoV-2 antigens (including spike subunits S1 and S2, receptor binding domain, and nucleocapsid) were assessed in serum collected on the day of admission using bead-based multiplex immunoassay panels., Results: We observed that body mass index (BMI) and SARS-CoV-2 antibodies were significantly elevated in patients with the highest COVID-19 disease severity. IP-10 was significantly elevated in COVID-19 patients and was associated with increased SARS-CoV-2 antibodies. Interactions among all available variables on COVID-19 disease severity were explored using a linear support vector machine model which supported the importance of BMI and SARS-CoV-2 antibodies., Conclusions: Our results confirm the known adverse association of BMI on COVID-19 severity and suggest that IP-10 and SARS-CoV-2 antibodies could be useful to identify patients most likely to experience the most severe forms of the disease., Competing Interests: None., (© 2023 Published by Elsevier B.V.)