Initial Evaluation of the Pediatric PROMIS® Health Domains in Children and Adolescents With Sickle Cell Disease

Background

The Patient Reported Outcomes Measurement Information System (PROMIS®) has developed pediatric self-report scales measuring several unidimensional health attributes (domains) suitable for use in clinical research, but these measures have not yet been validated in sickle cell disease (SCD).

Procedure

A convenience sample of SCD children, aged 8–17 years, from two sickle cell programs was recruited at routine clinic visits, including some for hydroxyurea monitoring or monthly transfusions. Children completed PROMIS pediatric items using an online data collection platform, the PROMIS Assessment Center Web site.

Results

A total of 235 participants (mean age 12.5 ± 2.8 years, 49.8% female) participated in the study. Adolescents (ages 12–17 years) reported significantly higher pain interference and depressive symptoms, and worse lower extremity physical functioning domain scores compared to younger children (ages 8–11 years). Female participants reported significantly higher pain interference, fatigue, and depressive symptoms, and worse lower extremity physical functioning domain scores compared with their male counterparts. Participants with hip or joint problems that limited usual activities reported significantly higher pain, fatigue, and depressive symptoms scores, and worse upper/lower extremity physical functioning scores as did participants who had experienced sickle pain in the previous 7 days.

Conclusions

PROMIS pediatric measures are feasible in a research setting and identify expected differences in known group comparisons in a sample of SCD children. The large domain score differences between those with or without SCD-related complications suggest the potential usefulness of these measures in clinical research, but further validation studies are needed, particularly in clinical practice settings.

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Carcinosarcoma of the upper urinary tract with an aggressive angiosarcoma component.

Carcinosarcoma of the upper urinary tract with an aggressive angiosarcoma component.

Cancer Biol Ther. 2016 Feb 18;:0

Authors: Urteaga JL, Pous AF, Tapia G, Areal J, Taron M

Abstract
Carcinosarcomas (CS) are biphasic tumors with malignant epithelial and mesenchymal elements. The sarcomatoid elements of CS can include chondrosarcoma, malignant fibrous histiocytoma, osteosarcoma, leiomyosarcoma, fibrosarcoma, or liposarcoma. CS of the upper urinary tract are extremely rare but are associated with a poor prognosis. We report a case of a 44-year-old man with a localized right renal pelvis mass treated with a right nephroureterectomy. The pathological examination showed a high-grade urothelial carcinoma of the renal pelvis, stage III (pT3aNxM0). A few days later, he developed lower back pain, hematuria, cough with hemoptoic sputum and progressive dyspnea. Radiological explorations showed multiple bilateral lung nodules and a retroperitoneal mass. A CT-guided biopsy of the retroperitoneal mass revealed a high-grade angiosarcoma. A review of the nephrectomy specimen showed a microscopic focus of angiosarcoma in the urothelial carcinoma. Therefore, the initial diagnosis was changed to CS of the renal pelvis with an angiosarcoma component. The patient developed progressive respiratory failure and died eight weeks after surgery. An autopsy revealed a large retroperitoneal mass with metastatic nodules to the abdominal wall, diaphragm, small intestine, liver, spleen, and lung. All lesions were angiosarcoma, with no evidence of urothelial carcinoma. This is the first case reported of a patient with CS of the upper urinary tract with an angiosarcoma component with a very aggressive course that caused the immediate appearance of multiple angiosarcoma metastases. We also describe the clinical and molecular characteristics of CS, which will help to contribute to a better understanding of this type of tumor.

PMID: 26891233 [PubMed - as supplied by publisher]

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Rapid induction of apoptosis in chronic lymphocytic leukemia cells by the microtubule disrupting agent BNC105.

Rapid induction of apoptosis in chronic lymphocytic leukemia cells by the microtubule disrupting agent BNC105.

Cancer Biol Ther. 2016 Jan 30;:1-9

Authors: Bates D, Feris EJ, Danilov AV, Eastman A

Abstract
Microtubule targeting agents, such as vinblastine, are usually thought to arrest cells in mitosis and subsequently induce apoptosis. However, they can also cause rapid induction of apoptosis in a cell-cycle phase independent manner. BNC105 is a novel vascular and microtubule disrupting drug that also induces apoptosis rapidly but with markedly increased potency compared to vinca alkaloids and combretastatin A4. BNC105 binds to the colchicine-binding site on tubulin resulting in activation of c-Jun N-terminal kinase (JNK), phosphorylation of ATF2, and induction of ATF3 and Noxa leading to acute apoptosis in chronic lymphocytic leukemia (CLL) cells. Apoptosis induced by BNC105 is dependent upon both JNK activation and Noxa induction. Normal leukocytes and one CLL sample also exhibited JNK activation but not Noxa induction and were resistant to BNC105. This study emphasizes the importance of Noxa and JNK for induction of apoptosis in CLL cells by microtubule targeting drugs, and highlights the potential of BNC105 as a potent therapeutic to treat haematopoietic malignancies.

PMID: 26891146 [PubMed - as supplied by publisher]

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Validating the Disruption of Proliferating Cell Nuclear Antigen Interactions in the Development of Targeted Cancer Therapeutics.

Validating the Disruption of Proliferating Cell Nuclear Antigen Interactions in the Development of Targeted Cancer Therapeutics.

Cancer Biol Ther. 2016 Feb 18;:0

Authors: Smith SJ, Hickey RJ, Malkas LH

Abstract
Human DNA replication and repair is a highly coordinated process involving the specifically timed actions of numerous proteins and enzymes. Many of these proteins require interaction with proliferating cell nuclear antigen (PCNA) for activation within the process. The interdomain connector loop (IDCL) of PCNA provides a docking site for many of those proteins, suggesting that this region is critically important in the regulation of cellular function. Previous work in this laboratory has demonstrated that a peptide mimicking a specific region of the IDCL (caPeptide) has the ability to disrupt key protein-protein interactions between PCNA and its binding partners, thereby inhibiting DNA replication within the cells. In this study, we confirm the ability of the caPeptide to disrupt DNA replication function using both intact cell and in vitro DNA replication assays. Further, we were able to demonstrate that treatment with caPeptide results in a decrease of polymerase δ activity that correlates with the observed decrease in DNA replication. We have also successfully developed a surface plasmon resonance (SPR) assay to validate the disruption of the PCNA-pol δ interaction with caPeptide.

PMID: 26889573 [PubMed - as supplied by publisher]

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Carcinosarcoma of the upper urinary tract with an aggressive angiosarcoma component.

Carcinosarcoma of the upper urinary tract with an aggressive angiosarcoma component.

Cancer Biol Ther. 2016 Feb 18;:0

Authors: Urteaga JL, Pous AF, Tapia G, Areal J, Taron M

Abstract
Carcinosarcomas (CS) are biphasic tumors with malignant epithelial and mesenchymal elements. The sarcomatoid elements of CS can include chondrosarcoma, malignant fibrous histiocytoma, osteosarcoma, leiomyosarcoma, fibrosarcoma, or liposarcoma. CS of the upper urinary tract are extremely rare but are associated with a poor prognosis. We report a case of a 44-year-old man with a localized right renal pelvis mass treated with a right nephroureterectomy. The pathological examination showed a high-grade urothelial carcinoma of the renal pelvis, stage III (pT3aNxM0). A few days later, he developed lower back pain, hematuria, cough with hemoptoic sputum and progressive dyspnea. Radiological explorations showed multiple bilateral lung nodules and a retroperitoneal mass. A CT-guided biopsy of the retroperitoneal mass revealed a high-grade angiosarcoma. A review of the nephrectomy specimen showed a microscopic focus of angiosarcoma in the urothelial carcinoma. Therefore, the initial diagnosis was changed to CS of the renal pelvis with an angiosarcoma component. The patient developed progressive respiratory failure and died eight weeks after surgery. An autopsy revealed a large retroperitoneal mass with metastatic nodules to the abdominal wall, diaphragm, small intestine, liver, spleen, and lung. All lesions were angiosarcoma, with no evidence of urothelial carcinoma. This is the first case reported of a patient with CS of the upper urinary tract with an angiosarcoma component with a very aggressive course that caused the immediate appearance of multiple angiosarcoma metastases. We also describe the clinical and molecular characteristics of CS, which will help to contribute to a better understanding of this type of tumor.

PMID: 26891233 [PubMed - as supplied by publisher]

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Rapid induction of apoptosis in chronic lymphocytic leukemia cells by the microtubule disrupting agent BNC105.

Rapid induction of apoptosis in chronic lymphocytic leukemia cells by the microtubule disrupting agent BNC105.

Cancer Biol Ther. 2016 Jan 30;:1-9

Authors: Bates D, Feris EJ, Danilov AV, Eastman A

Abstract
Microtubule targeting agents, such as vinblastine, are usually thought to arrest cells in mitosis and subsequently induce apoptosis. However, they can also cause rapid induction of apoptosis in a cell-cycle phase independent manner. BNC105 is a novel vascular and microtubule disrupting drug that also induces apoptosis rapidly but with markedly increased potency compared to vinca alkaloids and combretastatin A4. BNC105 binds to the colchicine-binding site on tubulin resulting in activation of c-Jun N-terminal kinase (JNK), phosphorylation of ATF2, and induction of ATF3 and Noxa leading to acute apoptosis in chronic lymphocytic leukemia (CLL) cells. Apoptosis induced by BNC105 is dependent upon both JNK activation and Noxa induction. Normal leukocytes and one CLL sample also exhibited JNK activation but not Noxa induction and were resistant to BNC105. This study emphasizes the importance of Noxa and JNK for induction of apoptosis in CLL cells by microtubule targeting drugs, and highlights the potential of BNC105 as a potent therapeutic to treat haematopoietic malignancies.

PMID: 26891146 [PubMed - as supplied by publisher]

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Validating the Disruption of Proliferating Cell Nuclear Antigen Interactions in the Development of Targeted Cancer Therapeutics.

Validating the Disruption of Proliferating Cell Nuclear Antigen Interactions in the Development of Targeted Cancer Therapeutics.

Cancer Biol Ther. 2016 Feb 18;:0

Authors: Smith SJ, Hickey RJ, Malkas LH

Abstract
Human DNA replication and repair is a highly coordinated process involving the specifically timed actions of numerous proteins and enzymes. Many of these proteins require interaction with proliferating cell nuclear antigen (PCNA) for activation within the process. The interdomain connector loop (IDCL) of PCNA provides a docking site for many of those proteins, suggesting that this region is critically important in the regulation of cellular function. Previous work in this laboratory has demonstrated that a peptide mimicking a specific region of the IDCL (caPeptide) has the ability to disrupt key protein-protein interactions between PCNA and its binding partners, thereby inhibiting DNA replication within the cells. In this study, we confirm the ability of the caPeptide to disrupt DNA replication function using both intact cell and in vitro DNA replication assays. Further, we were able to demonstrate that treatment with caPeptide results in a decrease of polymerase δ activity that correlates with the observed decrease in DNA replication. We have also successfully developed a surface plasmon resonance (SPR) assay to validate the disruption of the PCNA-pol δ interaction with caPeptide.

PMID: 26889573 [PubMed - as supplied by publisher]

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Clinical research for older adults in rural areas: the MINDED study experience

Abstract

Due to the growing need to make clinical decisions based on valid and objective scientific evidence, the number of randomized controlled trials (RCTs) has increased over the last three decades. Nevertheless, evidence-based medicine has still limited applicability in older adults, because they are often excluded from clinical trials. Evidence-based medicine is even more challenging in rural areas, as its remote environment provides additional barriers. Nevertheless, given the high prevalence of older adults living in rural settings, research in this type of environment has become crucial. This can only be accomplished by considering the multiple additional challenges of these regions. In this paper, we examine potential environmental, procedural, and participants' barriers to the management of a RCT in a rural area. Possible solutions and suggestions are provided based on our experience—from the Multidomain Intervention to preveNt Disability in ElDers (MINDED) project.

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Genetic variations frequencies in Wilms’ tumor: a meta-analysis and systematic review

Abstract

Over the last few decades, numerous biomarkers, have been confirmed and shown variations in the prevalence. Most of these studies were based on small sample sizes. We carried out a meta-analysis of the research published up to 15 September 2015 to obtain more precise and comprehensive outcome for genetic tests. In the present study, 70 studies out of 5175 papers were eligible for meta-analysis. Meta-analysis was done with Stata 12.0. Pooled prevalence for gene mutations (WT1, WTX, CTNNB1, TP53, MYCN, DROSHA and DGCR8) was 0.147 (0.109, 0.185), 0.149 (0.110, 0.186), 0.140 (0.100, 0.190), 0.474 (0.342, 0.606), 0.099 (0.063, 0.136), 0.096 (0.050, 0.141) and 0.037 (0.025, 0.049), respectively. Pooled prevalence of LOH at 1p, 11p, 11q, 16q, and 22q was 0.109 (0.084, 0.133), 0.334 (0.295, 0.373), 0.199 (0.146, 0.252), 0.151 (0.129, 0.172) and 0.148 (0.108, 0.189), respectively. Pooled prevalence of 1q and chromosome 12 gain was 0.218 (0.161, 0.275) and 0.273 (0.195, 0.350). The limited prevalence of currently known genetic alterations in Wilms' tumors indicates that significant drivers of initiation and progression remain to be discovered. Subgroup analyses indicate that the ethnicity maybe one of the sources of heterogeneity. However, in meta regression analyses, No study-level characteristics of indicators were found significant. In addition, Sensitivity analysis and the publication bias of some results hint us interpret those results with caution.

This article is protected by copyright. All rights reserved.

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Vasohibin-1 expression inhibits advancement of ovarian cancer producing various angiogenic factors

Abstract

Vasohibin-1 (VASH1) is a negative feedback regulator of angiogenesis, the first to be discovered, and was identified in vascular endothelial growth factor (VEGF)-stimulated vascular endothelial cells. VASH1 inhibits abnormal vascularization induced by various angiogenic factors including FGF and PDGF, in addition to VEGF. By focusing on this characteristic of VASH1, we investigated the anti-tumor effects of VASH1 expression on ovarian cancer cells that produce different angiogenic factors. By using a high VEGF-producing ovarian cancer cell line, SHIN-3, and a high PDGF-producing ovarian cancer cell line, KOC-2S, the cells were transfected with either a VEGF antagonist, soluble VEGF receptor-1 (sVEGFR-1, aka sFlt-1), or VASH1 genes to establish their respective cellular expression. The characteristics of these transfectants were compared with controls. We previously reported that the expression of sFlt-1 inhibited tumor vascularization and growth of high VEGF-producing ovarian cancer cells, reduced peritoneal dissemination and ascites development, and prolonged the survival time of the host. However, in the current study, the expression of sFlt-1 had no such effect on the high PDGF-producing ovarian cancer cells used here, whereas VASH1 expression inhibited tumor vascularization and growth, not only in high VEGF-producing cells, but also in high PDGF-producing cells, reduced their peritoneal dissemination and ascites, and prolonged the survival time of the host. These results suggest that VASH1 is an effective treatment for ovarian cancer cells that produce different angiogenic factors.

This article is protected by copyright. All rights reserved.

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Resisting resistance: Establishing new treatment options for CRPC patients

10.1080/15384047.2016.1139271<br/>Shaunna Beedie

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Rapid induction of apoptosis in chronic lymphocytic leukemia cells by the microtubule disrupting agent BNC105

10.1080/15384047.2016.1139245<br/>Darcy Bates

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