tbuckley/cabot-search huggingface dataset:
Association of Preoperative Anemia With Postoperative Mortality in Neonates
Authors: Nigel J. Hall
Journal: JAMA Pediatrics (2016)

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Pharmacogenetics of ABC transporters and drug metabolising enzymes and their influence on Irinotecan (CPT-11) elimination pathways in Asian cancer patients
Authors: C. Balram, E. H. Tan, Q. Zhou, Y. B. Cheung, C. Kibat, S. S. Leong
Journal: Journal of Clinical Oncology (2004)

2063 Background: CPT-11 has an extremely complex metabolic pathway and its disposition is greatly influenced by several enzymes (carboxylesterases, CYP3A4/5 and UGT1A1) and ABC transporters (ABCB1, ABCC2 and ABCG2). The objective of this study was to correlate SNPs in drug metabolising enzymes and ABC transporters proteins to the disposition kinetics of CPT-11 and its metabolites, SN-38 and SN-38G in Chinese nasopharyngeal carcinoma (NPC) patients (N=30). Methods: CPT-11 was administered at a fixed dose of 100 mg/m2 over 90 minutes. Pharmacokinetic and pharmacogenetic analysis were done on day 1 of cycle 1. All patients were genotyped for the following SNPs: CYP3A4*1B, *4, *5 and *6; CYP3A5*3 and *6; UGT1A1 5'UTR [T-3263G] and UGT1A1*28; ABCB1 [C1236T, G2677T/A, C3435T]; ABCC2 [5'UTR: C-24T; exon 4 C-49T]; and ABCG2 [-19572–19569 CTCA deletion, G34A, C376T, C421A]. Results: The estimated variant genotype frequencies were as follows: CYP3A5*3/*3 (11%), UGT1A1 [T-3263G (36%) and *28 (7%)], ABCB1 (25–39%), ABCC2 C-24T (4%) and C-49T (7%), ABCG2 [CTCA del (4%), G34A (4%), C421A (11%)]. All patients were wild-type for CYP3A4 SNPs. The clearance and relative extent of conversion of CPT-11 was 30.5±2.6 L/hr/m2 and 0.9±10.5%, respectively. A trend towards decreased CPT-11 clearance was noted for ABCB1 C3435T SNP with (CT+TT) carriers having lower clearance (p=0.072) and increased AUC0-∞(p=0.072) and Cmax (p=0.046) compared with CC carriers. A significant association was found between SN-38G Cmax and ABCB1C1236T polymorphism (p=0.037). A significant association was also found between ABCG2 G34A SNP and CPT-11 Cmax, with GG patients showing lower exposures compared with (GA+AA) patients (p=0.045). Conclusion: Although CPT-11 PK seems to be associated with ABC transporter SNPs, further validation of the results in a larger patient sample is required. No significant financial relationships to disclose.
B Cell Aplasia In a Patient with Relapsed B Cell Acute Lymphoblastic Leukemia Following Re-Induction and Consolidation with Autologous T Cells Genetically Targeted to the CD19 Antigen
Authors: Marco L Davila, Clare Taylor, Xiuyan Wang, Jolanta Stefanski, Malgorzata Olszewska, Shirley Bartido, Mark Frattini, Michel Sadelain, Isabelle Rivière, Renier J. Brentjens
Journal: Blood (2010)
Among Low-Income Respondents With Diabetes, High-Deductible Versus No-Deductible Insurance Sharply Reduces Medical Service Use
Authors: David L. Rabin, Anuradha Jetty, Stephen Petterson, Ziad Saqr, Allison Froehlich
Journal: Diabetes Care (2016)

OBJECTIVE To contrast the effect of private insurance and deductibles (by size) on medical service use, health status, and medical debt for adult respondents with diabetes with low and high incomes. RESEARCH DESIGN AND METHODS Using the 2011–2013 Medical Expenditure Panel Survey, bivariate and regression analyses were conducted to compare demographic characteristics, medical service use, diabetes care, and health status among privately insured adult respondents with diabetes, aged 18–64 years (N = 1,461) by lower (&amp;lt;200% of the federal poverty level) and higher (≥200% of the federal poverty level) income and deductible vs. no deductible (ND), low deductible ($1,000/$2,400) (LD), and high deductible (&amp;gt;$1,000/$2,400) (HD). The National Health Interview Survey 2012–2014 was used to analyze differences in medical debt and delayed/avoided needed care among adult respondents with diabetes (n = 4,058) by income. RESULTS Compared with privately insured respondents with diabetes with ND, privately insured lower-income respondents with diabetes with an LD report significant decreases in service use for primary care, checkups, and specialty visits (27%, 39%, and 77% lower, respectively), and respondents with an HD decrease use by 42%, 65%, and 86%, respectively. Higher-income respondents with an LD report significant decreases in specialty (28%) and emergency department (37%) visits. Diabetes care measures are similar by income and insurance; there were no changes in physical health status. Medical debt is similar by income, but deferred service use is two times greater for those indebted and with lower income. CONCLUSIONS Private insurance with a deductible substantially and problematically reduces medical service use for lower-income insured respondents with diabetes who have an HD; these patients are more likely to report forgoing needed medical services.
Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists
Authors: Mojgan Aghazadeh Tabrizi, Pier Giovanni Baraldi, Stefania Baraldi, Stefania Gessi, Stefania Merighi, Pier Andrea Borea
Journal: Medicinal Research Reviews (2016)

Abstract Transient receptor potential vanilloid 1 (TRPV1) is an ion channel expressed on sensory neurons triggering an influx of cations. TRPV1 receptors function as homotetramers responsive to heat, proinflammatory substances, lipoxygenase products, resiniferatoxin, endocannabinoids, protons, and peptide toxins. Its phosphorylation increases sensitivity to both chemical and thermal stimuli, while desensitization involves a calcium‐dependent mechanism resulting in receptor dephosphorylation. TRPV1 functions as a sensor of noxious stimuli and may represent a target to avoid pain and injury. TRPV1 activation has been associated to chronic inflammatory pain and peripheral neuropathy. Its expression is also detected in nonneuronal areas such as bladder, lungs, and cochlea where TRPV1 activation is responsible for pathology development of cystitis, asthma, and hearing loss. This review offers a comprehensive overview about TRPV1 receptor in the pathophysiology of chronic pain, epilepsy, cough, bladder disorders, diabetes, obesity, and hearing loss, highlighting how drug development targeting this channel could have a clinical therapeutic potential. Furthermore, it summarizes the advances of medicinal chemistry research leading to the identification of highly selective TRPV1 antagonists and their analysis of structure–activity relationships (SARs) focusing on new strategies to target this channel.
Abstract 2099: FoxM1 drives a feed-forward STAT3-activation signaling loop to promote the self-renewal and tumorigenicity of glioblastoma stem cells
Authors: Sicong Zhang, Ai-hua Gong, Ping Wei, Aidong Zhou, Jun Yao, Ying Yuan, Frederick Lang, Ganesh Rao, Suyun Huang
Journal: Cancer Research (2015)

Abstract The STAT3 signaling pathway is a nodal hub of gliomagenesis, but the mechanisms underlying elevated expression and activation of STAT3 are largely unknown. Here, we showed that FoxM1 was critical for STAT3 gene expression and protein activation. First, the expression of PDGF-A, one of the growth factor upstream of STAT3 directly correlated with the expression of FoxM1 in GBMs. FoxM1 bound to PDGF-A promoter to upregulate PDGF-A expression in GBM stem cells (GSCs) and mouse neural stem cells (NSCs). FoxM1 maintains stemness of GSCs partially via PDGF-A. Second, data from TCGA showed that GBMs expressed high levels of STAT3 as compared with normal brain. STAT3 expression directly correlated with the expression of FoxM1 in GBMs. FoxM1 regulated STAT3 expression by interacting with the β-catenin/TCF4 complex at STAT3 promoter. FoxM1 deficiency decreased both PDGF-A and STAT3 expressions in GSCs and NSCs and inhibited STAT3 activation by PDGF-A, EGF and IL-6, thereby abolished the stemness and tumorigenesis of GSCs. Moreover, constitutively active STAT3 rescued the inhibitory effects of FoxM1 knockdown on the stemness and tumorignecity of GSCs, suggesting FoxM1 regulates the stemness of GSCs by affecting STAT3 Furthermore, overexpression of FoxM1 reprogrammed glioma cells to GSCs-like cells, whereas inhibition of STAT3 diminished FoxM1-induced stemness and tumorigenesis. Collectively, these findings indicated that FoxM1 regulated the expression of both PDGF-A and STAT3 hence drived a feed-forward STAT3-activation signaling loop which was required for maintenance of self-renewal and tumorigenicity of GSCs. Citation Format: Sicong Zhang, Ai-hua Gong, Ping Wei, Aidong Zhou, Jun Yao, Ying Yuan, Frederick Lang, Ganesh Rao, Suyun Huang. FoxM1 drives a feed-forward STAT3-activation signaling loop to promote the self-renewal and tumorigenicity of glioblastoma stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2099. doi:10.1158/1538-7445.AM2015-2099
Abstract 1416: Granulocyte-colony stimulating factor (G-CSF) enhances stemness by inducing myeloid-derived suppressor cell (MDSC) in cervical cancer
Authors: Hiromasa Kuroda
Journal: Cancer Research (2015)

Abstract Objectives: Granulocyte-colony stimulating factor (G-CSF) is known to induce the myeloid-derived suppressor cell (MDSC) to stimulate the progression of uterine cervical cancer. The aim of the current study is to investigate the role of MDSC in the induction of cancer stem cells in uterine cervical cancer. Methods: We first established cervical cancer cell lines stably transfected with G-CSF expression vector (ME180-GCSF) or control vector (ME180-control). Then, using BALB/c nude mice subcutaneously inoculated with ME180-G-CSF or ME180-control cells, the effect of G-CSF on the induction of MDSCs (CD11b+Gr1+ cells) and cancer stem cells (ALDH-high cells) were assessed by flow cytometry. Using MDSCs isolated from the spleens of ME180-GCSF-bearing mice, we next investigated whether the MDSCs induce cancer stem cells in vitro. Finally, we analyzed the association between the G-CSF expression and ALDH1A1 expression in human cervical cancer specimens by immunohistochemistry. Results: 1) G-CSF induces MDSCs from mice bone marrow. 2) ME180-GCSF-derived tumors contain greater number of MDSCs and ALDH-high cells. 3) Co-incubation of ME180 with MDSCs cells increased the number of ALDH-high cells. 4) A positive correlation was observed between the tumor G-CSF expression and ALDH1A1 expression in human cervical cancers. Conclusions: G-CSF-induced MDSCs increase the number of cancer stem cells in uterine cervical cancer. Citation Format: Hiromasa Kuroda. Granulocyte-colony stimulating factor (G-CSF) enhances stemness by inducing myeloid-derived suppressor cell (MDSC) in cervical cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1416. doi:10.1158/1538-7445.AM2015-1416
454. Prior AAV2-hIL10 Infusion Decreases AAV9-Dependent Immunotoxicity in Rat Brain
Authors: Agnieszka Ciesielska, Piotr Hadaczek, Janine Beyer, John Forsayeth, Krystof Bankiewicz
Journal: Molecular Therapy (2015)

Cerebral infusion of AAV9 vectors encoding non-self proteins results in the initiation of a robust immune reaction at the site of injection due to the vector's ability to transduce antigen-presenting cells in the brain [1]. Infusion of AAV9 encoding a human gene, aromatic L-amino acid decarboxylase (hAADC), elicited an initial innate immune activation at the site of infusion that was succeeded by a robust adaptive immune response that included generation of hAADC antibodies, lymphocytic infiltration and cell-mediated elimination of transduced cells in the brain. In this study, we investigated whether the potent anti-inflammatory cytokine, human interleukin-10 (hIL10) could suppress this immune response. Four weeks prior to unilateral infusion of AAV9-hAADC into rat striatum, we infused AAV2-hIL10 bilaterally into striatum (control rats received bilaterally injection of AAV2-GFP). Six weeks after AAV9-hAADC injection, control rats revealed robust amphetamine-induced ipsilateral rotational behavior (956±203 (S.D.) turns/1 hour). In while, in AAV2-hIL10-treated rats ipsilateral rotations were reduced by 66 % compared with control rats and this effect persisted for at least 8 weeks. This neuroprotective effect of hIL10 was evident histologically. The number of surviving neurons (NeuN) was significantly increased in AAV2-hIL10-treated animals compared to AAV2-GFP-treated controls, and microglial and astrocytic activation was diminished. Whereas, in control rats, a significant number of hAADC-positive astrocytes was observed (GFAP/hAADC double fluorescent staining), astrocytic transduction in AAV2-hIL10-treated rats was almost completely suppressed. This somewhat puzzling result may be due to an effect of IL10 on astrocytic expression of an AAV9 receptor required for transduction. However, our findings suggest that expression of IL-10 in the brain may be a useful adjunctive therapy in the treatment of neurological diseases in which the expression of a foreign antigen is unavoidable.
Interim results from PX-171-006, a phase (Ph) II multicenter dose-expansion study of carfilzomib (CFZ), lenalidomide (LEN), and low-dose dexamethasone (loDex) in relapsed and/or refractory multiple myeloma (R/R MM).
Authors: M. Wang, W. Bensinger, T. Martin, M. Alsina, D. S. D. Siegel, N. Y. Gabrail, P. Hari, S. Singhal, R. A. Vescio, S. E. Assouline, L. A. Kunkel, M. Vallone, A. Wong, R. Niesvizky
Journal: Journal of Clinical Oncology (2011)

8025 Background: CFZ, a novel, selective epoxyketone proteasome inhibitor, produces durable responses and is well tolerated in patients (pts) with R/R MM, including those with significant comorbidities. LEN/loDex (Rd) is a current standard of care for relapsed MM. Bortezomib (BTZ) + RD using moderate- to high-dose Dex is also active; however, neuropathy can be dose-limiting. Combination of CFZ with Rd (CRd) may provide superior activity and tolerability. In the ph 1b dose-escalation study of CRd the maximum protocol dose (MPD) was reached. This ph II study further evaluated safety and activity of CRd in R/R MM pts. Methods: Eligible pts (≥18 yrs) with R/R MM after 1–3 prior therapies had ECOG PS of 0–2. The ph Ib MPD of CRd was: CFZ IV (Days [D] 1, 2, 8, 9, 15, 16; [20 mg/m2on D1–D2 of Cycle 1; 27 mg/m2 thereafter]), 25 mg LEN po (D1–21), and 40 mg loDex po (D1, 8, 15, 22) in 4-week cycles. Overall response rate (ORR) was assessed by IMWG criteria, with secondary assessment of clinical benefit response, duration of response, and time to progression. Results: 50 of 52 enrolled pts were evaluable for response. Of these, 39 received ≥2 prior therapies including BTZ (75%), LEN (69%), thalidomide (THAL, 42%), and BTZ + LEN (54%). No dose-limiting toxicities were reported. 11.5% of pts (6/52) reported drug-related serious adverse events (AEs). Hematologic AEs including grade ≥3 neutropenia (n=12), anemia (n=8), and thrombocytopenia (n=8) were reversible and manageable. Responses are detailed below (Table). Initial responses were rapid (generally within the first 2 cycles), improved with continuing therapy (≥3 mo), and were independent of prior treatment history and baseline characteristics. 20 pts remain on study. Conclusions: CRd is well-tolerated in pts previously treated with BTZ, LEN, and/or THAL. ORR was 78% and prolonged administration was possible (14–23 mo) with no new or overlapping toxicities. ASPIRE, a ph III open-label, international, multicenter trial comparing CRd to Rd in R/R MM, opened in July 2010 and is actively accruing pts. Response (n=50) N (%) CR/sCR 9 (18) VGPR 11 (22) PR 19 (38) MR 1 (2) SD 4 (8) ORR 39 (78)
71. Boosting the Immunogenicity of an Oncolytic Vaccinia Virus By Expression of DAI Can Enhance Anti-Tumor Immunity in Humanized Mice
Authors: Mari Hirvinen, Cristian Capasso, Kilian Guse, Mariangela Garofalo, Andrea Vitale, Marko Ahonen, Lukasz Kuryk, Markus Vähä-Koskela, Akseli Hemminki, Dario Greco, Vincenzo Cerullo
Journal: Molecular Therapy (2015)

In oncolytic virotherapy the ability of an oncolytic virus to activate immune system against the tumor is nowadays generally understood to be the major mechanism to fully fight the cancer and to achieve long-term anti-tumor effects. Vaccinia viruses (VV) are immunosuppressive viruses encoding for a plethora of genes for neutralization of the host immune responses. To overcome this problem, we developed an oncolytic VV that expresses intracellular pattern recognition receptor DAI to obtain a self-immuno-boosting system to activate the immune responses in the tumor. DAI (DNA-dependent activator of IFN-regulatory factors) is a cytosolic dsDNA sensor and a potent activator of innate immune responses. We showed that DAI is able to recognize vaccinia DNA and to induce IFN-mediated immune responses after VV infection in vitro. We have also shown by wide genome expression profile analyses that infection with DAI-expressing VV increases expression of several genes related to important immunological pathways such as DC migration, immunogenic cell death and chemokine production. Intra-tumoral treatments with DAI-armed VV resulted in significant reduction in the size of B16-OVA tumors in C57BL/6 mice due to increased levels of anti-tumor CD8+ T cells in the tumors. When we re-challenged the mice with the same tumor, the DAI-VV treated mice rejected the growth of the new tumor completely, which also indicates immunity established against the tumor. To even better illustrate the immunogenicity of our virus in vivo we performed studies in PBMC humanized mice – a model closer to human system. Human melanoma tumors (HS294T) were grown in NSG mice and human PBMCs were injected intravenously to create a human-like immune system. Tumors were treated two times with DAI-VV or controls. We showed enhanced control of tumor growth in the DAI-VV treated group of mice. We also observed elevated levels of various human immune cells (e.g. active CD8+ T cells and CD4+ T cells) in the DAI-VV treated mice. In an IFN-gamma ELISpot analysis we could see increase in the amount of activated human T cells against tumor antigens in splenocyte samples of the DAI-VV treated mice. We conclude that expression of DAI by an oncolytic VV is a promising way to self-amplify immunostimulatory and vaccine potency of an oncolytic vaccinia virus to trigger the innate – and eventually the long-lasting adaptive immune responses against cancer.
Abstract 1157: Potential mechanism for mitochondrial uncoupling protein 2 promotes skin carcinogenesis
Authors: Chunjing Zhang, Yunfeng Zhao
Journal: Cancer Research (2015)

Abstract Mitochondrial uncoupling has recently been proposed as a novel survival mechanism for cancer cells, However, there is no direct evidence supporting that uncoupling proteins promote carcinogenesis. Herein, we examined whether mitochondrial uncoupling affects mouse skin carcinogenesis using uncoupling protein 2 (UCP2) homozygous knockout mice, and explored the mechanisms of tumor promotion by mitochondrial uncoupling by overexpressing UCP2 in JB6 P+ cells, which are the only characterized skin cell model to study tumor promotion. The vivo results indicate that the rates of oxygen consumption were only decreased in the carcinogen-treated UCP2 knockout mice whereas glycolysis was only increased in the carcinogen-treated wild-type mice. The levels of metabolites pyruvate, malate and succinate showed different trends after carcinogen treatments between the wild-type and UCP2 knockout mice. In addition, UCP2 knockout decreases 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB2, especially on the regulation of the key enzyme in glycolysis), CyclinB1 and the oncoprotein Fra-1 expression during skin carcinogenesis. The vitro results indicate that overexpression of UCP2 enhanced colony formation in response to tumor promoter treatment. In addition, overexpression of UCP2 induced the upregulation of Fra-1 and PFKFB2 expression. Although UCP2 overexpression could suppress apoptosis in vitro, But UCP2 Knockout did not cause increase in apoptosis. This study provides the first in vivo evidence using UCP2 mice supporting that UCP2 promotes carcinogenesis. Although the current data are unable to answer the question of how UCP2 knockout suppresses skin cancer formation, an interesting and important finding is the adverse changes of the three metabolites and especially on the regulation of the key enzyme in glycolysis pathway during carcinogenesis, which provides a clue for future studies. Together with early studies showing that UCP2 is overexpressed in a number of human cancers and knockout of UCP2 significantly reduced the formation of both benign (papilloma) and malignant (squamous cell carcinoma) tumors in mice, UCP2 could be a potential target for cancer prevention and/or therapy. Citation Format: Chunjing Zhang, Yunfeng Zhao. Potential mechanism for mitochondrial uncoupling protein 2 promotes skin carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1157. doi:10.1158/1538-7445.AM2015-1157
PO30INTRA-OPERATIVE SEIZURES IN AWAKE CRANIOTOMY
Authors: Chin Lik Tan, Masood Hussain, Steve Roberts, Aarti Tahlan, Chittoor Rajaraman, Shailendra Achawal
Journal: Neuro-Oncology (2015)

INTRODUCTION: Intra-operative seizure is a recognised complication of awake craniotomy (AC) to resect/debulk intracerebral tumour. If not adequately controlled, it may lead to abandonment of the procedure. Here we reviewed the incidence of intra-operative seizure in all AC patients at a regional neurosurgical centre, and examined its association with tumour type and pre-operative use of anti-epileptic drugs (AEDs). METHOD: Review of patients' medical notes. RESULTS: In total, 42 AC were performed on 38 patients. 33.3% (14/42) AC were complicated by intra-operative seizures, resulting in 3 procedures being abandoned. Out of seven patients with low-grade glioma in this series, 71.4% (5/7) had intra-operative seizures. The incidence of intra-operative seizure was 40.0% for high-grade oligodendroglioma, 33.3% for anaplastic astrocytoma and 20.0% for glioblastoma multiforme. Out of all 38 patients, 33 had seizures as a presenting symptom. Of these, 36.4% (12/33) developed intra-operative seizures, while 20.0% (1/5) of those who did not present with a seizure developed intra-operative seizures. 30.6% (11/36) patients who received pre-operative AED developed seizures intra-operatively, compared to 100% (2/2) of those without pre-operative AED. CONCLUSION: 33.3% of patients who underwent AC developed intra-operative seizures. Patients with low-grade glioma were most at risk in our limited series. Pre-operative use of AEDs appeared to reduce the risk of intra-operative seizures. Larger studies are warranted.