tbuckley/cabot-search huggingface dataset:
Significance of prostate stem cell antigen expression in human lung cancer
Authors: Takeshi Kawaguchi, Masayuki Sho, Takashi Tojo, Takeo Nomi, Takahiro Akahori, Kaoru Hamada, Keiji Kushibe, Michitaka Kimura, Yoshiyuki Nakajima, Shigeki Taniguchi
Journal: Cancer Research (2007)

193   Despite the improvement of conventional antitumor therapies including chemotherapy, radiotherapy, and surgical resection, the prognosis of lung cancer patients remains extremely poor. Therefore, to improve patient survival, novel therapies need to be developed. Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol-anchored cell-surface protein belonging to the Ly-6/Thy-1 family of cell surface antigen. It has been originally identified to be an overexpressed gene in human prostate cancer. Its overexpression has been correlated with disease progression. Furthermore, recent studies have reported the expression of PSCA in a few other malignancies including pancreatic cancer. However, the clinical importance and function of PSCA expression in human malignancies was largely unknown. In this study, we tried to reveal the significance and therapeutic potential of PSCA in human lung cancer. We performed immunohistochemical analysis of PSCA expression using anti-human PSCA mAb in 55 lung cancer patients who underwent curative resection from Jury 2002 through December 2003. PSCA was stained mainly in the cytoplasm of tumor cells, and its expression was detected in 44 of 55 (80.0%). Patients without PSCA expression had a tendency to be at earlier stage than the positive patients, although differences did not reach statistical significance. Pathological stage classification was as follows: PSCA-positive; 25 in Stage I (56.8%), 9 in Stage II (16.4%), 9 in Stage III (16.4%), and 1 in Stage IV (2.2%), PSCA-negative; 9 in Stage I (81.8%), 1 in Stage II (9.1%), 1 in Stage III (9.1%), 0 in Stage IV (0%). Tumor size was 35.5±18.1 mm for PSCA positive and 31.9±11.8 for negative, respectively (mean ± standard deviation). While 16 out of 44 patients with positive PSCA expression had lymph node metastasis (36.4%: 28 in N0, 9 in N1, and 7 in N2), only one out of 11 patients with negative PSCA had lymph node metastasis (9.1%: 10 in N0 and 1 in N1). Furthermore, PSCA negative patients had a tendency to have a better prognosis than the positive patients (P = 0.072, the 3-year disease-free survival rate; 90.0% v.s. 62.3%). In conclusion, we demonstrate for the first time that PSCA was highly expressed in human lung cancer. Also we suggest that PSCA may be functionally critical for human lung cancer. Thus PSCA may be a novel therapeutic target for this fatal disease.
Novelty and Dopaminergic Modulation of Memory Persistence: A Tale of Two Systems
Authors: Adrian J. Duszkiewicz, Colin G. McNamara, Tomonori Takeuchi, Lisa Genzel
Journal: Trends in Neurosciences (2018)

Adaptation to the ever-changing world is critical for survival, and our brains are particularly tuned to remember events that differ from previous experiences. Novel experiences induce dopamine release in the hippocampus, a process which promotes memory persistence. While axons from the ventral tegmental area (VTA) were generally thought to be the exclusive source of hippocampal dopamine, recent studies have demonstrated that noradrenergic neurons in the locus coeruleus (LC) corelease noradrenaline and dopamine in the hippocampus and that their dopamine release boosts memory retention as well. In this opinion article, we propose that the projections originating from the VTA and the LC belong to two distinct systems that enhance memory of novel events. Novel experiences that share some commonality with past ones ('common novelty') activate the VTA and promote semantic memory formation via systems memory consolidation. By contrast, experiences that bear only a minimal relationship to past experiences ('distinct novelty') activate the LC to trigger strong initial memory consolidation in the hippocampus, resulting in vivid and long-lasting episodic memories.
Pancreatic stellate cells derived from human pancreatic cancer demonstrate aberrant SPARC-dependent ECM remodeling in 3D engineered fibrotic tissue of clinically relevant thickness
Authors: Hiroyoshi Y. Tanaka, Kentaro Kitahara, Naoki Sasaki, Natsumi Nakao, Kae Sato, Hirokazu Narita, Hiroshi Shimoda, Michiya Matsusaki, Hiroshi Nishihara, Atsushi Masamune, Mitsunobu R. Kano
Journal: Biomaterials (2018)
Adolescents and young adults with cancer care in Asia: The joint ESMO/SIOPE/SIOP ASIA survey
Authors: R. Dalvi, C.-K. Li, K. Yonemori, H. Ariffin, C.J. Lyu, M. Farid, J.R.N. Gonzales-Santos, Q. Zhou, S. Bielack, L. Brugieres, A. Blondeel, S. Essiaf, F.A. Peccatori, S. Jezdic, D. Stark, J.-Y. Douillard, E. Saloustros, G. Mountzios
Journal: Annals of Oncology (2018)
Abstract 17802: pH Sensitive Polyethylene Glycol-urokinase Nanogels Ameliorates the Severity of Ischemic Stroke in Rats by Effective Thrombolysis and Protection of Blood-brain Barrier
Authors: Wei Cui, Ran Liu, Haiqiang Jin, Yining Huang
Journal: Circulation (2015)

Background: pH sensitive polyethylene glycol-urokinase nanogels(PEG-UK) was reported previously as a new form of UK, which could release UK at certain pH value and has the same thrombolytic effect as naked UK on human clots in vitro. In this study, we evaluated its effect in rat model of ischemic stroke and further investigated possible mechanisms. Methods: Persistent middle cerebral artery occlusion were induced in adult Sprague-Dawley rats. pH distribution in the brain was mapped at 1 hour after ischemia through Needle type pH micro sensor and pH Optica Micro system. Thrombolytic effect of PEG-UK, such as dynamic levels of D-dimer, neurological deficts and infarction volume, were examined respectively. In spite of the overall performances, possible mechanisms were also explored, for example, the permeability of blood-brain barrier(BBB) reflected by Evans Blue(EB) leakage, BBB’s integrity via matrix metalloproteinase 9 (MMP9), tissue inhibitor of metalloproteinase protein-1 (TIMP-1) and Claudin5, and extent of apoptosis and neurotoxicity standed by Caspase9 and N-methyl-D-aspartic acid receptor 1(NMDAR1). Results: In ischemic hemisphere, pH value near cortex was obviously lower than that in deeper white matter. Averagely, occlusion for 1 hour induced the decline of pH value for about 0.49, and the lowest value reached to 6.32. Treatment with PEG-UK brought obvious alleviation of neurological deficts in acute phase( P =0.001). A significant reduction of relative infarction volume was also proved in PEG-UK rats( P &lt;0.001). As to the permeability of BBB, the leakage of EB in PEG-UK group was the least among three groups( P =0.001). What’s more, the sustain of the expression of TIMP-1( P =0.032) and Claudin5( P &lt;0.001) and the inhibition of upregulation of MMP9( P &lt;0.001) were all concluded in PEG-UK group. Besides, both the expression of NMDAR1( P &lt;0.001) and Caspase9( P =0.013) in PEG-UK treated rats were much less. Conclusions: Our findings indicated that treatment with PEG-UK ameliorated the severity of ischemic stroke, accompanied by neuroprotection through keeping the integrity of BBB and inhibiting apoptosis and neurotoxicity. PEG-UK may further inhibit hemorrhagic transformation by its BBB protection effect.
Influence of hepatic steatosis on the outcomes of patients with chronic hepatitis B treated with entecavir and tenofovir
Authors: David Sooik Kim, Mi Young Jeon, Hye Won Lee, Beom Kyung Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Kwang-Hyub Han, Seung Up Kim
Journal: Clinical and Molecular Hepatology (2018)

The influence of hepatic steatosis (HS) on chronic hepatitis B (CHB) is unclear. We evaluated the influence of the degree of HS, assessed using the controlled attenuation parameter (CAP) of transient elastography (TE), on treatment outcomes in CHB patients initiated on antiviral therapy.A total of 334 patients who were initiated on entecavir or tenofovir between 2007 and 2016 with available TE results were recruited.Of the total study population, 146 (43.7%) patients had HS (CAP > 238 dB/m). Three-hundred-three patients (90.7%) achieved complete virological response (CVR) (hepatitis B virus DNA<12 IU/L), and 25 patients (7.5%) developed hepatocellular carcinoma (HCC). Among hepatitis B e antigen (HBeAg)-positive patients (n=172, 51.5%), 37 (21.5%) experienced HBeAg loss. On univariate analysis, CAP value was not associated with the probability of HCC development (P=0.380). However, lower CAP value was independently associated with higher probability of HBeAg loss among HBeAg-positive patients (hazard ratio [HR]=0.991, P=0.026) and with CVR achievement in the entire study population (HR=0.996, P=0.004). The cumulative incidence of HBeAg loss among HBeAg-positive patients was significantly higher in patients without HS than in those with HS (log-rank, P=0.022).CAP values were not correlated with HCC development in patients initiated on entecavir and tenofovir. However, CAP values were negatively correlated with the probability of HBeAg loss among HBeAg-positive patients and with CVR achievement.
TLR8 and its endogenous ligand miR-21 contribute to neuropathic pain in murine DRG
Authors: Zhi-Jun Zhang, Jian-Shuang Guo, Si-Si Li, Xiao-Bo Wu, De-Li Cao, Bao-Chun Jiang, Peng-Bo Jing, Xue-Qiang Bai, Chun-Hua Li, Zi-Han Wu, Ying Lu, Yong-Jing Gao
Journal: The Journal of Experimental Medicine (2018)

Toll-like receptors (TLRs) are nucleic acid–sensing receptors and have been implicated in mediating pain and itch. Here we report that Tlr8−/− mice show normal itch behaviors, but have defects in neuropathic pain induced by spinal nerve ligation (SNL) in mice. SNL increased TLR8 expression in small-diameter IB4+ DRG neurons. Inhibition of TLR8 in the DRG attenuated SNL-induced pain hypersensitivity. Conversely, intrathecal or intradermal injection of TLR8 agonist, VTX-2337, induced TLR8-dependent pain hypersensitivity. Mechanistically, TLR8, localizing in the endosomes and lysosomes, mediated ERK activation, inflammatory mediators’ production, and neuronal hyperexcitability after SNL. Notably, miR-21 was increased in DRG neurons after SNL. Intrathecal injection of miR-21 showed the similar effects as VTX-2337 and inhibition of miR-21 in the DRG attenuated neuropathic pain. The present study reveals a previously unknown role of TLR8 in the maintenance of neuropathic pain, suggesting that miR-21–TLR8 signaling may be potential new targets for drug development against this type of chronic pain.
Persistent neuronal DNA damage after brain irradiation as detected by γ-H2AX expression in histological sections
Authors: Merriline Satyamitra, Philip Tofilon, Kevin Camphausen
Journal: Cancer Research (2007)

1066  Radiotherapy remains a major treatment modality for primary and metastatic neoplasms located in the central nervous system (CNS). However, the radiation dose that can be administered in these treatment situations is severely limited by the potential for injury to the normal CNS tissue. Among the manifestations of radiation-induced CNS damage is the onset of cognitive deficits. Whereas the target cells for radiation-induced CNS necrosis have not been clearly defined, it would appear that neurons are likely to play some role in the generation of cognitive deficits. Thus, to begin to address the mechanisms responsible, we used γ-H2AX foci to evaluate the induction and repair of DNA double strand breaks (DSBs) in hippocampal neurons after brain irradiation. Adult C57/Bl mice were locally irradiated with single doses of 4 to 20Gy, their brains harvested at times from 1h to 3 months, slides prepared from formalin fixed paraffin embedded tissue and processed for dual immuno-fluorescent staining of γ-H2AX (DSBs) and NeuN (neuron identification). At 1h after 4Gy there were clearly measurable γ-H2AX foci in the neurons (approximately 12 foci/cell). The number of foci declined steadily from 1 to 6h post-exposure; by 24h the number of foci was reduced to 3-4 foci/cell (p
A Path Forward for Regenerative Medicine
Authors: Alexander C. Fanaroff, Valarie Morrow, Mitchell W. Krucoff, Jonathan H. Seltzer, Emerson C. Perin, Doris A. Taylor, Leslie W. Miller, Andreas M. Zeiher, Francisco Fernández-Avilés, Douglas W. Losordo, Timothy D. Henry, Thomas J. Povsic
Journal: Circulation Research (2018)

Although clinical trials of cell-based approaches to cardiovascular disease have yielded some promising results, no cell-based therapy has achieved regulatory approval for a cardiovascular indication. To broadly assess the challenges to regulatory approval and identify strategies to facilitate this goal, the Cardiac Safety Research Consortium sponsored a session during the Texas Heart Institute International Symposium on Cardiovascular Regenerative Medicine in September 2017. This session convened leaders in cardiovascular regenerative medicine, including participants from academia, the pharmaceutical industry, the US Food and Drug Administration, and the Cardiac Safety Research Consortium, with particular focus on treatments closest to regulatory approval. A goal of the session was to identify barriers to regulatory approval and potential pathways to overcome them. Barriers identified include manufacturing and therapeutic complexity, difficulties identifying an optimal comparator group, limited industry capacity for funding pivotal clinical trials, and challenges to demonstrating efficacy on clinical end points required for regulatory decisions. Strategies to overcome these barriers include precompetitive development of a cell therapy registry network to enable dual-purposing of clinical data as part of pragmatic clinical trial design, development of standardized terminology for product activity and end points to facilitate this registry, use of innovative statistical methods and quality of life or functional end points to supplement outcomes such as death or heart failure hospitalization and reduce sample size, involvement of patients in determining the research agenda, and use of the Food and Drug Administration’s new Regenerative Medicine Advanced Therapy designation to facilitate early discussion with regulatory authorities when planning development pathways.
Phenotypic Refinement of Heart Failure in a National Biobank Facilitates Genetic Discovery
Authors: Krishna G. Aragam, Mark Chaffin, Rebecca T. Levinson, Gregory McDermott, Seung Hoan Choi, M. Benjamin Shoemaker, Mary E. Haas, Lu-Chen Weng, Mark E. Lindsay, J. Gustav Smith, Christopher Newton-Cheh, Dan M. Roden, Barry London, Quinn S. Wells, Patrick T. Ellinor, Sekar Kathiresan, Steven A. Lubitz, Heather L. Bloom, Samuel C. Dudley, Alaa A. Shalaby, Raul Weiss, Rebecca Gutmann, Samir Saba
Journal: Circulation (2019)

Heart failure (HF) is a morbid and heritable disorder for which the biological mechanisms are incompletely understood. We therefore examined genetic associations with HF in a large national biobank, and assessed whether refined phenotypic classification would facilitate genetic discovery.We defined all-cause HF among 488 010 participants from the UK Biobank and performed a genome-wide association analysis. We refined the HF phenotype by classifying individuals with left ventricular dysfunction and without coronary artery disease as having nonischemic cardiomyopathy (NICM), and repeated a genetic association analysis. We then pursued replication of lead HF and NICM variants in independent cohorts, and performed adjusted association analyses to assess whether identified genetic associations were mediated through clinical HF risk factors. In addition, we tested rare, loss-of-function mutations in 24 known dilated cardiomyopathy genes for association with HF and NICM. Finally, we examined associations between lead variants and left ventricular structure and function among individuals without HF using cardiac magnetic resonance imaging (n=4158) and echocardiographic data (n=30 201).We identified 7382 participants with all-cause HF in the UK Biobank. Genome-wide association analysis of all-cause HF identified several suggestive loci (P<1×10-6), the majority linked to upstream HF risk factors, ie, coronary artery disease (CDKN2B-AS1 and MAP3K7CL) and atrial fibrillation (PITX2). Refining the HF phenotype yielded a subset of 2038 NICM cases. In contrast to all-cause HF, genetic analysis of NICM revealed suggestive loci that have been implicated in dilated cardiomyopathy (BAG3, CLCNKA-ZBTB17). Dilated cardiomyopathy signals arising from our NICM analysis replicated in independent cohorts, persisted after HF risk factor adjustment, and were associated with indices of left ventricular dysfunction in individuals without clinical HF. In addition, analyses of loss-of-function variants implicated BAG3 as a disease susceptibility gene for NICM (loss-of-function variant carrier frequency=0.01%; odds ratio,12.03; P=3.62×10-5).We found several distinct genetic mechanisms of all-cause HF in a national biobank that reflect well-known HF risk factors. Phenotypic refinement to a NICM subtype appeared to facilitate the discovery of genetic signals that act independently of clinical HF risk factors and that are associated with subclinical left ventricular dysfunction.
Abstract 14707: Functional Cardiac Regeneration by Statin-nanoparticle Loaded Stem Cells in Myocardial Infarction
Authors: Masaaki, Chinatsu Shiraoka, Yoshinori Koishi, Shintaro Nemoto
Journal: Circulation (2017)

Introduction: Clinical trials of autologous adipose-derived stem cell (AdSC) therapy for ischemic heart diseases (IHD) are now on-going, however, transplantation of small number of AdSCs has been r...
Investigation of chemotherapy-induced tumor angiogenesis: Rationale for combination of nab-paclitaxel with anti-VEGF therapy
Authors: Vuong Trieu, Sophia Ran, Neil Desai
Journal: Cancer Research (2007)

4636  Background: VEGF levels in breast cancer patients decreased after 2 anthracycline cycles, but subsequently increased compared with pretreatment (Mills, 2004, Clin Cancer Res 10: 4998), suggesting that repetitive chemotherapeutic treatments may trigger aggressive production of VEGF and stimulate reactionary angiogenesis in the tumor environment. Here, we investigated the effect of nab-paclitaxel (Abraxane, ABX) on tumor VEGF production and angiogenesis as a basis for a combination therapy with anti-angiogenesis agents.  Methods: To demonstrate chemotherapy-induced angiogenesis in vitro, conditioned medium was collected from human breast carcinoma MDA-MB-231 and HUVEC cells with or without exposure to ABX at below IC50 concentrations (5 ng/mL). Endogenous production of VEGF, FGF-2, and IL-8 were analyzed by ELISA. Chemotherapy-induced VEGF production was evaluated in vivo using MB-231 xenograft treated (qdx5) with saline, doxorubicin (10 mg/kg), solvent-based paclitaxel (Taxol, 10 mg/kg), or ABX (15 mg/kg), followed by VEGF quantitation of the tumor extract on day 12. To demonstrate chemotherapy-induced angiogenesis in vivo, MX-1, MESA, and MESA-DX tumor xenografts (N=5/group) were treated with saline or ABX at 13.4 mg/kg or 30 mg/kg (qdx5). The treated tumors were harvested after 11 days and microvessel density (MVD) quantitated by CD31 staining and reported as % CD31 of tissue.  Results: MB-231 and HUVEC cells increased production of VEGF and IL-8 (but not FGF-2) after exposure to low dose of ABX. MB-231 tumors treated with one cycle of saline, doxorubicin, solvent-based paclitaxel, or ABX exhibited significant tumor shrinkage (p  Conclusion: ABX treatment triggered reactionary angiogenesis both in vitro (increased VEGF production) and in vivo (increased VEGF production and increased MVD by CD-31 staining). Increased MVD was noted only in tumors sensitive to ABX. These data suggest a biologic basis for combination of ABX with anti-angiogenic therapy against VEGF.
Accounting for proximal variants improves neoantigen prediction
Authors: Jasreet Hundal, Susanna Kiwala, Yang-Yang Feng, Connor J. Liu, Ramaswamy Govindan, William C. Chapman, Ravindra Uppaluri, S. Joshua Swamidass, Obi L. Griffith, Elaine R. Mardis, Malachi Griffith
Journal: Nature Genetics (2018)
GP at Hand: patient eligibility restrictions are lifted after NHS review
Authors: Gareth Iacobucci
Journal: BMJ (2018)

Babylon’s GP at Hand service is to remove its current clinical restrictions on which patients can use it, after a review by NHS England.

The service, which launched in November 2017, had been accused of “cherry picking” healthy, younger patients after its website advised that it may not be appropriate for older people and patients with more complex health needs such as pregnant women or people with learning disabilities.12

But Hammersmith and Fulham Clinical Commissioning Group, which hosts the service at an NHS GP surgery, will lift the restrictions after it receives clinical assurance from NHS England at a board meeting …
Endothelial cells act as gatekeepers for LTβR-dependent thymocyte emigration
Authors: Kieran D. James, Emilie J. Cosway, Beth Lucas, Andrea J. White, Sonia M. Parnell, Manuela Carvalho-Gaspar, Alexei V. Tumanov, Graham Anderson, William E. Jenkinson
Journal: The Journal of Experimental Medicine (2018)

The emigration of mature thymocytes from the thymus is critical for establishing peripheral T cell compartments. However, the pathways controlling this process and the timing of egress in relation to postselection developmental stages are poorly defined. Here, we reexamine thymocyte egress and test current and opposing models in relation to the requirement for LTβR, a regulator of thymic microenvironments and thymocyte emigration. Using cell-specific gene targeting, we show that the requirement for LTβR in thymocyte egress is distinct from its control of thymic epithelium and instead maps to expression by endothelial cells. By separating emigration into sequential phases of perivascular space (PVS) entry and transendothelial migration, we reveal a developmentally ordered program of egress where LTβR operates to rate limit access to the PVS. Collectively, we show the process of thymic emigration ensures only the most mature thymocytes leave the thymus and demonstrate a role for LTβR in the initiation of thymus emigration that segregates from its control of medulla organization.
Cost-effectiveness of nivolumab plus ipilimumab as first-line therapy in advanced renal-cell carcinoma
Authors: Bin Wu, Qiang Zhang, Jie Sun
Journal: Journal for ImmunoTherapy of Cancer (2018)

Nivolumab plus ipilimumab improves overall survival and is associated with less toxicity compared with sunitinib in the first-line setting of advanced renal-cell carcinoma (RCC). The current study aimed to assess the cost-effectiveness of nivolumab plus ipilimumab for first-line treatment of advanced RCC from the payer perspectives high- and middle-income regions.A decision-analytic model was constructed to evaluate the health and economic outcomes of first-line sunitinib and nivolumab plus ipilimumab treatment associated with advanced RCC. The clinical and utility data were obtained from published reports. The cost data were acquired for the payer perspectives of the United States (US), United Kingdom (UK), and China. Sensitivity analyses were performed to test the uncertainties of the results. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were used.Nivolumab plus ipilimumab gained 0.70-0.76 QALYs compared with sunitinib. Our analysis determined the following ICERs for nivolumab plus ipilimumab over sunitinib in first-line advanced RCC treatment: US $ 85,506 /QALY; UK $ 126,499/QALY; and China $ 4682/QALY. Sensitivity analyses found the model outputs to be most affected for body weight and for the prices of nivolumab, sunitinib and ipilimumab.Nivolumab plus ipilimumab as first-line treatment could gain more health benefits for advanced RCC in comparison with standard sunitinib, which is considered to be cost-effective in the US and China but not in the UK.
Survey of diet and physical activity in new cases of young breast cancer patients in Taiwan
Authors: H. Feng, H.-C. Chen, I.-C. Chen, C.-H. Lin, Y.-S. Lu, W.-H. Kuo, M.-Y. Wang, C.-S. Huang, A.-L. Cheng, W.-W. Chen, P.-R. Chen
Journal: Annals of Oncology (2018)