tbuckley/cabot-search huggingface dataset:
Abstract 313: Changes in Autophagic Flux in Patients Undergoing Cardiac Surgery
Authors: Salik Jahania, David Sengstock, Peter Vaitkevicius, Redah Mahmood, Fahed Sabagh, Kristyn Hagood, Bruce Ito, Allen Andres, Roberta A Gottlieb, Robert M Mentzer
Journal: Circulation Research (2012)

Autophagy is an endogenous survival mechanism and adaptive response to cellular stress. We hypothesized that autophagy plays an important cardioprotective role in humans and would be accelerated during the ischemic stress of conventional heart surgery. In a prospective study to test this hypothesis, we measured key autophagy proteins (Beclin-1, Atg5-12, p62) in cardiac tissue from 5 patients undergoing cardiac surgery. Right atrial biopsies were obtained before and after cessation of cardiopulmonary bypass (CPB). In 4 of these patients, CPB was associated with a marked decrease in cardiac Beclin-1, Atg5-12, and p62. We believe that depletion of these factors, particularly p62, reflects a brisk increase in autophagic flux (Fig. 1). In one patient (#02), autophagic flux appeared to be impaired. This occurred in an aged patient with characteristics of metabolic syndrome (MetS) who had the highest predicted operative morbidity/mortality. While the number of patients studied is small and insufficient to reach any definitive conclusions, these preliminary data confirm the feasibility of studying autophagy in the human heart and suggest that ischemic stress during heart surgery is associated with a marked upregulation of autophagic flux. A better understanding of the role of autophagy could lead to the development of new cardioprotective strategies. [Figure 1: Changes in cardiac autophagy proteins in patients undergoing heart surgery before and after cross-clamping the aorta (after restoration of myocardial blood flow).]
Immunotherapy in non-small cell lung cancer and the abscopal effect.
Authors: Syed Imran Mustafa Jafri, Faizan Malik, Naveed Ali, Mary Naglak, Mark L. Sundermeyer
Journal: Journal of Clinical Oncology (2017)

e18104 Background: Advanced research and better understanding of the human immune system has led to the development of targeted immunotherapy such as PD-1 inhibitors. We studied patients with both squamous and non-squamous Non-Small Cell Lung Cancer in a community setting who are being treated with Nivolumab. Our primary objective was to determine response to therapy (overall response rate-ORR). Our secondary objective was to study the abscopal response of our population and if the tumor response was better in those patients who received radiotherapy in the preceding 6 months of the start of immunotherapy Methods: Data were summarized using descriptive statistics including means, standard deviations, medians, frequencies and percentages. Chi square analyses were used to make comparisons between response and categorical variables. Overall response rate was calculated by combining people with partial and complete response. All p-values were two tailed and a level of ≤ 0.05 was considered significant. Results: Out of 21 patients, eight (38%) did not show any disease progression. Five out of these eight patients (23% of total study population) had stable disease. Three remaining patients had partial response to the treatment. The ORR was 14% which is comparable to 20% and 19% ORR in the CheckMate trials for nivolumab. Thirteen (62%) patients had progressive disease. Our study showed no significant effect of radiotherapy on disease response to nivolumab. There was one incidence of treatment discontinuation permanently due to the side effects of Nivolumab. Conclusions: Immunotherapy is a promising new option in lung cancer treatment. Fewer side effects and improved survival compared to traditional second line chemotherapy makes it more appealing. In our study group, nivolumab has shown ORR of 14% and stable disease in an additional 23% of the patients resulting in a disease control rate of 37%.
The Novel BET Inhibitor PLX51107 Has In Vitro and In Vivo Activity Against Acute Myeloid Leukemia
Authors: Nicole R. Grieselhuber, Shaneice R. Mitchell, Shelley Orwick, Bonnie K. Harrington, Virginia M. Goettl, Alison R. Walker, Bhavana Bhatnagar, Alice S. Mims, Rebecca B. Klisovic, Sumithra Vasu, William Blum, James S. Blachly, David M. Lucas, Ramiro Garzon, Rosa Lapalombella, John C. Byrd
Journal: Blood (2016)
Effects of combination of anti-stathmin therapy and chemotherapy on prostate tumor growth in vivo
Authors: Sucharita Mistry, George Atweh
Journal: Cancer Research (2008)

2382   Stathmin, a microtubule-destabilizing factor, is expressed at high levels in prostate cancer (PC). We had previously shown that stathmin inhibition interferes with the proliferation of PC cells. Here, we investigated the effects of anti-stathmin therapy in combination with taxol and/or etoposide in mouse models of human PC. We used a bicistronic adenoviral (Ad) vector that coexpresses green fluorescent protein (GFP) and a ribozyme (Rz) that targets human stathmin mRNA. Twenty-seven animals were injected subcutaneously at four different sites, each with 5x10 6  LNCaP cells/site. We initiated treatment after the mice developed tumors of 0.4-0.5 cm in size. Mice bearing established LNCaP xenografts were divided into 9 groups of 3 mice each. Group I was injected with PBS alone. Groups 2, 3, 4 & 5 were injected with control Ad.GFP (1x10 8  vp/injection). At the same time, taxol (10 mg/kg/injection), etoposide (5 mg/kg/injection) & taxol + etoposide (at indicated doses) was co-administered in groups 3, 4 & 5 respectively. Similarly, groups 6, 7, 8 & 9 were injected with Ad.Rz.GFP (1x10 8  vp/injection) anti-stathmin adenovirus. Groups 7, 8 & 9 were also given taxol, etoposide & taxol + etoposide respectively at the same doses. The adenovirus & the drugs were administered at subtherapeutic doses that were selected based on dose response experiments. All drugs were injected i.p. & the adenoviruses were injected intratumorally once a week for a total of 3 injections. Changes in tumor growth were monitored in the different groups for another 6-8 weeks. Tumors in animals injected with PBS (group 1) or the control Ad.GFP (group 2) continued to grow & reach larger sizes. The growth of the tumors in animals treated with drugs alone (groups 3-5) or Ad.Rz.GFP alone (group 6) was modestly slowed down compared to control groups. However, the rate of tumor growth in animals treated with Ad.Rz.GFP was markedly slower than animals treated with drugs alone. When animals were treated with a combination of anti-stathmin therapy & taxol (group 7), complete regression was observed in 60% of the tumors, partial (≥ 40%) regression in 20% of the tumors & 20% of the tumors were stabilized. Similarly, animals treated with a combination of anti-stathmin therapy & etoposide (group 8) showed complete regression in 44% of the tumors, partial regression in 22% of the tumors & 33% of the tumors were stabilized. Interestingly, when mice were treated with combination of anti-stathmin therapy, taxol & etoposide (group 9), complete regression was achieved in nearly 100% of the tumors. Although inhibition of tumor growth was significantly greater in all 3 combination treatment groups compared to groups treated with single agent alone, combination of anti-stathmin therapy, taxol & etoposide had the most profound inhibition of tumorigenicity. These findings are highly relevant for the treatment of PC since taxol & etoposide are two of the most active agents in PC.
Abstract P078: Dysregulated Calcium Handling in a Conditional Cardiac Myosin Binding Protein C Knockout Model of Hypertrophic Cardiomyopathy
Authors: E M Capes, Peter P Chen, Daniel P Fitzsimons, Hector H Valdivia, Richard L Moss
Journal: Circulation Research (2011)

Heritable cardiomyopathy (HCM) is the leading cause of sudden cardiac arrest (SCA) in young people, affecting 1 in 500 individuals. HCM is chiefly caused by mutations in myofibrillar proteins of the cardiac sarcomere, and cardiac myosin binding protein-C (cMyBP-C, encoded by MYBPC3) is one of the most commonly affected. cMyBP-C, an accessory protein that binds tightly to myosin, has an important role in thick filament regulation. Mice with genetic ablation of MYBPC3 exhibit cardiac hypertrophy, reduced ejection fraction, and increased relaxation times in vivo . Experiments with explanted hearts from these mice exhibit greater susceptibility to arrhythmias compared to WT, suggesting derangement of Ca 2+ handling. The molecular mechanisms underlying the progression of HCM are poorly understood, and are difficult to tease apart in constitutive knock out models due to potential compensatory changes that can mask important aspects of the disease phenotype. We used a tamoxifen-induced conditional MYBPC3 knock out mouse to investigate the onset and progression of the disease before development of overt hypertrophy. We recorded Ca 2+ transients in enzymatically isolated cardiomyocytes at several pacing frequencies using a META LSM 510 confocal microscope. We found that cell shortening in conditional CMs (con-CMs) was reduced by as much as 54% (e.g., 5.46% ± 0.869 in con-CMs, vs. 11.91% ± 0.423 shortening in WT-CMs). Ca 2+ release was often dissynchronous, possibly indicating remodeling at the diads. Ca 2+ transient amplitude was significantly lower in con-CMs across all pacing frequencies (reduced by at least 22%; e.g., fluorescence intensity ratios of 7.983 ± 0.537 in con-CMs vs. 10.332 ± 0.502 in WT CMs). Further, the time constant of transient decay (tau) was dramatically increased in con-CMs (mean 217.27 ± 18.052 msec for con-CMs vs. 107.44 ± 4.045 msec in WT CMs). In some cells (∼5%), this prolongation of transient decay was so profound (e.g., up to 600 milliseconds) that a second Ca 2+ release occurred before [Ca 2+ ] i could return to baseline. These data suggest that conditional knock out of cMyBP-C produces not only contractile dysfunction, but also pro-arrhythmic alterations in Ca 2+ handling.
Penetration of Ultraviolet Radiation Into Skin, as a Factor in Carcinogenesis
Authors: John S. Kirby-Smith, Harold F. Blum, Hugh G. Grady
Journal: JNCI Journal of the National Cancer Institute (1942)

Penetration of Ultraviolet Radiation Into Skin, as a Factor in Carcinogenesis Get access John S. Kirby-Smith, John S. Kirby-Smith assistant physicist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Harold F. Blum, Harold F. Blum senior pharmacologist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Hugh G. Grady Hugh G. Grady acting assistant surgeon National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 2, Issue 5, April 1942, Pages 403–412, https://doi.org/10.1093/jnci/2.5.403 Published: 01 April 1942
Abstract 17285: A Selective Transforming Growth Factor-β and Growth Differentiation Factor-15 Ligand Trap Attenuates Pulmonary Hypertension
Authors: Lai-Ming Yung, Samuel D Paskin-Flerlage, Ivana Nikolic, Scott Pearsall, Ravindra Kumar, Paul B Yu
Journal: Circulation (2014)

Introduction: Excessive Transforming Growth Factor-β (TGF-β) signaling has been implicated in pulmonary arterial hypertension (PAH), based on activation of TGF-β effectors and transcriptional targets in affected lungs and the ability of TGF-β type I receptor (ALK5) inhibitors to improve experimental PAH. However, clinical use of ALK5 inhibitors has been limited by cardiovascular toxicity. Hypothesis: We tested whether or not selective blockade of TGF-β and Growth Differentiation Factor (GDF) ligands using a recombinant TGFβ type II receptor extracellular domain Fc fusion protein (TGFBRII-Fc) could impact experimental PAH. Methods: Male SD rats were injected with monocrotaline (MCT) and received vehicle or TGFBRII-Fc (15 mg/kg, twice per week, i.p.). C57BL/6 mice were treated with SU-5416 and hypoxia (SUGEN-HX) and received vehicle or TGFBRII-Fc. RNA-Seq was used to profile transcriptional changes in lungs of MCT rats. Circulating levels of GDF-15 were measured in 241 PAH patients and 41 healthy controls. Human pulmonary artery smooth muscle cells were used to examine signaling in vitro . Results: TGFBRII-Fc is a selective ligand trap, inhibiting the ability of GDF-15, TGF-β1, TGF-β3, but not TGF-β2 to activate SMAD2/3 in vitro . In MCT rats, prophylactic treatment with TGFBRII-Fc normalized expression of TGF-β transcriptional target PAI-1, attenuated PAH and vascular remodeling. Delayed administration of TGFBRII-Fc in rats with established PAH at 2.5 weeks led to improved survival, decreased PAH and remodeling at 5 weeks. Similar findings were observed in SUGEN-HX mice. No valvular abnormalities were found with TGFBRII-Fc treatment. RNA-Seq revealed GDF-15 to be the most highly upregulated TGF-β ligand in the lungs of MCT rats, with only modest increases in TGF-β1 and no change in TGF-β2/3 observed, suggesting a dominant role of GDF-15 in the pathophysiology of this model. Plasma levels of GDF-15 were significantly increased in patients with diverse etiologies of WHO Group I PAH. Conclusions: These findings demonstrate that a selective TGF-β/GDF-15 trap attenuates experimental PAH, remodeling and mortality, without causing valvulopathy. These data highlight the potential role of GDF-15 as a pathogenic molecule and therapeutic target in PAH.
T790M EGFR Mutation Detection in Cerebrospinal Fluid and Response to Osimertinib in a Lung Cancer Patient with Meningeal Carcinomatosis
Authors: Hugo Gortais, Catherine Daniel, François-Clément Bidard, Emmanuelle Jeannot, Céline Callens, Luc Cabel
Journal: Journal of Thoracic Oncology (2017)
Exceptional Response to Nivolumab Rechallenge in Metastatic Renal Cell Carcinoma with Parallel Changes in Genomic Profile
Authors: Nazli Dizman, Paulo Bergerot, Cristiane Bergerot, Richard B. Lanman, Victoria M. Raymond, Kimberly C. Banks, Jeremy Jones, Sumanta K. Pal
Journal: European Urology (2017)
PWE-040 Prevalent Round Stage Shift in the National Bowel Cancer Screening Programme in Wales; Data from the First 3 Years at a Single Screening Centre: Abstract PWE-040 Table 1
Authors: J J Hurley, A B Hawthorne, J Torkington, J Green, S Dolwani
Journal: Gut (2013)

<h3>Introduction</h3> Colorectal cancer screening is based on early detection of cancers and removal of premalignant polyps though this adenoma to carcinoma sequence is thought to progress over several years. The Bowel Screening Programme in Wales based on guaiac FOBt and colonoscopy for individuals resting positive began roll-out in October 2008, with the aim of reducing mortality through cancer detection at an early stage. The aim of this study was to investigate whether screen detected cancers in Cardiff and the Vale of Glamorgan demonstrated any shift in the stage of cancer during the first three years of screening (initial prevalent round). <h3>Methods</h3> Data was collected prospectively to compare the staging of colorectal cancer diagnosed in the BCSP with cancers diagnosed in the non-screening population in the same geographical region from 1st October 2008 to 31st December 2011. All information was cross checked with Cancer Registry data. <h3>Results</h3> Screen detected cancer was found in 69 individuals (44 male, 25 female), with a positive predictive value of colonoscopy (after positive FOB testing) of 8.7%. Complete clinical staging was available for all 69 individuals; two patients did not undergo surgical resection due to the presence of metastases after radiological staging. There were 696 non-screening detected cancers during the same time period. For the purposes of this analysis, polyp cancers (cancer that was removed by endoscopic means at the time of colonoscopy/flexible sigmoidoscopy) were included in Duke’s stage A, except for one polyp cancer that required subsequent surgical resection and was staged as Duke’s C1. The results are shown in table 1. Three-quarters of cancers diagnosed in the BCSP were Dukes A or B, compared to 44.1% in the non-screening population. Of Duke’s D cancers, only 2.8% were diagnosed through screening, with 27% diagnosed in the non screening population (p &lt; 0.0001). <h3>Conclusion</h3> This data strongly supports significant stage shift of colorectal cancer even within the initial prevalent round in this single Bowel Cancer Screening centre in Wales that the benefits of screening may be demonstrable in outcomes at a relatively early stage of the programme. <h3>Disclosure of Interest</h3> None Declared.
Compassionate use of the PASCAL transcatheter mitral valve repair system for patients with severe mitral regurgitation: a multicentre, prospective, observational, first-in-man study
Authors: Fabien Praz, Konstantinos Spargias, Michael Chrissoheris, Lutz Büllesfeld, Georg Nickenig, Florian Deuschl, Robert Schueler, Neil P Fam, Robert Moss, Moody Makar, Robert Boone, Jeremy Edwards, Aris Moschovitis, Saibal Kar, John Webb, Ulrich Schäfer, Ted Feldman, Stephan Windecker
Journal: The Lancet (2017)
Combination of dura turning-over and decompressive craniectomy: a new pattern of surgery for cerebral infarction caused by craniocerebral gunshot injury
Authors: Qi-Yong Mei, Yao Li, Chao He, Hong-Wei Shan, Yun-Kun Wang, Yan Dong, Ming-Kun Yu, Li-Jun Hou
Journal: Military Medical Research (2017)

Craniocerebral gunshot injury refers to a wound caused by a bullet passing through or lodged in brain tissue, resulting in the loss of function of a certain area or other fatal damage to the human brain. Craniocerebral gunshot injury is usually life-threatening and is very common in modern warfare, accounting for the majority of battle casualties. Most of the patients suffer from acute cerebral infarction caused by vascular injury. Lack of early and solid battlefield emergency medical interference adds to the risk of death among the wounded. We present a 24-year-old man who was shot with a shotgun from a distance of 15 m in an accidental injury. Forty-seven grapeshots were found on his body surface by physical examination. A computed tomography (CT) scan demonstrated large areas of low-density shadows in his right parietal lobe and right temporal lobe with the midline shifting to the left side 2 days later. Afterwards, the patient was transferred to our emergency medical center at Changzheng Hospital in Shanghai. Cranial computed tomography angiography (CTA) showed a high-density shadow in the initial part of the right middle cerebral artery. The branches after the initial part were obliterated. Prompt medical attention and decompressive craniotomy (DC) surgery contributed to the final recovery from cerebral infarction of this patient. Bullets can penetrate or be lodged in the brain, causing intracranial hypertension. The bullets lodged in the brain can result in stenosis and embolism of a cerebral artery, causing acute cerebral infarction. Combining dura turning-over surgery with DC surgery can not only decrease intracranial pressure, which can increase the blood supply for hypertension-induced vessel stenosis, but also help vessels outside the dura mater grow into ischemic areas of the cerebral cortex. However, this new pattern of surgery needs further support from evidence-based medicine.
金属イオン支援自己集合錯体からのミノサイクリンの局所送達は脊髄損傷後の神経保護と機能回復を促進する【Powered by NICT】
Authors: Wang Zhicheng, Nong Jia, B Shultz Robert, Zhang Zhiling, Kim Taegyo, J Tom Veronica, K Ponnappan Ravi, Zhong Yinghui
Journal: Biomaterials (2017)
Considerations on POEMS associated optic neuropathy
Authors: Julio González Martín‐Moro, Inés Contreras Martín, María Castro‐Rebollo, Belén Pilo de la Fuente
Journal: American Journal of Hematology (2017)

We have read with great interest the article of Dispenzieri on POEMS syndrome.1 As ophthalmologists and neurologists specialized in the field of Neuro-ophthalmology, we would like to address some issues regarding the terminology and the ocular manifestations of this rare condition. It is true that the term papilledema has been commonly used to refer to the optic neuropathy that is present in many patients with this paraneoplasic disorder. However, papilledema is defined as optic disk swelling secondary to increased intracranial pressure. The pathogeny of the optic neuropathy that develops in patients with POEMS syndrome, is poorly understood, but increased intracranial pressure seems to be absent in most cases and the drugs that are commonly used to treat cranial hypertension are uneffective in these patients. As in the case of ascites, optic neuropathy and the other ocular manifestations of POEMS are not the consequence of pathologic pressure gradients. The generalized hyperpermeability that these patients suffer and the improvement that has been reported in patients treated with antiVEGF agents2, 3 support the hypothesis that hyperpermeability is the main mechanism leading to optic disc swelling. Indeed certain papers have demonstrated a correlation between ocular manifestations of POEMS syndrome and VEGF levels.3-5 The type of optic neuropathy that these patients suffer is not easy to classify. It is usually bilateral (as papilledema), but intracranial pressure is not elevated in most patients, therefore the term papilledema would seem to be inaccurate. From a pathogenic point of view optic disc swelling induced by cytokines should probably be considered a form of optic neuritis. However, inflammatory neuropathies often associate pain with eye movements and usually produce severe visual loss (reduced visual acuity and visual field damage) while POEMS patients in many cases present only minor visual disturbance and the visual prognosis, despite months of persistent swelling is not bad. We suggest that a specific term should be agreed upon to refer to optic neuropathy in POEMS syndrome. Some alternatives would be hyperpermeability induced optic neuropathy, VEGF induced optic neuropathy, cytocine induced optic neuropathy, POEMS associated papillomegalia or just POEMS associated optic neuropathy.With the advent of OCT technology, non-invasive monitoring of small changes in choroid, retina and the optic nerve is possible. These changes seem to be closely correlated with the course of the disease and the response to treatment. This will call for a greater collaboration between ophthalmologists and the other physicians involved in the management of this disease. None. None.
窒素ドープ量依存性を有するグラフェン量子ドット高効率二重モダリティ光力学的抗菌療法とバイオイメージングのための【Powered by NICT】
Authors: Kuo Wen-Shuo, Chen Hua-Han, Chen Shih-Yao, Chang Chia-Yuan, Chen Pei-Chi, Hou Yung-I, Shao Yu-Ting, Kao Hui-Fang, Lilian Hsu Chih-Li, Chen Yi-Chun, Chen Shean-Jen, Wu Shang-Rung, Wang Jiu-Yao
Journal: Biomaterials (2017)