tbuckley/cabot-search huggingface dataset:
Resolution of pre-cancerous and non-melanoma skin cancers after immune checkpoint inhibitor treatments.
Authors: Marlana M. Orloff, Bahar Dasgeb, Michael J. Mastrangelo, Peter Koblenzer, Daria Kemp, Ryan Michael Weight, Asad Javed, Erin Sharpe-Mills, Takami Sato
Journal: Journal of Clinical Oncology (2016)

e14540 Background: Checkpoint inhibitors such as anti-CTLA4 and anti-PD1 antibodies have changed the standard care for advanced melanoma. However, there has been little reported on the effectiveness in non-melanoma skin cancers. Here we report on three cases where patients were treated with checkpoint inhibitors for other indications and had dramatic improvement of their pre-cancerous lesions and non-melanoma skin cancers. Methods: Observations regarding pre-cancerous and non-melanoma skin lesions were made during treatment with checkpoint inhibitors. Results:Case 1: A 72-year old man presented with numerous basal cell carcinomas (BCC), squamous cell carcinomas (SCC), and a Stage IIB primary cutaneous melanoma (T3bN0M0). His primary melanoma was treated surgically. At 9 months, he developed a local recurrence and distant metastases to the mediastinum and bone. He was started on combination ipilimumab and nivolumab. After 2 months, his melanoma regressed and all existing cutaneous BCC and SCC were resolved. One year later, there have been no new skin carcinomas. Case 2:A 67-year old man with history of SCC of the lung initially presented with cutaneous metastasis. At the time, he also had a number of primary cutaneous SCCs that were biopsy proven. He was started on nivolumab and had improvement of his metastatic lung carcinoma and resolution of numerous primary SCCs. Case 3:A 86-year old woman presented with a Stage IIA (T3aN0M0) melanoma of the right shin that was treated surgically. Four years later, she developed metastatic disease to the right pelvis. At her metastatic presentation, she was also noted to have extensive solar and senile elastosis with diffuse actinic keratoses (AK). She received two doses of ipilimumab followed by two doses of pembrolizumab, at which time there was complete resolution of the AKs. Conclusions: Our observation indicates that checkpoint inhibitor therapy may be effective for the treatment of cancerous and pre-cancerous non-melanoma skin lesions including AK, BCC, and SCC. This could be a potential new indication for checkpoint inhibitors to prevent invasive and time-consuming measures such as repeated surgeries, radiation and to produce much better cosmetic outcomes.
구연 : 비알코올성 지방간 모델에서 Peroxisomal Proliferator Activated Receptor alpha 발현양상
Authors: 김경오, 임형준, 장윤정, 김진용, 박종재, 김재선, 박영태, 최경묵, 백세현, 연종은, 변관수, 이창홍
Journal: Clinical and Molecular Hepatology (2003)

배경/목적: 비알코올성 지방간은 미국에서 이미 간질환중 가장 높은 유병율을 보이는 질환이며 국내에서도 그 발생 빈도가 차츰 증가되고 있는 것으로 추정된다. 많은 수의 환자가 당뇨, 비만, 고지혈증 등의 유발인자를 동반하여 metabolic syndrome의 일환으로 생각되고 있으며 인슐린 저항성이 가장 중요한 병인으로 생각된다. 간세포에서의 long chain fatty acid, very long chain fatty acid의 베타 산화는 peroxisome에서 주로 일어나며 acyl Co-A oxidase, enoyl-CoA hydratase/3-hydroxyacyl-coA dehydrogenase multifunctional protein, ketoacyl coA thiolase 등이 관여하여 fatty acid를 acyl-CoA 로 전환시킨다. 따라서 간세포 내 중성지방의 침착을 보이는 비알콜성 지방간 질환의 발생에 베타산화와 관련된 이와 같은 효소들과 이들의 발현과 밀접한 관계가 있는 peroxisomal peroxisomal proliferator activated receptor alpha (이하 PPAR alpha)는 질환의 발생과 진행에 중요한 역할을 할 것으로 추측된다. 본 연구의 목적은 비 알코올성 지방간 모델을 이용하여 peroxisome 베타산화의 시발 효소인 acyl coA oxidase와 PPAR alpha의 발현 양상을 밝히는데 있다. 대상과 방법: 지방간이 발생하는 OLETF 모델을 사용하였다. 지방간이 발생하지 않는 정상 대조군과 지방간 발생 군에서 간 조직을 얻고 단백질을 용출하였다. western blot을 시행하여 대조군과 지방간 군에서 PPAR alpha의 발현을 관찰하였다. 간 조직에서 RNA를 추출하여 역전사 시킨 후 Real-Time PCR을 시행하여 acyl coA oxidase 및 PPAR alpha의 발현양상을 비교하였다. 결과: 단백발현을 분석하여 각 군에서의 평균을 AU (arbitrary Unit)로 표시하였다. PPAR alpha의 단백 발현을 살펴보면 연령 12주, 28주에 대조군이 53, 49 AU를 보이는데 반해 지방간군은 각각 9, 37 AU로 PPAR alpha단백발현이 현저히 감소하였다. Real-time PCR을 시행하여 PPAR alpha 및 acyl coA oxidase mRNA 발현을 조사하였으며 각각의 Ct 값을 얻고 대조군에 대한 비율로 표시하였다. 지방간 군에서는 PPAR alpha mRNA발현이 각각12주, 28주에 대조군의 3%와 26%로 현저한 감소를 보였다. 지방간 군에서의 Acyl coA oxidase mRNA 발현은 12주에 대조군의 63%로 의미있게 감소하였다. 결론: 비 알코올성 지방간 모델에서는 정상 대조군에 비하여 PPAR alpha 및 acyl coA oxidase의 단백 발현 및 mRNA 발현이 감소하며 이는 peroxisome에서의 long chain fatty acid의 베타 산화과정의 장애를 유발시켜 비 알코올성 지방간 질환의 생성 및 발달에 기여하리라 생각된다.
18F-PBR06 Versus 11C-PBR28 PET for Assessing White Matter Translocator Protein Binding in Multiple Sclerosis
Authors: Tarun Singhal, Kelsey O'Connor, Shipra Dubey, Anthony P. Belanger, Shelley Hurwitz, Renxin Chu, Shahamat Tauhid, Marie F. Kijewski, Marcelo F. DiCarli, Howard L. Weiner, Rohit Bakshi
Journal: Clinical Nuclear Medicine (2018)

Background and Purpose 18 F-PBR06 and 11 C-PBR28 are second-generation PET radioligands targeting the 18-kd translocator protein to assess microglial activation. We directly compared 18 F-PBR06 and 11 C-PBR28 for detecting brain translocator protein binding in multiple sclerosis (MS). Methods Six patients with MS (4 women; mean age ± SD, 32.1 ± 4.9 [range, 23.5–37.4 years]; Expanded Disability Status Scale score 2.3 ± 1.2 [range, 1.0–4.0]) underwent brain PET with both ligands, along with 3-T MRI. MRI was coregistered to the summed 60- to 90-minute PET images. SUV ratios (SUVRs), derived by normalization to global brain radioactivity, were obtained for whole-brain white matter (WM), supratentorial WM, normal-appearing WM (NAWM), and T2 (fluid-attenuated inversion recovery) hyperintense and T1 hypointense MS WM lesions. The highest mean SUVR for the fluid-attenuated inversion-recovery lesional slices was defined as SUVRmax. Results 18 F-PBR06 and 11 C-PBR28 were moderately intercorrelated for whole-brain WM SUVR ( r = 0.83, P = 0.04) and supratentorial WM SUVR ( r = 0.81, P = 0.05) but not for SUVRs of NAWM, T1 lesions, T2 lesions, or SUVRmax. Both tracers demonstrated that SUVR was higher in NAWM than in T1 and T2 lesions (all P &lt; 0.05). 18 F-PBR06 (but not 11 C-PBR28) demonstrated a higher SUVR in T1 versus T2 lesions (0.85 ± 0.07 vs 0.78 ± 0.03, P = 0.03). 18 F-PBR06-derived (but not 11 C-PBR28) SUVRmax correlated with both Expanded Disability Status Scale score ( r = 0.82, P = 0.04) and timed 25-ft walking speed ( r = 0.89, P = 0.01). Conclusions Our preliminary results suggest an association between microglial activation and physical disability in MS. Microglial detection in lesions was not interchangeable between the tracers, with a higher clinical relevance suggested for 18 F-PBR06.
Abstract 205: Overexpression of the Mitochondrial F <sub>o</sub> F <sub>1</sub> ATP Synthase regulators ATP12 and ATP5J are Protective against Ischemia-Reperfusion Injury in the Heart
Authors: Jason Karch, Demetria M Michael, Matthew J Brody, Onur Kanisicak, Bryan D Maliken, Michelle A Sargent, Jeffery D Molkentin
Journal: Circulation Research (2017)

Loss of cardiomyocytes by necrotic cell death is a substantial underlying problem in progressive heart failure. One crucial step that is required for regulated necrosis to ensue is the opening of the mitochondrial permeability transition pore (MPTP), which is triggered by elevations in mitochondrial matrix calcium and reactive oxygen species levels. Opening of the MPTP causes permeabilization of the inner mitochondrial membrane and collapse of the electrochemical proton gradient required for ATP production. The latest model of the MPTP consists of the F o F 1 ATP synthase as the pore forming component within the inner mitochondrial membrane, although the mechanistic aspects of how the ATP synthase generates the pore is unknown. Two regulators of the ATP synthase, ATP12 and ATP5J, were identified in an unbiased calcium overload necrotic cell death screen using a lenti-viral gain-of-function library containing over 13,000 human cDNAs. ATP12 is an assembly factor of the F 1 component of the ATP synthase where it directly binds to the α-subunit and prevents homo-oligomerization. ATP5J is a component of the peripheral stalk that links the F o and F 1 portions of the ATP synthase together. To test if overexpression of ATP12 or ATP5J is indeed protective as we identified in the screen, here we generated cardiac-specific transgenic mice expressing each of these proteins. When subjected to ischemia-reperfusion injury, both ATP5J and ATP12 overexpressing mice were significantly protected. Additionally, mitochondria isolated from the overexpressing hearts demonstrated increased mitochondrial calcium uptake, a hallmark of MPTP desensitization. These data provide evidence that ATP12 and ATP5J are novel inhibitors of MPTP opening through their association with the F o F 1 ATP synthase and thus protect against necrotic cell death.
Adeno-Associated Virus Vectors as Therapeutic and Investigational Tools in the Cardiovascular System
Authors: SerenaZacchigna, LorenaZentilin, MauroGiacca
Journal: Circulation Research (2014)

The use of vectors based on the small parvovirus adeno-associated virus has gained significant momentum during the past decade. Their high efficiency of transduction of postmitotic tissues in vivo, such as heart, brain, and retina, renders these vectors extremely attractive for several gene therapy applications affecting these organs. Besides functional correction of different monogenic diseases, the possibility to drive efficient and persistent transgene expression in the heart offers the possibility to develop innovative therapies for prevalent conditions, such as ischemic cardiomyopathy and heart failure. Therapeutic genes are not only restricted to protein-coding complementary DNAs but also include short hairpin RNAs and microRNA genes, thus broadening the spectrum of possible applications. In addition, several spontaneous or engineered variants in the virus capsid have recently improved vector efficiency and expanded their tropism. Apart from their therapeutic potential, adeno-associated virus vector...
Preservation of sebaceous glands and peroxisome proliferator-activated receptor gamma expression in central centrifugal cicatricial alopecia
Authors: Yemisi Dina, Walaa Borhan, Gulsun Erdag, Ginette A. Okoye, Rajni Sharma, Powell Perng, Crystal Aguh
Journal: Journal of the American Academy of Dermatology (2018)
Frequency of Loss of Function Variants in <i>LRRK2</i> in Parkinson Disease
Authors: Cornelis Blauwendraat, Xylena Reed, Demis A. Kia, Ziv Gan-Or, Suzanne Lesage, Lasse Pihlstrøm, Rita Guerreiro, J. Raphael Gibbs, Marya Sabir, Sarah Ahmed, Jinhui Ding, Roy N. Alcalay, Sharon Hassin-Baer, Alan M. Pittman, Janet Brooks, Connor Edsall, Dena G. Hernandez, Sun Ju Chung, Stefano Goldwurm, Mathias Toft, Claudia Schulte, Jose Bras, Nicholas W. Wood, Alexis Brice, Huw R. Morris, Sonja W. Scholz, Mike A. Nalls, Andrew B. Singleton, Mark R. Cookson
Journal: JAMA Neurology (2018)

<h3>Importance</h3> Pathogenic variants in<i>LRRK2</i>are a relatively common genetic cause of Parkinson disease (PD). Currently, the molecular mechanism underlying disease is unknown, and gain and loss of function (LOF) models of pathogenesis have been postulated.<i>LRRK2</i>variants are reported to result in enhanced phosphorylation of substrates and increased cell death. However, the double knockout of<i>Lrrk2</i>and its homologue<i>Lrrk1</i>results in neurodegeneration in a mouse model, suggesting that disease may occur by LOF. Because LRRK2 inhibitors are currently in development as potential disease-modifying treatments in PD, it is critical to determine whether LOF variants in<i>LRRK2</i>increase or decrease the risk of PD. <h3>Objective</h3> To determine whether<i>LRRK1</i>and<i>LRRK2</i>LOF variants contribute to the risk of developing PD. <h3>Design, Setting, and Participants</h3> To determine the prevailing mechanism of LRRK2-mediated disease in human populations, next-generation sequencing data from a large case-control cohort (&gt;23 000 individuals) was analyzed for LOF variants in<i>LRRK1</i>and<i>LRRK2</i>. Data were generated at 5 different sites and 5 different data sets, including cases with clinically diagnosed PD and neurologically normal control individuals. Data were collected from 2012 through 2017. <h3>Main Outcomes and Measures</h3> Frequencies of<i>LRRK1</i>and<i>LRRK2</i>LOF variants present in the general population and compared between cases and controls. <h3>Results</h3> Among 11 095 cases with PD and 12 615 controls,<i>LRRK1</i>LOF variants were identified in 0.205% of cases and 0.139% of controls (odds ratio, 1.48; SE, 0.571; 95% CI, 0.45-4.44;<i>P</i> = .49) and<i>LRRK2</i>LOF variants were found in 0.117% of cases and 0.087% of controls (odds ratio, 1.48; SE, 0.431; 95% CI, 0.63-3.50;<i>P</i> = .36). All association tests suggested lack of association between<i>LRRK1</i>or<i>LRRK2</i>variants and PD. Further analysis of lymphoblastoid cell lines from several heterozygous LOF variant carriers found that, as expected, LRRK2 protein levels are reduced by approximately half compared with wild-type alleles. <h3>Conclusions and Relevance</h3> Together these findings indicate that haploinsufficiency of<i>LRRK1</i>or<i>LRRK2</i>is neither a cause of nor protective against PD. Furthermore, these results suggest that kinase inhibition or allele-specific targeting of mutant<i>LRRK2</i>remain viable therapeutic strategies in PD.
A Subpopulation of Cardiomyocytes Expressing α-Skeletal Actin Is Identified by a Specific Polyclonal Antibody
Authors: SophieClément, ChristineChaponnier, GiulioGabbiani
Journal: Circulation Research (1999)

Abstract—The NH2-terminal decapeptide of α-skeletal actin that contains a primary sequence specific for this isoform was used to raise a polyclonal antibody in rabbits. Using sequential affinity chromatography, we recovered from serum antibodies reacting exclusively with α-skeletal actin when tested by immunoblotting and immunofluorescence. Epitope mapping by means of competition assays with synthetic peptides indicated that the acetyl group and the first 9 amino acids are essential for specificity. The monospecific antibody was then used to investigate the distribution of α-skeletal actin in the myocardium of newborn and normal or hypertensive (with or without fibrotic areas) adult rats. Immunostaining of normal heart revealed that α-skeletal actin is diffusely distributed within practically all myocardial fibers of the newborn rat, whereas it is restricted to a small proportion of adult rat cardiomyocytes, which appear intensely stained. A correlation, albeit not complete, was found between the distribu...
Nanocatalyst Complex Can Dephosphorylate Key Proteins in MAPK Pathway for Cancer Therapy
Authors: Rongbing Tang, Yuexiao Jia, Wenshu Zheng, Qiang Feng, Wenfu Zheng, Xingyu Jiang
Journal: Advanced Healthcare Materials (2018)

Abstract Controlling phosphorylation processes of proteins is a facile way for manipulating cell fates. Herein, a synergistic therapeutic strategy utilizing a near‐infrared (NIR)‐responsive nanocatalyst (NC) complex is presented, which is comprised of photoactive NC and protein phosphatase 2A (PP2A), to synergistically inhibit hyperphosphorylation of mitogen‐activated protein kinase (MAPK) pathway for cancer therapy, as an example of many biological processes this approach can apply to. NIR‐triggered release of PP2A specially dephosphorylates and inactivates mitogen‐activated protein kinase kinase (MAP2K, also known as MEK) and extracellular regulated protein kinases (ERK) in the MAPK pathway, meanwhile, the NIR‐triggered activation of NC decreases the level of intracellular adenosine triphosphate to attenuate protein phosphorylation of MEK and ERK. The synergistic therapeutics effectively suppress melanoma progression by inhibiting hyperphosphorylation of the MAPK pathway. In addition, the nanocatalyst complex reduces the risk of drug‐resistance through inhibiting a rebound of RAS‐GTP. The NIR‐responsive nanocatalyst complex paves a novel way for cancer therapeutics.
Direct replications in the era of open sampling
Authors: Gabriele Paolacci, Jesse Chandler
Journal: Behavioral and Brain Sciences (2018)

Abstract Data collection in psychology increasingly relies on “open populations” of participants recruited online, which presents both opportunities and challenges for replication. Reduced costs and the possibility to access the same populations allows for more informative replications. However, researchers should ensure the directness of their replications by dealing with the threats of participant nonnaiveté and selection effects.
Abstract P205: Neighborhood Socioeconomic Status and Long-term Incidence of Cancer After Myocardial Infarction
Authors: Yariv Gerber, Uri Goldbourt, Tal Hasin, Gali Cohen, Lital Keinan-Boker
Journal: Circulation (2016)

Background: Higher cancer incidence rates in patients with cardiovascular disease compared with the general population were recently documented in several European and North American settings. While different mechanisms were proposed to account for the association, the possibility of differential detection cannot be ruled out. We evaluated cancer incidence and case-fatality according to neighborhood socioeconomic status (NSES) in a cohort of myocardial infarction (MI) survivors. Methods: Patients aged ≤65 years admitted to hospital in central Israel with first MI in 1992-1993 were followed up for cancer (via the National Cancer Registry) and death (via the Population Registry) through 2011. NSES was estimated at baseline through a composite census-derived index (measured on a 1-20 scale) developed by the Israel Central Bureau of Statistics, along with other socio-demographic and clinical variables. Fine and Gray subdistribution hazard regression models were used to assess the hazard ratio (HR) for cancer associated with NSES, with death considered a competing event; Cox models were then used to assess the association with case fatality among incident cancer cases. Results: Among 1380 cancer-free patients at baseline (mean age, 54 years; 81% men), 230 developed cancer during a mean (SD) follow-up of 14 (6) years. The age-adjusted HR for cancer was 1.24 (95% CI: 1.08-1.41) per 1 SD increase in NSES. Further adjustment for individual SES measures and clinical variables (including smoking) did not weaken the association (HR=1.26, 95% CI: 1.09-1.46). Conversely, among patients diagnosed with cancer, NSES was associated with reduced mortality risk (age-adjusted HR=0.78, 95% CI: 0.65-0.93; multivariable-adjusted HR=0.80, 95% CI: 0.64-0.99). Conclusions: Residing in an affluent neighborhood was associated with higher incidence and lower case fatality rate of cancer post-MI, which, to some extent, may reflect detection bias due to increased medical surveillance.
Diffuse Liver Metastasis From Nasopharyngeal Carcinoma Found by 18F-FDG PET/CT Scans
Authors: Xin-Yun Zhang, Xiao-Yue Chen, Guo-Qiang Zhang, Quan-Yong Luo
Journal: Clinical Nuclear Medicine (2018)

A 54-year-old man with a history of nasopharyngeal carcinoma was treated with TPF (docetaxel + cisplatin + 5-fluorouracil) neoadjuvant chemotherapy, presented with clinical features of acute hepatic failure. F-FDG PET/CT revealed diffuse hepatic radioactivity uptake without pathological radioactivity elsewhere in the body and similar to superscan by bone scan. Increased focal uptake of FDG was more commonly seen in nasopharyngeal carcinoma with metastatic involvement of the liver. This unusual liver superscan indicated that patients with nasopharyngeal carcinoma may show diffuse hepatic involvement by cancer cells and inspired our interests.
Targeting the HTLV-I-Regulated BATF3/IRF4 Transcriptional Network in Adult T Cell Leukemia/Lymphoma
Authors: Masao Nakagawa, Arthur L. Shaffer, Michele Ceribelli, Meili Zhang, George Wright, Da Wei Huang, Wenming Xiao, John Powell, Michael N. Petrus, Yibin Yang, James D. Phelan, Holger Kohlhammer, Sigrid P. Dubois, Hee Min Yoo, Emmanuel Bachy, Daniel E. Webster, Yandan Yang, Weihong Xu, Xin Yu, Hong Zhao, Bonita R. Bryant, Joji Shimono, Takashi Ishio, Michiyuki Maeda, Patrick L. Green, Thomas A. Waldmann, Louis M. Staudt
Journal: Cancer Cell (2018)
Are eltrombopag plasma and skin hyperpigmentation related? The eyes have it
Authors: George M. Rodgers, Amanda L. Kurtti, Jeffrey A. Gilreath
Journal: American Journal of Hematology (2018)

Eltrombopag is an oral thrombopoietin receptor agonist used to treat immune thrombocytopenia (ITP), thrombocytopenia associated with hepatitis C and interferon therapy, and patients with severe aplastic anemia (SAA). Doses of eltrombopag used to treat the first two indications range from 12.5 to 75 mg/day, while doses used to treat aplastic anemia range from 150 to 300 mg/day (high-dose). Multiple reports have discussed separately plasma and skin changes resulting from high-dose eltrombopag, but to date, no report has unified each of these findings in a single patient. A previously reported patient with SAA was treated with eltrombopag monotherapy1 beginning at 75 mg and titrating up to 150 mg daily; she developed abnormal skin hyperpigmentation (Image 1). Compared with the baseline photograph, after 7 months of high-dose eltrombopag therapy, the patient had a “jaundiced-like” appearance of both skin and sclera. However, liver function tests remained normal during this time. Interestingly, plasma from our patient with SAA also showed marked, brownish discoloration compared with normal appearing plasma taken from a patient not treated with eltrombopag (Image 2). Eltrombopag is a reddish-brown to yellow powder that, when in solution, has been shown to change color based upon the pH of its environment.2 Lower drug doses (25-75 mg/day) have not been reported to result in plasma or serum discoloration, but patients receiving higher drug doses (≥150 mg/day) have been reported to cause discolored blood samples2 or skin hyperpigmentation.3, 4 Eltrombopag is widely distributed into peripheral tissues, including kidneys, skin and ocular tissues.5 Some reports indicate potential interference of high eltrombopag concentrations with certain chemistry assays, depending upon instrumentation and methodology.2, 6 However, this is the first report to unify all three types of discoloration suggesting it is the molecule itself responsible for absorbing and reflecting certain wavelengths of light giving rise to the abnormal coloring of these respective tissues and fluids. While hyperpigmentation may be alarming to both patients and providers, we know of no adverse clinical sequelae resulting from the pigmentation of tissues and plasma with eltrombopag. Additional reports have demonstrated skin pigment reversibility upon eltrombopag discontinuation.4 As high-dose eltrombopag usage expands in treating hematopoietic disorders, clinicians and patients should be aware of these phenomena. Nothing to report.
Abstract 19683: Reperfusion Therapy With Rapamycin Prevents Myocardial Injury by Induction of Cardiac MicroRNA-302a in Diabetic Rabbits
Authors: Arun Samidurai, Ramzi A Ockaili, Scott M Filippone, Chad K Cain, Juan F Torrado, Fadi N Salloum, Rakesh C Kukreja, Anindita Das
Journal: Circulation (2016)

Background: Diabetes is a major risk factor for myocardial infarction (MI). Persistent activation of the mammalian target of rapamycin (mTOR) leads to diabetic complications and plays a critical ro...