tbuckley/cabot-search huggingface dataset:
Cytoplasmic components of apoptosis by irofulven revealed by cell-free apoptotic systems
Authors: Jan M. Woynarowski, Barbara A. Woynarowska, Alex V. Trevino, Richard A. Salinas, Mary P. Moyer, Stephen J. Waters
Journal: Cancer Research (2004)

5185  The potent induction of apoptosis in various types of tumor cells, contrasted to largely reversible non-apoptotic effects in normal cells is one of the hallmarks of a novel dual-action DNA- and protein-alkylating drug, irofulven (hydroxymethylacylfulvene). Previous studies suggested the contribution of both nuclear and cytoplasmic signaling to apoptosis by irofulven. To better understand the nature of the differential responses of tumor and normal cells, we used a cell-free apoptosis mimicking system consisting of isolated nuclei and cytosolic extracts. We examined homologous and heterologous mixes of nuclei and cytosols from cancer cells (CEM and LNCaP-Pro5), which initiate apoptosis in response to irofulven, and from normal cells (NCM 460), which display a non-apoptotic cytostatic response. Cytosols were obtained either from untreated or drug-treated cells. In the latter case, irofulven concentrations were adjusted to provide equal levels of intracellular drug-macromolecule adducts in each cell line. Nuclei from all three cell types incubated in the presence of cytosols from untreated cells retained their morphologic integrity for several hours as evaluated by fluorescence microscopy following Hoechst 333421 staining. However, incubation of nuclei with cytosols from irofulven-treated CEM and LNCaP-Pro5 cancer cells resulted in characteristic apoptotic changes: partial chromatin condensation, nuclei breakage, and the release of small chromatin fragments. These changes were observed with nuclei from both apoptosis-prone cancer cells and apoptosis-resistant normal cells. In striking contrast, cytosols from irofulven-treated normal NCM 460 cells did not change the morphology of nuclei from any of the three cell lines. In addition, exposure of cytosols from untreated cancer cells to irofulven (prior to incubation with nuclei) resulted in apoptosis in both cancer and normal nuclei. However, the preincubation of cytosols from normal cells with the drug had marginal effects on the nuclear morphology. A similar pattern of responses, although weaker than those of irofulven, was observed for helenalin, an anticancer sesquiterpenoid drug, which reacts only with proteins. These findings demonstrate that irofulven-induced pro-apoptotic changes in cancer cells involve cytosolic factors. Nuclei in normal NCM 460 cells are not inherently resistant to irofulven-induced apoptosis. However, apoptotic signals in these cells are attenuated at the cytoplasmic level. The possibility that cytoplasmic factors influence cell sensitivity to apoptosis is consistent with our hypothesis that apoptotic effects of irofulven originate not only from DNA damage but also from protein damage. (Supported by CA78706, CA80936, and MGI Pharma, Inc).
Overcoming anti-PEG antibody mediated accelerated blood clearance of PEGylated liposomes by pre-infusion with high molecular weight free PEG
Authors: Morgan D. McSweeney, Lauren S.L. Price, Timothy Wessler, Elizabeth C. Ciociola, Leah B. Herity, Joseph A. Piscitelli, Alexander C. DeWalle, Taylor N. Harris, Andy K.P. Chan, Ran Sing Saw, Peiqi Hu, J. Charles Jennette, M. Gregory Forest, Yanguang Cao, Stephanie A. Montgomery, William C. Zamboni, Samuel K. Lai
Journal: Journal of Controlled Release (2019)
First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma
Authors: Bryan G. Allen, Kellie L. Bodeker, Mark C. Smith, Varun Monga, Sonia Sandhu, Raymond Hohl, Thomas Carlisle, Heather Brown, Nancy Hollenbeck, Sandy Vollstedt, Jeremy D. Greenlee, Matthew A. Howard, Kranti A. Mapuskar, Steven N. Seyedin, Joseph M. Caster, Karra A. Jones, Joseph J. Cullen, Daniel Berg, Brett A. Wagner, Garry R. Buettner, Mindi J. TenNapel, Brian J. Smith, Douglas R. Spitz, John M. Buatti
Journal: Clinical Cancer Research (2019)

Standard treatment for glioblastoma (GBM) includes surgery, radiation therapy (RT), and temozolomide (TMZ), yielding a median overall survival (OS) of approximately 14 months. Preclinical models suggest that pharmacologic ascorbate (P-AscH-) enhances RT/TMZ antitumor effect in GBM. We evaluated the safety of adding P-AscH- to standard RT/TMZ therapy.This first-in-human trial was divided into an RT phase (concurrent RT/TMZ/P-AscH-) and an adjuvant (ADJ) phase (post RT/TMZ/P-AscH- phase). Eight P-AscH- dose cohorts were evaluated in the RT phase until targeted plasma ascorbate levels were achieved (≥20 mmol/L). In the ADJ phase, P-AscH- doses were escalated in each subject at each cycle until plasma concentrations were ≥20 mmol/L. P-AscH- was infused 3 times weekly during the RT phase and 2 times weekly during the ADJ phase continuing for six cycles or until disease progression. Adverse events were quantified by CTCAE (v4.03).Eleven subjects were evaluable. No dose-limiting toxicities occurred. Observed toxicities were consistent with historical controls. Adverse events related to study drug were dry mouth and chills. Targeted ascorbate plasma levels of 20 mmol/L were achieved in the 87.5 g cohort; diminishing returns were realized in higher dose cohorts. Median progression-free survival (PFS) was 9.4 months and median OS was 18 months. In subjects with undetectable MGMT promoter methylation (n = 8), median PFS was 10 months and median OS was 23 months.P-AscH-/RT/TMZ is safe with promising clinical outcomes warranting further investigation.
Treating port wine stain birthmarks by using dynamic optical coherence tomography–guided settings
Authors: Mitalee P. Christman, Hao Feng, Jon Holmes, Roy G. Geronemus
Journal: Journal of the American Academy of Dermatology (2019)

Port wine stain birthmarks often require multiple treatments with the 595-nm pulsed dye laser. Settings are usually derived from clinical experience or trial and error, requiring multiple treatments until optimal improvement. The classical therapeutic endpoint is purpuric change, which often imposes a substantial recovery period on patients.
Risk of acute arterial events associated with treatment of inflammatory bowel diseases: nationwide French cohort study
Authors: Julien Kirchgesner, Nynne Nyboe Andersen, Fabrice Carrat, Tine Jess, Laurent Beaugerie
Journal: Gut (2019)

Objective Patients with IBD are at increased risk of acute arterial events. Antitumour necrosis factor (TNF) agents and thiopurines may, via their anti-inflammatory properties, lower the risk of acute arterial events. The aim of this study was to assess the impact of thiopurines and anti-TNFs on the risk of acute arterial events in patients with IBD. Design Patients aged 18 years or older and affiliated to the French national health insurance with a diagnosis of IBD were followed up from 1 April 2010 until 31 December 2014. The risks of acute arterial events (including ischaemic heart disease, cerebrovascular disease and peripheral artery disease) were compared between thiopurines and anti-TNFs exposed and unexposed patients with marginal structural Cox proportional hazard models adjusting for baseline and time-varying demographics, medications, traditional cardiovascular risk factors, comorbidities and IBD disease activity. Results Among 177 827 patients with IBD (96 111 (54%) women, mean age at cohort entry 46.2 years (SD 16.3), 90 205 (50.7%) with Crohn’s disease (CD)), 4145 incident acute arterial events occurred (incidence rates: 5.4 per 1000 person-years). Compared with unexposed patients, exposure to anti-TNFs (HR 0.79, 95% CI 0.66 to 0.95), but not to thiopurines (HR 0.93, 95% CI 0.82 to 1.05), was associated with a decreased risk of acute arterial events. The magnitude in risk reduction was highest in men with CD exposed to anti-TNFs (HR 0.54, 95% CI 0.40 to 0.72). Conclusion Exposure to anti-TNFs is associated with a decreased risk of acute arterial events in patients with IBD, particularly in men with CD.
Erratum. SGLT2 Inhibitors in Combination Therapy: From Mechanisms to Clinical Considerations in Type 2 Diabetes Management. Diabetes Care 2018;41:1543–1556
Authors: Michaël J.B. van Baar, Charlotte C. van Ruiten, Marcel H.A. Muskiet, Liselotte van Bloemendaal, Richard G. IJzerman, Daniël H. van Raalte
Journal: Diabetes Care (2019)
Horizontal Transfer of Promiscuous Activity from Nonphotosynthetic Bacteria Contributed to Evolution of Chlorophyll Degradation Pathway
Authors: Daichi Obata, Atsushi Takabayashi, Ryouichi Tanaka, Ayumi Tanaka, Hisashi Ito
Journal: Molecular Biology and Evolution (2019)

Abstract The relationship between enzymes and substrates does not perfectly match the “lock and key” model, because enzymes act on molecules other than their true substrate in different catalytic reactions. Such biologically nonfunctional reactions are called “promiscuous activities.” Promiscuous activities are apparently useless, but they can be an important starting point for enzyme evolution. It has been hypothesized that enzymes with low promiscuous activity will show enhanced promiscuous activity under selection pressure and become new specialists through gene duplication. Although this is the prevailing scenario, there are two major problems: 1) it would not apply to prokaryotes because horizontal gene transfer is more significant than gene duplication and 2) there is no direct evidence that promiscuous activity is low without selection pressure. We propose a new scenario including various levels of promiscuous activity throughout a clade and horizontal gene transfer. STAY-GREEN (SGR), a chlorophyll a—Mg dechelating enzyme, has homologous genes in bacteria lacking chlorophyll. We found that some bacterial SGR homologs have much higher Mg-dechelating activities than those of green plant SGRs, while others have no activity, indicating that the level of promiscuous activity varies. A phylogenetic analysis suggests that a bacterial SGR homolog with high dechelating activity was horizontally transferred to a photosynthetic eukaryote. Some SGR homologs acted on various chlorophyll molecules that are not used as substrates by green plant SGRs, indicating that SGR acquired substrate specificity after transfer to eukaryotes. We propose that horizontal transfer of high promiscuous activity is one process of new enzyme acquisition.
Perioperative Dynamic Changes in Circulating Tumor DNA in Patients with Lung Cancer (DYNAMIC)
Authors: Kezhong Chen, Heng Zhao, Yanbin Shi, Fan Yang, Lien Tu Wang, Guannan Kang, Yuntao Nie, Jun Wang
Journal: Clinical Cancer Research (2019)

No study has investigated the precise perioperative dynamic changes in circulating tumor DNA (ctDNA) in any patients with early-stage cancer. This study (DYNAMIC) investigated perioperative dynamic changes in ctDNA and determined the appropriate detection time of ctDNA-based surveillance for surgical patients with lung cancer.Experimental Design: Consecutive patients who underwent curative-intent lung resections were enrolled prospectively (NCT02965391). Plasma samples were obtained at multiple prespecified time points including before surgery (time A), during surgery after tumor resection (time B-time D), and after surgery (time P1-time P3). Next-generation sequencing-based detection platform was performed to calculate the plasma mutation allele frequency. The primary endpoint was ctDNA half-life after radical tumor resection.Thirty-six patients showed detectable mutations in time A. The plasma ctDNA concentration showed a rapid decreasing trend after radical tumor resection, with the average mutant allele fraction at times A, B, C, and D being 2.72%, 2.11%, 1.14%, and 0.17%, respectively. The median ctDNA half-life was 35.0 minutes. Patients with minimal residual disease (MRD) detection had a significant slower ctDNA half-life than those with negative MRD (103.2 minutes vs. 29.7 minutes, P = 0.001). The recurrence-free survival of patients with detectable and undetectable ctDNA concentrations at time P1 was 528 days and 543 days, respectively (P = 0.657), whereas at time P2 was 278 days and 637 days, respectively (P = 0.002).ctDNA decays rapidly after radical tumor resection. The ctDNA detection on the third day after R0 resection can be used as the baseline value for postoperative lung cancer surveillance.
PAHSAs enhance hepatic and systemic insulin sensitivity through direct and indirect mechanisms
Authors: Peng Zhou, Anna Santoro, Odile D. Peroni, Andrew T. Nelson, Alan Saghatelian, Dionicio Siegel, Barbara B. Kahn
Journal: Journal of Clinical Investigation (2019)

Palmitic acid esters of hydroxy stearic acids (PAHSAs) are bioactive lipids with antiinflammatory and antidiabetic effects. PAHSAs reduce ambient glycemia and improve glucose tolerance and insulin sensitivity in insulin-resistant aged chow- and high-fat diet–fed (HFD-fed) mice. Here, we aimed to determine the mechanisms by which PAHSAs improve insulin sensitivity. Both acute and chronic PAHSA treatment enhanced the action of insulin to suppress endogenous glucose production (EGP) in chow- and HFD-fed mice. Moreover, chronic PAHSA treatment augmented insulin-stimulated glucose uptake in glycolytic muscle and heart in HFD-fed mice. The mechanisms by which PAHSAs enhanced hepatic insulin sensitivity included direct and indirect actions involving intertissue communication between adipose tissue and liver. PAHSAs inhibited lipolysis directly in WAT explants and enhanced the action of insulin to suppress lipolysis during the clamp in vivo. Preventing the reduction of free fatty acids during the clamp with Intralipid infusion reduced PAHSAs' effects on EGP in HFD-fed mice but not in chow-fed mice. Direct hepatic actions of PAHSAs may also be important, as PAHSAs inhibited basal and glucagon-stimulated EGP directly in isolated hepatocytes through a cAMP-dependent pathway involving Gαi protein–coupled receptors. Thus, this study advances our understanding of PAHSA biology and the physiologic mechanisms by which PAHSAs exert beneficial metabolic effects.
Acquired Generalized Lipodystrophy: A New Cause of Anti-PD-1 Immune-Related Diabetes
Authors: Alexandre Jehl, Christine Cugnet-Anceau, Corinne Vigouroux, Anne L. Legeay, Stéphane Dalle, Olivier Harou, Lucien Marchand, Olivier Lascols, Cyrielle Caussy, Charles Thivolet, Martine Laville, Emmanuel Disse
Journal: Diabetes Care (2019)

OBJECTIVE Anti–programmed cell death-1 (anti-PD-1) antibodies have revolutionized advanced cancer therapy. Anti-PD-1 therapy is responsible for immune-related adverse events, with frequent endocrine manifestations, including acute-onset type 1 diabetes. Acquired generalized lipodystrophy (AGL) is a rare disease, believed to be immune mediated, characterized by loss of adipose tissue and insulin resistance–associated complications. RESEARCH DESIGN AND METHODS We describe the first reported case of AGL induced by immune checkpoint therapy. RESULTS A 62-year-old woman with metastatic melanoma treated with nivolumab was referred for major hyperglycemia, hypertriglyceridemia, and nonalcoholic steatohepatitis. She had presented with a rapidly progressive generalized loss of subcutaneous adipose tissue. Diabetes was associated with severe insulin resistance and undetectable plasma leptin. Subcutaneous biopsy revealed atrophic adipose tissue infiltrated with cytotoxic CD8+ T lymphocytes and fibrosis. CONCLUSIONS AGL is an additional immune-related adverse event of anti-PD-1 therapy that leads to severe insulin resistance–associated complications.
Phase I Trial of Well-Differentiated Neuroendocrine Tumors (NETs) with Radiolabeled Somatostatin Antagonist 177Lu-Satoreotide Tetraxetan
Authors: Diane Reidy-Lagunes, Neeta Pandit-Taskar, Joseph A. O'Donoghue, Simone Krebs, Kevin D. Staton, Serge K. Lyashchenko, Jason S. Lewis, Nitya Raj, Mithat Gönen, Christian Lohrmann, Lisa Bodei, Wolfgang A. Weber
Journal: Clinical Cancer Research (2019)

Radiolabeled somatostatin receptor 2 (SSTR2) antagonists have shown higher tumor uptake and tumor-to-organ ratios than somatostatin agonists in preclinical models of neuroendocrine tumors (NETs). We performed a phase I study to evaluate the safety and efficacy of SSTR2 antagonist 177Lu-satoreotide tetraxetan.Twenty patients with advanced SSTR2-positive NETs were treated with 177Lu-satoreotide tetraxetan. Patients first underwent a dosimetry study with 177Lu-satoreotide tetraxetan to determine the therapeutic activity that could be safely administered. This activity was split into two equal cycles to be delivered 3 months apart. The maximum activity was 7.4 GBq per cycle.Of 20 patients with NETs (one lung, seven small bowel, nine pancreatic, one gastric, one rectal, one kidney; mean prior treatments: three), six received one cycle of 177Lu- satoreotide tetraxetan and 14 received two cycles. Hematologic toxicity after cycle 1 was mild-moderate and reversed before cycle 2. However, grade 4 hematologic toxicity occurred in four of seven (57%) patients after cycle 2 of 177Lu-satoreotide tetraxetan. The study was suspended, and the protocol modified to limit the cumulative absorbed bone marrow dose to 1 Gy and to reduce prescribed activity for cycle 2 by 50%. The best overall response rate was 45% [5% complete response (1/20), 40% partial response (8/20)]; with 40% stable disease (8/20) and 15% progression of disease (3/20). Median progression-free survival (PFS) was 21.0 months (95% CI, 13.6-NR).In this trial of heavily treated NETs, preliminary data are promising for the use of 177Lu-satoreotide tetraxetan. Additional studies are ongoing to determine optimal therapeutic dose/schedule.
Metal stent impaction in scope channel successfully rescued by argon plasma coagulation with double scope method
Authors: Koji Nagaike, Shiro Hayashi, Yuichi Satomoto, Hirokazu Sasakawa, Kengo Nagai, Yuichi Yoshida, Masafumi Naito
Journal: Endoscopy (2019)

An 89-year-old woman with a history of malignant biliary obstruction caused by unresectable intraductal papillary mucinous carcinoma (IPMC) was admitted for cholangitis due to plastic stent occlusion, which had been inserted for the ingrowth occlusion of a covered self-expandable metal stent (CSEMS) ([Fig. 1]).
Pilot randomized trial of a transdisciplinary geriatric intervention for older adults with cancer.
Authors: Paul Kay, Areej El-Jawahri, Charn-Xin Fuh, Brandon Temel, Sophia Landay, Daniel Lage, Esteban Franco-Garcia, Erin Scott, Erin Stevens, Terrence O'Malley, Supriya Gupta Mohile, William Dale, Lara Traeger, Vicki Jackson, Joseph Greer, Jennifer S. Temel, Ryan David Nipp
Journal: Journal of Clinical Oncology (2019)

11549 Background: Oncologists often struggle with managing the unique care needs of older adults with cancer. We sought to determine the feasibility of delivering a transdisciplinary geriatric intervention designed to address the geriatric (physical function &amp; comorbidity) and palliative care (symptoms &amp; prognostic understanding) needs of older adults with cancer. Methods: We randomly assigned patients age ≥65 with newly diagnosed incurable gastrointestinal (GI) or lung cancer to receive a transdisciplinary geriatric intervention or usual care. Intervention patients received two visits with a geriatrician who was trained to address patients’ palliative care needs in addition to conducting a geriatric assessment. We defined the intervention as feasible if &gt; 70% of patients enrolled in the study and &gt; 75% completed study visits and surveys. At baseline and week 12, we assessed patients’ quality of life (QOL, Functional Assessment of Cancer Therapy General), symptoms (Edmonton Symptom Assessment System), and communication confidence (Perceived Efficacy in Patient Physician Interactions). As this was a pilot study, we calculated mean change scores in outcomes and estimated intervention effect sizes (ES). Results: From 2/2017-6/2018, we randomized 62 patients (55.9% enrollment rate [most common reason for refusal was feeling too ill]; median age = 72.3 [range 65.2-91.8]; 45.2% female; cancer types: 56.5% GI, 43.5% lung). Among intervention patients, 82.1% attended the first visit and 76.2% attended both. Overall, 77.8% completed all study surveys. Compared to usual care, intervention patients had less decrement in QOL scores (-0.77 vs -3.84, ES = .21), greater reduction in the number of moderate/severe symptoms (-0.69 vs +1.04, ES = .58), and more improvement in communication confidence (+1.06 vs -0.80, ES = .38). Conclusions: In this trial of older adults with advanced cancer, more than half enrolled in the study and over 75% of those who enrolled completed all study visits and surveys. Our effect size estimates suggest that a transdisciplinary intervention targeting patients’ geriatric and palliative care needs may be a promising approach to improve patients’ QOL, symptom burden, and communication confidence. Clinical trial information: NCT02868112.
Sleep Duration and Sleep Quality in Caregivers of Patients With Dementia
Authors: Chenlu Gao, Nikita Y. Chapagain, Michael K. Scullin
Journal: JAMA Network Open (2019)

<h3>Importance</h3> In the United States, 16 million family caregivers provide long-term care for patients with dementia. Although one's physical, mental, and cognitive health depends on sleep, many caregivers experience chronic stress, and stress is typically associated with worse sleep quantity and quality. <h3>Objective</h3> To quantify the extent, nature, and treatability of sleep problems in dementia caregivers. <h3>Data Sources</h3> PubMed and Scopus databases were systematically searched for articles published through June 2018 using the following keywords:<i>caregiver</i>or<i>spouse</i>or<i>caretaker</i>AND<i>sleep</i>or<i>circadian</i>AND<i>dementia</i>or<i>Alzheimer</i>. Backward citation tracking was performed, and corresponding authors were contacted for additional data to conduct meta-analyses and pooled analyses. <h3>Study Selection</h3> Two reviewers independently screened 805 studies to identify those that reported sleep duration or sleep quality in caregivers of patients with dementia. <h3>Data Extraction and Synthesis</h3> Following the PRISMA guidelines, 2 reviewers independently extracted data from all studies and conducted National Heart, Lung, and Blood Institute study quality assessments. Meta-analyses with random-effects models were performed to evaluate sleep duration, sleep quality, and sleep interventions in dementia caregivers. <h3>Main Outcomes and Measures</h3> Sleep quality and total sleep time were measured by polysomnography, actigraphy, and self-report. <h3>Results</h3> Thirty-five studies were analyzed with data from 3268 caregivers (pooled mean age [SD of sample means], 63.48 [5.99] years; 76.7% female) were analyzed. Relative to age-matched control noncaregiver adults, caregivers had lower sleep durations akin to losing 2.42 to 3.50 hours each week (Hedges<i>g</i> = −0.29; 95% CI, −0.48 to −0.09;<i>P</i> = .01). Sleep quality was significantly lower in caregivers (Hedges<i>g</i> = −0.66; 95% CI, −0.89 to −0.42;<i>P</i> &lt; .001), but caregivers who underwent sleep intervention trials had better sleep quality than caregivers who did not receive a sleep intervention (Hedges<i>g</i> = 0.35; 95% CI, 0.20-0.49;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> Sleep debt is known to have cumulative associations with physical, mental, and cognitive health; therefore, poor sleep quality in dementia caregivers should be recognized and addressed. Although the caregiving role is stressful and cognitively demanding by its nature, better sleep quality was observed in caregivers who received low-cost behavioral interventions.
Resistance to apoptosis underpins the corticosteroid insensitivity of group 2 innate lymphoid cells
Authors: Jian Luo, Yanqiu Wu, Rahul Shrimanker, Simei Go, Yuan Ye, Clare Hardman, Janina Nahler, Yi-Ling Chen, Linda Stöger, Ni Zeng, Wei Liu, Lara Reed, Aviva M. Tolkovsky, Paul Klenerman, Graham Ogg, Ian D. Pavord, Luzheng Xue
Journal: Journal of Allergy and Clinical Immunology (2019)