tbuckley/cabot-search huggingface dataset:
Adverse Events Associated With Immune Checkpoint Inhibitors
Authors: Halis Kaan Akturk, Aaron W. Michels
Journal: JAMA (2019)

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A Novel TNF-α-Targeting Aptamer for TNF-α-Mediated Acute Lung Injury and Acute Liver Failure
Authors: Wei-Yun Lai, Jen-Wei Wang, Bo-Tsang Huang, Emily Pei-Ying Lin, Pan-Chyr Yang
Journal: Theranostics (2019)

Rationale:The TNF-α pathway plays as a double-edged sword that simultaneously regulates cell apoptosis and proliferation.The dysregulated TNF-α signaling can trigger cytokine storms that lead to profound cell death during the phase of acute tissue injury.On the other hand, an optimal level of TNF-α signaling is required for tissue repair following the acute injury phase.The TNF-α pathway is commonly upregulated in acute lung injury (ALI) and acute liver failure (ALF).Previous studies investigated the feasibility of adopting protein-based TNF-α blockers as disease modifiers in ALI and ALF, but none of these came out with a positive result.One of the potential reasons that resides behind the failure of the trials might be the long half-life of these inhibitors that led to undesired side effects.Developing alternative TNF-α blockers with manageable half-lives remain an unmet need in this regard. Methods:In the current study, we developed a novel TNF-α-targeting aptamer (aptTNF-α) and its PEG-derivate (aptTNF-α-PEG) with antagonistic functions.We investigated the in vivo antagonistic effects using mouse ALI and ALF models. Results:Our data showed that aptTNF-α possessed good in vitro binding affinity towards human/mouse TNF-α and successfully targeted TNF-α in vivo.In the mouse ALI model, aptTNF-α/aptTNF-α-PEG treatment attenuated the severity of LPS-induced ALI, as indicated by the improvement of oxygen saturation and lung injury scores, the reduction of protein-rich fluid leakage and neutrophil infiltration in the alveolar spaces, and the suppression of pro-inflammatory cytokines/chemokines expressions in the lung tissues.In the mouse ALF model, we further showed that aptTNF-α/aptTNF-α-PEG treatment not only attenuated the degree of hepatocyte damage upon acute injury but also potentiated early regeneration of the liver tissues. Conclusion:The results implicated potential roles of aptTNF-α/aptTNF-α-PEG in ALI and ALF.The data also suggested their translational potential as a new category of TNF-α blocking agent.
HSR19-102: Direct and Indirect Economic Burden of Cervical Cancer (CxCa) in the United States in 2015: A Mixed-Methods Analysis
Authors: Chizoba Nwankwo, Shelby L. Corman, Ruchit Shah, Youngmin Kwon
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: An estimated 12,820 women in the United States will be diagnosed with CxCa in 2018, with 4,210 deaths from the disease. The economic burden of CxCa, both in terms of healthcare costs and lost productivity, has not been adequately studied. Methods: This was a mixed-methods study that evaluated the direct and indirect costs of CxCa using data from the Medical Expenditure Panel Survey (MEPS) for prevalent CxCa cases and the National Center for Health Statistics (NCHS) for deaths due to CxCa. Total healthcare costs and number of work days missed were compared between CxCa cases and controls in MEPS, using propensity scores calculated from baseline demographics and comorbidities. Missed work was converted to costs using the average hourly wage for women in 2015. Per-patient incremental healthcare and lost work productivity costs were then multiplied by the number of prevalent cases of CxCa in 2015 obtained from the Surveillance, Epidemiology, and End Results Program (SEER). NCHS data on the age-stratified number of CxCa deaths per year (1935–2015) and life expectancy data from the Social Security Administration were then used to calcluate the number of women who would be alive in 2015 if they had not died from CxCa and the lost earnings resulting from early mortality. The primary study outcome was the total direct and indirect cost of CxCa in 2015, calculated as the sum of the incremental direct healthcare costs, incremental lost productivity costs due to missed work, and lost productivity costs resulting from early death due to CxCa. Results: An estimated 257,524 women were alive with CxCa in 2015. Total healthcare costs were $4,221 higher, and an additional 0.37 work days were missed in women with CxCa compared to propensity-matched controls. Of the 488,475 women who died of CxCa prior to 2015, 108,832 would be alive in 2015 and 38,540 would be part of the workforce. Lost earnings in 2015 attributable to these deaths totaled $2.19 billion. The total economic burden of CxCa in the United States in 2015 was thus estimated at $3.3 billion (Table 1). Conclusions: CxCa was responsible for nearly $3.3 billion in direct and indirect costs in 2015. Early death among women with CxCa was the biggest driver of total economic burden.
Polymalic acid chlorotoxin nanoconjugate for near-infrared fluorescence guided resection of glioblastoma multiforme
Authors: Rameshwar Patil, Anna Galstyan, Tao Sun, Ekaterina S. Shatalova, Pramod Butte, Adam N. Mamelak, Christine Carico, David S. Kittle, Zachary B. Grodzinski, Antonella Chiechi, Hui Ding, Keith L. Black, Julia Y. Ljubimova, Eggehard Holler
Journal: Biomaterials (2019)

Maximal surgical resection of glioma remains the single most effective treatment. Tools to guide the resection while avoiding removal of normal brain tissues can aid surgeons in achieving optimal results. One strategy to achieve this goal is to rely upon interoperative fluorescence staining of tumor cells in vivo, that can be visualized by the surgeon during resection. Towards this goal we have designed a biodegradable fluorescent mini nano imaging agent (NIA) with high specificity for U87MG glioma cells and previously unmet high light emission. The NIA is the conjugate of polymalic acid (PMLA) with chlorotoxin for tumor targeting, indocyanine green (ICG) for NIR fluorescence and the tri-leucin peptide as fluorescence enhancer. PMLA as a multivalent platform carries several molecules of ICG and the other ligands. The NIA recognizes multiple sites on glioma cell surface, demonstrated by the effects of single and combined competitors. Systemic IV injection into xenogeneic mouse model carrying human U87MG glioblastoma indicated vivid tumor cell binding and internalization of NIA resulting in intensive and long-lasting tumor fluorescence. The NIA is shown to greatly improve tumor removal supporting its utility in clinical applications.
Abstract 220: Plasma Extracellular RNAs In Lv Remodeling Post MI
Authors: Ashish S Yeri, Kirsty Danielson, Xiaojun Liu, Ravi Shah, Fernando Camacho, Kahraman Tanriverdi, Chunyang Xiao, Cory Tschabrunn, Elad Anter, Jane Freedman, Raymond Kwong, Anthony Rosenzweig, Yaoyu Wang, Saumya Das
Journal: Circulation Research (2017)

Despite significant declines in early mortality after acute myocardial infarction (MI), heart failure (HF) remains a significant chronic complication following MI. Small non-coding RNAs are short (&lt;200 nt) RNA transcripts that regulate networks of gene expression in cardiovascular disease (CVD), including fibrosis, atherosclerosis and arrhythmia. We hypothesized that plasma circulating extracellular RNAs (ex-RNAs) would be associated with cardiac remodeling by cardiac magnetic resonance in humans post-MI and dysregulated in animal models of ischemia. First, we found that plasma circulating ex-RNA profiles by RNA-seq are distinct in individuals with prior MI relative to healthy individuals without cardiovascular disease with several novel ex-RNAs detected (e.g., y-RNAs; Figure 1 ). Principal components of candidate RNAs selected from differential expression n RNA-seq were associated with LV phenotypes post-MI, specifically LV mass and fibrosis at 4-6 weeks post-MI and change in LV mass at 6 months. In animal and cellular models of ischemia, we found that (1) candidate miRNAs found in humans were expressed in a temporally and cell-specific fashion in the myocardium and (2) candidate miRNA expression increased in cardiomyocyte culture after hypoxia/reoxygenation. Collectively, these data add to a burgeoning literature implicating plasma circulating ex-RNAs as functional markers of acute cardiovascular disease involved in cardiac remodeling en route to HF.
HSR19-111: Disparities in Guideline-Concordant Care Among HER2 Positive Metastatic Breast Cancer Patients
Authors: Ami M. Vyas, Hilary Aroke, Stephen J. Kogut
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: We examined guideline-concordant care among women with HER2+ MBC and determined the magnitude of differences in guideline-concordant care between those with positive and negative hormone receptor (HR) status by utilizing a non-linear decomposition technique. Methods: We conducted a retrospective observational cohort study using the Surveillance, Epidemiology, End Results-Medicare linked database. The study cohort consisted of women age &gt;66 years diagnosed with HER2+ MBC in 2010–2013 (N=241). Guideline-concordant initial care within 6 months of cancer diagnosis was defined as per NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). A multivariate logistic regression was performed to identify the significant predictors of guideline-concordant care. A post-regression non-linear decomposition was conducted to examine the magnitude of disparities in guideline concordant care by women’s HR status. Results: 76.8% of the study cohort received guideline-concordant care, while 23.2% did not. As compared to those who did not receive guideline-concordant care, women who received guideline-concordant care were significantly more likely to have positive HR status (adjusted odds ratio (AOR)=2.11; P =.04), had good performance status (AOR=3.46; P =.0008), and had a higher number of oncology visits (AOR=8.05; P &lt;.0001). With 1 year increase in age at cancer diagnosis, there was 5% lesser likelihood of receiving guideline-concordant care (AOR=0.95; P =.04). From the decomposition analysis, 19.0% of the disparity in guideline-concordant care between women with positive and negative HR status was explained by differences in their characteristics. Enabling characteristics (marital status, census-level income, and education) explained the highest (22.8%) proportion of the disparity, followed by external environmental factors (location of residence, SEER region, hospitals offering oncology services) at 5.3%, and need-related factors (tumor grade, comorbidity, performance status, number of metastases) at 3.2%. Conclusion: Almost one quarter of the study cohort did not receive guideline-concordant care. There are opportunities to improve cancer care for women with negative HR status who have lower socioeconomic status. The high unexplained portion of differences in guideline-concordant care (81.0%) can be due to patient preferences for treatment, propensity to seek care, and organizational and physician-level factors not captured in the database.
Abstract #3617: Hypofractionated stereotactic radiotherapy as salvage therapy for recurrent low grade glioma
Authors: Shannon Fogh, Charles Glass, Brendan Carry, David Andrews, Beverly Downes, Adam Dicker, Maria Werner-Wasik
Journal: Cancer Research (2009)

Purpose: Previous studies have reported encouraging survival results and favorable toxicity data with stereotactic radiation therapy (SRT) for patients with persistent or progressive high grade glioma following standard therapy. We sought to determine the efficacy and tolerability of hypofractionated SRT (H-SRT) in patients presenting with recurrent low grade gliomas. To our knowledge this is the largest cohort of low grade patients treated with H-SRT for recurrent disease. Materials and Methods: Between 1994 and 2008, 22 patients with clinical and/or radiographic imaging evidence of glioma progression following initial treatment were treated with hypofractionated stereotactic radiation therapy (H-SRT). All patients were initially diagnosed with WHO grade II tumors and received standard irradiation at initial diagnosis. Nine of the 22 patients received chemotherapy with H-SRT of which Temador was the most common regimen. The most commonly prescribed radiation regimen was 35 Gy in 3.5 Gy fractions. The primary endpoints of the study were median survival time (MST), neurological, clinical, and radiographic response and CNS toxicity. Results: MST from the date of diagnosis was 74 months (10-192 mo). MST from reirradiation was 9 months. Eleven patients (50%) experienced a response following H-SRT at six week follow up as indicated by either decrease in steroid dose or neurologic improvement. No patients demonstrated clinically significant acute morbidity, and all patients were able to complete the prescribed radiation dose. No patient required hospitalization or surgery for early acute or delayed toxicity. MST of patients receiving chemotherapy with H-SRT was 127 months compared to 30.5 months in patients receiving reirradiation only. Median survival from H-SRT was 17 months for patients receiving chemotherapy with H-SRT and 4 months for patients receiving H-SRT only. Conclusions: The current study represents the largest series to examine the efficacy and tolerability of H-SRT re-irradiation for recurrent low grade gliomas. The low toxicity profile and evidence of symptom improvement associated with this regimen justify further evaluation. Chemotherapy given with re-irradiation demonstrated superior survival and should be investigated in future trials.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3617.
Paediatrician who “groomed a community” to conceal child abuse is sentenced to 79 years
Authors: Owen Dyer
Journal: BMJ (2019)

A Pennsylvania paediatrician whose medical licence was revoked 19 years ago—then reinstated after a local campaign—will spend the rest of his life in prison after being convicted in the abuse of 31 children.

Johnnie Barto, 71, pleaded guilty to charges of indecent assault, corruption of minors, and endangering child welfare in the abuse of two relatives. He pleaded no contest to similar charges relating to 29 patients, accepting his punishment without admitting guilt. His youngest victim was two weeks old.

He was sentenced to 79 to 158 years of imprisonment. “All I can say is that the justice system is not perfect, but it worked the second time,” Judge Patrick Kiniry said.

Barto gave no apology or statement, but sat impassively as dozens of victims testified before sentencing. …
Double-blind, placebo-controlled, randomized trial on low-dose azithromycin prophylaxis in patients with primary antibody deficiencies
Authors: Cinzia Milito, Federica Pulvirenti, Francesco Cinetto, Vassilios Lougaris, Annarosa Soresina, Antonio Pecoraro, Alessandra Vultaggio, Maria Carrabba, Giuseppe Lassandro, Alessandro Plebani, Giuseppe Spadaro, Andrea Matucci, Giovanna Fabio, Rosa Maria Dellepiane, Baldassarre Martire, Carlo Agostini, Damiano Abeni, Stefano Tabolli, Isabella Quinti
Journal: Journal of Allergy and Clinical Immunology (2019)

BackgroundLacking protective antibodies, patients with primary antibody deficiencies (PADs) experience frequent respiratory tract infections, leading to chronic pulmonary damage. Macrolide prophylaxis has proved effective in patients with chronic respiratory diseases.ObjectiveWe aimed to test the efficacy and safety of orally administered low-dose azithromycin prophylaxis in patients with PADs.MethodsWe designed a 3-year, double-blind, placebo-controlled, randomized clinical trial to test whether oral azithromycin (250 mg administered once daily 3 times a week for 2 years) would reduce respiratory exacerbations in patients with PADs and chronic infection–related pulmonary diseases. The primary end point was the number of annual respiratory exacerbations. Secondary end points included time to first exacerbation, additional antibiotic courses, number of hospitalizations, and safety.ResultsEighty-nine patients received azithromycin (n = 44) or placebo (n = 45). The number of exacerbations was 3.6 (95% CI, 2.5-4.7) per patient-year in the azithromycin arm and 5.2 (95% CI, 4.1-6.4) per patient-year in the placebo arm (P = .02). In the azithromycin group the hazard risk for having an acute exacerbation was 0.5 (95% CI, 0.3-0.9; P = .03), and the hazard risk for hospitalization was 0.5 (95% CI, 0.2-1.1; P = .04). The rate of additional antibiotic treatment per patient-year was 2.3 (95% CI, 2.1-3.4) in the intervention group and 3.6 (95% CI, 2.9-4.3) in the placebo group (P = .004). Haemophilus influenzae and Streptococcus pneumoniae were the prevalent isolates, and they were not susceptible to macrolides in 25% of patients of both arms. Azithromycin's safety profile was comparable with that of placebo.ConclusionThe study reached the main outcome centered on the reduction of exacerbation episodes per patient-year, with a consequent reduction in additional courses of antibiotics and risk of hospitalization.Graphical abstract
H<sub>2</sub>Se Induces Reductive Stress in HepG2 Cells and Activates Cell Autophagy by Regulating the Redox of HMGB1 Protein under Hypoxia
Authors: Xiaohong Pan, Xiaoxiao Song, Cheng Wang, Tingting Cheng, Dongrui Luan, Kehua Xu, Bo Tang
Journal: Theranostics (2019)

Rationale: Selenium has been shown to have chemotherapeutic effects against cancer.However, the anti-cancer mechanism of selenium is not fully understood, and the role of hydrogen selenide (H 2 Se), which is a common metabolite of dietary selenium compounds, has not been elucidated due to the lack of detection methods.In this study, we revealed a new anti-cancer mechanism of selenite with the help of a H 2 Se fluorescent probe.Methods: HepG2 cells were cultured under a simulated tumor hypoxic microenvironment.The H 2 Se and H 2 O 2 levels were detected by fluorescent probes in living cells and in mice.Autophagic and apoptotic proteins were detected by Western blotting.The redox of HMGB1 protein were analyzed by non-reducing sodium dodecyl sulfate polyacrylamide gel electrophoresis.Results: After pharmacological doses of Na 2 SeO 3 treatment of HepG2 cells under hypoxic conditions, high levels of H 2 Se were produced before cell death.The H 2 Se accumulation resulted in reductive stress instead of oxidative stress, which was induced by Na 2 SeO 3 treatment under normoxic conditions.Furthermore, H 2 Se targeted the HMGB1 protein and induced cell autophagy.H 2 Se could interrupt the disulfide bond in HMGB1 and promote its secretion.The reduced HMGB1 outside the cells stimulated cell autophagy by inhibiting the Akt/mTOR axis.Here, autophagy played a dual role, i.e., mild autophagy inhibited apoptosis, while excessive autophagy led to autophagy-associated cell death.Conclusions: These results show that H 2 Se plays a key role during HepG2 cell death induced by selenite.Our findings reveal a new anti-cancer mechanism of selenite and provide a new research area for selenium studies.
Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma (aBCC): 18-month update of the pivotal ERIVANCE BCC study.
Authors: Aleksandar Sekulic, Michael R. Migden, Nicole Basset-Seguin, Claus Garbe, Anja Gesierich, Christopher D. Lao, Chris Miller, Laurent Mortier, Dedee F. Murrell, Omid Hamid, Fernando Quevedo, Dirk Schadendorf, Jeannie Hou, Huibin Yue
Journal: Journal of Clinical Oncology (2013)

9037 Background: Therapies for aBCC, which includes metastatic (m) and locally advanced (la) BCC, are limited. Abnormal Hedgehog pathway signaling is a key driver in BCC pathogenesis. Primary analysis of the pivotal ERIVANCE BCC trial of vismodegib, an oral hedgehog pathway inhibitor (HPI), demonstrated an objective response rate (ORR) of 30% and 43%, in mBCC and laBCC patients, respectively, with a median duration of response (DOR) of 7.6 months. We present safety and investigator (INV) assessed efficacy results 18 months (29 May 2012) after primary analysis (26 Nov 2010). Methods: Multicenter, international, nonrandomized study in patients (N=104) with radiographically measurable mBCC or laBCC (surgery inappropriate due to multiple recurrence, or substantial morbidity or deformity anticipated) receiving 150 mg oral vismodegib daily until disease progression or intolerable toxicity. Key secondary endpoints included INV-assessed ORR, progression-free survival (PFS), DOR, overall survival (OS), and safety. Results: At data cutoff, 21 patients continued to undergo protocol-specified assessments and 56 patients were in survival follow-up. The median dose intensity was comparable with primary analysis. ORR was 48.5%, mBCC; 60.3%, laBCC, comparable with primary analysis. However, median DOR improved (mBCC=14.7; laBCC=20.3 months). The median OS for mBCC was 30.9 months but not estimable in laBCC. Adverse events remained consistent, with muscle spasm, alopecia, dysgeusia, weight decrease, and fatigue most frequently reported. Eleven more deaths were reported in the update period after primary analysis; these occurred in survival follow-up and were not drug-related. Conclusions: Vismodegib is the first FDA-approved HPI; thus, long-term efficacy and safety data are particularly relevant. 18-month update data confirmed prolonged responses and consistent safety in vismodegib-treated aBCC patients. Clinical trial information: NCT00833417.