tbuckley/cabot-search huggingface dataset:
Activation of Cascade‐Like Antitumor Immune Responses through In Situ Doxorubicin Stimulation and Blockade of Checkpoint Coinhibitory Receptor TIGIT
Authors: Tian Tian, Jingguo Wang, Fan Yin, Miaomiao Wu, Wei He, Xuefu Wang, Zhengbao Zha, Hua Wang
Journal: Advanced Healthcare Materials (2021)

Abstract Although T cell centered immune checkpoint blockade (ICB) therapies have shown unprecedented success in various cancer types, only a minority of patients benefit from these treatments due to the lack of neoantigen burden and exhaustion of tumor‐infiltrating immune stimulating cells. Inspired by the crucial role of NK cell based immunity and potential immunostimulating effect of chemotherapeutic drugs, the therapeutic efficiency on tumor inhibition through combination of doxorubicin (DOX) and blockade of TIGIT (T‐cell Ig and ITIM domain), a coinhibitory receptor expressed by both NK and T cells, in a matrix metalloproteinase 2 (MMP‐2)‐degradable hydrogel is thoroughly evaluated in this study. Due to the distinct release kinetics from destructed framework of hydrogels, the differentially released DOX and anti‐TIGIT monoclonal antibody (aTIGIT) molecules can elicit immunogenic tumor microenvironment and reverse the exhaustion of NK and effector T cells to realize not only durable localized tumor inhibition but also systemic and long‐lasting immune memory responses. Thus, this work pioneers the union of chemotherapeutic drugs and NK cell centered ICB therapies for activating cascade‐like antitumor immune responses through eliciting immunogenic tumor microenvironment and boosting both innate and adaptive immunity.
Ultrasonic particles: An approach for targeted gene delivery
Authors: Aidan P.G. Walsh, Henry N. Gordon, Karlheinz Peter, Xiaowei Wang
Journal: Advanced Drug Delivery Reviews (2021)

Gene therapy has been widely investigated for the treatment of genetic, acquired, and infectious diseases. Pioneering work utilized viral vectors; however, these are suspected of causing serious adverse events, resulting in the termination of several clinical trials. Non-viral vectors, such as lipid nanoparticles, have attracted significant interest, mainly due to their successful use in vaccines in the current COVID-19 pandemic. Although they allow safe delivery, they come with the disadvantage of off-target delivery. The application of ultrasound to ultrasound-sensitive particles allows for a direct, site-specific transfer of genetic materials into the organ/site of interest. This process, termed ultrasound-targeted gene delivery (UTGD), also increases cell membrane permeability and enhances gene uptake. This review focuses on the advances in ultrasound and the development of ultrasonic particles for UTGD across a range of diseases. Furthermore, we discuss the limitations and future perspectives of UTGD.
P47.07 KEAPSAKE Study of Telaglenastat vs Placebo Plus Standard-of-Care in 1L KEAP1/NRF2-Mutated Non-Squamous Metastatic NSCLC
Authors: D.R. Spigel, W. Akerley, M. Evangelist, M. Johnson, B. Levy, T. Owonikoko, P. Paik, T. Papagiannakopoulos, K. Reckamp, L. Akella, S. Holland, Y. Jenkins, E. Kuriakose, N. Rizvi
Journal: Journal of Thoracic Oncology (2021)
マウスとマカクにおける最小侵襲性光遺伝学的刺激のための超高感度ステップ機能オプシン【JST・京大機械翻訳】
Authors: Gong Xin, Mendoza-Halliday Diego, T Ting Jonathan, Kaiser Tobias, Sun Xuyun, M Bastos Andre, D Wimmer Ralf, Guo Baolin, Chen Qian, Zhou Yang, Pruner Maxwell, Wu Carolyn W.-H., Park Demian, Deisseroth Karl, Barak Boaz, S Boyden Edward, K Miller Earl, M Halassa Michael, Fu Zhanyan, Bi Guoqiang, Desimone Robert, Feng Guoping
Journal: Neuron (2020)
Rethinking the Goals of Diabetes Prevention Programs
Authors: Briana Mezuk, Julie Ober Allen
Journal: Diabetes Care (2021)

In September 2001, the Centers for Disease Control and Prevention (CDC) issued a press release stating that “twin epidemics of diabetes and obesity continue to threaten the health of Americans” but that encouraging new studies (i.e., the Diabetes Prevention Program [DPP] experimental trial) indicated that type 2 diabetes could be prevented and that “promoting healthy lifestyles should be a national priority” (1). Twenty years later, this press release could be issued today with almost no revision and be completely accurate. In 2001, 6.4% of the U.S. population had diagnosed diabetes; currently 10.5% of Americans do (2). Today’s prevalence closely matches projections made in 1992 based on “the overly pessimistic assumption that there will be no scientific or medical discoveries to reduce the prevalence of diabetes” (3).

Yet, strategies for preventing diabetes have been developed in the intervening years. In 2001, the DPP made history as one of a handful of clinical trials that was stopped early because the risk-benefit ratio so clearly favored the experimental interventions over placebo (4). This remarkable efficacy buoyed support for wide-scale implementation of the DPP “lifestyle” arm, which had the goals of promoting ≥5% weight loss and ≥150 min of weekly physical activity. Achievement of these two goals was demonstrated in the DPP trial to significantly reduce type 2 diabetes risk short-term (within 5 years).

Enthusiasm for the DPP trial sharply contrasted with the challenges of implementing diabetes prevention in the broader population (5,6). There is limited evidence that participants in subsequent iterations of the DPP provided in clinical and community settings …
Evaluation of progress toward universal health coverage in Myanmar: A national and subnational analysis
Authors: Zlatko Nikoloski, Alistair McGuire, Elias Mossialos
Journal: PLoS Medicine (2021)

Background Universal health coverage (UHC) encompasses 2 main components: access to essential healthcare services and protection from financial hardship when using healthcare. This study examines Myanmar’s efforts to achieve UHC on a national and subnational level. It is a primer of studying the concept of UHC on a subnational level, and it also establishes a baseline for assessing future progress toward reaching UHC in Myanmar. Methods and findings The study uses the Demographic and Health Survey (2015) and the Myanmar Living Conditions Survey (MLCS; 2017) and adapts a previously developed UHC index to provide insights into the main barriers preventing the country’s progress toward UHC. We find a negative correlation between the UHC index and the state/region poverty levels. The equity of access analysis reveals significant pro-rich inequity in access to all essential healthcare services. Socioeconomic status and limited availability of healthcare infrastructure are the main driving forces behind the unequal access to interventions that are crucial to achieving UHC by 2030. Finally, financial risk protection analysis shows that the poor are less likely to use healthcare services, and, once they do, they are at a greater risk of suffering financial catastrophe. Limitations of this study revolve around its correlational, rather than causal, nature. Conclusions We suggest a 2-pronged approach to help Myanmar achieve UHC: Government and state authorities should reduce the financial burden of seeking healthcare, and, coupled with this, significant investment in and expansion of health infrastructure and the health workforce should be made, particularly in the poorer and more remote states.
Development of ‘Core Outcome Sets’ for meningioma in clinical studies: The COSMIC project
Authors: Christopher Millward, Sumirat Keshwara, Abdurrahman Islim, Nisaharan Srikandarajah, Tony Marson, Paula Williamson, Michael Jenkinson
Journal: Neuro-Oncology (2021)

Abstract Aims To date, meningioma clinical trial activity has been limited, but a number of high-quality studies are underway, with more in development. There is heterogeneity in the outcomes reported in meningioma clinical trials. The COSMIC Project will develop two ‘Core Outcome Sets’ (COS) through comprehensive, transparent, consensus methodology; to ensure outcomes relevant to key stakeholders are reported within and across future meningioma clinical studies. The first will be for use in clinical effectiveness trials (COSMIC: Intervention), the second will be for use in clinical studies of incidental meningioma (COSMIC: Observation). Method Three systematic literature reviews will be performed to generate a long-list of outcomes potentially relevant to meningioma patients, healthcare professionals, researchers, and other stakeholder groups. The first systematic review will present the outcomes reported in published and ongoing meningioma clinical effectiveness trials. The second systematic review will present patient-reported outcomes (PRO) from the measurement tools utilised in meningioma PRO studies. The third systematic review will present the outcomes reported in published and ongoing clinical studies of untreated meningioma. Outcomes will be deduplicated, unique outcomes categorised according to the taxonomy presented by COMET, and the lists combined. The long-list of outcomes will be prioritised through two, 2-round, modified eDelphi surveys including meningioma patients, healthcare professionals, researchers, and other stakeholder groups. Undecided outcomes from both eDelphi surveys will be ratified at two, one-day consensus meeting, with representation from all key stakeholder groups. Results We have formed a study advisory group with international representation from key organisations. The project already has confirmed support from the International Consortium on Meningioma (ICOM), the European Association of Neuro-Oncology (EANO), the Response Assessment in Neuro-Oncology Patient-Reported Outcome group (RANO-PRO), the Society for Neuro-Oncology (SNO), British Neuro-Oncology Society (BNOS), Society of British Neurological Surgeons (SBNS), The Brain Tumour Charity (TBTC), and Brainstrust. Conclusion Standardising minimum outcome reporting in meningioma clinical effectiveness trials and meningioma clinical studies, through the development of these two COS will ensure outcomes reported are relevant to key stakeholder groups, including patients, whilst reducing research waste for a disease with increasing clinical trial activity. We seek to raise awareness of this project and invite participation from a wide range of stakeholders to ensure that the final COS reflects the opinion of the neuro-oncology community. Registration will take place via the study website www.thecosmicproject.org between June-August 2021.
Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database
Authors: Peter C Taylor, Tsutomu Takeuchi, Gerd R Burmester, Patrick Durez, Josef S Smolen, Walter Deberdt, Maher Issa, Jorge Ross Terres, Natalia Bello, Kevin L Winthrop
Journal: Annals of the Rheumatic Diseases (2021)

To report long-term safety from the completed extension trial of baricitinib, an oral selective Janus kinase inhibitor, in patients with active rheumatoid arthritis (RA).
Pancreatic cancer: an increasing global public health concern
Authors: Citadel J Cabasag, Jacques Ferlay, Mathieu Laversanne, Jerome Vignat, Andras Weber, Isabelle Soerjomataram, Freddie Bray
Journal: Gut (2021)

Intercellular adhesion molecule-1 (ICAM-1) binds circulating leukocytes through interactions with beta 2 integrins, LFA-1, and macrophage Ag-1. The phosphorothioate antisense oligodeoxynucleotide, IP-3082, specific for ICAM-1 mRNA inhibited ICAM-1, but not vascular cell adhesion molecule-1, mRNA induction and expression of ICAM-1 molecules by mouse endothelioma cells. Scrambled control oligonucleotides were ineffective. Untreated C3H (H-2k) mice rejected C57BL/10 (H-2b) heart allografts with a mean survival time of 7.7 +/- 1.4 days. Administration i.v. of IP-3082 by a 7-day osmotic pump prolonged the survival of heart allografts in a dose-dependent fashion: 1.25 mg/kg, to 11 +/- 0 days; 2.5 mg/kg, to 12 +/- 2.7 days; 5 mg/kg, to 14.1 +/- 2.7 days; and 10 mg/kg, to 15.3 +/- 5.8 days (all p &lt; 0.01). Control IP-1082 (10 mg/kg) was ineffective (7 +/- 0.8 days). Although 7-day anti-LFA-1 mAb (50 micrograms/day; i.p.) prolonged allograft survival to 14.1 +/- 2.7 days, the addition of IP-3082 (5.0 mg/kg x 7 days) induced donor-specific transplantation tolerance (&gt; 150 days). Furthermore, IP-3082 (5 mg/kg x 7 days) acted synergistically with antilymphocyte serum, rapamycin, and brequinar, but not cyclosporin A: a single antilymphocyte serum (0.2 ml) i.p. injection alone prolonged graft survival to 10 +/- 0.5 days (p &lt; 0.01) and in combination with IP-3082 (5 mg/kg), to 32.2 +/- 8.3 days (p &lt; 0.001); rapamycin (0.1 mg/kg x 7 days; i.v.) alone prolonged survival to 13 +/- 7.5 days (p &lt; 0.01), and with IP-3082, to 32.4 +/- 8.9 days (p &lt; 0.03); brequinar (0.5 mg/kg x 7 days; oral gavage) alone to 12 +/- 2.4 days (p &lt; 0.05), and with IP-3082 (5 mg/kg), to 38.8 +/- 30.2 days (p &lt; 0.01); in contrast, cyclosporin A (5 mg/kg x 7 days; i.v.) alone produced graft survival of 9.8 +/- 1.3 days (p &lt; 0.1 and in combination with IP-3082 (5 mg/kg), produced survival of 7.8 +/- 3.5 days (NS). Thus, antisense oligonucleotides may proffer a selective gene-targeted immunosuppressive therapy for organ transplantation.
Abstract 5314: Domain <sup>2114–2149</sup> Within RyR2 Plays a Key Role for Correcting Channel Disorder in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
Authors: Takeshi Yamamoto, Masafumi Yano, Takeshi Suetomi, Makoto Ono, Xiaojuan Xu, Hitoshi Uchinoumi, Hiroki Tateishi, Shinichi Okuda, Shigeki Kobayashi, Masunori Matsuzaki
Journal: Circulation (2008)

We recently identified the K201(JTV519)-binding site as domain2114–2149 of the ryanodine receptor (RyR2), and the binding of K201 to this domain corrects the defective inter-domain interaction between N-terminal (0–600) and central regions (2000–2500) of RyR2 in pacing-induced failing hearts. Here, we further investigated the role of the domain peptide2114–2149 (DP 2114–2149 ) on the Ca 2+ release in human CPVT-associated RyR2 R2474S/+ knock-in (KI) mice model. The KI mice revealed no structural or histological abnormality in hearts, and also had no contractile or relaxation dysfunction at rest. In all KI mice (n= 6), however, bi-directional ventricular tachycardia (VT) was observed after exercise with treadmill (Ex:6/6), but not observed in wild-type (WT) mice (Ex:0/7 ). In saponin-permeabilized cardiomyocytes from WT and KI mice, line scan images in cardiomyocytes were obtained to measure local Ca 2+ release events using a confocal microscopy with Rhod-2; [Ca 2+ ] was buffered at 30 nM by 0.5 mM EGTA. In KI, the frequency of Ca 2+ sparks (SpF: s −1 ·100μm −1 ) was much more increased in response to cAMP (0.1–1 μM) than in WT (KI:19.2±0.4 vs WT:14.9±0.4; at [cAMP]= 0.3 μM , p&lt;0.01). DP 2114–2149 abolished the cAMP-induced increase in SpF in KI. Sarcoplasmic reticulum (SR) vesicles were isolated from WT and KI hearts (n=4), then RyR2 was fluorescently labeled with methylcoumarin acetamido (MCA) using DP 2460–2495 (DPc10), which harbors the same mutation site in CPVT as KI mice;R2474S, as a site-directing carrier. Addition of cAMP (1 μM) to the SR from KI (but not WT) mice reduced stabilizing interactions between the N-terminal 1–600 and central domains 2000–2500 (i.e. domain unzipping), as assessed by the quenching of the MCA fluorescence by a large-size fluorescence quencher (Kq: 1.16 in KI: 1.10 in WT). Interestingly, DP 2114–2149 corrected this domain unzipping in KI (Kq:1.13), although DP 2114–2149 had no effect on the cAMP-induced increase in Ser2808 phosphorylation. In conclusion, RyR2 mutation seen in human CPVT may causatively induce hyper-activated channel gating in response to PKA phosphorylation, via defective inter-domain interaction. Correction of the defective inter-domain interaction may be a new therapeutic strategy against CPVT.
Current evidence on dietary intakes of fatty acids and mortality
Authors: Sina Naghshi, Omid Sadeghi
Journal: BMJ (2021)

Findings from the associations between dietary intakes of different fatty acids and longevity are of particular interest to researchers, healthcare providers, and patients. Based on our meta-analysis of 41 articles from cohort studies, dietary intake of alpha linolenic acid (ALA) was associated with a reduced risk of mortality from all causes, cardiovascular disease, and coronary heart disease, and a slightly higher risk of cancer mortality. In a mixed diet, however, ALA is consumed with other fatty acids with different effects. Therefore, finding the effects of other fatty acids might help us to determine the overall effect of a diet that includes fats.
Distinct TNF-alpha and HLA polymorphisms associate with fibrotic and non-fibrotic subtypes of hypersensitivity pneumonitis
Authors: C. Freitas, B. Lima, N. Melo, P. Mota, H. Novais-Bastos, H. Alves, O. Sokhatska, L. Delgado, A. Morais
Journal: Pulmonology (2021)

Since Hypersensitivity Pneumonitis (HP) categorization in fibrotic and nonfibrotic/inflammatory types seems to be more consistent with the distinctive clinical course and outcomes, recent international guidelines recommended the use of this classification. Moreover, fibrotic subtype may share immunogenetic and pathophysiological mechanisms with other fibrotic lung diseases. To investigate HLA -A, -B, -DRB1 and TNF-α –308 gene polymorphisms among fibrotic and nonfibrotic HP patients due to avian exposure, also in comparison with asymptomatic exposed controls. We prospectively enrolled 40 HP patients, classified as fibrotic or nonfibrotic/inflammatory, and 70 exposed controls. HLA and TNF-α polymorphisms were determined by polymerase chain reaction–sequence specific primer amplification. While HLA alleles were not associated to HP susceptibility, fibrotic HP patients showed increased frequencies of HLA A*02 (46.7% vs 25.7%; OR=2.53, p = 0.02) and HLA DRB1*14 (10.0% vs 0.7%; OR=15.44, p=0.02) alleles when compared with exposed controls, although not statistically significant after correction for multiple comparisons. TNF-α G/G genotype (associated with low TNF-α production) frequencies were significantly increased among the non-fibrotic/inflammatory HP patients comparatively to fibrotic presentations (88% vs 60%; RR=0.44; p=0.04) and controls (88% vs 63%, OR 4.33, p=0.037). Also, these patients had a significantly increased frequency of the G allele (94.0% vs 73.3%, RR=0.44, p=0.01), while fibrotic HP patients predominantly presented the A allele (26.7% vs 6.0%, RR=2.28, p=0.01). Our results support the hypothesis that fibrotic and non-fibrotic HP subtypes exhibit a distinct profile of TNF-α and HLA polymorphisms, which may be relevant to predict disease course and better define treatment strategies.
Abstract 18368: Social Network Health Interventions: Can Mayweather and Pacquiao “Knock-out” Health Disparities?
Authors: Martin Cadeiras, Min Choi, Charlotte Starling, Saad Soroya, Maral Bakir, Eleanor Chang, Gene Lim, Tom Mone, Mario Deng, Ronaldo Menezes
Journal: Circulation (2015)

Background: A key factor underlying health disparity is the lack of interrelatedness. Social Media has become a very popular form of interaction among both minorities and non-minorities. Any single day millions interact through social media reducing the distance between people from diverse cultural backgrounds. We hypothesized that targeted social network intervention strategies effectively reach minorities to promote cardiovascular disease awareness. Method: We used the popular social media platform Twitter to deliver content during regular times or during major events involving people with mixed backgrounds. We first developed a diverse social media community; we then engaged with the audience, identified influencers and delivered different types of content at different moments, linked or unlinked to trending hashtags. We evaluated general social media metrics including impressions, engagement and behavior. Results: There was a significant variation in our ability to reach the audience, cause an impression and trigger a behavior. Trending Hashtag targeting was associated with the highest exposure, however with low engagement rates. Influencer-driven content delivery was linked to highest enrichment and intermediate exposure while non-targeted content delivery was associated with the lowest exposure and engagement rates. Other factors including the time of delivery, quality, type and content were also important determinants of effectiveness. The figure shows an example of a single “tweet” during the May 2, 2015 Mayweather-Pacquiao Box event and the exposed network. Conclusion: Carefully planned Social Network Health interventions are highly effective to reach and engage mixed audiences and influence peers to increase awareness about cardiovascular health. Social media and big data analytics allows the development of novel strategies responsive to the specific needs of culturally diverse audiences.
交差中和抗体の組み合わせはSARS-CoV-2およびSARS-CoV偽ウイルス感染を予防する【JST・京大機械翻訳】
Authors: Liu Hejun, Yuan Meng, Huang Deli, Bangaru Sandhya, Zhao Fangzhu, D Lee Chang-Chun, Peng Linghang, Barman Shawn, Zhu Xueyong, Nemazee David, R Burton Dennis, J van Gils Marit, W Sanders Rogier, Kornau Hans-Christian, Reincke S. Momsen, Pruess Harald, Kreye Jakob, C Wu Nicholas, B Ward Andrew, A Wilson Ian
Journal: Cell Host & Microbe (2021)
Avoid doing chest x rays in infants with typical bronchiolitis
Authors: Jeremy N Friedman, Tessa Davis, Aarani Somaskanthan, Amy Ma
Journal: BMJ (2021)

### What you need to know Bronchiolitis is a viral lower respiratory tract infection occurring mainly in the winter months, most commonly caused by respiratory syncytial virus (RSV). It is seen primarily in infancy but occurs up to 2 years of age and is the most common indication for hospitalisation in this age group. Ninety percent of children are infected with RSV in their first 2 years, and up to 40% will experience bronchiolitis during the initial infection.1 Bronchiolitis usually begins with a viral upper respiratory tract prodrome (rhinorrhoea and cough) followed by increasing respiratory effort (tachypnoea and/or accessory muscle use) with wheezing and/or crackles heard on chest auscultation. Diagnosis and assessment of disease severity is based on history and physical examination findings and does not require any confirmatory testing (box 1).1 Box 1 ### Guidance on optimal assessment of infants with bronchiolitis12RETURN TO TEXT
P40.15 Proton Pump Inhibitors, Prior Therapy and Survival in Patients Treated With Immune Checkpoint Inhibitors for Advanced NSCLC
Authors: M. Husain, M. Xu, S. Patel, A. Johns, M. Grogan, M. Li, G. Lopez, A. Miah, R. Hoyd, Y. Liu, M. Muniak, T. Haddad, G. Tinoco, K. Kendra, G. Otterson, C. Presley, D. Spakowicz, D. Owen
Journal: Journal of Thoracic Oncology (2021)
Real-world Use of and Spending on New Oral Targeted Cancer Drugs in the US, 2011-2018
Authors: Mengyuan Fu, Huseyin Naci, Christopher M. Booth, Bishal Gyawali, Austin Cosgrove, Sengwee Toh, Ziyue Xu, Xiaodong Guan, Dennis Ross-Degnan, Anita K. Wagner
Journal: JAMA Internal Medicine (2021)

Launch prices of new cancer drugs in the US have substantially increased in recent years despite growing concerns about the quantity and quality of evidence supporting their approval by the US Food and Drug Administration (FDA).
Effectiveness of heterologous ChAdOx1 nCoV-19 and mRNA prime-boost vaccination against symptomatic Covid-19 infection in Sweden: A nationwide cohort study
Authors: Peter Nordström, Marcel Ballin, Anna Nordström
Journal: The Lancet Regional Health - Europe (2021)

The effectiveness of heterologous prime-boost Coronavirus disease 2019 (Covid-19) vaccination is currently unknown.