tbuckley/cabot-search huggingface dataset:
Novel agents and regimens for hematological malignancies: recent updates from 2020 ASH annual meeting
Authors: Jing-Zhou Hou, Jing Christine Ye, Jeffrey J. Pu, Hongtao Liu, Wei Ding, Hong Zheng, Delong Liu
Journal: Journal of Hematology & Oncology (2021)

Antibodies and chimeric antigen receptor-engineered T cells (CAR-T) are increasingly used for cancer immunotherapy. Small molecule inhibitors targeting cellular oncoproteins and enzymes such as BCR-ABL, JAK2, Bruton tyrosine kinase, FLT3, BCL-2, IDH1, IDH2, are biomarker-driven chemotherapy-free agents approved for several major hematological malignancies. LOXO-305, asciminib, "off-the-shelf" universal CAR-T cells and BCMA-directed immunotherapeutics as well as data from clinical trials on many novel agents and regimens were updated at the 2020 American Society of Hematology (ASH) Annual Meeting. Major developments and updates for the therapy of hematological malignancies were delineated at the recent Winter Symposium and New York Oncology Forum from the Chinese American Hematologist and Oncologist Network (CAHON.org). This study summarized the latest updates on novel agents and regimens for hematological malignancies from the 2020 ASH annual meeting.
Early and Midtreatment Mortality in Palliative Radiotherapy: Emphasizing Patient Selection in High-Quality End-of-Life Care
Authors: Matthew S. Ning, Prajnan Das, David I. Rosenthal, Bouthaina S. Dabaja, Zhongxing Liao, Joe Y. Chang, Daniel R. Gomez, Ann H. Klopp, G. Brandon Gunn, Pamela K. Allen, Paige L. Nitsch, Rachel B. Natter, Tina M. Briere, Joseph M. Herman, Rebecca Wells, Albert C. Koong, Mary Frances McAleer
Journal: Journal of the National Comprehensive Cancer Network (2021)

Palliative radiotherapy (RT) is effective, but some patients die during treatment or too soon afterward to experience benefit. This study investigates end-of-life RT patterns to inform shared decision-making and facilitate treatment consistent with palliative goals.All patients who died ≤6 months after initiating palliative RT at an academic cancer center between 2015 and 2018 were identified. Associations with time-to-death, early mortality (≤30 days), and midtreatment mortality were analyzed.In total, 1,620 patients died ≤6 months from palliative RT initiation, including 574 (34%) deaths at ≤30 days and 222 (14%) midtreatment. Median survival was 43 days from RT start (95% CI, 41-45) and varied by site (P<.001), ranging from 36 (head and neck) to 53 days (dermal/soft tissue). On multivariable analysis, earlier time-to-death was associated with osseous (hazard ratio [HR], 1.33; P<.001) and head and neck (HR, 1.45; P<.001) sites, multiple RT courses ≤6 months (HR, 1.65; P<.001), and multisite treatments (HR, 1.40; P=.008), whereas stereotactic technique (HR, 0.77; P<.001) and more recent treatment year (HR, 0.82; P<.001) were associated with longer survival. No difference in time to death was noted among patients prescribed conventional RT in 1 to 10 versus >10 fractions (median, 40 vs 47 days; P=.272), although the latter entailed longer courses. The 30-day mortality group included 335 (58%) inpatients, who were 27% more likely to die midtreatment (P=.031). On multivariable analysis, midtreatment mortality among these inpatients was associated with thoracic (odds ratio [OR], 2.95; P=.002) and central nervous system (CNS; OR, 2.44; P=.002) indications, >5-fraction courses (OR, 3.27; P<.001), and performance status of 3 to 4 (OR, 1.63; P=.050). Conversely, palliative/supportive care consultation was associated with decreased midtreatment mortality (OR, 0.60; P=.045).Earlier referrals and hypofractionated courses (≤5-10 treatments) should be routinely considered for palliative RT indications, given the short life expectancies of patients at this stage in their disease course. Providers should exercise caution for emergent thoracic and CNS indications among inpatients with poor prognoses due to high midtreatment mortality.
Landscape connectivity for yellow fever: a proxy approach to detect displacement and circulation through environmental corridors and interfaces
Authors: André Luís Acosta, Adriano Pinter, Nuno Faria, Ester Sabino, Maria Anice Mureb Sallum
Journal: The Lancet Planetary Health (2021)

BackgroundYellow fever is an arboviral haemorrhagic disease transmitted by mosquitoes in the tropical regions of Africa and South America. WHO estimates that there are 200 000 severe cases and 30 000 deaths worldwide annually. In Brazil, the wild cycle of yellow fever (also termed urban cycle) occurs through transmission between non-human primates with infected mosquitoes of the Haemagogus and Sabethes genus as intermediaries. Serological analysis of deceased primates is the main monitoring method; however, in many cases, these primates die in remote zones, making the geographical monitoring of yellow fever occurrences difficult. Even so, zoonotic surveillance authorities have observed geographical patterns in yellow fever circulation, especially associated with the ecological connectivity between forest fragments with certain sizes and characteristics. However, several potential displacement corridors connecting geographical points with positive cases remain unknown. Unexpectedly, other routes apparently favourable to primate circulation appear to act as a barrier to yellow fever against displacement. The determination of landscape and ecological characteristics acting on this primate (and viral) circulation is essential for prediction and mapping of displacement corridors and susceptible zones, favouring decision making in planning preventive and proactive actions to combat yellow fever.MethodsWith use of field data for yellow fever-positive primate distribution, we applied landscape connectivity mapping, combining circuit theory and random walk approaches to determine the most environmentally suitable routes or corridors for the displacement of infected primates among positive cases. Based on the extensive experience of zoonotic surveillance authorities in the field, we established a set of relevant variables (eg, forest cover, path sizes, topography, and climate) to generate the resistance surface (ie, a variable that gives ascending values denoting the level of difficulty of an organism to move across the landscape) for São Paulo state, Brazil.FindingsThe preliminary results show a series of potential displacement routes and geographical barriers, providing unprecedented information on environmental affinities and limits for wild yellow fever displacement. These detected routes and points of high susceptibility for yellow fever can be used for field monitoring geographical prioritisation.InterpretationBased on our final results, authorities will be able to define priority sites for primate serological sampling, and determine unsampled and susceptible remote locations where they need to survey for positive or negative cases, filling geographical gaps, and improving the understanding of the wild cycle of yellow fever in Brazil.FundingFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; 2019/12988-7 and 2018/14389-0).
Mechanisms of enhancer action: the known and the unknown
Authors: Anil Panigrahi, Bert W. O’Malley
Journal: Genome biology (2021)

Abstract Differential gene expression mechanisms ensure cellular differentiation and plasticity to shape ontogenetic and phylogenetic diversity of cell types. A key regulator of differential gene expression programs are the enhancers, the gene-distal cis -regulatory sequences that govern spatiotemporal and quantitative expression dynamics of target genes. Enhancers are widely believed to physically contact the target promoters to effect transcriptional activation. However, our understanding of the full complement of regulatory proteins and the definitive mechanics of enhancer action is incomplete. Here, we review recent findings to present some emerging concepts on enhancer action and also outline a set of outstanding questions.
mRNA therapeutics in cancer immunotherapy
Authors: Jan D. Beck, Daniel Reidenbach, Nadja Salomon, Ugur Sahin, Özlem Türeci, Mathias Vormehr, Lena M. Kranz
Journal: Molecular Cancer (2021)

Synthetic mRNA provides a template for the synthesis of any given protein, protein fragment or peptide and lends itself to a broad range of pharmaceutical applications, including different modalities of cancer immunotherapy. With the ease of rapid, large scale Good Manufacturing Practice-grade mRNA production, mRNA is ideally poised not only for off-the shelf cancer vaccines but also for personalized neoantigen vaccination. The ability to stimulate pattern recognition receptors and thus an anti-viral type of innate immune response equips mRNA-based vaccines with inherent adjuvanticity. Nucleoside modification and elimination of double-stranded RNA can reduce the immunomodulatory activity of mRNA and increase and prolong protein production. In combination with nanoparticle-based formulations that increase transfection efficiency and facilitate lymphatic system targeting, nucleoside-modified mRNA enables efficient delivery of cytokines, costimulatory receptors, or therapeutic antibodies. Steady but transient production of the encoded bioactive molecule from the mRNA template can improve the pharmacokinetic, pharmacodynamic and safety properties as compared to the respective recombinant proteins. This may be harnessed for applications that benefit from a higher level of expression control, such as chimeric antigen receptor (CAR)-modified adoptive T-cell therapies. This review highlights the advancements in the field of mRNA-based cancer therapeutics, providing insights into key preclinical developments and the evolving clinical landscape.
IL-6 signaling in macrophages is required for immunotherapy-driven regression of tumors
Authors: Elham Beyranvand Nejad, Camilla Labrie, Marit J van Elsas, Jan Willem Kleinovink, Hans-Willi Mittrücker, Kees L M C Franken, Sylvia Heink, Thomas Korn, Ramon Arens, Thorbald van Hall, Sjoerd H van der Burg
Journal: Journal for ImmunoTherapy of Cancer (2021)

High serum interleukin (IL-6) levels may cause resistance to immunotherapy by modulation of myeloid cells in the tumor microenvironment. IL-6 signaling blockade is tested in cancer, but as this inflammatory cytokine has pleiotropic effects, this treatment is not always effective. IL-6 and IL-6R blockade was applied in an IL-6-mediated immunotherapy-resistant TC-1 tumor model (TC-1.IL-6) and immunotherapy-sensitive TC-1. Effects on therapeutic vaccination-induced tumor regression, recurrence and survival as well on T cells and myeloid cells in the tumor microenvironment were studied. The effects of IL-6 signaling in macrophages under therapy conditions were studied in Il6rafl/fl×LysMcre+ mice. Our therapeutic vaccination protocol elicits a strong tumor-specific CD8+ T-cell response, leading to enhanced intratumoral T-cell infiltration and recruitment of tumoricidal macrophages. Blockade of IL-6 signaling exacerbated tumor outgrowth, reflected by fewer complete regressions and more recurrences after therapeutic vaccination, especially in TC-1.IL-6 tumor-bearing mice. Early IL-6 signaling blockade partly inhibited the development of the vaccine-induced CD8+ T-cell response. However, the main mechanism was the malfunction of macrophages during therapy-induced tumor regression. Therapy efficacy was impaired in Il6rafl/fl×LysMcre+ but not cre-negative control mice, while no differences in the vaccine-induced CD8+ T-cell response were found between these mice. IL-6 signaling blockade resulted in decreased expression of suppressor of cytokine signaling 3, essential for effective M1-type function in macrophages, and increased expression of the phagocytic checkpoint molecule signal-regulatory protein alpha by macrophages. IL-6 signaling is critical for macrophage function under circumstances of immunotherapy-induced tumor tissue destruction, in line with the acute inflammatory functions of IL-6 signaling described in infections.
Hepatitis C Virus and Atherosclerosis in Patients With Type 2 Diabetes
Authors: Michiaki Fukui, Yoshihiro Kitagawa, Naoto Nakamura, Toshikazu Yoshikawa
Journal: JAMA (2003)

fornia from 1995 through 1999.The authors concluded that "crosswalk markings alone may do little to protect older pedestrians [from] being struck by a motor vehicle as they cross the street at an urban intersection."Koepsell et al also reported that the benefit of crosswalk markings on the risk of injuries to older pedestrians was limited to those intersections that lacked a vehicle stop sign (15% for case and 18% for control sites).Koepsell et al ruled out the possibility that their results could be explained by later painting of the crosswalks after the collisions had occurred.It is unclear, however, whether the collision sites had been marked before the study period because they were already known to have a higher risk of conflict between vehicles and pedestrians.Indeed, a recent study 2 provides evidence of clusters of pedestrian-motor vehicle collisions at intersections of major arteries and corridors.It is possible that the reported association between crosswalk markings may reflect the higher traffic density and past experience of injury risk leading to the need of the crosswalk markings in the first place.Koepsell et al also found little effect of devices such as warning signs or speed humps.A more effective approach to the prevention of injuries might be to lower vehicle speed and to divert the traffic flow away from intersections frequented by pedestrians.
Abstract 13389: Syndemic of Unhealthy Alcohol Use, Smoking, and Depressive Symptoms is Associated With Incident Cardiovascular Disease Among Those With and Without Hiv-Infection
Authors: Natalie Chichetto, Suman Kundu, Matthew S Freiberg, Adeel Butt, Stephen Crystal, Robert Cook, R. Scott Braithwaite, David Fiellin, Maria Khan, Kendall Bryant, Julie Gaither, Shirish Barve, Kristina Crothers, Roger Bedimo, Alberta L Warner, Hilary A Tindle
Journal: Circulation (2019)

Introduction: Unhealthy alcohol use, smoking, and depressive symptoms are risk factors for cardiovascular disease (CVD). Little is known about the prevalence of their co-occurrence -termed a syndem...
Abstract 280: Evaluation of Cerebral Blood Oxygenation by NIRS During Asphyxia Cardiac Arrest and Resuscitation in Rats
Authors: Tsukasa Yagi, Koichiro Shinozaki, Yu Okuma, Tai Yin, Mitsuaki Nishikimi, Takeyuki Kiguchi, Taku Iwami, Lance B Becker
Journal: Circulation (2019)

Background: Clinical investigators have focused on the real-time evaluation of cerebral blood oxygenation (CBO) by near-infrared spectroscopy (NIRS) during cardiopulmonary resuscitation (CPR). A previous study showed that an abrupt increase of Oxy-hemoglobin (Hb) concentration and tissue oxygenation index (TOI) was associated with the timing of return of spontaneous circulation (ROSC). However, it is not clear how TOI decreases in cardiac arrest (CA) and increases by resuscitation. Therefore, this study aimed to assess CBO with asphyxia CA and its association with CPR to ROSC in rats Method: Male Sprague-Dawley rats were used. We attached NIRS (NIRO-200NX, Hamamatsu Photonics, Japan) from nasion to upper cervical spine in rats. 10-minute asphyxia was given to induce CA. After CA, mechanical ventilation was restarted, and manual CPR was performed. We examined the mean arterial pressure (MAP), end-tidal carbon dioxide (ETCO2), and Oxy/Deoxy-Hb and TOI. Results: Out of 12 rats, 9 obtained sustained ROSC. After the induction of asphyxia, TOI rapidly dropped, and as subsequent CPR was undergoing, Oxy-Hb, Deoxy-Hb, and TOI increased in synchrony with chest compressions. And then, an abrupt increase in MAP, ETCO2, and TOI observed at the time of ROSC. Conclusion: Recent CPR guidelines suggest a use of ETCO2 during CPR since its abrupt increase is a reasonable indicator of ROSC. TOI can be an alternative of ETCO2, and in addition, it has the potential to serve as monitoring CBO during CPR and subsequently in post-ROSC care.
Potentially Preventable Readmissions After Surgery
Authors: Bruce L. Hall, Sheyda Namazie-Kummer
Journal: JAMA Network Open (2021)

Craig S. Brown, MD, MSc; John R. Montgomery, MD, MSc; Pooja U. Neiman, MD; Glenn K. Wakam, MD; Thomas C. Tsai, MD, MPH; Justin B. Dimick, MD, MPH; John W. Scott, MD, MPH
Selective Modulation of a Pan-Essential Protein as a Therapeutic Strategy in Cancer
Authors: Clare F. Malone, Neekesh V. Dharia, Guillaume Kugener, Alexandra B. Forman, Michael V. Rothberg, Mai Abdusamad, Alfredo Gonzalez, Miljan Kuljanin, Amanda L. Robichaud, Amy Saur Conway, Joshua M. Dempster, Brenton R. Paolella, Nancy Dumont, Volker Hovestadt, Joseph D. Mancias, Scott T. Younger, David E. Root, Todd R. Golub, Francisca Vazquez, Kimberly Stegmaier
Journal: Cancer Discovery (2021)

Cancer dependency maps, which use CRISPR/Cas9 depletion screens to profile the landscape of genetic dependencies in hundreds of cancer cell lines, have identified context-specific dependencies that could be therapeutically exploited. An ideal therapy is both lethal and precise, but these depletion screens cannot readily distinguish between gene effects that are cytostatic or cytotoxic. Here, we use a diverse panel of functional genomic screening assays to identify NXT1 as a selective and rapidly lethal in vivo relevant genetic dependency in MYCN-amplified neuroblastoma. NXT1 heterodimerizes with NXF1, and together they form the principal mRNA nuclear export machinery. We describe a previously unrecognized mechanism of synthetic lethality between NXT1 and its paralog NXT2: their common essential binding partner NXF1 is lost only in the absence of both. We propose a potential therapeutic strategy for tumor-selective elimination of a protein that, if targeted directly, is expected to cause widespread toxicity. SIGNIFICANCE: We provide a framework for identifying new therapeutic targets from functional genomic screens. We nominate NXT1 as a selective lethal target in neuroblastoma and propose a therapeutic approach where the essential protein NXF1 can be selectively eliminated in tumor cells by exploiting the NXT1-NXT2 paralog relationship.See related commentary by Wang and Abdel-Wahab, p. 2129.This article is highlighted in the In This Issue feature, p. 2113.
Bovine spongiform encephalopahy and Creutzfeldt-Jakob disease
Authors: P. Brown
Journal: BMJ (1996)

The identification of 10 cases of a highly stereotyped clinicopathological variant of Creutzfeldt-Jakob disease (CJD) in adolescents and young adults occurring in Britain within the past 24 months (R G Will, J Ironside, et al, personal communication) is cause for serious rethinking about the possibility of human infection from bovine spongiform encephalopathy (BSE).

Typically, “sporadic” (idiopathic) cases of Creutzfeldt-Jakob disease begin in the sixth or seventh decade of life with a loss of memory or, less commonly, with behavioural changes or higher cortical function deficits such as dysphasia or dyslexia. Over several weeks the mental deterioration progresses to frank dementia in association with abnormalities of vision or coordination, rigidity, and involuntary movements (especially myoclonic jerks), which often occur in synchrony with periodic spike waves on electroencephalography.2 Death usually occurs within six months, and at necropsy the brain shows a pathognomonic spongiosis with neuronal loss and gliosis in …
Abstract PO-007: 18O-substituted nucleosides combined with proton beam: “Theranostic transformation.”
Authors: Tyvin Rich, Dongfeng Pan, Mahendra Chordia, Cynthia Keppel, Mira Jung, Dalong Pang, David Beylin, Scott Grindrod, Anatoly Dritschilo
Journal: Clinical Cancer Research (2021)

Abstract Therapeutic protons (PRT) cause atomic transmutation of 18O to 18F producing positrons and release neutrons. We hypothesize that targeted production of 18F may be achieved with an 18O containing nucleoside that incorporates into DNA and when exposed to PRT alters local chemical behavior. PRT radiation sensitization (RS) was tested in SQ20-B squamous carcinoma and PC3 prostate cancer cells treated with 18O substituted C2-18O-thymidine (18O-TD), C2-18O-Uridine (18O-UD) and also the thymidine analogs IUdR and substituted 5’-18O-5-iododeoxyuridine (18O-IUdR). Proton RS data are reported for Log phase cells exposed to these substituted nucleosides at physiologic concentrations of 5 -10 µM for 48 hours and re-plated in fresh media. PRT 24 hours later delivered 1 to 9 Gy using an 85 MeV beam at the Bragg peak. Survival fractions were determined by colony assays in triplicate for combined treatment vs. PRT alone. The single hit multi-target model was applied to demonstrate RS with dose modification factors of 1.2 for 18O-TD, 1.3 for IUdR, and 1.5 for 18O-IUdR. RS was not seen with 18O-TD, 18O-UD, or H218O irradiated with gamma rays, nor those treated with 18O-UD or H218O combined with PRT (no changes in D0). PRT of H218O with 10 Gy yielded positron emission tomography images in vitro initiated &amp;gt;45 minutes after PRT with a decay signal with T1/2 of ~111 min. We conclude that 18O-substituted nucleosides activated by therapeutic PRT create in situ 18F that may open up new strategies for RS. A wide PRT therapeutic window could result from the metabolic, physical, and chemical effects of “theranostic transmutation” with 18O labelled nucleosides. Citation Format: Tyvin Rich, Dongfeng Pan, Mahendra Chordia, Cynthia Keppel, Mira Jung, Dalong Pang, David Beylin, Scott Grindrod, Anatoly Dritschilo. 18O-substituted nucleosides combined with proton beam: “Theranostic transformation.” [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-007.
Knee orthopedics as a template for the temporomandibular joint
Authors: Benjamin J. Bielajew, Ryan P. Donahue, M. Gabriela Espinosa, Boaz Arzi, Dean Wang, David C. Hatcher, Nikolaos K. Paschos, Mark E.K. Wong, Jerry C. Hu, Kyriacos A. Athanasiou
Journal: Cell Reports Medicine (2021)

Although the knee joint and temporomandibular joint (TMJ) experience similar incidence of cartilage ailments, the knee orthopedics field has greater funding and more effective end-stage treatment options. Translational research has resulted in the development of tissue-engineered products for knee cartilage repair, but the same is not true for TMJ cartilages. Here, we examine the anatomy and pathology of the joints, compare current treatments and products for cartilage afflictions, and explore ways to accelerate the TMJ field. We examine disparities, such as a 6-fold higher article count and 2,000-fold higher total joint replacement frequency in the knee compared to the TMJ, despite similarities in osteoarthritis incidence. Using knee orthopedics as a template, basic and translational research will drive the development and implementation of clinical products for the TMJ. With more funding opportunities, training programs, and federal guidance, millions of people afflicted with TMJ disorders could benefit from novel, life-changing therapeutics.