tbuckley/cabot-search huggingface dataset:
Ixazomib as Postinduction Maintenance for Patients With Newly Diagnosed Multiple Myeloma Not Undergoing Autologous Stem Cell Transplantation: The Phase III TOURMALINE-MM4 Trial
Authors: Meletios A. Dimopoulos, Ivan Špička, Hang Quach, Albert Oriol, Roman Hájek, Mamta Garg, Meral Beksac, Sara Bringhen, Eirini Katodritou, Wee-Joo Chng, Xavier Leleu, Shinsuke Iida, María-Victoria Mateos, Gareth Morgan, Alexander Vorog, Richard Labotka, Bingxia Wang, Antonio Palumbo, Sagar Lonial
Journal: Journal of Clinical Oncology (2020)

Maintenance therapy prolongs progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) not undergoing autologous stem cell transplantation (ASCT) but has generally been limited to immunomodulatory agents. Other options that complement the induction regimen with favorable toxicity are needed.The phase III, double-blind, placebo-controlled TOURMALINE-MM4 study randomly assigned (3:2) patients with NDMM not undergoing ASCT who achieved better than or equal to partial response after 6-12 months of standard induction therapy to receive the oral proteasome inhibitor (PI) ixazomib or placebo on days 1, 8, and 15 of 28-day cycles as maintenance for 24 months. The primary endpoint was PFS since time of randomization.Patients were randomly assigned to receive ixazomib (n = 425) or placebo (n = 281). TOURMALINE-MM4 met its primary endpoint with a 34.1% reduction in risk of progression or death with ixazomib versus placebo (median PFS since randomization, 17.4 v 9.4 months; hazard ratio [HR], 0.659; 95% CI, 0.542 to 0.801; P < .001; median follow-up, 21.1 months). Ixazomib significantly benefitted patients who achieved complete or very good partial response postinduction (median PFS, 25.6 v 12.9 months; HR, 0.586; P < .001). With ixazomib versus placebo, 36.6% versus 23.2% of patients had grade ≥ 3 treatment-emergent adverse events (TEAEs); 12.9% versus 8.0% discontinued treatment because of TEAEs. Common any-grade TEAEs included nausea (26.8% v 8.0%), vomiting (24.2% v 4.3%), and diarrhea (23.2% v 12.3%). There was no increase in new primary malignancies (5.2% v 6.2%); rates of on-study deaths were 2.6% versus 2.2%.Ixazomib maintenance prolongs PFS with no unexpected toxicity in patients with NDMM not undergoing ASCT. To our knowledge, this is the first PI demonstrated in a randomized clinical trial to have single-agent efficacy for maintenance and is the first oral PI option in this patient population.
Systems Science Approaches for Global Environmental Health Research: Enhancing Intervention Design and Implementation for Household Air Pollution (HAP) and Water, Sanitation, and Hygiene (WASH) Programs
Authors: Joshua Rosenthal, Raphael E. Arku, Jill Baumgartner, Joe Brown, Thomas Clasen, Joseph N.S. Eisenberg, Peter Hovmand, Pamela Jagger, Douglas A. Luke, Ashlinn Quinn, Gautam N. Yadama
Journal: Environmental Health Perspectives (2020)

Background: Two of the most important causes of global disease fall in the realm of environmental health: household air pollution (HAP) and poor water, sanitation, and hygiene (WASH) conditions. Interventions, such as clean cookstoves, household water treatment, and improved sanitation facilities, have great potential to yield reductions in disease burden. However, in recent trials and implementation efforts, interventions to improve HAP and WASH conditions have shown few of the desired health gains, raising fundamental questions about current approaches. Objectives: We describe how the failure to consider the complex systems that characterize diverse real-world conditions may doom promising new approaches prematurely. We provide examples of the application of systems approaches, including system dynamics, network analysis, and agent-based modeling, to the global environmental health priorities of HAP and WASH research and programs. Finally, we offer suggestions on how to approach systems science. Methods: Systems science applied to environmental health can address major challenges by a) enhancing understanding of existing system structures and behaviors that accelerate or impede aims; b) developing understanding and agreement on a problem among stakeholders; and c) guiding intervention and policy formulation. When employed in participatory processes that engage study populations, policy makers, and implementers, systems science helps ensure that research is responsive to local priorities and reflect real-world conditions. Systems approaches also help interpret unexpected outcomes by revealing emergent properties of the system due to interactions among variables, yielding complex behaviors and sometimes counterintuitive results. Discussion: Systems science offers powerful and underused tools to accelerate our ability to identify barriers and facilitators to success in environmental health interventions. This approach is especially useful in the context of implementation research because it explicitly accounts for the interaction of processes occurring at multiple scales, across social and environmental dimensions, with a particular emphasis on linkages and feedback among these processes. https://doi.org/10.1289/EHP7010
Abstract IA25: Targeting MEK1/2 inhibitor resistance in RAS-mutated cancers
Authors: Conan Kinsey, Soledad Camolotto, Amelie Boespflug, Katrin Gullien, Amanda Truong, Mona Foth, Jill Shea, Michael Seipp, Jeffrey Yap, Lance Burrell, David Lum, Jonathan Whisenant, Courtney Cavalier, Kaitren Rehbein, Stephanie Cutler, Kajsa Afotler, Alana Welm, Bryan Welm, Courtney Scaife, Eric Snyder, Martin McMahon
Journal: Cancer Research (2020)

Abstract Although the RAF&amp;gt;MEK&amp;gt;ERK MAP kinase pathway is key to the development of many RAS-mutated cancers, efforts to target this pathway with pharmacologic inhibitors have failed to deliver clinical benefit to patients. Here we show that inhibition of RAS&amp;gt;RAF&amp;gt;MEK&amp;gt;ERK signaling in RAS-mutated cancer cell lines elicits autophagy, a process of cellular recycling that protects cancer cells from the potentially cytotoxic effects of RAF&amp;gt;MEK&amp;gt;ERK pathway inhibition. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic antiproliferative effects against cell lines in vitro and promotes regression of xenografted patient-derived tumors in mice. Finally, treatment of a cancer patient with the combination of trametinib plus hydroxychloroquine resulted in a partial, but nonetheless striking, disease response. These data suggest that this combination therapy may represent a novel strategy to target RAS-driven malignancies such as melanoma, lung, and pancreatic cancer. Citation Format: Conan Kinsey, Soledad Camolotto, Amelie Boespflug, Katrin Gullien, Amanda Truong, Mona Foth, Jill Shea, Michael Seipp, Jeffrey Yap, Lance Burrell, David Lum, Jonathan Whisenant, Courtney Cavalier, Kaitren Rehbein, Stephanie Cutler, Kajsa Afotler, Alana Welm, Bryan Welm, Courtney Scaife, Eric Snyder, Martin McMahon. Targeting MEK1/2 inhibitor resistance in RAS-mutated cancers [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA25.
Sushma Sharma
Authors: Devesh Sharma
Journal: BMJ (2020)

Mum worked in anaesthetics at this time and participated in a married women’s training scheme in Leicester, which she enjoyed  Mum was always keen to attend social events, she went to the weddings of some of Abha’s friends’ children, which she thoroughly enjoyed, and she enthusiastically took part in the dancing  Family planning doctor (b 1932;q Amritsar 1955;DA), died from acute myeloid leukaemia and coronavirus infection on 25 April 2020
Multiplexed endoscopic imaging of Barrett’s neoplasia using targeted fluorescent heptapeptides in a phase 1 proof-of-concept study
Authors: Jing Chen, Yang Jiang, Tse-Shao Chang, Bishnu Joshi, Juan Zhou, Joel H Rubenstein, Erik J Wamsteker, Richard S Kwon, Henry Appelman, David G Beer, Danielle K Turgeon, Eric J Seibel, Thomas D Wang
Journal: Gut (2020)

Improved methods for early cancer detection arising from Barrett’s oesophagus (BE) are still needed. Imaging molecular expression patterns in BE patients can target neoplasia. We demonstrate a multiplexed fluorescence imaging approach to detect premalignant lesions with two fluorescently labeled heptapeptides specific for EGFR and ErbB2. Twenty-two BE patients underwent endoscopic imaging with a multimodal scanning fiber endoscope (mmSFE). In this pilot study, 92% of neoplastic lesions could be imaged by comparison with pathology, with only 11% false positives. This first-in-human study demonstrates feasibility to concurrently detect multiple targets in vivo and potential for early detection of cancers that are molecularly heterogeneous.

### Background

Oesophageal adenocarcinoma (EAC) is a deadly disease that has increased dramatically in incidence over the past several decades.1 2 Endoscopic screening with white light illumination and random biopsy is limited by sampling error.3 Dysplasia often presents with flat architecture and patchy distribution.4 EGFR and ErbB2 are transmembrane tyrosine kinase receptors that stimulate epithelial cell growth, proliferation and differentiation.5 Overexpression of these targets reflects a higher risk for cancer progression.6–8 Multiplexed imaging methods take advantage of the broad spectrum of light over the visible and near-infrared (NIR) regimen. We aim to demonstrate clinical feasibility to visualise EGFR and ErbB2 expression simultaneously in vivo to detect Barrett’s neoplasia.

### Methods

Consecutive patients referred for either evaluation or therapy of Barrett’s neoplasia were recruited for the study (NCT03589443). An mmSFE was designed to collect multiplexed fluorescence images concurrently. Target/background (T/B) ratios were calculated for each fluorescence image. More details on the methods and the multiplexed imaging technology can be found in the online supplemental file.

### Supplementary data

[gutjnl-2020-322945supp001.pdf]

### Results

The peptide QRHKPRE specific for EGFR was labelled with Cy5 via a GGGSK linker, (figure 1A).9 KSPNPRF, specific for ErbB2, was labelled with IRDye800 via a GGGSC linker (figure 1B). …
Inflammation and Coagulation during Critical Illness and Long-Term Cognitive Impairment and Disability
Authors: Nathan E. Brummel, Christopher G. Hughes, Jennifer L. Thompson, James C. Jackson, Pratik Pandharipande, J. Brennan McNeil, Rameela Raman, Onur M. Orun, Lorraine B. Ware, Gordon R. Bernard, E. Wesley Ely, Timothy D. Girard
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: The biological mechanisms of long-term cognitive impairment and disability after critical illness are unclear.Objectives: To test the hypothesis that markers of acute inflammation and coagulation are associated with subsequent long-term cognitive impairment and disability.Methods: We obtained plasma samples from adults with respiratory failure or shock on Study Days 1, 3, and 5 and measured concentrations of CRP (C-reactive protein), IFN-γ, IL-1β, IL-6, IL-8, IL-10, IL-12, MMP-9 (matrix metalloproteinase-9), TNF-α (tumor necrosis factor-α), soluble TNF receptor 1, and protein C. At 3 and 12 months after discharge, we assessed global cognition, executive function, and activities of daily living. We analyzed associations between markers and outcomes using multivariable regression, adjusting for age, sex, education, comorbidities, baseline cognition, doses of sedatives and opioids, stroke risk (in cognitive models), and baseline disability scores (in disability models).Measurements and Main Results: We included 548 participants who were a median (interquartile range) of 62 (53-72) years old, 88% of whom were mechanically ventilated, and who had an enrollment Sequential Organ Failure Assessment score of 9 (7-11). After adjusting for covariates, no markers were associated with long-term cognitive function. Two markers, CRP and MMP-9, were associated with greater disability in basic and instrumental activities of daily living at 3 and 12 months. No other markers were consistently associated with disability outcomes.Conclusions: Markers of systemic inflammation and coagulation measured early during critical illness are not associated with long-term cognitive outcomes and demonstrate inconsistent associations with disability outcomes. Future studies that pair longitudinal measurement of inflammation and related pathways throughout the course of critical illness and during recovery with long-term outcomes are needed.
Nanoscale microenvironment engineering based on layer-by-layer self-assembly to regulate hair follicle stem cell fate for regenerative medicine
Authors: Peng Chen, Yong Miao, Feifei Zhang, Junfei Huang, Yuxin Chen, Zhexiang Fan, Lunan Yang, Jin Wang, Zhiqi Hu
Journal: Theranostics (2020)

Hair regenerative medicine, a promising strategy for the treatment of hair loss, will likely involve the transplantation of autologous hair follicular stem cells (HFSCs) and dermal papilla cells (DPCs) into regions of hair loss. Cyclic hair regeneration results from the periodic partial activation of HFSCs. However, previous studies have not successfully achieved large-scale HFSC expansion in vitro without the use of feeder cells, with a lack of research focused on regulating HFSC fate for hair follicular (HF) regeneration. Hence, an emerging focus in regenerative medicine is the reconstruction of natural extracellular matrix (ECM) regulatory characteristics using biomaterials to generate cellular microenvironments for expanding stem cells and directing their fate for tissue regeneration. Methods: HFSCs were coated with gelatin and alginate using layer-by-layer (LbL) self-assembly technology to construct biomimetic ECM for HFSCs; after which transforming growth factor (TGF)-β2 was loaded into the coating layer, which served as a sustained-release signal molecule to regulate the fate of HFSCs both in vitro and in vivo. In vitro experiments (cell culture and siRNA) were employed to investigate the molecular mechanisms involved and in vivo implantation was carried out to evaluate hair induction efficiency. Results: Nanoscale biomimetic ECM was constructed for individual HFSCs, which allowed for the stable amplification of HFSCs and maintenance of their stem cell properties. TGF-β2 loading into the coating layer induced transformation of CD34+ stem cells into highly proliferating Lgr5+ stem cells, similar to the partial activation of HFSCs in HF regeneration. Thus, LbL coating and TGF-β2 loading partially reconstructed the quiescent and activated states, respectively, of stem cells during HF regeneration, thereby mimicking the microenvironment that regulates stem cell fate for tissue regeneration during HF cycling. Improved HF regeneration was achieved when the two HFSC states were co-transplanted with neonatal mouse dermal cells into nude mice. Conclusion: This study provides novel methods for the construction of stem cell microenvironments and experimental models of HF regeneration for the treatment of hair loss.
Autologous Retinal Transplantation for Primary and Refractory Macular Holes and Macular Hole Retinal Detachments
Authors: Stavros N. Moysidis, Nicole Koulisis, Sean D. Adrean, Steve Charles, Naren Chetty, Jay Kumar Chhablani, Javier Cisneros Cortes, Sherif N. Embabi, Carmelina Gordon, Ninel Z. Gregori, Ahmed Habib, Hany Hamza, Hisham Hassaan, Tarek S. Hassan, Odette Houghton, Kazuaki Kadonosono, Shunji Kusaka, Alberto La Mantia, Chi-Chun Lai, Xhevat Lumi, Takatoshi Maeno, Mohamed Moghazy Mahgoub, Samir Mohamed El Baha, Virgilio Morales-Cantón, Mohamed Nowara, Ogugua Ndubuisi Okonkwo, Barbara Parolini, Flavio A. Rezende, Izabela Rogalinska, Sergio Rojas, David H. Steel, Marcin Stopa, An-Lun Wu, Keiko Yamada, Mitsunori Yamada, Tamer H. Mahmoud
Journal: Ophthalmology (2020)
Advances and novel developments in environmental influences on the development of atopic diseases
Authors: Shifaa Suhayl Alkotob, Cade Cannedy, Katharina Harter, Hesam Movassagh, Bibek Paudel, Mary Prunicki, Vanitha Sampath, Tamara Schikowski, Eric Smith, Qi Zhao, Claudia Traidl‐Hoffmann, Kari C. Nadeau
Journal: Allergy (2020)

Although genetic factors play a role in the etiology of atopic disease, the rapid increases in the prevalence of these diseases over the last few decades suggest that environmental, rather than genetic factors are the driving force behind the increasing prevalence. In modern societies, there is increased time spent indoors, use of antibiotics, and consumption of processed foods and decreased contact with farm animals and pets, which limit exposure to environmental allergens, infectious parasitic worms, and microbes. The lack of exposure to these factors is thought to prevent proper education and training of the immune system. Increased industrialization and urbanization have brought about increases in organic and inorganic pollutants. In addition, Caesarian birth, birth order, increased use of soaps and detergents, tobacco smoke exposure and psychosomatic factors are other factors that have been associated with increased rate of allergic diseases. Here, we review current knowledge on the environmental factors that have been shown to affect the development of allergic diseases and the recent developments in the field.
COVID-19 and mass incarceration: a call for urgent action
Authors: Alexandria Macmadu, Justin Berk, Eliana Kaplowitz, Marquisele Mercedes, Josiah D Rich, Lauren Brinkley-Rubinstein
Journal: The Lancet Public Health (2020)

COVID-19 and mass incarceration: a call for urgent actionAs of September 23, 2020, the USA had both the highest number of COVID-19 cases and the largest incarcerated population in the world.Approximately 2•3 million people are currently incarcerated in prisons and jails in the USA.More than 6•5 million individuals are under daily correctional supervision, which includes probation and parole, representing 2•6% of the entire US adult population.Due to systemic racism, Black people have been disproportionately affected by mass incarceration and COVID-19.Nearly one-third of Black men will face imprisonment during their lifetime, 1 and Black communities have a markedly higher burden of COVID-19 cases and mortality than White populations. 2onsidering the inextricable link between the health of Black communities and the US criminal legal system, jails and prisons are uniquely positioned to advance health equity and community health, particularly during the ongoing response to the COVID-19 pandemic.Concurrently, the discrimination and criminalisation of additional stigmatised groups-including people who are poor, who use drugs, and those who have mental health disorders-have deepened and reinforced health disparities.Calls for deliberate anti-racist action have been made across the nation following the murders of George Floyd, Breonna Taylor, Jacob Blake, and countless others at the hands of police.Police brutality is culturally salient and demands our attention, however, it only represents a small proportion of the damage inflicted by the criminal legal system on Black communities.Stark racial differences in the relative number of police stops, arrests, plea deals, guilty verdicts, and time served are among the most obvious and profound examples of systemic racism in the USA today.Correspondingly, social justice movements to abolish these inequities will be ineffectual without close attention to the racial politics of imprisonment.Jails and prisons have been severely affected by the COVID-19 pandemic.In the USA, more than 40 of the 50 largest clustered outbreaks in the country have occurred in jails and prisons. 3Compared with the general population, the number of COVID-19 cases is 5•5 times higher among people who are incarcerated. 4However, racial disparities in testing and case rates remain
Functional analysis of human beta defensin-1 in prostate cancer
Authors: Jamila K. Belgrave, Rebecca S. Bullard, Willietta Gibson, Carlton D. Donald
Journal: Cancer Research (2004)

2682  Defensins are small 3-4 kDa peptides clustered on the short arm of chromosome 8 (segment 8p22-8p23) that have been shown to have antimicrobial activities. It has been demonstrated that there are chromosomal deletions in the 8pter-p23 regions in a variety of cancers including prostatic carcinoma. Additionally, there is a positive correlation between deletions in 8pter-p23 region and poor prognosis in prostate cancer. Furthermore, it has been postulated that there may be three separate potential tumor suppressor genes located in the 8pter-8p23 region. However, no specific gene has been identified and nothing is known about their function in prostate cancer. Human β-defensin-1 (hBD-1) is located at chromosome position 8p23.2. We have recently demonstrated that there is cancer-specific loss of hBD-1in malignant prostatic clinical samples, while high levels of expression are maintained in benign regions. Overall, 82% of prostate cancers exhibit either complete loss of hBD-1 protein expression or only minimal expression, while the adjacent benign epithelium retained expression in all cases. We report here the further characterization of hBD-1. In vitro functional analysis demonstrates that hBD-1 has cytotoxic activity against prostate cancer cells. These studies further suggest that hBD-1 may have tumor suppressive activities in cancer.
LT-171-861, a novel FLT3 inhibitor, shows excellent preclinical efficacy for the treatment of FLT3 mutant acute myeloid leukemia
Authors: Zhou Yu, Jiaying Du, Hui Hui, Shaoxin Kan, Tongxin Huo, Kai Zhao, Tao Wu, Qinglong Guo, Na Lu
Journal: Theranostics (2020)

Rationale: Acute myeloid leukemia (AML) is a common type of haematological malignancy. Several studies have shown that neoplasia in AML is enhanced by tyrosine kinase pathways. Recently, given that aberrant activation of Fms-like tyrosine receptor kinase 3 (FLT3) acts as a critical survival signal for cancer cells in 20‒30% patients with AML, inhibition of FLT3 may be a potential therapeutic strategy. Therefore, we identified LT-171-861, a novel kinase inhibitor with remarkable inhibitory activity against FLT3, in preclinical models of AML. Methods: We determined the inhibitory effects of LT-171-861 in vitro using AML cell lines and transformed BaF3 cells. Target engagement assays were used to verify the interaction between LT-171-861 and FLT3. Finally, a subcutaneous model and a bone marrow engrafted model were used to evaluate the antitumor effects of LT‑171‑861 in vivo. Results: Our data demonstrated that LT-171-861 had high affinity for FLT3 protein. We also showed that LT-171-861 had an inhibitory effect on FLT3 mutants in cellular assays. Moreover, LT-171-861 had a growth-inhibitory effect on human AML cell lines harboring FLT3 internal tandem duplications (FLT3-ITD) such as FLT3-D835Y, FLT3‑ITD-N676D, FLT3-ITD-D835Y, FLT3-ITD-F691L, FLT3-ITD-Y842C and AML blasts from patients with FLT3-ITD. Furthermore, LT-171-861 showed potent antileukemic efficacy against AML cells. We also show the efficacy of LT‑171-861 in a subcutaneous implantation model and a bone marrow engrafted model in vivo, where administration of LT-171-861 led to almost complete tumor regression and increased survival. Conclusions: Overall, this study not only identifies LT-171-861 as a potent FLT3 inhibitor, but also provides a rationale for the upcoming clinical trial of LT-171-861 in patients with AML and FLT3-ITD mutations.