tbuckley/cabot-search huggingface dataset:
Emulating interactions between microorganisms and tumor microenvironment to develop cancer theranostics
Authors: Tongmeng Jiang, Tao Yang, Yingfan Chen, Yao Miao, Yajing Xu, Honglin Jiang, Mingying Yang, Chuanbin Mao
Journal: Theranostics (2022)

The occurrence of microorganisms has been confirmed in the tumor microenvironment (TME) of many different organs.Microorganisms (e.g., phage, virus, bacteria, fungi, and protozoa) present in TME modulate TME to inhibit or promote tumor growth in species-dependent manners due to the special physiological and pathological features of each microorganism.Such microorganism-TME interactions have recently been emulated to turn microorganisms into powerful cancer theranostic agents.To facilitate scientists to explore microorganisms-TME interactions further to develop improved cancer theranostics, here we critically review the characteristics of different microorganisms that can be found in TME, their interactions with TME, and their current applications in cancer diagnosis and therapy.Clinical trials of using microorganisms for cancer theranostics are also summarized and discussed.Moreover, the emerging technology of whole-metagenome sequencing that can be employed to precisely determine microbiota spectra is described.Such technology enables scientists to gain an in-depth understanding of the species and distributions of microorganisms in TME.Therefore, scientists now have new tools to identify microorganisms (either naturally present in or introduced into TME) that can be used as effective probes, monitors, vaccines, or drugs for potentially advancing cancer theranostics to clinical applications.
Inhibition of WEE1 Is Effective in<i>TP53</i>- and<i>RAS</i>-Mutant Metastatic Colorectal Cancer: A Randomized Trial (FOCUS4-C) Comparing Adavosertib (AZD1775) With Active Monitoring
Authors: Jenny F. Seligmann, David J. Fisher, Louise C. Brown, Richard A. Adams, Janet Graham, Philip Quirke, Susan D. Richman, Rachel Butler, Enric Domingo, Andrew Blake, Emma Yates, Michael Braun, Fiona Collinson, Rob Jones, Ewan Brown, Emma de Winton, Timothy C. Humphrey, Mahesh Parmar, Richard Kaplan, Richard H. Wilson, Matthew Seymour, Timothy S. Maughan
Journal: Journal of Clinical Oncology (2021)

PURPOSE Outcomes in RAS-mutant metastatic colorectal cancer (mCRC) remain poor and patients have limited therapeutic options. Adavosertib is the first small-molecule inhibitor of WEE1 kinase. We hypothesized that aberrations in DNA replication seen in mCRC with both RAS and TP53 mutations would sensitize tumors to WEE1 inhibition. METHODS Patients with newly diagnosed mCRC were registered into FOCUS4 and tested for TP53 and RAS mutations. Those with both mutations who were stable or responding after 16 weeks of chemotherapy were randomly assigned 2:1 between adavosertib and active monitoring (AM). Adavosertib (250 mg or 300 mg) was taken orally once on days 1-5 and days 8-12 of a 3-week cycle. The primary outcome was progression-free survival (PFS), with a target hazard ratio (HR) of 0.5 and 80% power with a one-sided 0.025 significance level. RESULTS FOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) were RAS/TP53-mutant. Sixty-nine patients were randomly assigned from 25 UK hospitals (adavosertib = 44; AM = 25). Adavosertib was associated with a PFS improvement over AM (median 3.61 v 1.87 months; HR = 0.35; 95% CI, 0.18 to 0.68; P = .0022). Overall survival (OS) was not improved with adavosertib versus AM (median 14.0 v 12.8 months; HR = 0.92; 95% CI, 0.44 to 1.94; P = .93). In prespecified subgroup analysis, adavosertib activity was greater in left-sided tumors (HR = 0.24; 95% CI, 0.11 to 0.51), versus right-sided (HR = 1.02; 95% CI, 0.41 to 2.56; interaction P = .043). Adavosertib was well-tolerated; grade 3 toxicities were diarrhea (9%), nausea (5%), and neutropenia (7%). CONCLUSION In this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for RAS/TP53-mutant mCRC. Further testing is required in this sizable population of unmet need.
A diagonal and social protection plus approach to meet the challenges of the COVID-19 syndemic: cash transfers and intimate partner violence interventions in Latin America
Authors: Merike Blofield, Felicia M Knaul, Renzo Calderón-Anyosa, Amber Peterman, Juliana Martinez Franzoni, Megan O'Donnell, Flavia Bustreo
Journal: The Lancet Global Health (2021)

Latin America has been particularly hard hit by the COVID-19 syndemic, including the associated economic fallout that has threatened the livelihoods of most families. Social protection platforms and policies should have a crucial role in safeguarding individual and family wellbeing; however, the response has been insufficient to address the scale of the crisis. In this Viewpoint, we focus on two policy challenges of the COVID-19 syndemic: rapidly and effectively providing financial support to the many families that lost livelihoods, and responding to and mitigating the increased risk of intimate partner violence (IPV). We argue that building programmatic linkages between social protection platforms, particularly cash transfers, and IPV prevention, mitigation, and response services, creates synergies that can promote freedom from both poverty and violence.
Comparison of 6-Month Outcomes of Survivors of COVID-19 versus Non–COVID-19 Critical Illness
Authors: Carol L. Hodgson, Alisa M. Higgins, Michael J. Bailey, Anne M. Mather, Lisa Beach, Rinaldo Bellomo, Bernie Bissett, Ianthe J. Boden, Scott Bradley, Aidan Burrell, D. James Cooper, Bentley J. Fulcher, Kimberley J. Haines, Isabelle T. Hodgson, Jack Hopkins, Alice Y. M. Jones, Stuart Lane, Drew Lawrence, Lisa van der Lee, Jennifer Liacos, Natalie J. Linke, Lonni Marques Gomes, Marc Nickels, George Ntoumenopoulos, Paul S. Myles, Shane Patman, Michelle Paton, Gemma Pound, Sumeet Rai, Alana Rix, Thomas C. Rollinson, Claire J. Tipping, Peter Thomas, Tony Trapani, Andrew A. Udy, Christina Whitehead, Shannah Anderson, Ary Serpa Neto, Meredith Young, Jasmin Board, Phoebe McCracken, Emma-Leah Martin, Nicola Burgess, Kirsty Hearn, David Brewster, Alyssa Waanders, Shannon Simpson, Yasmin de Silva, Jonathon Barrett, Gabrielle Hanlon, Jenna Lang, Sarah Burleigh, Elisha Killer, Michael Wang, Lauren O’Connor, Lauren Thomas, Lucy Dennis, Joanna Caruana, Wisam Al-Bassam, Morag Shealy, Marianne Chapman, Stephanie O’Connor, Janne Sheehan, Emily Alexander, Amanda Sukkar, Liesl Davis, Francis Bass, Naomi Hammond, Anne O’Connor, Elizabeth Yarad, Richard Totaro, Heidi Buhr, Nazmeen Reddy, Wendy Chaseling, Kelvin Ip, Oystein Tronstad, Alison Mahoney, Cadi Fanning, Hariette Esterman, Alexia Kozary, Bronte Scott
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

The outcomes of survivors of critical illness due to coronavirus disease (COVID-19) compared with non-COVID-19 are yet to be established.
Combined noncanonical NF-κB agonism and targeted BET bromodomain inhibition reverse HIV latency ex vivo
Authors: Shane D. Falcinelli, Jackson J. Peterson, Anne-Marie W. Turner, David Irlbeck, Jenna Read, Samuel L.M. Raines, Katherine S. James, Cameron Sutton, Anthony Sanchez, Ann Emery, Gavin Sampey, Robert Ferris, Brigitte Allard, Simon Ghofrani, Jennifer L. Kirchherr, Caroline Baker, JoAnn D. Kuruc, Cynthia L. Gay, Lindsey I. James, Guoxin Wu, Paul Zuck, Inmaculada Rioja, Rebecca C. Furze, Rab K. Prinjha, Bonnie J. Howell, Ronald Swanstrom, Edward P. Browne, Brian D. Strahl, Richard M. Dunham, Nancie M. Archin, David M. Margolis
Journal: Journal of Clinical Investigation (2022)

Latency reversal strategies for HIV cure using inhibitor of apoptosis protein (IAP) antagonists (IAPi) induce unprecedented levels of latent reservoir expression without immunotoxicity during suppressive antiretroviral therapy (ART). However, full targeting of the reservoir may require combinatorial approaches. A Jurkat latency model screen for IAPi combination partners demonstrated synergistic latency reversal with bromodomain (BD) and extraterminal domain protein inhibitors (BETi). Mechanistic investigations using CRISPR-CAS9 and single-cell RNA-Seq informed comprehensive ex vivo evaluations of IAPi plus pan-BET, bD-selective BET, or selective BET isoform targeting in CD4+ T cells from ART-suppressed donors. IAPi+BETi treatment resulted in striking induction of cell-associated HIV gag RNA, but lesser induction of fully elongated and tat-rev RNA compared with T cell activation–positive controls. IAPi+BETi resulted in HIV protein induction in bulk cultures of CD4+ T cells using an ultrasensitive p24 assay, but did not result in enhanced viral outgrowth frequency using a standard quantitative viral outgrowth assay. This study defines HIV transcriptional elongation and splicing as important barriers to latent HIV protein expression following latency reversal, delineates the roles of BET proteins and their BDs in HIV latency, and provides a rationale for exploration of IAPi+BETi in animal models of HIV latency.
Optimising the water we eat—rethinking policy to enhance productive and sustainable use of water in agri-food systems across scales
Authors: Stefan Uhlenbrook, Winston Yu, Petra Schmitter, Douglas Mark Smith
Journal: The Lancet Planetary Health (2022)

Sustainable and resilient food systems depend on sustainable and resilient water management. Resilience is characterised by overlapping decision spaces and scales and interdependencies among water users and competing sectors. Increasing water scarcity, due to climate change and other environmental and societal changes, makes putting caps on the consumption of water resources indispensable. Implementation requires an understanding of different domains, actors, and their objectives, and drivers and barriers to transformational change. We suggest a scale-specific approach, in which agricultural water use is embedded in a larger systems approach (including natural and human systems). This approach is the basis for policy coherence and the design of effective incentive schemes to change agricultural water use behaviour and, therefore, optimise the water we eat.
Predicting the mutational drivers of future SARS-CoV-2 variants of concern
Authors: M. Cyrus Maher, Istvan Bartha, Steven Weaver, Julia di Iulio, Elena Ferri, Leah Soriaga, Florian A. Lempp, Brian L. Hie, Bryan Bryson, Bonnie Berger, David L. Robertson, Gyorgy Snell, Davide Corti, Herbert W. Virgin, Sergei L. Kosakovsky Pond, Amalio Telenti
Journal: Science Translational Medicine (2022)

SARS-CoV-2 evolution threatens vaccine- and natural infection-derived immunity as well as the efficacy of therapeutic antibodies. To improve public health preparedness, we sought to predict which existing amino acid mutations in SARS-CoV-2 might contribute to future variants of concern. We tested the predictive value of features comprising epidemiology, evolution, immunology, and neural network-based protein sequence modeling, and identified primary biological drivers of SARS-CoV-2 intra-pandemic evolution. We found evidence that ACE2-mediated transmissibility and resistance to population-level host immunity has waxed and waned as a primary driver of SARS-CoV-2 evolution over time. We retroactively identified with high accuracy (area under the receiver operator characteristic curve, AUROC=0.92-0.97) mutations that will spread, at up to four months in advance, across different phases of the pandemic. The behavior of the model was consistent with a plausible causal structure wherein epidemiological covariates combine the effects of diverse and shifting drivers of viral fitness. We applied our model to forecast mutations that will spread in the future and characterize how these mutations affect the binding of therapeutic antibodies. These findings demonstrate that it is possible to forecast the driver mutations that could appear in emerging SARS-CoV-2 variants of concern. We validate this result against Omicron, showing elevated predictive scores for its component mutations prior to emergence, and rapid score increase across daily forecasts during emergence. This modeling approach may be applied to any rapidly evolving pathogens with sufficiently dense genomic surveillance data, such as influenza, and unknown future pandemic viruses.
ALKBH5 Facilitates Hypoxia-Induced Paraspeckle Assembly and IL8 Secretion to Generate an Immunosuppressive Tumor Microenvironment
Authors: Feng Dong, Xiaoyang Qin, Baofeng Wang, Qian Li, Jinyang Hu, Xuan Cheng, Dongsheng Guo, Fangling Cheng, Chuan Fang, Yanli Tan, Han Yan, You He, Xiaoyu Sun, Ye Yuan, Hang Liu, Ting Li, Yingying Zhao, Chunsheng Kang, Xudong Wu
Journal: Cancer Research (2021)

The dynamic changes of RNA N6-methyl-adenosine (m6A) during cancer progression contribute to quick adaption to microenvironmental changes. Here, we profiled the cancer cell m6A dynamics in the hypoxic tumor niche and its pathological consequences in glioblastoma multiforme (GBM). The m6A demethylase ALKBH5 was induced in GBM models under hypoxic conditions and was associated with a hypoxic gene signature in GBM patient samples. Depletion or inactivation of ALKBH5 in GBM cells significantly suppressed hypoxia-induced tumor-associated macrophage (TAM) recruitment and immunosuppression in allograft tumors. Expression and secretion of CXCL8/IL8 were significantly suppressed in ALKBH5-deficient tumors. However, ALKBH5 did not regulate CXCL8 m6A directly. Instead, hypoxia-induced ALKBH5 erased m6A deposition from the lncRNA NEAT1, stabilizing the transcript and facilitating NEAT1-mediated paraspeckle assembly, which led to relocation of the transcriptional repressor SFPQ from the CXCL8 promoter to paraspeckles and, ultimately, upregulation of CXCL8/IL8 expression. Accordingly, ectopic expression of CXCL8 in ALKBH5-deficient GBM cells partially restored TAM recruitment and tumor progression. Together, this study links hypoxia-induced epitranscriptomic changes to the emergence of an immunosuppressive microenvironment facilitating tumor evasion. SIGNIFICANCE: Hypoxia induces tumor immune microenvironment remodeling through an ALKBH5-mediated epigenetic and epitranscriptomic mechanism, providing potential immunotherapeutic strategies for treating glioblastoma.
Replication of SARS-CoV-2 in adipose tissue determines organ and systemic lipid metabolism in hamsters and humans
Authors: Martin Zickler, Stephanie Stanelle-Bertram, Sandra Ehret, Fabian Heinrich, Philine Lange, Berfin Schaumburg, Nancy Mounogou Kouassi, Sebastian Beck, Michelle Y Jaeckstein, Oliver Mann, Susanne Krasemann, Maria Schroeder, Dominik Jarczak, Axel Nierhaus, Stefan Kluge, Manuela Peschka, Hartmut Schlüter, Thomas Renné, Klaus Pueschel, Andreas Kloetgen, Ludger Scheja, Benjamin Ondruschka, Joerg Heeren, Guelsah Gabriel
Journal: Cell Metabolism (2021)
Abstract 11631: A Critical Role of Parathyroid Hormone in the Development of Pulmonary Hypertension
Authors: Yusuke Joki, Hakuoh Konishi, Kiyoshi Takasu, Tohru Minamino
Journal: Circulation (2021)

Background: Pulmonary hypertension (PH) is characterized by increased pulmonary artery pressure and develops right heart failure. Parathyroid hormone (PTH) is secreted from parathyroid gland and play a critical role in calcium homeostasis. Recent studies have suggested that PTH also acts on the cardiovascular system and affects cardiovascular prognosis. We hypothesized that PTH would play a role in the pathogenesis of PH. Object: This study aimed to investigate the effect of PTH on pulmonary hemodynamics. Method: We measured serum PTH levels in patients who were suspected of PH and underwent right heart catheter examination. We used two types of PH animal models, hypoxia (Hx)-induced PH mouse model and Sugen/hypoxia (SuHx)-induced PH rat model. Hx mice were administered PTH daily for 3 weeks. SuHx rats underwent parathyroidectomy, after which they received SuHx treatment for 10weeks. We measured physical data and right ventricular systolic pressure (RVSP) in these models. We cultured pulmonary artery smooth muscle cell (PASMC) treated with PTH to analyze cell signaling, proliferation and migration. Result: We enrolled 20 participants. PTH concentration was significantly correlated with mean pulmonary artery pressure and pulmonary vascular resistance. PTH treatment exacerbated right ventricular hypertrophy and increased RVSP (33.6mmHg vs. 48.2mmHg) in Hx mice compared with non-treated Hx mice(Figure). Conversely, parathyroidectomy significantly attenuated right ventricular hypertrophy and reduced RVSP (54.2mmHg vs. 29.3mmHg) in SuHx rats compared with sham-operated SuHx rats. PTH promoted migration and proliferation through ERK signaling in PASMC. Conclusion: Our clinical and experimental data demonstrated a critical role of PTH in the development of PH and suggested that PTH would be a novel therapeutic target for PH treatment.
Cigarette smoke promotes colorectal cancer through modulation of gut microbiota and related metabolites
Authors: Xiaowu Bai, Hong Wei, Weixin Liu, Olabisi Oluwabukola Coker, Hongyan Gou, Changan Liu, Liuyang Zhao, Chuangen Li, Yunfei Zhou, Guoping Wang, Wei Kang, Enders Kwok-wai Ng, Jun Yu
Journal: Gut (2022)

Objective Cigarette smoking is a major risk factor for colorectal cancer (CRC). We aimed to investigate whether cigarette smoke promotes CRC by altering the gut microbiota and related metabolites. Design Azoxymethane-treated C57BL/6 mice were exposed to cigarette smoke or clean air 2 hours per day for 28 weeks. Shotgun metagenomic sequencing and liquid chromatography mass spectrometry were parallelly performed on mice stools to investigate alterations in microbiota and metabolites. Germ-free mice were transplanted with stools from smoke-exposed and smoke-free control mice. Results Mice exposed to cigarette smoke had significantly increased tumour incidence and cellular proliferation compared with smoke-free control mice. Gut microbial dysbiosis was observed in smoke-exposed mice with significant differential abundance of bacterial species including the enrichment of Eggerthella lenta and depletion of Parabacteroides distasonis and Lactobacillus spp. Metabolomic analysis showed increased bile acid metabolites, especially taurodeoxycholic acid (TDCA) in the colon of smoke-exposed mice. We found that E. lenta had the most positive correlation with TDCA in smoke-exposed mice. Moreover, smoke-exposed mice manifested enhanced oncogenic MAPK/ERK (mitogen-activated protein kinase/extracellular signal‑regulated protein kinase 1/2) signalling (a downstream target of TDCA) and impaired gut barrier function. Furthermore, germ-free mice transplanted with stools from smoke-exposed mice (GF-AOMS) had increased colonocyte proliferation. Similarly, GF-AOMS showed increased abundances of gut E. lenta and TDCA, activated MAPK/ERK pathway and impaired gut barrier in colonic epithelium. Conclusion The gut microbiota dysbiosis induced by cigarette smoke plays a protumourigenic role in CRC. The smoke-induced gut microbiota dysbiosis altered gut metabolites and impaired gut barrier function, which could activate oncogenic MAPK/ERK signalling in colonic epithelium.
The ZIP8/SIRT1 axis regulates alveolar progenitor cell renewal in aging and idiopathic pulmonary fibrosis
Authors: Jiurong Liang, Guanling Huang, Xue Liu, Forough Taghavifar, Ningshan Liu, Yizhou Wang, Nan Deng, Changfu Yao, Ting Xie, Vrishika Kulur, Kristy Dai, Ankita Burman, Simon C. Rowan, S. Samuel Weigt, John Belperio, Barry Stripp, William C. Parks, Dianhua Jiang, Paul W. Noble
Journal: Journal of Clinical Investigation (2022)

Type 2 alveolar epithelial cells (AEC2s) function as progenitor cells in the lung. We have shown previously that failure of AEC2 regeneration results in progressive lung fibrosis in mice and is a cardinal feature of idiopathic pulmonary fibrosis (IPF). In this study, we identified deficiency of a specific zinc transporter, SLC39A8 (ZIP8), in AEC2s from both IPF lungs and lungs of old mice. Loss of ZIP8 expression was associated with impaired renewal capacity of AEC2s and enhanced lung fibrosis. ZIP8 regulation of AEC2 progenitor function was dependent on SIRT1. Replenishment with exogenous zinc and SIRT1 activation promoted self-renewal and differentiation of AEC2s from lung tissues of IPF patients and old mice. Deletion of Zip8 in AEC2s in mice resulted in impaired AEC2 renewal, increased susceptibility to bleomycin injury, and development of spontaneous lung fibrosis. Therapeutic strategies to restore zinc metabolism and appropriate SIRT1 signaling could improve AEC2 progenitor function and mitigate ongoing fibrogenesis.
Development and validation of BLOOMY prediction scores for 14-day and 6-month mortality in hospitalised adults with bloodstream infections: a multicentre, prospective, cohort study
Authors: Evelina Tacconelli, Siri Göpel, Beryl P Gladstone, Simone Eisenbeis, Florian Hölzl, Michael Buhl, Anna Górska, Chiara Cattaneo, Alexander Mischnik, Siegbert Rieg, Anna M Rohde, Britta Kohlmorgen, Jane Falgenhauer, Janina Trauth, Nadja Käding, Evelyn Kramme, Lena M Biehl, Sarah V Walker, Silke Peter, Petra Gastmeier, Trinad Chakraborty, Maria JGT Vehreschild, Harald Seifert, Jan Rupp, Winfried V Kern, Elke Lemke, Norbert Thoma, Solvy Wolke, Can Imirzalioglu, Susanne Herold, Nicole Tewes, Moritz Fritzenwanker, Jörg Janne Vehreschild, Annika Yanina Classen, David Tobys, Paul Higgins, Yannic Blum, Matthias Kleipaß, Lisa Höltig, Katharina Nagel, Kristina Schmauder, Larissa Künstle, Elisabeth Stoll, Ariane Gertraud Dinkelacker, Gabriele Peyerl-Hoffmann, Georg Häcker, Heike Spitznagel, Sara Christina Olawumi-Hurter
Journal: The Lancet Infectious Diseases (2022)
The Need for New Treatments Targeting MPNST: The Potential of Strategies Combining MEK Inhibitors with Antiangiogenic Agents
Authors: Teresa González-Muñoz, AeRang Kim, Nancy Ratner, Héctor Peinado
Journal: Clinical Cancer Research (2022)

Abstract Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft-tissue sarcomas that represent an important clinical challenge, particularly given their strong tendency to relapse and metastasize and their relatively poor response to conventional therapies. To date, targeted, noncytotoxic treatments have demonstrated limited clinical success with MPNSTs, highlighting the need to explore other key pathways to find novel, improved therapeutic approaches. Here, we review evidence supporting the crucial role of the RAS/MEK/ERK pathway and angiogenesis in MPNST pathogenesis, and we focus on the potential of therapies targeting these pathways to treat this disease. We also present works suggesting that the combination of MEK inhibitors and antiangiogenic agents could represent a promising therapeutic strategy to manage MPNSTs. In support of this notion, we discuss the preclinical rational and clinical benefits of this combination therapy in other solid tumor types. Finally, we describe other emerging therapeutic approaches that could improve patient outcomes in MPNSTs, such as immune-based therapies.
Population Prevalence of Hypercapnic Respiratory Failure from Any Cause
Authors: Yewon Chung, Frances L. Garden, Guy B. Marks, Hima Vedam
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Population Prevalence of Hypercapnic Respiratory Failure from Any Cause." American Journal of Respiratory and Critical Care Medicine, 205(8), pp. 966–967
Donor and recipient polygenic risk scores influence the risk of post-transplant diabetes
Authors: Abraham Shaked, Bao-Li Loza, Elisabet Van Loon, Kim M. Olthoff, Weihua Guan, Pamala A. Jacobson, Andrew Zhu, Claire E. Fishman, Hui Gao, William S. Oetting, Ajay K. Israni, Giuliano Testa, James Trotter, Goran Klintmalm, Maarten Naesens, Sumeet K. Asrani, Brendan J. Keating
Journal: Nature Medicine (2022)