tbuckley/cabot-search huggingface dataset:
A microbiome-directed therapeutic food for children recovering from severe acute malnutrition
Authors: Steven J. Hartman, Matthew C. Hibberd, Ishita Mostafa, Nurun N. Naila, Md. Munirul Islam, Mahabub Uz Zaman, Sayeeda Huq, Mustafa Mahfuz, Md. Tazul Islam, Kallol Mukherji, Vaha Akbary Moghaddam, Robert Y. Chen, Michael A. Province, Daniel M. Webber, Suzanne Henrissat, Bernard Henrissat, Nicolas Terrapon, Dmitry A. Rodionov, Andrei L. Osterman, Michael J. Barratt, Tahmeed Ahmed, Jeffrey I. Gordon
Journal: Science Translational Medicine (2024)

Globally, severe acute malnutrition (SAM), defined as a weight-for-length z -score more than three SDs below a reference mean (WLZ &lt; −3), affects 14 million children under 5 years of age. Complete anthropometric recovery after standard, short-term interventions is rare, with children often left with moderate acute malnutrition (MAM; WLZ −2 to −3). We conducted a randomized controlled trial (RCT) involving 12- to 18-month-old Bangladeshi children from urban and rural sites, who, after initial hospital-based treatment for SAM, received a 3-month intervention with a microbiome-directed complementary food (MDCF-2) or a calorically more dense, standard ready-to-use supplementary food (RUSF). The rate of WLZ improvement was significantly greater in MDCF-2–treated children ( P = 8.73 × 10 −3 ), similar to our previous RCT of Bangladeshi children with MAM without antecedent SAM ( P = 0.032). A correlated meta-analysis of plasma levels of 4520 proteins in both RCTs revealed 215 positively associated with WLZ (largely representing musculoskeletal and central nervous system development) and 44 negatively associated (primarily related to immune activation). Moreover, the positively associated proteins were significantly enriched by MDCF-2 ( q = 1.1 × 10 −6 ). Characterizing the abundances of 754 bacterial metagenome-assembled genomes in serially collected fecal samples disclosed the effects of acute rehabilitation for SAM on the microbiome and how, during treatment for MAM, specific strains of Prevotella copri function at the intersection between MDCF-2 glycan metabolism and anthropometric recovery. These results provide a rationale for further testing the generalizability of MDCF efficacy and for identifying biomarkers to define treatment responses.
LRRK2 regulates production of reactive oxygen species in cell and animal models of Parkinson’s disease
Authors: Matthew T. Keeney, Emily M. Rocha, Eric K. Hoffman, Kyle Farmer, Roberto Di Maio, Julie Weir, Weston G. Wagner, Xiaoping Hu, Courtney L. Clark, Sandra L. Castro, Abigail Scheirer, Marco Fazzari, Briana R. De Miranda, Sean A. Pintchovski, William D. Shrader, Patrick J. Pagano, Teresa G. Hastings, J. Timothy Greenamyre
Journal: Science Translational Medicine (2024)

Oxidative stress has long been implicated in Parkinson’s disease (PD) pathogenesis, although the sources and regulation of reactive oxygen species (ROS) production are poorly defined. Pathogenic mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are associated with increased kinase activity and a greater risk of PD. The substrates and downstream consequences of elevated LRRK2 kinase activity are still being elucidated, but overexpression of mutant LRRK2 has been associated with oxidative stress, and antioxidants reportedly mitigate LRRK2 toxicity. Here, using CRISPR-Cas9 gene-edited HEK293 cells, RAW264.7 macrophages, rat primary ventral midbrain cultures, and PD patient–derived lymphoblastoid cells, we found that elevated LRRK2 kinase activity was associated with increased ROS production and lipid peroxidation and that this was blocked by inhibitors of either LRRK2 kinase or NADPH oxidase 2 (NOX2). Oxidative stress induced by the pesticide rotenone was ameliorated by LRRK2 kinase inhibition and was absent in cells devoid of LRRK2. In a rat model of PD induced by rotenone, a LRRK2 kinase inhibitor prevented the lipid peroxidation and NOX2 activation normally seen in nigral dopaminergic neurons in this model. Mechanistically, LRRK2 kinase activity was shown to regulate phosphorylation of serine-345 in the p47 phox subunit of NOX2. This, in turn, led to translocation of p47 phox from the cytosol to the membrane-associated gp91 phox (NOX2) subunit, activation of the NOX2 enzyme complex, and production of ROS. Thus, LRRK2 kinase activity may drive cellular ROS production in PD through the regulation of NOX2 activity.
A peptide encoded by upstream open reading frame of <i>MYC</i> binds to tropomyosin receptor kinase B and promotes glioblastoma growth in mice
Authors: Fanying Li, Kailin Yang, Xinya Gao, Maolei Zhang, Danling Gu, Xujia Wu, Chenfei Lu, Qiulian Wu, Deobrat Dixit, Ryan C. Gimple, Yongping You, Stephen C. Mack, Yu Shi, Tiebang Kang, Sameer A. Agnihotri, Michael D. Taylor, Jeremy N. Rich, Nu Zhang, Xiuxing Wang
Journal: Science Translational Medicine (2024)

MYC promotes tumor growth through multiple mechanisms. Here, we show that, in human glioblastomas, the variant MYC transcript encodes a 114–amino acid peptide, MYC pre-mRNA encoded protein (MPEP), from the upstream open reading frame (uORF) MPEP . Secreted MPEP promotes patient-derived xenograft tumor growth in vivo, independent of MYC through direct binding, and activation of tropomyosin receptor kinase B (TRKB), which induces downstream AKT-mTOR signaling. Targeting MPEP through genetic ablation reduced growth of patient-derived 4121 and 3691 glioblastoma stem cells. Administration of an MPEP-neutralizing antibody in combination with a small-molecule TRKB inhibitor reduced glioblastoma growth in patient-derived xenograft tumor–bearing mice. The overexpression of MPEP in surgical glioblastoma specimens predicted a poor prognosis, supporting its clinical relevance. In summary, our results demonstrate that tumor-specific translation of a MYC -associated uORF promotes glioblastoma growth, suggesting a new therapeutic strategy for glioblastoma.
Phase Ib Study for the Combination of Doxorubicin, Dacarbazine, and Nivolumab as the Upfront Treatment in Patients With Advanced Leiomyosarcoma: A Study by the Spanish Sarcoma Group (GEIS)
Authors: Javier Martin-Broto, Roberto Diaz-Beveridge, David Moura, Rafael Ramos, Javier Martinez-Trufero, Irene Carrasco, Ana Sebio, Enrique González-Billalabeitia, Antonio Gutierrez, Javier Fernandez-Jara, Laura Hernández-Vargas, Josefina Cruz, Claudia Valverde, Nadia Hindi
Journal: Journal of Clinical Oncology (2024)

PURPOSE Doxorubicin, alongside a select group of cytotoxic agents, is capable of inducing an adaptive immune response via a well-established peculiar type of tumor cell death called immunogenic cell death (ICD). We hypothesize that combining doxorubicin and dacarbazine with nivolumab may enhance therapeutic efficacy by exerting synergy in the ICD circuit. We hereby present a phase Ib trial with this combination. PATIENTS AND METHODS Patients with advanced leiomyosarcoma and anthracycline-naïve were eligible. The initial dose level consisted of doxorubicin 75 mg/m 2 once on day 1, once every three weeks, followed by dacarbazine 400 mg/m 2 once on days 1 and 2, once every three weeks, plus nivolumab 360 mg once on day 2, once every 3 weeks, for six courses and then 1 year of nivolumab. A (–1) dose level was the same regimen but with nivolumab 240 mg. A classic 3 + 3 phase-I design was used to determine the recommended phase-II dose (RP2D). Secondary end points included overall response rate, safety profile, survival, and translational research. RESULTS From January 2002 to July 2023, 24 patients were enrolled and 23 were evaluable for efficacy, excluding one patient because of noncompliant dose. All patients were treated with the initial dose level, then the RP2D. Toxicity was mild, with the most frequent being grade 4 toxicity neutropenia (16.7%) and thrombocytopenia (8.3%), while no grade 5 toxicity occurred. The centrally reviewed objective response rate was as follows: partial response 56.5%, stable disease 39.1%, and progression 4.4%. The 6-month progression-free survival (PFS) rate was 80% (95% CI, 63 to 98). Dynamic increases of HMGB1 in blood significantly correlated with longer PFS. CONCLUSION This scheme of doxorubicin, dacarbazine, and nivolumab is feasible and well tolerated. Clinical activity is encouraging and the prognostic impact of HMGB1 supports the relevance of ICD activation. Further clinical research is already underway with this concept in leiomyosarcoma.
Cancer Immunotherapy Trials Network 12: Pembrolizumab in HIV-Associated Kaposi Sarcoma
Authors: Kathryn Lurain, Ramya Ramaswami, Irene Ekwede, Vanessa Eulo, Gaurav Goyal, Manoj Menon, Thomas A. Odeny, Elad Sharon, Michael J. Wagner, Chia-Ching (Jackie) Wang, Nina Bhardwaj, Philip A. Friedlander, Maher Abdul-Hay, Elena M. Cornejo Castro, Nazzarena Labo, Vickie Ann Marshall, Wendell Miley, Kyle Moore, Romin Roshan, Denise Whitby, Angela Shaulov Kask, Judith Kaiser, Emma Han, Anna Wright, Robert Yarchoan, Steven P. Fling, Thomas S. Uldrick
Journal: Journal of Clinical Oncology (2024)

PURPOSE Cancer Immunotherapy Trials Network 12 demonstrated safety of pembrolizumab in treating advanced cancer in people with HIV. Here, we report results of the Kaposi sarcoma (KS) cohort. METHODS In this multicenter phase I trial, we enrolled participants with HIV-associated KS on antiretroviral therapy with CD4 + ≥50 cells/μL and HIV plasma RNA &lt;200 copies/mL. Pembrolizumab 200 mg intravenously was administered once every 3 weeks for up to 35 cycles. The primary end point was safety, and the secondary end point was KS response by modified AIDS Clinical Trials Group Criteria. RESULTS Thirty-two cisgender men enrolled with baseline median CD4 + T-cell count of 274 cells/µL. All but nine participants had received previous systemic KS therapy. Participants received a median of 11 cycles of pembrolizumab (range, 1-35). Sixty-six percent had grade ≥1 treatment-emergent adverse events, including one death from polyclonal KS herpesvirus–related B-cell lymphoproliferation. Thirty-one percent had ≥one immune-mediated AEs (imAEs) with 25% requiring systemic steroids. In 29 participants with evaluable KS, the overall response rate (ORR) was 62.1% (95% CI, 42.3 to 79.3) and did not differ by CD4 + T-cell count. ORR in the eight participants with evaluable disease without previous KS therapy was 87.5% (95% CI, 47.3 to 99.7). Median duration of response (DOR) was not reached, and the Kaplan-Meier estimate of DOR of ≥12 months was 92.3% (95% CI, 56.6 to 98.8). Median progression-free survival was 28.2 months (95% CI, 4.2 to noncalculable). CONCLUSION Pembrolizumab yielded a high rate of durable responses in HIV-associated KS. imAEs were successfully managed with standard guidelines.
Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis: One Decade Later
Authors: Larissa Nekhlyudov, Laura A. Levit, Patricia A. Ganz
Journal: Journal of Clinical Oncology (2024)

In 2012, the National Academies of Sciences, Engineering, and Medicine convened a committee charged with addressing the quality of cancer care in the United States and providing recommendations to policymakers and the cancer care community on strategies to improve cancer care delivery from the time of diagnosis through end-of-life. The resulting committee report, titled Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis (2013), presented a conceptual framework that included six interconnected components of care with corresponding recommendations. Over the past decade, the delivery of high-quality of cancer care has become more challenging and increasingly demanding on the workforce. In this manuscript, we review the goals and recommendations made in 2013, describe progress to date, and offer insights into future dedicated efforts and/or new strategies needed to achieve high-quality cancer care.
Long-Term Risk of Subsequent Neoplasms in 5-Year Survivors of Childhood Neuroblastoma: A Dutch Childhood Cancer Survivor Study-LATER 3 Study
Authors: Aimée S.R. Westerveld, Godelieve A.M. Tytgat, Hanneke M. van Santen, Max M. van Noesel, Jacqueline Loonen, Andrica C.H. de Vries, Marloes Louwerens, Maria M.W. Koopman, Margriet van der Heiden-van der Loo, Geert O. Janssens, Ronald R. de Krijger, Cecile M. Ronckers, Helena J.H. van der Pal, Leontien C.M. Kremer, Jop C. Teepen
Journal: Journal of Clinical Oncology (2024)

PURPOSE Neuroblastoma survivors have an increased risk of developing subsequent malignant neoplasms (SMNs), but the risk of subsequent nonmalignant neoplasms (SNMNs) and risk factors are largely unknown. We analyzed the long-term risks and associated risk factors for developing SMNs and SNMNs in a well-characterized cohort of 5-year neuroblastoma survivors. METHODS We included 563 5-year neuroblastoma survivors from the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER cohort, diagnosed during 1963-2014. Subsequent neoplasms were ascertained by linkages with the Netherlands Cancer Registry and the Dutch Nationwide Pathology Databank (Palga) and medical chart review. We calculated standardized incidence ratios (SIRs), absolute excess risk (AER), and cumulative incidences. Multivariable competing risk regression analysis was used to evaluate risk factors. RESULTS In total, 23 survivors developed an SMN and 60 an SNMN. After a median follow-up of 23.7 (range, 5.0-56.3) years, the risk of SMN was elevated compared with the general population (SIR, 4.0; 95% CI, 2.5 to 5.9; AER per 10,000 person-years, 15.1). The 30-year cumulative incidence was 3.4% (95% CI, 1.9 to 6.0) for SMNs and 10.4% (95% CI, 7.3 to 14.8) for SNMNs. Six survivors developed an SMN after iodine-metaiodobenzylguanidine ( 131I MIBG) treatment. Survivors treated with 131I MIBG had a higher risk of developing SMNs (subdistribution hazard ratio [SHR], 5.7; 95% CI, 1.8 to 17.8) and SNMNs (SHR, 2.6; 95% CI, 1.2 to 5.6) compared with survivors treated without 131I MIBG; results for SMNs were attenuated in high-risk patients only (SMNs SHR, 3.6; 95% CI, 0.9 to 15.3; SNMNs SHR, 1.5; 95% CI, 0.7 to 3.6). CONCLUSION Our results demonstrate that neuroblastoma survivors have an elevated risk of developing SMNs and a high risk of SNMNs. 131I MIBG may be a treatment-related risk factor for the development of SMN and SNMN, which needs further validation. Our results emphasize the need for awareness of subsequent neoplasms and the importance of follow-up care.
Association of Participation in Medicare's Oncology Care Model With Spending, Utilization, and Quality Outcomes Among Commercially Insured and Medicare Advantage Members
Authors: Samyukta Mullangi, Benjamin Ukert, Andrea Devries, David Debono, Jason Santos, Michael J. Fisch, Stephen M. Schleicher, Amol S. Navathe, Justin E. Bekelman, Aaron L. Schwartz, Ravi B. Parikh
Journal: Journal of Clinical Oncology (2024)

PURPOSE The Oncology Care Model (OCM), a value-based payment model for traditional Medicare beneficiaries with cancer, yielded total spending reductions that were outweighed by incentive payments, resulting in net losses to the Centers for Medicare &amp; Medicaid Services. We studied whether the OCM yielded spillover effects in total episode spending, utilization, and quality among commercially insured and Medicare Advantage (MA) members, who were not targeted by the program. PATIENTS AND METHODS This observational study used administrative claims from a large national payer, yielding 157,189 total patients with commercial insurance or MA with solid malignancies who initiated 229,376 systemic anticancer therapy episodes before (2012-2015) and during (2016-2021) the OCM at 125 OCM-participating practices (a subset of total OCM practices) and a 1:10 propensity-matched set of 860 non-OCM practices. We used difference-in-differences analyses to assess the association between the OCM and total episode spending, defined as medical spending during a 6-month episode. Secondary outcomes included hospitalization and emergency department (ED) utilization and quality measures. RESULTS From the pre-OCM to the OCM period, mean total episode payments increased from $45,504 in US dollars (USD) to $46,239 USD for OCM-participating practices, and increased from $50,519 USD to $58,591 USD for non-OCM practices (adjusted difference-in-differences –$6,287 USD [95% CI, –$10,076 USD to –$2,498 USD], P = .001). The OCM was associated with adjusted spending decreases for both high-risk (–$6,756 USD [95% CI, –$10,731 USD to –$2,781 USD], P = .001) and low-risk (–$4,171 USD [95% CI, –$7,799 USD to –$543 USD], P = .025) episodes. OCM-associated spending reductions were strongest for outpatient (–$5,243 USD [95% CI, –$8,589 USD to –$1,897 USD], P = .002) and infused/injected anticancer drug (–$3,031 USD [95% CI, –$5,193 USD to –$869 USD], P = .006) spending. There were no associations between OCM participation and changes in hospital or ED utilization nor quality of care. CONCLUSION The OCM was associated with reductions in spending for nontargeted members, a spillover effect.
Aggressive Lymphoma after CD19 CAR T-Cell Therapy
Authors: Guido Kobbe, Monika Brüggemann, Ben-Niklas Baermann, Laura Wiegand, Heiko Trautmann, Schayan Yousefian, Silvana Libertini, Hans D. Menssen, Harald J. Maier, Peter Ulrich, Jingbo Gao, Peter-Martin Bruch, Nora Liebers, Aleksandar Radujkovic, Marc Seifert, Christina Schniederjohann, Nagarajan Paramasivam, Donnacha Fitzgerald, Maximilian Seidel, Irene Esposito, Ulrich Germing, Ron-Patrick Cadeddu, Kathrin Nachtkamp, Paul Jäger, Thomas Ulrych, Johannes C. Fischer, Jutta M. Rox, Frederik Giesel, Raphael Koch, Gerald Antoch, Jörg H.W. Distler, Sven G. Meuth, Malte Jacobsen, Daniel Hübschmann, Junyan Lu, Ingram Iaccarino, Simon Haas, Frederik Damm, Sascha Dietrich
Journal: New England Journal of Medicine (2024)

The development of a fatal, clonal, autonomously proliferating CD4-CD8- chimeric antigen receptor (CAR)+ peripheral T-cell lymphoma (PTCL) occurred 1 month after a patient received treatment with tisagenlecleucel for relapsed primary central nervous system lymphoma. The PTCL had a clonal T-cell receptor rearrangement, which was already detectable in the apheresis product for CAR T-cell manufacturing and 7 months earlier for autologous transplantation. Somatic
Standard or Extended Lymphadenectomy for Muscle-Invasive Bladder Cancer
Authors: Seth P. Lerner, Catherine Tangen, Robert S. Svatek, Siamak Daneshmand, Kamal S. Pohar, Eila Skinner, Anne Schuckman, Arthur I. Sagalowsky, Norm D. Smith, Ashish M. Kamat, Wassim Kassouf, Melissa Plets, Rick Bangs, Theresa M. Koppie, Ajjai Alva, Francisco G. La Rosa, Sumanta K. Pal, Adam S. Kibel, Daniel J. Canter, Ian M. Thompson
Journal: New England Journal of Medicine (2024)

Whether extended lymphadenectomy is associated with improved disease-free and overall survival, as compared with standard lymphadenectomy, among patients with localized muscle-invasive bladder cancer undergoing radical cystectomy is unclear.
Complement Biosensors Identify a Classical Pathway Stimulus in Complement-Mediated Thrombotic Microangiopathy
Authors: Michael Arthur Cole, Nikhil Ranjan, Gloria F Gerber, Xiang-Zuo Pan, Daniel Flores-Guerrero, George McNamara, Shruti Chaturvedi, C. John Sperati, Keith R McCrae, Robert A. Brodsky
Journal: Blood (2024)
Contributions of Inflammation to Cardiometabolic Heart Failure with Preserved Ejection Fraction
Authors: Edward B. Thorp, Mallory Filipp
Journal: Annual Review of Pathology Mechanisms of Disease (2024)

The most common form of heart failure is heart failure with preserved ejection fraction (HFpEF). While heterogeneous in origin, the most common form of HFpEF is the cardiometabolic manifestation. Obesity and aging promote systemic inflammation that appears integral to cardiometabolic HFpEF pathophysiology. Accumulation of immune cells within the heart, fueled by an altered metabolome, contribute to cardiac inflammation and fibrosis. In spite of this, broad anti-inflammatory therapy has not shown significant benefit in patient outcomes. Thus, understanding of the nuances to metabolic and age-related inflammation during HFpEF is paramount for more targeted interventions. Here, we review clinical evidence of inflammation in the context of HFpEF and summarize our mechanistic understanding of immunometabolic inflammation, highlighting pathways of therapeutic potential along the way.
Long-term efficacy and safety of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): extended follow-up of an open-label, multicentre, randomised, non-inferiority trial
Authors: Ruth L Goodall, Andrew J Nunn, Sarah K Meredith, Adamu Bayissa, Anuj K Bhatnagar, Chen-Yuan Chiang, Francesca Conradie, Narendran Gopalan, Meera Gurumurthy, Bruce Kirenga, Nana Kiria, Daniel Meressa, Ronelle Moodliar, Nosipho Ngubane, Mohammed Rassool, Karen Sanders, Rajesh Solanki, S Bertel Squire, Mekonnen Teferi, Gabriela Torrea, Bazarragchaa Tsogt, Elena Tudor, Armand Van Deun, I D Rusen
Journal: The Lancet Respiratory Medicine (2024)
Adverse obstetric outcomes in female survivors of adolescentand young adult cancers – Authors' reply
Authors: Raoul C Reulen, Ceren Sunguc, David L Winter, Gavin Rudge, Angela Polanco, Katherine A Birchenall, Melanie Griffin, W Hamish B Wallace, Richard A Anderson, Michael M Hawkins
Journal: The Lancet Oncology (2024)
Microbiome characterization of skin biopsies in Spanish patients with hidradenitis suppurativa shows a decrease in D1 and H1 lineages of <i>Cutibacterium acnes</i>
Authors: Jorge Romaní, Carles Rosés, François Brillet, Javier Fernández-Vela, Carlos Muñoz-Santos, María José Fábrega, Lorena Toloza, María Pol, Marc Güell, Antonio Guilabert
Journal: British Journal of Dermatology (2024)

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder, with dysbiosis and loss of Cutibacterium acnes commonly observed in affected skin. This study analyzed the microbiome of lesional, perilesional, and healthy skin samples, finding significant differences, including increased Mycoplasma and Bacillus in lesional skin. The reduction of Cutibacterium variants D1 and H1 in HS-affected skin highlights their potential as therapeutic targets, suggesting a strategy of topical replacement therapy.
Correction: Nac1 promotes stemness and regulates myeloid‑derived cell status in triple‑negative breast cancer
Authors: Chrispus Ngule, Ruyi Shi, Xingcong Ren, Hongyan Jia, Felix Oyelami, Dong Li, Younhee Park, Jinhwan Kim, Hami Hemati, Yi Zhang, Xiaofang Xiong, Andrew Shinkle, Nathan L Vanderford, Sara Bachert, Binhua P Zhou, Jianlong Wang, Jianxun Song, Xia Liu, Jin-Ming Yang
Journal: Molecular Cancer (2024)
Ex Vivo Venetoclax Sensitivity Predicts Clinical Response in Acute Myeloid Leukemia in the Prospective VenEx Trial
Authors: Sari Kytölä, Ida Maria Vänttinen, Tanja Ruokoranta, Anu Partanen, Annasofia Holopainen, Joseph Saad, Milla E.L. Kuusisto, Sirpa Koskela, Riikka Katariina Räty, Maija Itälä-Remes, Imre Västrik, Minna Suvela, Alun Owen Parsons, Kimmo Porkka, Krister Wennerberg, Caroline A. Heckman, Tero Jalkanen, Teppo Huttunen, Pia Ettala, Johanna Rimpiläinen, Timo Siitonen, Marja Pyörälä, Heikki Kuusanmäki, Mika Kontro
Journal: Blood (2024)