tbuckley/cabot-search huggingface dataset:
Selected Articles from This Issue
Journal: Clinical Cancer Research (2023)

Highlights| December 15 2023 Selected Articles from This Issue Author & Article Information Online ISSN: 1557-3265 Print ISSN: 1078-0432 ©2023 American Association for Cancer Research2023American Association for Cancer Research Clin Cancer Res (2023) 29 (24): 4991. https://doi.org/10.1158/1078-0432.CCR-29-24-HI Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record December 15 2023 Citation Selected Articles from This Issue. Clin Cancer Res 15 December 2023; 29 (24): 4991. https://doi.org/10.1158/1078-0432.CCR-29-24-HI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Patients with HR+/HER2+ breast cancer often experience metastasis to the viscera or central nervous system (CNS) and diminished response to HR and HER2 targeted therapies, due in part to cyclin D1/CDK4/6 signaling and leading to high mortality rates. Current chemotherapeutic regimens are accompanied by unwanted side effects, and thus alternative therapeutic strategies targeting HER2 and hormone receptor signaling pathways that maximize efficacy while minimizing adverse events (AEs) are needed. In this phase Ib/II clinical trial, Shagisultanova and colleagues assess the safety and efficacy of the HER2 inhibitor tucatinib in combination with the aromatase inhibitor letrozole and the CDK4/6 inhibitor palbociclib (TLP) in HR+/HER2+ metastatic breast cancer patients. The phase II dose was well tolerated with manageable grade ≥ 3 AEs. The authors report an overall median progression free survival (mPFS) of 8.4 months, with a mPFS of 10.0 months in patients without CNS metastases... You do not currently have access to this content.
All Roads Lead to Rome: YAP/TAZ Activity Influences Efficacy of KRASG12C Inhibitors
Authors: Christian W. Johnson, Kevin M. Haigis
Journal: Cancer Research (2023)

Abstract The development of direct inhibitors of KRASG12C represents a monumental step forward in the field of oncology. Nevertheless, there is considerable opportunity to enhance response rates to KRASG12C inhibitors. In this issue of Cancer Research, three investigative teams explore the modulation of KRASG12C inhibitor activity in lung, colorectal, and pancreatic cancers using CRISPR-based knockout screens. While each group identified and validated a variety of genes and pathways conferring resistance to KRASG12C inhibition, all three groups converged upon activation of YAP/TAZ as a common means of resistance. While coinhibition of KRASG12C and YAP/TAZ did not cause complete tumor regression in xenograft models, combining YAP/TAZ inhibition was capable of significantly extending the response of tumors to KRASG12C inhibition. See related articles by Mukhopadhyay et al., p. 4095, Edwards et al., p. 4112, and Prahallad et al., p. 4130
Retraction: A New Class of Quinoline-Based DNA Hypomethylating Agents Reactivates Tumor Suppressor Genes by Blocking DNA Methyltransferase 1 Activity and Inducing Its Degradation
Authors: Jharna Datta, Kalpana Ghoshal, William A. Denny, Swarna A. Gamage, Darby G. Brooke, Pasit Phiasivongsa, Sanjeev Redkar, Samson T. Jacob
Journal: Cancer Research (2023)

This article (1) has been retracted at the request of the editors. Following an institutional review by The Ohio State University (Columbus, OH), the primary affiliation for several of the authors, it was determined that:In Fig. 4A, the same image was used to represent the P16-U-R1 PCR band in the SGI-1027–12d and SGI-1027–15d lanes. In addition, the same image was used to represent the P16-M-R2 PCR band in the Control, Decitabine-12d, and Decitabine-15d lanes.In Fig. 4B, the same image was used to represent the TIMP-3-M PCR band in the Decitabine-7d and SGI-1027–5d lanes.In Fig. 5B, the same image was used to represent the GAPDH Western blot band in the untreated, SGI-1027 6 h, and SGI-1027 12 h lanes.As a result of these findings, the institution recommended retraction and, upon internal review, the editors agreed with this recommendation.A copy of this Retraction Notice was sent to the last known e-mail addresses for 8 of the 8 authors. One author (Samson T. Jacob) did not agree to the retraction; 7 authors (Jharna Datta, Kalpana Ghoshal, William A. Denny, Swarna A. Gamage, Darby G. Brooke, Pasit Phiasivongsa, and Sanjeev Redkar) did not respond. Samson T. Jacob did not agree to the retraction and stands by the reproducibility of the experimental data and the conclusions of the article.
HEG1 Protects Against Atherosclerosis by Regulating Stable Flow-Induced KLF2/4 Expression in Endothelial Cells
Authors: Ian A. Tamargo, Kyung In Baek, Chenbo Xu, Dong Won Kang, Yerin Kim, Aitor Andueza, Darian Williams, Catherine Demos, Nicolas Villa-Roel, Sandeep Kumar, Christian Park, Rachel Choi, Janie Johnson, Seowon Chang, Paul Kim, Sheryl Tan, Kiyoung Jeong, Shoutaro Tsuji, Hanjoong Jo
Journal: Circulation (2023)

Atherosclerosis preferentially occurs in arterial regions of disturbed blood flow, and stable flow (s-flow) protects against atherosclerosis by incompletely understood mechanisms.
Impact of the COVID-19 pandemic on prevalence of highly resistant microorganisms in hospitalised patients in the Netherlands, March 2020 to August 2022
Authors: Wieke Altorf-van der Kuil, Cornelia CH Wielders, Romy D Zwittink, Sabine C de Greeff, Dave A Dongelmans, Ed J Kuijper, Daan W Notermans, Annelot F Schoffelen
Journal: Eurosurveillance (2023)

BackgroundThe COVID-19 pandemic resulted in adaptation in infection control measures, increased patient transfer, high occupancy of intensive cares, downscaling of non-urgent medical procedures and decreased travelling.AimTo gain insight in the influence of these changes on antimicrobial resistance (AMR) prevalence in the Netherlands, a country with a low AMR prevalence, we estimated changes in demographics and prevalence of six highly resistant microorganisms (HRMO) in hospitalised patients in the Netherlands during COVID-19 waves (March-June 2020, October 2020-June 2021, October 2021-May 2022 and June-August 2022) and interwaves (July-September 2020 and July-September 2021) compared with pre-COVID-19 (March 2019-February 2020).MethodsWe investigated data on routine bacteriology cultures of hospitalised patients, obtained from 37 clinical microbiological laboratories participating in the national AMR surveillance. Demographic characteristics and HRMO prevalence were calculated as proportions and rates per 10,000 hospital admissions.ResultsAlthough no significant persistent changes in HRMO prevalence were detected, some relevant non-significant patterns were recognised in intensive care units. Compared with pre-COVID-19 we found a tendency towards higher prevalence of meticillin-resistant
Mpox outbreak in France: epidemiological characteristics and sexual behaviour of cases aged 15 years or older, 2022
Authors: Catarina Krug, Arnaud Tarantola, Emilie Chazelle, Erica Fougère, Annie Velter, Anne Guinard, Yvan Souares, Anna Mercier, Céline François, Katia Hamdad, Laetitia Tan-Lhernould, Anita Balestier, Hana Lahbib, Nicolas Etien, Pascale Bernillon, Virginie De Lauzun, Julien Durand, Myriam Fayad, Henriette De Valk, François Beck, Didier Che, Bruno Coignard, Florence Lot, Alexandra Mailles
Journal: Eurosurveillance (2023)

Background Locally-acquired mpox cases were rarely reported outside Africa until May 2022, when locally-acquired-mpox cases occurred in various European countries. Aim We describe the mpox epidemic in France, including demographic and behavioural changes among a subset of cases, during its course. Methods Data were retrieved from the enhanced national surveillance system until 30 September 2022. Laboratory-confirmed cases tested positive for monkeypox virus or orthopoxviruses by PCR; non-laboratory-confirmed cases had clinical symptoms and an epidemiological link to a laboratory-confirmed case. A subset of ≥ 15-year-old male cases, notified until 1 August, was interviewed for epidemiological, clinical and sexual behaviour information. Association of symptom-onset month with quantitative outcomes was evaluated by t- or Wilcoxon tests, and with binary outcomes, by Pearson’s chi-squared or Fisher exact tests. Results A total of 4,856 mpox cases were notified, mostly in Île-de-France region (62%; 3,025/4,855). Cases aged ≥ 15 years were predominantly male (97%; 4,668/4,812), with 37 years (range: 15–81) as mean age. Between May and July, among the subset interviewed, mpox cases increased in regions other than Île-de-France, and mean age rose from 35 (range: 21–64) to 38 years (range: 16–75; p = 0.007). Proportions of cases attending men-who-have-sex-with-men (MSM) meeting venues declined from 60% (55/91) to 46% (164/359; p = 0.012); median number of sexual partners decreased from four (interquartile range (IQR): 1–10) to two (IQR: 1–4; p &lt; 0.001). Conclusion Changes in cases’ characteristics during the epidemic, could reflect virus spread from people who were more to less behaviourally vulnerable to mpox between May and July, or MSM reducing numbers of sexual partners as recommended.
Acidosis-mediated increase in IFN-γ-induced PD-L1 expression on cancer cells as an immune escape mechanism in solid tumors
Authors: Philipp Knopf, Dimitri Stowbur, Sabrina H. L. Hoffmann, Natalie Hermann, Andreas Maurer, Valentina Bucher, Marilena Poxleitner, Bredi Tako, Dominik Sonanini, Balaji Krishnamachary, Sanhita Sinharay, Birgit Fehrenbacher, Irene Gonzalez-Menendez, Felix Reckmann, David Bomze, Lukas Flatz, Daniela Kramer, Martin Schaller, Stephan Forchhammer, Zaver M. Bhujwalla, Leticia Quintanilla-Martinez, Klaus Schulze-Osthoff, Mark D. Pagel, Marieke F. Fransen, Martin Röcken, André F. Martins, Bernd J. Pichler, Kamran Ghoreschi, Manfred Kneilling
Journal: Molecular Cancer (2023)

Immune checkpoint inhibitors have revolutionized cancer therapy, yet the efficacy of these treatments is often limited by the heterogeneous and hypoxic tumor microenvironment (TME) of solid tumors. In the TME, programmed death-ligand 1 (PD-L1) expression on cancer cells is mainly regulated by Interferon-gamma (IFN-γ), which induces T cell exhaustion and enables tumor immune evasion. In this study, we demonstrate that acidosis, a common characteristic of solid tumors, significantly increases IFN-γ-induced PD-L1 expression on aggressive cancer cells, thus promoting immune escape. Using preclinical models, we found that acidosis enhances the genomic expression and phosphorylation of signal transducer and activator of transcription 1 (STAT1), and the translation of STAT1 mRNA by eukaryotic initiation factor 4F (elF4F), resulting in an increased PD-L1 expression. We observed this effect in murine and human anti-PD-L1-responsive tumor cell lines, but not in anti-PD-L1-nonresponsive tumor cell lines. In vivo studies fully validated our in vitro findings and revealed that neutralizing the acidic extracellular tumor pH by sodium bicarbonate treatment suppresses IFN-γ-induced PD-L1 expression and promotes immune cell infiltration in responsive tumors and thus reduces tumor growth. However, this effect was not observed in anti-PD-L1-nonresponsive tumors. In vivo experiments in tumor-bearing IFN-γ-/- mice validated the dependency on immune cell-derived IFN-γ for acidosis-mediated cancer cell PD-L1 induction and tumor immune escape. Thus, acidosis and IFN-γ-induced elevation of PD-L1 expression on cancer cells represent a previously unknown immune escape mechanism that may serve as a novel biomarker for anti-PD-L1/PD-1 treatment response. These findings have important implications for the development of new strategies to enhance the efficacy of immunotherapy in cancer patients.
Human serous cavity macrophages and dendritic cells possess counterparts in the mouse with a distinct distribution between species
Authors: Jichang Han, Alexandre Gallerand, Emma C. Erlich, Beth A. Helmink, Iris Mair, Xin Li, Shaina R. Eckhouse, Francesca M. Dimou, Baddr A. Shakhsheer, Hannah M. Phelps, Mandy M. Chan, Rachel L. Mintz, Daniel D. Lee, Joel D. Schilling, Conor M. Finlay, Judith E. Allen, Claudia V. Jakubzick, Kathryn J. Else, Emily J. Onufer, Nan Zhang, Gwendalyn J. Randolph
Journal: Nature Immunology (2023)
DELE1 haploinsufficiency causes resistance to mitochondrial stress-induced apoptosis in monosomy 5/del(5q) AML
Authors: Jean-François Spinella, Jalila Chagraoui, Céline Moison, Vincent P. Lavallée, Isabel Boivin, Deanne Gracias, Sylvie Lavallée, Guillaume Richard Carpentier, François Beliveau, Josée Hébert, Guy Sauvageau
Journal: Leukemia (2023)

Monosomy 5 and deletions of the chromosome 5q (-5/del(5q)) are recurrent events in de novo adult acute myeloid leukemia (AML), reaching up to 40% of cases in secondary AML. These chromosome anomalies are associated with TP53 mutations and with very poor prognosis. Using the large Leucegene genomic and transcriptomic dataset composed of 48 -5/del(5q) patient specimens and 367 control AML, we identified DELE1 - located in the common deleted region - as the most consistently downregulated gene in these leukemias. DELE1 encodes a mitochondrial protein recently characterized as the relay of mitochondrial stress to the cytosol through a newly defined OMA1-DELE1-HRI pathway which ultimately leads to the activation of ATF4, the master transcription factor of the integrated stress response. Here, we showed that the partial loss of DELE1 expression observed in -5/del(5q) patients was sufficient to significantly reduce the sensitivity to mitochondrial stress in AML cells. Overall, our results suggest that DELE1 haploinsufficiency could represent a new driver mechanism in -5/del(5q) AML.
Antimicrobial Drug Penetration Is Enhanced by Lung Tissue Inflammation and Injury
Authors: Johannes Geilen, Matthias Kainz, Bernhard Zapletal, Asami Naka, Johanna Tichy, Walter Jäger, Michaela Böhmdorfer, Markus Zeitlinger, Marcus J. Schultz, Tanja Stamm, Valentin Ritschl, Silvana Geleff, Edda Tschernko
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: Pneumonia is a frequent and feared complication in intubated critically ill patients. Tissue concentrations of antimicrobial drugs need to be sufficiently high to treat the infection and also prevent development of bacterial resistance. It is uncertain whether pulmonary inflammation and injury affect antimicrobial drug penetration into lung tissue.Objectives: To determine and compare tissue and BAL fluid concentrations of ceftaroline fosamil and linezolid in a model of unilateral acute lung injury in pigs and to evaluate whether dose adjustment is necessary to reach sufficient antimicrobial concentrations in injured lung tissue.Methods: After induction of unilateral acute lung injury, ceftaroline fosamil and linezolid were administered intravenously. Drug concentrations were measured in lung tissue through microdialysis and in blood and BAL fluid samples during the following 8 hours. The primary endpoint was the tissue concentration area under the concentration curve in the first 8 hours (AUC0–8 h) of the two antimicrobial drugs.Measurements and Main Results: In 10 pigs, antimicrobial drug concentrations were higher in inflamed and injured lung tissue compared with those in uninflamed and uninjured lung tissue (median ceftaroline fosamil AUC0–8 h [and interquartile range] = 26.7 mg ⋅ h ⋅ L−1 [19.7–39.0] vs. 16.0 mg ⋅ h ⋅ L−1 [13.6–19.9], P = 0.02; median linezolid AUC0–8 h 76.0 mg ⋅ h ⋅ L−1 [68.1–96.0] vs. 54.6 mg ⋅ h ⋅ L−1 [42.7–60.9], P = 0.01), resulting in a longer time above the minimal inhibitory concentration and in higher peak concentrations and dialysate/plasma ratios. Penetration into BAL fluid was excellent for both antimicrobials, but without left-to-right differences (ceftaroline fosamil, P = 0.78; linezolid, P = 1.00).Conclusions: Tissue penetration of two commonly used antimicrobial drugs for pneumonia is enhanced by early lung tissue inflammation and injury, resulting in longer times above the minimal inhibitory concentration. Thus, lung tissue inflammation ameliorates antimicrobial drug penetration during the acute phase.
Proactive Algorithm Monitoring to Ensure Health Equity
Authors: Mark Sendak, Suresh Balu, Adrian F. Hernandez
Journal: JAMA Network Open (2023)

Marshall H. Chin, MD, MPH; Nasim Afsar-Manesh, MD, MBA, MHM; Arlene S. Bierman, MD, MS; Christine Chang, MD, MPH; Caleb J. Colón-Rodríguez, DrPH, MHSA; Prashila Dullabh, MD; Deborah Guadalupe Duran, PhD; Malika Fair, MD, MPH; Tina Hernandez-Boussard, PhD, MPH, MS; Maia Hightower, MD, MPH, MBA; Anjali Jain, MD; William B. Jordan, MD, MPH; Stephen Konya; Roslyn Holliday Moore, MS; Tamra Tyree Moore, JD; Richard Rodriguez, MPH; Gauher Shaheen, PhD; Lynne Page Snyder, PhD, MPH; Mithuna Srinivasan, PhD; Craig A. Umscheid, MD, MS; Lucila Ohno-Machado, MD, PhD, MBA
Development of Deep Ensembles to Screen for Autism and Symptom Severity Using Retinal Photographs
Authors: Jae Han Kim, JaeSeong Hong, Hangnyoung Choi, Hyun Goo Kang, Sangchul Yoon, Jung Yeon Hwang, Yu Rang Park, Keun-Ah Cheon
Journal: JAMA Network Open (2023)

Importance Screening for autism spectrum disorder (ASD) is constrained by limited resources, particularly trained professionals to conduct evaluations. Individuals with ASD have structural retinal changes that potentially reflect brain alterations, including visual pathway abnormalities through embryonic and anatomic connections. Whether deep learning algorithms can aid in objective screening for ASD and symptom severity using retinal photographs is unknown. Objective To develop deep ensemble models to differentiate between retinal photographs of individuals with ASD vs typical development (TD) and between individuals with severe ASD vs mild to moderate ASD. Design, Setting, and Participants This diagnostic study was conducted at a single tertiary-care hospital (Severance Hospital, Yonsei University College of Medicine) in Seoul, Republic of Korea. Retinal photographs of individuals with ASD were prospectively collected between April and October 2022, and those of age- and sex-matched individuals with TD were retrospectively collected between December 2007 and February 2023. Deep ensembles of 5 models were built with 10-fold cross-validation using the pretrained ResNeXt-50 (32×4d) network. Score-weighted visual explanations for convolutional neural networks, with a progressive erasing technique, were used for model visualization and quantitative validation. Data analysis was performed between December 2022 and October 2023. Exposures Autism Diagnostic Observation Schedule–Second Edition calibrated severity scores (cutoff of 8) and Social Responsiveness Scale–Second Edition T scores (cutoff of 76) were used to assess symptom severity. Main Outcomes and Measures The main outcomes were participant-level area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity. The 95% CI was estimated through the bootstrapping method with 1000 resamples. Results This study included 1890 eyes of 958 participants. The ASD and TD groups each included 479 participants (945 eyes), had a mean (SD) age of 7.8 (3.2) years, and comprised mostly boys (392 [81.8%]). For ASD screening, the models had a mean AUROC, sensitivity, and specificity of 1.00 (95% CI, 1.00-1.00) on the test set. These models retained a mean AUROC of 1.00 using only 10% of the image containing the optic disc. For symptom severity screening, the models had a mean AUROC of 0.74 (95% CI, 0.67-0.80), sensitivity of 0.58 (95% CI, 0.49-0.66), and specificity of 0.74 (95% CI, 0.67-0.82) on the test set. Conclusions and Relevance These findings suggest that retinal photographs may be a viable objective screening tool for ASD and possibly for symptom severity. Retinal photograph use may speed the ASD screening process, which may help improve accessibility to specialized child psychiatry assessments currently strained by limited resources.
Racial Equity in Living Donor Kidney Transplant Centers, 2008-2018
Authors: Lisa M. McElroy, Tyler Schappe, Dinushika Mohottige, LaShara Davis, Sarah B. Peskoe, Virginia Wang, Jane Pendergast, L. Ebony Boulware
Journal: JAMA Network Open (2023)

Importance It is unclear whether center-level factors are associated with racial equity in living donor kidney transplant (LDKT). Objective To evaluate center-level factors and racial equity in LDKT during an 11-year time period. Design, Setting, and Participants A retrospective cohort longitudinal study was completed in February 2023, of US transplant centers with at least 12 annual LDKTs from January 1, 2008, to December 31, 2018, identified in the Health Resources Services Administration database and linked to the US Renal Data System and the Scientific Registry of Transplant Recipients. Main Outcomes and Measures Observed and model-based estimated Black-White mean LDKT rate ratios (RRs), where an RR of 1 indicates racial equity and values less than 1 indicate a lower rate of LDKT of Black patients compared with White patients. Estimated yearly best-case center-specific LDKT RRs between Black and White individuals, where modifiable center characteristics were set to values that would facilitate access to LDKT. Results The final cohorts of patients included 394 625 waitlisted adults, of whom 33.1% were Black and 66.9% were White, and 57 222 adult LDKT recipients, of whom 14.1% were Black and 85.9% were White. Among 89 transplant centers, estimated yearly center-level RRs between Black and White individuals accounting for center and population characteristics ranged from 0.0557 in 2008 to 0.771 in 2018. The yearly median RRs ranged from 0.216 in 2016 to 0.285 in 2010. Model-based estimations for the hypothetical best-case scenario resulted in little change in the minimum RR (from 0.0557 to 0.0549), but a greater positive shift in the maximum RR from 0.771 to 0.895. Relative to the observed 582 LDKT in Black patients and 3837 in White patients, the 2018 hypothetical model estimated an increase of 423 (a 72.7% increase) LDKTs for Black patients and of 1838 (a 47.9% increase) LDKTs for White patients. Conclusions and Relevance In this cohort study of patients with kidney failure, no substantial improvement occurred over time either in the observed or the covariate-adjusted estimated RRs. Under the best-case hypothetical estimations, modifying centers’ participation in the paired exchange and voucher programs and increased access to public insurance may contribute to improved racial equity in LDKT. Additional work is needed to identify center-level and program-specific strategies to improve racial equity in access to LDKT.