bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanical assessment of proprietary and improvised pelvic binders for use in the prehospital environment
Authors: Howe Thomas John , Claireaux H , Fox H , Morgan G , McMenemy L , Masouros S D , Ramasamy A
Published: August 2023

Introduction

Pelvic fractures often result from high-energy trauma and are associated with a 10% mortality rate and significant morbidity. Pelvic binders are applied in suspected pelvic injury to stabilise fractured bone, decrease bleeding and potentiate tamponade. A binder must hold the pelvis with sufficient force for this effect to be achieved. This study aims to quantify the ability of proprietary and improvised pelvic binders to hold a target tensile force over time.

Methods

The ability of three proprietary and three improvised binders to hold a binding force for 2 hours was tested. A uniaxial materials testing machine was used to tension each binder to 150 N and then hold the displacement for 2 hours; the drop in tension over time was recorded for each binder. The ability to hold tension above 130 N after 2 hours was set as the metric of binder performance.

Results

The median tension at 2 hours was above 130 N for the SAM Pelvic Sling II and T-POD Pelvic Stabilisation Device and was below 130 N for the Prometheus Pelvic Splint, field-expedient pelvic splint (FES) and the Personal Clothing System-Multi-Terrain Pattern Combat Trousers binders. The tension in the improvised FES after 2 hours was approximately at the target 130 N; however, in 40% of the tests, it held above 130 N.

Conclusions

Binders varied in their ability to maintain sufficient tension to treat a pelvic fracture over the 2-hour testing period. The FES performed well under our testing regime; with relatively low cost and weight, it represents a good alternative to proprietary binders for the austere environment.
Survey on Epileptic Seizure Detection on Varied Machine Learning Algorithms
Authors: Fatma Nusrat , Singh Pawan , Siddiqui Mohammad Khubeb
Published: August 2023

Epilepsy is an unavoidable major persistent and critical neurological disorder that influences the human brain. Moreover, this is apparently distinguished via its recurrent malicious seizures. A seizure is a phase of synchronous, abnormal innervations of a neuron’s population which might last from seconds to a few minutes. In addition, epileptic seizures are transient occurrences of complete or partial irregular unintentional body movements that combine with consciousness loss. As epileptic seizures rarely occurred in each patient, their effects based on physical communications, social interactions, and patients’ emotions are considered, and treatment and diagnosis are undergone with crucial implications. Therefore, this survey reviews 65 research papers and states an important analysis on various machine-learning approaches adopted in each paper. The analysis of different features considered in each work is also done. This survey offers a comprehensive study on performance attainment in each contribution. Furthermore, the maximum performance attained by the works and the datasets used in each work is also examined. The analysis on features and the simulation tools used in each contribution is examined. At the end, the survey expanded with different research gaps and their problem which is beneficial to the researchers for promoting advanced future works on epileptic seizure detection.
A Dual-branch Learning Model with Gradient-balanced Loss for Long-tailed Multi-label Text Classification
Authors: Yao Yitong , Zhang Jing , Zhang Peng , Sun Yueheng
Published: August 2023

Multi-label text classification has a wide range of applications in the real world. However, the data distribution in the real world is often imbalanced, which leads to serious long-tailed problems. For multi-label classification, due to the vast scale of datasets and existence of label co-occurrence, how to effectively improve the prediction accuracy of tail labels without degrading the overall precision becomes an important challenge. To address this issue, we propose
A Dual-Branch Learning Model with Gradient-Balanced Loss (DBGB)
based on the paradigm of existing pre-trained multi-label classification SOTA models. Our model consists of two main long-tailed module improvements. First, with the shared text representation, the dual-classifier is leveraged to process two kinds of label distributions; one is the original data distribution and the other is the under-sampling distribution for head labels to strengthen the prediction for tail labels. Second, the proposed gradient-balanced loss can adaptively suppress the negative gradient accumulation problem related to labels, especially tail labels. We perform extensive experiments on three multi-label text classification datasets. The results show that the proposed method achieves competitive performance on overall prediction results compared to the state-of-the-art methods in solving the multi-label classification, with significant improvement on tail-label accuracy.
Hierarchical Transformer with Spatio-temporal Context Aggregation for Next Point-of-interest Recommendation
Authors: Xie Jiayi , Chen Zhenzhong
Published: August 2023

Next point-of-interest (POI) recommendation is a critical task in location-based social networks, yet remains challenging due to a high degree of variation and personalization exhibited in user movements. In this work, we explore the latent hierarchical structure composed of multi-granularity short-term structural patterns in user check-in sequences. We propose a Spatio-Temporal context AggRegated Hierarchical Transformer (STAR-HiT) for next POI recommendation, which employs stacked hierarchical encoders to recursively encode the spatio-temporal context and explicitly locate subsequences of different granularities. More specifically, in each encoder, the global attention layer captures the spatio-temporal context of the sequence, while the local attention layer performed within each subsequence enhances subsequence modeling using the local context. The sequence partition layer infers positions and lengths of subsequences from the global context adaptively, such that semantics in subsequences can be well preserved. Finally, the subsequence aggregation layer fuses representations within each subsequence to form the corresponding subsequence representation, thereby generating a new sequence of higher-level granularity. The stacking of hierarchical encoders captures the latent hierarchical structure of the check-in sequence, which is used to predict the next visiting POI. Extensive experiments on three public datasets demonstrate that the proposed model achieves superior performance while providing explanations for recommendations.
Four Decades of Chief Information Officer Research: A Literature Review and Research Agenda Based on Main Path Analysis
Authors: Kratzer Simon , Westner Markus , Strahringer Susanne
Published: August 2023

Despite the relevance and maturity of the Chief Information Officer (CIO) research field, no studies exist that exhaustively summarize the current body of knowledge, focusing on the development of the field over its entire timespan. The paper at hand addresses this research gap and presents an exhaustive literature review on the CIO research field using main path analysis. We identify the central papers in CIO research and eight main research streams by quantitatively and qualitatively analyzing 466 papers. We find that established research streams, e.g., 'Evolving role of the CIO' and 'CIO hierarchical position and relationships' as well as recently emerging research streams, e.g., 'CIO as business enabler' and 'CIOs and IT security,' draw growing attention. Based on our findings, we develop promising further avenues for research in the CIO field.
The Evolutionary Ecology of Plant Chemical Defenses: From Molecules to Communities
Authors: Endara María-José , Forrister Dale L. , Coley Phyllis D.
Published: August 2023

Classic theory relates herbivore pressure to the ecology and evolution of plant defenses. Here, we summarize current trends in the study of plant–herbivore interactions and how they shape the evolution of plant chemical defenses, host choice, and community composition and diversity. Inter- and intraspecific variation in defense investment is driven by resource availability. The evolution of defenses at deeper nodes of plant phylogeny is conserved, yet defenses are highly labile at the tips. On an ecological timescale, while greater specialization of tropical herbivores enhances local diversity by reducing the performance of plants with similar defenses, in temperate ecosystems with more generalist herbivores, rare defense profiles are at a disadvantage. On an evolutionary timescale, host choice by herbivores is largely determined by plant defenses rather than host phylogeny, leading to evolutionary tracking by herbivores rather than cocladogenesis. The interplay between plants and herbivores shapes both the origin and maintenance of diversity.
Computational Social Psychology
Authors: Cushman Fiery
Published: August 2023

Social psychologists attempt to explain how we interact by appealing to basic principles of how we think. To make good on this ambition, they are increasingly relying on an interconnected set of formal tools that model inference, attribution, value-guided decision making, and multi-agent interactions. By reviewing progress in each of these areas and highlighting the connections between them, we can better appreciate the structure of social thought and behavior, while also coming to understand when, why, and how formal tools can be useful for social psychologists.
Amperometric Determination of Hydrazine Using Au Nanoparticle Incorporated CMK-3 Modified Glassy Carbon Electrode
Authors: Rajaram Rajendran , Kumar Sachin , Sudharsan S , Raj Rayappan Pavul , Ramanujam Kothandaraman , Neelakantan Lakshman
Published: August 2023

In this work, ordered mesoporous carbon (CMK-3) was synthesized using the nano-casting method, in which Au nanoparticles were incorporated using the citrate-reduction method. It was characterized using various physicochemical techniques like XRD, Raman, HRSEM, BET, and HRTEM. The synthesized material was utilized as an electrocatalyst for the electrochemical determination of hydrazine (HZ). From the cyclic voltammetric studies, it is understood that the bare as well as CMK-3 modified glassy carbon electrodes fail to produce a signal against HZ. On the contrary, Au nanoparticle incorporated CMK-3 modified glassy carbon electrode (AuNP-CMK-3/GCE) senses the analyte at the applied overpotential of 0.22 V. The electrode exhibits a linear variation in sensitivity in the concentration range of 0.1 mM to 1 mM with a regression coefficient value of 0.9967. Using the amperometric measurements, the sensitivity of the electrode was investigated and it is concluded that the electrode is able to produce a signal against the target analyte in the concentration range of 3–27 μM with the R2 value of 0.9964. Further, the sensitivity and limit of detection (LOD) of the electrode against HZ were found as 0.00289 μA μM−1 and 1 μM, respectively. The selectivity of the electrode was examined in the presence of other interferents, which revealed that the electrode is selective to HZ. The real-time applicability of the electrode was ascertained in the water samples collected from the ponds.
Synthesis and Characterization of Zn0.5Co0.5Fe2O4 Nanoparticles for Gas Sensing Applications
Authors: Prakshale R. D. , Bangale S. V. , Kamble M. M. , Sonawale S. B.
Published: August 2023

In this study, Zn0.5Co0.5Fe2O4 nanoparticles were synthesized by solution combustion method. The solution combustion method is a convenient, chief, environment friendly, and capable for the synthesis of high-quality nanomaterials. As prepared Zn0.5Co0.5Fe2O4 were annealed at 800 °C. The electrical, thermal, structural, magnetic, morphological and gas sensing properties of the synthesised materials has been studied in details. The spinel crystal structure was confirmed from X-ray diffraction, with average crystalline size of 37 nm. The elemental compositions in the synthesized powder were estimated using EDX spectra. The magnetic nature of the material was confirmed from vibrating sample magnetometer (VSM), conducted at room temperature with highest applied field of 15 KOe and it shows ferromagnetic behaviour. The nearly spherical particles shapes were observed from TEM and FESEM images. The fabricated thick films of the synthesised material were exposed to various gases like NH3, Cl2, H2, CO2 and LPG at different temperatures. It was observed that the gas sensing responses depends on their operating temperature. Additionally, the sensor has a quick response time and a speedy recovery time. The gas sensing results demonstrated that Zn0.5Co0.5Fe2O4 is a novel gas sensor material with good sensitivity and selectivity to LPG compared to other gases. The probable LPG gas sensing mechanism is schematically represented in this paper. This study provides, Zn0.5Co0.5Fe2O4 synthesised using low-cost solution combustion technique has a great potential in future gas sensing fields.
Insights Regarding the Role of Inflammasomes in Leukemia: What Do We Know?
Authors: Alves-Hanna Fabíola Silva , Crespo-Neto Juniel Assis , Nogueira Glenda Menezes , Pereira Daniele Sá , Lima Amanda Barros , Ribeiro Thaís Lohana Pereira , Santos Vitória Giovanna Rodrigues , Fonseca Joey Ramone Ferreira , Magalhães-Gama Fábio , Sadahiro Aya , Costa Allyson Guimarães
Published: August 2023

Inflammation is a physiological mechanism of the immune response and has an important role in maintaining the hematopoietic cell niche in the bone marrow. During this process, the participation of molecules produced by innate immunity cells in response to a variety of pathogen-associated molecular patterns and damage-associated molecular patterns is observed. However, chronic inflammation is intrinsically associated with leukemogenesis, as it induces DNA damage in hematopoietic stem cells and contributes to the creation of the preleukemic clone. Several factors influence the malignant transformation within the hematopoietic microenvironment, with inflammasomes having a crucial role in this process, in addition to acting in the regulation of hematopoiesis and its homeostasis. Inflammasomes are intracellular multimeric complexes responsible for the maturation and secretion of the proinflammatory cytokines interleukin-1β and interleukin-18 and the cell death process via pyroptosis. Therefore, dysregulation of the activation of these complexes may be a factor in triggering several diseases, including leukemias, and this has been the subject of several studies in the area. In this review, we summarized the current knowledge on the relationship between inflammation and leukemogenesis, in particular, the role of inflammasomes in different types of leukemias, and we describe the potential therapeutic targets directed at inflammasomes in the leukemic context.
Characterization and Prognosis of Biological Microenvironment in Lung Adenocarcinoma through a Disulfidptosis-Related lncRNAs Signature
Authors: Yang Zhuo , Cao Shenglan , Wang Fangli , Du Kangming , Hu Fang
Published: August 2023

Background. The role of disulfidptosis-related lncRNAs remains unclear in lung adenocarcinoma. Methods. Analysis in R software was conducted using different R packages, which are based on the public data from The Cancer Genome Atlas (TCGA) database. The transwell assay was used to evaluate the invasion and migration abilities of lung cancer cells. Results. In our study, we identified 1401 lncRNAs significantly correlated with disulfidptosis-related genes (|Cor| > 0.3 and

P
<
0.05

). Then, we constructed a prognosis model consisting of 11 disulfidptosis-related lncRNAs, including AL133445.2, AL442125.1, AC091132.2, AC090948.1, AC020765.2, CASC8, AL606834.1, LINC00707, OGFRP1, U91328.1, and GASAL1. This prognosis model has satisfactory prediction performance. Also, the risk score and clinical information were combined to develop a nomogram. Analyses of biological enrichment and immune-related data were used to identify underlying differences between patients at high-risk and low-risk groups. Moreover, we noticed that the immunotherapy nonresponders have higher risk scores. Meanwhile, patients at a high risk responded more strongly to docetaxel, paclitaxel, and vinblastine. Furthermore, further analysis of the model lncRNA OGFRP1 was conducted, including clinical, immune infiltration, biological enrichment analysis, and a transwell assay. We discovered that by inhibiting OGFRP1, the invasion and migration abilities of lung cancer cells could be remarkably hindered. Conclusion. The results of our study can provide directions for future research in the relevant areas. Moreover, the prognosis signature we identified has the potential for clinical application.
Prognostic Factors for Cancer‐Specific Survival and Disease‐Free Interval of Dogs with Mammary Carcinomas
Authors: Soares Elaine da Silva , Valente Fabrício Luciani , Rocha Carolina Camargos , Real Pereira Carlos Eduardo , Sarandy Thaís Barroso , de Oliveira Fabiano Luiz Dulce , de Morais Calado Sabrina Loise , Borges Andréa Pacheco Batista
Published: August 2023

Canine mammary tumors (CMTs) are the most diagnosed neoplasms in dogs; however, there are few studies analyzing the influence of epidemiological, clinicopathological, and histopathological data on cancer‐specific survival (CSS), disease‐free interval (DFI), and overall survival (OS) in a large cohort. To contribute to the understanding of the biological behavior of this neoplasm, 385 cases were analyzed, 89% malignant, 4% benign, and 7% non‐neoplastic lesions. Among the dogs diagnosed with malignant neoplasms, 86% had early clinical stages (I–III), while 14% had regional or distant metastasis at the time of diagnosis. Carcinoma in a mixed tumor was the most frequent histological type with 44% of the cases and had the best prognosis. Analyzed factors such as the presence of pseudocyesis, previous history of the disease, advanced clinical stage (IV‐V), and presence of ulceration obtained significant results for CSS, DFI, and OS through univariate analysis and had a negative impact on the survival of the patients. Multivariate analysis showed that histological grading and age proved to be the best independent parameters for the prognostic evaluation of CSS and DFI in this study. These factors were also significant in the overall survival analysis. Therefore, these parameters should be considered valuable risk and prognostic factors for CMTs.
Therapeutic Vaccination against Human Papillomavirus Type 16 for the Treatment of High-Grade Anal Intraepithelial Neoplasia in HIV+ Men
Authors: Gosens Karien C.M. , van der Burg Sjoerd H. , Welters Marij J.P. , Boekestijn Sanne , Loof Nikki M. , Quint Wim G.V. , van Noesel Carel J.M. , van der Wal Allard C. , Richel Olivier , Krebber Wilhelmus J.T.A. , Melief Cornelis J.M. , de Vries Henry J.C. , Prins Jan M.
Published: August 2023

Purpose:

Anal cancer is increasing in HIV+ men who have sex with men (MSM). Treatment options for its precursor, high-grade anal intraepithelial neoplasia (HGAIN), are suboptimal. In this phase I to II dose-finding study, we assessed the safety and efficacy of the human papillomavirus type 16 (HPV16) synthetic long peptide vaccine (SLP-HPV-01) in HIV+ MSM with HPV16-positive HGAIN.

Patients and Methods:

Four dosage schedules (1-5-10; 5-10-20; 10-20-40; and 40-40-40-40 μg) of SLP-HPV-01 were administered intradermally with a 3-week interval in 10 patients per dose level (DL). In each dose group, 5 patients also received 1 μg/kg pegylated IFNα-2b subcutaneously. Primary endpoints were safety and regression of HGAIN at 3, 6, and 12 months.

Results:

Eighty-one of 134 screened patients (60%) had HPV16-negative HGAIN lesions, leaving 53 eligible patients. Thirteen patients were excluded, leaving 40 men. The vaccine was well tolerated. One patient developed a generalized rash. The highest dosage level induced the strongest immune responses. There was no indication for stronger reactivity in the IFNα groups. Up to 18 months of follow-up, 8/38 intention-to-treat patients had a complete clinical and histologic response and one had a partial response (in total 9/38, 23.7%). At the highest dosage level, the clinical response was 4/10 (40%). Stronger immune responses were detected among clinical responders.

Conclusions:

The highest DL is safe, immunogenic, and associated with clinical responses to HPV16-induced lesions. However, as the majority of HGAIN is caused by the other HPV types, further studies should aim at pan-HPV vaccination to prevent or treat HGAIN.
Single-Cell RNA Analysis Reveals Cell-Intrinsic Functions of CAR T Cells Correlating with Response in a Phase II Study of Lymphoma Patients
Authors: Sarén Tina , Ramachandran Mohanraj , Gammelgård Gustav , Lövgren Tanja , Mirabello Claudio , Björklund Åsa K. , Wikström Kristina , Hashemi Jamileh , Freyhult Eva , Ahlström Håkan , Amini Rose-Marie , Hagberg Hans , Loskog Angelica , Enblad Gunilla , Essand Magnus
Published: August 2023

Purpose:

Although CD19 chimeric antigen receptor T cells (CAR-T) therapy has shown remarkable success in B-cell malignancies, a substantial fraction of patients do not obtain a long-term clinical response. This could be influenced by the quality of the individual CAR-T infusion product. To shed some light on this, clinical outcome was correlated to characteristics of CAR-T infusion products.

Patients and Methods:

In this phase II study, patients with B-cell lymphoma (n = 23) or leukemia (n = 1) received one or two infusions of third-generation CD19-directed CAR-Ts (2 × 108/m2). The clinical trial was registered at clinicaltrials.gov: NCT03068416. We investigated the transcriptional profile of individual CD19 CAR-T infusion products using targeted single-cell RNA sequencing and multicolor flow cytometry.

Results:

Two CAR-T infusions were not better than one in the settings used in this study. As for the CAR-T infusion products, we found that effector-like CD8+CAR-Ts with a high polyfunctionality, high cytotoxic and cytokine production profile, and low dysfunctional signature were associated with clinical response. An extended ex vivo expansion time during CAR-T manufacturing negatively influenced the proportion of effector CD8+CAR-Ts in the infusion product.

Conclusions:

We identified cell-intrinsic characteristics of effector CD8+CAR-Ts correlating with response that could be used as an indicator for clinical outcome. The results in the study also serve as a guide to CAR-T manufacturing practices.
Depth of Radiographic Response and Time to Tumor Regrowth Predicts Overall Survival Following Anti-VEGF Therapy in Recurrent Glioblastoma
Authors: Ellingson Benjamin M. , Hagiwara Akifumi , Morris Connor J. , Cho Nicholas S. , Oshima Sonoko , Sanvito Francesco , Oughourlian Talia C. , Telesca Donatello , Raymond Catalina , Abrey Lauren E. , Garcia Josep , Aftab Dana T. , Hessel Colin , Rachmilewitz Minei Tamar , Harats Dror , Nathanson David A. , Wen Patrick Y. , Cloughesy Timothy F.
Published: August 2023

Purpose:

Antiangiogenic therapies are known to cause high radiographic response rates due to reduction in vascular permeability resulting in a lower degree of contrast extravasation. In this study, we investigate the prognostic ability for model-derived parameters describing enhancing tumor volumetric dynamics to predict survival in recurrent glioblastoma treated with antiangiogenic therapy.

Experimental Design:

N = 276 patients in two phase II trials were used as training data, including bevacizumab ± irinotecan (NCT00345163) and cabozantinib (NCT00704288), and N = 74 patients in the bevacizumab arm of a phase III trial (NCT02511405) were used for validation. Enhancing volumes were estimated using T1 subtraction maps, and a biexponential model was used to estimate regrowth (g) and regression (d) rates, time to tumor regrowth (TTG), and the depth of response (DpR). Response characteristics were compared to diffusion MR phenotypes previously shown to predict survival.

Results:

Optimized thresholds occurred at g = 0.07 months−1 (phase II: HR = 0.2579, P = 5 × 10−20; phase III: HR = 0.2197, P = 5 × 10−5); d = 0.11 months−1 (HR = 0.3365, P < 0.0001; HR = 0.3675, P = 0.0113); TTG = 3.8 months (HR = 0.2702, P = 6 × 10−17; HR = 0.2061, P = 2 × 10−5); and DpR = 11.3% (HR = 0.6326, P = 0.0028; HR = 0.4785, P = 0.0206). Multivariable Cox regression controlling for age and baseline tumor volume confirmed these factors as significant predictors of survival. Patients with a favorable pretreatment diffusion MRI phenotype had a significantly longer TTG and slower regrowth.

Conclusions:

Recurrent glioblastoma patients with a large, durable radiographic response to antiangiogenic agents have significantly longer survival. This information is useful for interpreting activity of antiangiogenic agents in recurrent glioblastoma.
Supplementary table 3 from Spectrum of Response to Platinum and PARP Inhibitors in Germline BRCA–Associated Pancreatic Cancer in the Clinical and Preclinical Setting
Authors: Stossel Chani , Raitses-Gurevich Maria , Atias Dikla , Beller Tamar , Glick Gorman Yulia , Halperin Sharon , Peer Eyal , Denroche Robert E. , Zhang Amy , Notta Faiyaz , Wilson Julie M. , O'Kane Grainne M. , Haimov Talmoud Elina , Amison Nora , Schvimer Michael , Salpeter Seth J. , Bar Vered , Zundelevich Adi , Tirosh Itay , Tal Rotem , Dinstag Gal , Kinar Yaron , Eliezer Yonatan , Ben-David Uri , Gavert Nancy S. , Straussman Ravid , Gallinger Steven J. , Berger Raanan , Golan Talia
Published: August 2023

20 genes in DDR resistance
Supplementary table 2 from Spectrum of Response to Platinum and PARP Inhibitors in Germline BRCA–Associated Pancreatic Cancer in the Clinical and Preclinical Setting
Authors: Stossel Chani , Raitses-Gurevich Maria , Atias Dikla , Beller Tamar , Glick Gorman Yulia , Halperin Sharon , Peer Eyal , Denroche Robert E. , Zhang Amy , Notta Faiyaz , Wilson Julie M. , O'Kane Grainne M. , Haimov Talmoud Elina , Amison Nora , Schvimer Michael , Salpeter Seth J. , Bar Vered , Zundelevich Adi , Tirosh Itay , Tal Rotem , Dinstag Gal , Kinar Yaron , Eliezer Yonatan , Ben-David Uri , Gavert Nancy S. , Straussman Ravid , Gallinger Steven J. , Berger Raanan , Golan Talia
Published: August 2023

Clinical data of analyzed BRCA PDAC patients
Supplementary Table S6 from Clinical Activity and Exploratory Resistance Mechanism of Milademetan, an MDM2 Inhibitor, in Intimal Sarcoma with MDM2 Amplification: An Open-Label Phase Ib/II Study
Authors: Koyama Takafumi , Shimizu Toshio , Kojima Yuki , Sudo Kazuki , Okuma Hitomi Sumiyoshi , Shimoi Tatsunori , Ichikawa Hitoshi , Kohsaka Shinji , Sadachi Ryo , Hirakawa Akihiro , Yoshida Akihiko , Ando Reiko Makihara , Ueno Toshihide , Yanagaki Mitsuru , Matsui Naoko , Nakamura Kenichi , Yamamoto Noboru , Yonemori Kan
Published: August 2023

Targeted sequencing analysis of cell-free DNA samples
Supplementary Table S5B from Clinical Activity and Exploratory Resistance Mechanism of Milademetan, an MDM2 Inhibitor, in Intimal Sarcoma with MDM2 Amplification: An Open-Label Phase Ib/II Study
Authors: Koyama Takafumi , Shimizu Toshio , Kojima Yuki , Sudo Kazuki , Okuma Hitomi Sumiyoshi , Shimoi Tatsunori , Ichikawa Hitoshi , Kohsaka Shinji , Sadachi Ryo , Hirakawa Akihiro , Yoshida Akihiko , Ando Reiko Makihara , Ueno Toshihide , Yanagaki Mitsuru , Matsui Naoko , Nakamura Kenichi , Yamamoto Noboru , Yonemori Kan
Published: August 2023

Whole-exome sequencing and RNA sequencing analyses of tumor tissue samples at pre-and post-treatment
Supplementary figure 2 from Spectrum of Response to Platinum and PARP Inhibitors in Germline BRCA–Associated Pancreatic Cancer in the Clinical and Preclinical Setting
Authors: Stossel Chani , Raitses-Gurevich Maria , Atias Dikla , Beller Tamar , Glick Gorman Yulia , Halperin Sharon , Peer Eyal , Denroche Robert E. , Zhang Amy , Notta Faiyaz , Wilson Julie M. , O'Kane Grainne M. , Haimov Talmoud Elina , Amison Nora , Schvimer Michael , Salpeter Seth J. , Bar Vered , Zundelevich Adi , Tirosh Itay , Tal Rotem , Dinstag Gal , Kinar Yaron , Eliezer Yonatan , Ben-David Uri , Gavert Nancy S. , Straussman Ravid , Gallinger Steven J. , Berger Raanan , Golan Talia
Published: August 2023

Mechanisms of resistance in glBRCA PDAC
Supplementary Table S1 from Clinical Activity and Exploratory Resistance Mechanism of Milademetan, an MDM2 Inhibitor, in Intimal Sarcoma with MDM2 Amplification: An Open-Label Phase Ib/II Study
Authors: Koyama Takafumi , Shimizu Toshio , Kojima Yuki , Sudo Kazuki , Okuma Hitomi Sumiyoshi , Shimoi Tatsunori , Ichikawa Hitoshi , Kohsaka Shinji , Sadachi Ryo , Hirakawa Akihiro , Yoshida Akihiko , Ando Reiko Makihara , Ueno Toshihide , Yanagaki Mitsuru , Matsui Naoko , Nakamura Kenichi , Yamamoto Noboru , Yonemori Kan
Published: August 2023

Representativeness of study participant
Supplementary Figure S4B from Clinical Activity and Exploratory Resistance Mechanism of Milademetan, an MDM2 Inhibitor, in Intimal Sarcoma with MDM2 Amplification: An Open-Label Phase Ib/II Study
Authors: Koyama Takafumi , Shimizu Toshio , Kojima Yuki , Sudo Kazuki , Okuma Hitomi Sumiyoshi , Shimoi Tatsunori , Ichikawa Hitoshi , Kohsaka Shinji , Sadachi Ryo , Hirakawa Akihiro , Yoshida Akihiko , Ando Reiko Makihara , Ueno Toshihide , Yanagaki Mitsuru , Matsui Naoko , Nakamura Kenichi , Yamamoto Noboru , Yonemori Kan
Published: August 2023

Anti-tumor activity
Supplementary Figure S2 from Clinical Activity and Exploratory Resistance Mechanism of Milademetan, an MDM2 Inhibitor, in Intimal Sarcoma with MDM2 Amplification: An Open-Label Phase Ib/II Study
Authors: Koyama Takafumi , Shimizu Toshio , Kojima Yuki , Sudo Kazuki , Okuma Hitomi Sumiyoshi , Shimoi Tatsunori , Ichikawa Hitoshi , Kohsaka Shinji , Sadachi Ryo , Hirakawa Akihiro , Yoshida Akihiko , Ando Reiko Makihara , Ueno Toshihide , Yanagaki Mitsuru , Matsui Naoko , Nakamura Kenichi , Yamamoto Noboru , Yonemori Kan
Published: August 2023

Pharmacokinetics
Supplementary_Table3 from Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hürthle Cell Carcinoma
Authors: Gopal Raj K. , Vantaku Venkata R. , Panda Apekshya , Reimer Bryn , Rath Sneha , To Tsz-Leung , Fisch Adam S. , Cetinbas Murat , Livneh Maia , Calcaterra Michael J. , Gigliotti Benjamin J. , Pierce Kerry A. , Clish Clary B. , Dias-Santagata Dora , Sadow Peter M. , Wirth Lori J. , Daniels Gilbert H. , Sadreyev Ruslan I. , Calvo Sarah E. , Parangi Sareh , Mootha Vamsi K.
Published: August 2023

Supplementary Table3 provides the RNAseq analysis
Table S9 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: August 2023

Supplementary Table 9: Sources of antibodies
Table S8 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: August 2023

Supplementary Table 8: Comparison of clinical safety data for SHP2 inhibitors
Table S7 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: August 2023

Supplementary Table 7: Adverse events for Dose Level 1 patients
Supplementary Figures S1-S7 from Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hürthle Cell Carcinoma
Authors: Gopal Raj K. , Vantaku Venkata R. , Panda Apekshya , Reimer Bryn , Rath Sneha , To Tsz-Leung , Fisch Adam S. , Cetinbas Murat , Livneh Maia , Calcaterra Michael J. , Gigliotti Benjamin J. , Pierce Kerry A. , Clish Clary B. , Dias-Santagata Dora , Sadow Peter M. , Wirth Lori J. , Daniels Gilbert H. , Sadreyev Ruslan I. , Calvo Sarah E. , Parangi Sareh , Mootha Vamsi K.
Published: August 2023

Supplementary Figure 1: Mitochondrial and nuclear DNA alterations in an HCC cohort. Related to Figure 1. Supplementary Figure 2: Transcriptomic landscape of HCC. Related to Figure 2. Supplementary Figure 3: Metabolic signatures of HCC. Related to Figure 3. Supplementary Figure 4: Authentic models of HCC. Related to Figure 4. Supplementary Figure 5: CRISPR screen identifies vulnerability to GPX4 loss in HCC. Related to Figure 5. Supplementary Figure 6: NCI-HCC xenografts are sensitive to ferroptosis. Related to Figure 6. Supplementary Figure 7: Differential effects of OXPHOS inhibition on ferroptosis. Related to Figure 7.
Table S6 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: August 2023

Supplementary Table 6: Disposition of all patients enrolled to Dose Level 1
Figure 7 from Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hürthle Cell Carcinoma
Authors: Gopal Raj K. , Vantaku Venkata R. , Panda Apekshya , Reimer Bryn , Rath Sneha , To Tsz-Leung , Fisch Adam S. , Cetinbas Murat , Livneh Maia , Calcaterra Michael J. , Gigliotti Benjamin J. , Pierce Kerry A. , Clish Clary B. , Dias-Santagata Dora , Sadow Peter M. , Wirth Lori J. , Daniels Gilbert H. , Sadreyev Ruslan I. , Calvo Sarah E. , Parangi Sareh , Mootha Vamsi K.
Published: August 2023

Complex I regulates sensitivity to ferroptosis. A, Schematic of electron (e−) flow from NADH into OXPHOS complexes with site of action for NDI1 (yellow arrow) and piericidin. CoQ, coenzyme Q. B, Cell growth for NCI-HCC cells expressing mitoGFP or NDI1 ± pyruvate. Mean ± SD; n = 2, representative of 3 experiments. Significance tested with unpaired t test: ***, P < 0.001; ns, P > 0.05. mitoGFP, mitochondrial-localized GFP. C, Seahorse XFe96 Analyzer traces of OCR and ECAR in NCI-HCC cells expressing mitoGFP or NDI1 with drug injections (dotted vertical lines). Mean ± SD; n = 5 representative of 2 experiments. D, Dose–response curves for RSL3 plotted as normalized cell number for NCI-HCC cells expressing mitoGFP or NDI1, with brightfield microscopy images. Scale bars, 250 μm; mean ± SD; n = 2, representative of 3 experiments. Pier, piericidin. E, Dose–response curves with normalized cell number for RSL3 ± piericidin in Nthy-ori 3-1 cells expressing mitoGFP or NDI1, with brightfield microscopy images. Scale bars, 250 μm. Mean ± SD; n = 2, representative of 3 experiments. For D and E, break in the x-axis is to allow visualization of 0 nmol/L RSL3, and significance tested with extra sum-of-squares F test: ***, P < 0.0001; ns, P > 0.05. See also Supplementary Fig. S7.
Table S1 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: August 2023

Supplementary Table 1: X-ray crystallography data collection and refinement statistics
Supplementary Methods from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: August 2023

Supplementary Data Title Page, Methods, References
Supplementary Table 1 from The MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study
Authors: LoRusso Patricia , Yamamoto Noboru , Patel Manish R. , Laurie Scott A. , Bauer Todd M. , Geng Junxian , Davenport Teffany , Teufel Michael , Li Jian , Lahmar Mehdi , Gounder Mrinal M.
Published: August 2023

Study representativeness table
Supplementary Methods from The MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study
Authors: LoRusso Patricia , Yamamoto Noboru , Patel Manish R. , Laurie Scott A. , Bauer Todd M. , Geng Junxian , Davenport Teffany , Teufel Michael , Li Jian , Lahmar Mehdi , Gounder Mrinal M.
Published: August 2023

Criteria for enrollment and dose-limiting toxicities
Figure S1 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: August 2023

Supplementary Figure 1: Comparison of the structures of PF-07284892, RMC445507, TNO155 bound to SHP2
Supplementary Table S2 from Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia
Authors: Kan Winnie L. , Dhagat Urmi , Kaufmann Kerstin B. , Hercus Timothy R. , Nero Tracy L. , Zeng Andy G.X. , Toubia John , Barry Emma F. , Broughton Sophie E. , Gomez Guillermo A. , Benard Brooks A. , Dottore Mara , Cheung Tung Shing Karen S. , Boutzen Héléna , Samaraweera Saumya E. , Simpson Kaylene J. , Jin Liqing , Goodall Gregory J. , Begley C. Glenn , Thomas Daniel , Ekert Paul G. , Tvorogov Denis , D'Andrea Richard J. , Dick John E. , Parker Michael W. , Lopez Angel F.
Published: August 2023

Summary of the key interactions in the IL-3R ternary complex in the IL-3R ternary complex crystal structure.
Table S9 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Patient and clinical information for the IPMN samples included in the COMET cohort.
Table S6 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Differentially expressed genes between LG and HGPDAC perilesional spots.
Table S4 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Differentially expressed genes between LG and HGPDAC epilesional spots.
Figure S3 from Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia
Authors: Kan Winnie L. , Dhagat Urmi , Kaufmann Kerstin B. , Hercus Timothy R. , Nero Tracy L. , Zeng Andy G.X. , Toubia John , Barry Emma F. , Broughton Sophie E. , Gomez Guillermo A. , Benard Brooks A. , Dottore Mara , Cheung Tung Shing Karen S. , Boutzen Héléna , Samaraweera Saumya E. , Simpson Kaylene J. , Jin Liqing , Goodall Gregory J. , Begley C. Glenn , Thomas Daniel , Ekert Paul G. , Tvorogov Denis , D'Andrea Richard J. , Dick John E. , Parker Michael W. , Lopez Angel F.
Published: August 2023

IL3Rα P248 at the IL-3R assembly interface is critical for cell differentiation.
Figure S2 from Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia
Authors: Kan Winnie L. , Dhagat Urmi , Kaufmann Kerstin B. , Hercus Timothy R. , Nero Tracy L. , Zeng Andy G.X. , Toubia John , Barry Emma F. , Broughton Sophie E. , Gomez Guillermo A. , Benard Brooks A. , Dottore Mara , Cheung Tung Shing Karen S. , Boutzen Héléna , Samaraweera Saumya E. , Simpson Kaylene J. , Jin Liqing , Goodall Gregory J. , Begley C. Glenn , Thomas Daniel , Ekert Paul G. , Tvorogov Denis , D'Andrea Richard J. , Dick John E. , Parker Michael W. , Lopez Angel F.
Published: August 2023

Key interactions between distinct residues in the IL-3R ternary complex crystal structure.
Figure S1 from Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia
Authors: Kan Winnie L. , Dhagat Urmi , Kaufmann Kerstin B. , Hercus Timothy R. , Nero Tracy L. , Zeng Andy G.X. , Toubia John , Barry Emma F. , Broughton Sophie E. , Gomez Guillermo A. , Benard Brooks A. , Dottore Mara , Cheung Tung Shing Karen S. , Boutzen Héléna , Samaraweera Saumya E. , Simpson Kaylene J. , Jin Liqing , Goodall Gregory J. , Begley C. Glenn , Thomas Daniel , Ekert Paul G. , Tvorogov Denis , D'Andrea Richard J. , Dick John E. , Parker Michael W. , Lopez Angel F.
Published: August 2023

IL3Rα/βc transcript and protein expression ratio in AML patient samples.
Table S17 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Markers per clusters generated from ST analyses of two pancreas specimens collected from Kras;Gnas mice.
Table S16 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Top regulons in LG NKX6-2 positive and negative IPMN spots predicted with SCENIC.
Table S12 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Differentially expressed genes between NKX6-2 "high", "mid", and "low" spots.
Table S11 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Counts and percentage of NKX6-2 positive nuclei in HG vs LG IPMN samples as determined by quantification of the COMET images.
Data from Mitochondrial-Encoded Complex I Impairment Induces a Targetable Dependency on Aerobic Fermentation in Hürthle Cell Carcinoma of the Thyroid
Authors: Frank Anderson R. , Li Vicky , Shelton Spencer D. , Kim Jiwoong , Stott Gordon M. , Neckers Leonard M. , Xie Yang , Williams Noelle S. , Mishra Prashant , McFadden David G.
Published: August 2023

Abstract
A metabolic hallmark of cancer identified by Warburg is the increased consumption of glucose and secretion of lactate, even in the presence of oxygen. Although many tumors exhibit increased glycolytic activity, most forms of cancer rely on mitochondrial respiration for tumor growth. We report here that Hürthle cell carcinoma of the thyroid (HTC) models harboring mitochondrial DNA-encoded defects in complex I of the mitochondrial electron transport chain exhibit impaired respiration and alterations in glucose metabolism. CRISPR–Cas9 pooled screening identified glycolytic enzymes as selectively essential in complex I–mutant HTC cells. We demonstrate in cultured cells and a patient-derived xenograft model that small-molecule inhibitors of lactate dehydrogenase selectively induce an ATP crisis and cell death in HTC. This work demonstrates that complex I loss exposes fermentation as a therapeutic target in HTC and has implications for other tumors bearing mutations that irreversibly damage mitochondrial respiration.
Significance:
HTC is enriched in somatic mtDNA mutations predicted to affect complex I of the electron transport chain (ETC). We demonstrate that these mutations impair respiration and induce a therapeutically tractable reliance on aerobic fermentation for cell survival. This work provides a rationale for targeting fermentation in cancers harboring irreversible genetically encoded ETC defects.

See related article by Gopal et al., p. 1904.

This article is highlighted in the In This Issue feature, p. 1749