tbuckley/cabot-search huggingface dataset:
Dual Agonists for Management of Metabolic Dysfunction–Associated Steatohepatitis
Authors: Fasiha Kanwal
Journal: New England Journal of Medicine (2024)

Metabolic dysfunction–associated steatohepatitis (MASH) is the most common liver disease worldwide, and its prevalence is increasing rapidly.1 Yet, effective treatments for MASH remain scarce. Obesity plays a central role in MASH. Glucagon-like peptide-1 (GLP-1) receptor agonists are emerging as the most promising antiobesity treatments2 and could serve as an option for patients with MASH. Few studies have examined the efficacy of GLP-1 receptor agonists in MASH. In a phase 2 trial, treatment with semaglutide — a GLP-1 receptor agonist — led to resolution of steatohepatitis in 40 to 59% of patients but fell short of showing a significant reduction in . . .
Case 23-2024: A 78-Year-Old Woman with Rapidly Progressive Dementia
Authors: Eric E Smith, Saurabh Rohatgi, Jenny J Linnoila, Maria Martinez-Lage
Journal: New England Journal of Medicine (2024)

A 78-year-old woman with a history of breast and lung cancers presented with confusion. MRI of the head revealed hyperintensities in the anterior and medial temporal lobes. A diagnosis was made.
Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults
Authors: Mark R Litzow, Zhuoxin Sun, Ryan J Mattison, Elisabeth M Paietta, Kathryn G Roberts, Yanming Zhang, Janis Racevskis, Hillard M Lazarus, Jacob M Rowe, Daniel A Arber, Matthew J Wieduwilt, Michaela Liedtke, Julie Bergeron, Brent L Wood, Yaqi Zhao, Gang Wu, Ti-Cheng Chang, Wenchao Zhang, Keith W Pratz, Shira N Dinner, Noelle Frey, Steven D Gore, Bhavana Bhatnagar, Ehab L Atallah, Geoffrey L Uy, Deepa Jeyakumar, Tara L Lin, Cheryl L Willman, Daniel J DeAngelo, Shejal B Patel, Michelle A Elliott, Anjali S Advani, Dimitrios Tzachanis, Pankit Vachhani, Rupali R Bhave, Elad Sharon, Richard F Little, Harry P Erba, Richard M Stone, Selina M Luger, Charles G Mullighan, Martin S Tallman
Journal: New England Journal of Medicine (2024)

Many older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission.
Tyrosine Kinase Inhibitors With and Without Up-Front Stereotactic Radiosurgery for Brain Metastases From <i>EGFR</i> and <i>ALK</i> Oncogene–Driven Non–Small Cell Lung Cancer (TURBO-NSCLC)
Authors: Luke R.G. Pike, Emily Miao, Lillian A. Boe, Tejas Patil, Brandon S. Imber, Nathaniel J. Myall, Erqi L. Pollom, Caressa Hui, Vera Qu, Jacob Langston, Veronica Chiang, Michael Grant, Sarah B. Goldberg, Joshua D. Palmer, Rahul N. Prasad, Tony J.C. Wang, Albert Lee, Catherine A. Shu, Lanyi Nora Chen, Nicholas J. Thomas, Steve E. Braunstein, Brian D. Kavanagh, D. Ross Camidge, Chad G. Rusthoven
Journal: Journal of Clinical Oncology (2024)

PURPOSE Newer-generation tyrosine kinase inhibitors (TKIs) for non–small cell lung cancer (NSCLC) with epidermal growth factor receptor ( EGFR ) mutations and anaplastic lymphoma kinase ( ALK ) rearrangements have demonstrated high CNS activity. The optimal use of up-front stereotactic radiosurgery (SRS) for brain metastases (BM) in patients eligible for CNS-penetrant TKIs is controversial, and data to guide patient management are limited. MATERIALS AND METHODS Data on TKI-naïve patients with EGFR- and ALK-driven NSCLC with BM treated with CNS-penetrant TKIs with and without up-front SRS were retrospectively collected from seven academic centers in the United States. Time-to-CNS progression and overall survival (OS) were analyzed, with multivariable adjustment in Fine &amp; Gray and Cox proportional hazards models for clinically relevant factors. RESULTS From 2013 to 2022, 317 patients were identified (200 TKI-only and 117 TKI + SRS). Two hundred fifty (79%) and 61 (19%) patients received osimertinib and alectinib, respectively. Patients receiving TKI + SRS were more likely to have BM ≥1 cm ( P &lt; .001) and neurologic symptoms ( P &lt; .001) at presentation. Median OS was similar between the TKI and TKI + SRS groups (median 41 v 40 months, respectively; P = .5). On multivariable analysis, TKI + SRS was associated with a significant improvement in time-to-CNS progression (hazard ratio [HR], 0.63 [95% CI, 0.42 to 0.96]; P = .033). Local CNS control was significantly improved with TKI + SRS (HR, 0.30 [95% CI, 0.16 to 0.55]; P &lt; .001), whereas no significant differences were observed in distant CNS control. Subgroup analyses demonstrated a greater benefit from TKI + SRS in patients with BM ≥1 cm in diameter for time-to-CNS progression and CNS progression-free survival. CONCLUSION The addition of up-front SRS to CNS-penetrant TKI improved time-to-CNS progression and local CNS control, but not OS, in patients with BM from EGFR - and ALK-driven NSCLC. Patients with larger BM (≥1 cm) may benefit the most from up-front SRS.
AFDN deficiency promotes liver tropism of metastatic colorectal cancer
Authors: Shaoxia Liao, Jingwen Deng, Mengli Deng, Chaoyi Chen, Fengyan Han, Kehong Ye, Chenxia Wu, Lvyuan Pan, Maode Lai, Zhe Tang, Honghe Zhang
Journal: Cancer Research (2024)

Abstract Liver metastasis is a major cause of morbidity and mortality in patients with colorectal cancer. A better understanding of the biological mechanisms underlying liver tropism and metastasis in colorectal cancer could help to identify improved prevention and treatment strategies. In this study, we performed genome-wide CRISPR loss-of-function screening in a mouse colorectal cancer model and identified deficiency of AFDN, a protein involved in establishing and maintaining cell–cell contacts, as a driver of liver metastasis. Elevated AFDN expression was correlated with prolonged survival in patients with colorectal cancer. AFDN-deficient colorectal cancer cells preferentially metastasized to the liver but not in the lungs. AFDN loss in colorectal cancer cells at the primary site promoted cancer cell migration and invasion by disrupting tight intercellular junctions. Additionally, CXCR4 expression was increased in AFDN-deficient colorectal cancer cells via the JAK-STAT signaling pathway, which reduced the motility of AFDN-deficient colorectal cancer cells and facilitated their colonization of the liver. Collectively, these data shed light on the mechanism by which AFDN deficiency promotes liver tropism in metastatic colorectal cancer. Significance: A CRISPR screen reveals AFDN loss as a mediator of liver tropism in colorectal cancer metastasis by decreasing tight junctions in the primary tumor and increasing interactions between cancer cells and hepatocytes.
m6A-Mediated Induction of 7-Dehydrocholesterol Reductase Stimulates Cholesterol Synthesis and cAMP Signaling to Promote Bladder Cancer Metastasis
Authors: Youmiao Zeng, Yongbo Luo, Keyuan Zhao, Sheng Liu, Kaiwen Wu, Yudong Wu, Kaixuan Du, Wenbang Pan, Yiheng Dai, Yuanhao Liu, Mengda Ren, Fengyan Tian, Lijie Zhou, Chaohui Gu
Journal: Cancer Research (2024)

Dysregulation of cholesterol homeostasis occurs in multiple types of tumors and promotes cancer progression. Investigating the specific processes that induce abnormal cholesterol metabolism could identify therapeutic targets to improve cancer treatment. In this investigation, we observed upregulation of 7-dehydrocholesterol reductase (DHCR7), a vital enzyme involved in the synthesis of cholesterol, within bladder cancer tissues in comparison to normal tissues, which was correlated with increased bladder cancer metastasis. Increased expression of DHCR7 in bladder cancer was attributed to decreased mRNA degradation mediated by YTHDF2. Loss or inhibition of DHCR7 reduced bladder cancer cell invasion in vitro and metastasis in vivo. Mechanistically, DHCR7 promoted bladder cancer metastasis by activating the cAMP/protein kinase A/FAK pathway. Specifically, DHCR7 increased cAMP levels by elevating cholesterol content in lipid rafts, thereby facilitating the transduction of signaling pathways mediated by cAMP receptors. DHCR7 additionally enhanced the cAMP signaling pathway by reducing the concentration of 7-dehydrocholesterol and promoting the transcription of the G protein-coupled receptor, namely gastric inhibitory polypeptide receptor. Overall, these findings demonstrate that DHCR7 plays an important role in bladder cancer invasion and metastasis by modulating cholesterol synthesis and cAMP signaling. Furthermore, inhibition of DHCR7 shows promise as a viable therapeutic strategy for suppressing bladder cancer invasion and metastasis. Significance: Inhibiting DHCR7 induces cholesterol metabolism reprogramming and lipid raft remodeling to inactivate the cAMP/protein kinase A/FAK axis and suppress bladder cancer metastasis, indicating the therapeutic potential of targeting DHCR7.
FOXP4 is a Direct YAP1 Target that Promotes Gastric Cancer Stemness and Drives Metastasis
Authors: Xiaoli Liu, Bonan Chen, Fuda Xie, Kit Yee. Wong, Alvin Ho-Kwan. Cheung, Jinglin Zhang, Qian Wu, Canbin Fang, Jintao Hu, Shouyu Wang, Dazhi Xu, Jianwu Chen, Yuzhi Wang, Chi Chun. Wong, Huarong Chen, William Ka Kei. Wu, Jun Yu, Michael W.Y. Chan, Chi Man. Tsang, Kwok Wai. Lo, Gary M.K. Tse, Ka-Fai To, Wei Kang
Journal: Cancer Research (2024)

Abstract The Hippo–YAP1 pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration. Dysregulation of Hippo–YAP1 signaling promotes initiation and progression of several types of cancer, including gastric cancer. As the Hippo–YAP1 pathway regulates expression of thousands of genes, it is important to establish which target genes contribute to the oncogenic program driven by YAP1 to identify strategies to circumvent it. In this study, we identified a vital role of forkhead box protein 4 (FOXP4) in YAP1-driven gastric carcinogenesis by maintaining stemness and promoting peritoneal metastasis. Loss of FOXP4 impaired gastric cancer spheroid formation and reduced stemness marker expression, whereas FOXP4 upregulation potentiated cancer cell stemness. RNA sequencing analysis revealed SOX12 as a downstream target of FOXP4, and functional studies established that SOX12 supports stemness in YAP1-induced carcinogenesis. A small-molecule screen identified 42-(2-tetrazolyl) rapamycin as a FOXP4 inhibitor, and targeting FOXP4 suppressed gastric cancer tumor growth and enhanced the efficacy of 5-fluorouracil chemotherapy in vivo. Collectively, these findings revealed that FOXP4 upregulation by YAP1 in gastric cancer regulates stemness and tumorigenesis by upregulating SOX12. Targeting the YAP1–FOXP4–SOX12 axis represents a potential therapeutic strategy for gastric cancer. Significance: Hippo–YAP1 signaling maintains stemness in gastric cancer by upregulating FOXP4, identifying FOXP4 as a stemness biomarker and therapeutic target that could help improve patient outcomes.
Utility of the 70-Gene MammaPrint Assay for Prediction of Benefit From Extended Letrozole Therapy in the NRG Oncology/NSABP B-42 Trial
Authors: Priya Rastogi, Hanna Bandos, Peter C. Lucas, Laura J. van ‘t Veer, Jia-Perng J. Wei, Charles E. Geyer, Louis Fehrenbacher, Stephen K.L. Chia, Adam M. Brufsky, Janice M. Walshe, Gamini S. Soori, Shaker R. Dakhil, Soonmyung Paik, Sandra M. Swain, Andrea R. Menicucci, M. William Audeh, Norman Wolmark, Eleftherios P. Mamounas
Journal: Journal of Clinical Oncology (2024)

MammaPrint (MP) determines distant metastatic risk and may improve patient selection for extended endocrine therapy (EET). This study examined MP in predicting extended letrozole therapy (ELT) benefit in patients with early-stage breast cancer (BC) from the NSABP B-42 trial.
Reply to C.T. Matava et al
Authors: Sarah Alexander, John A. Kairalla, Sumit Gupta, Emily Hibbitts, Hannah Weisman, Doralina Anghelescu, Naomi J. Winick, Kevin R. Krull, Wanda L. Salzer, Michael J. Burke, Lia Gore, Meenakshi Devidas, Leanne Embry, Elizabeth A. Raetz, Stephen P. Hunger, Mignon L. Loh, Kristina K. Hardy
Journal: Journal of Clinical Oncology (2024)
Platinum-Based Chemotherapy Induces Opposing Effects on Immunotherapy Response-Related Spatial and Stromal Biomarkers in the Bladder Cancer Microenvironment
Authors: Maksim A. Chelushkin, Jeroen van Dorp, Sandra van Wilpe, Iris M. Seignette, Jan-Jaap J. Mellema, Maartje Alkemade, Alberto Gil-Jimenez, Dennis Peters, Wim Brugman, Chantal F. Stockem, Erik Hooijberg, Annegien Broeks, Bas W.G. van Rhijn, Laura S. Mertens, Antoine G. van der Heijden, Niven Mehra, Maurits L. van Montfoort, Lodewyk F.A. Wessels, Daniel J. Vis, Michiel S. van der Heijden
Journal: Clinical Cancer Research (2024)

Platinum-based chemotherapy and immune checkpoint inhibitors are key components of systemic treatment for muscle-invasive and advanced urothelial cancer. The ideal integration of these two treatment modalities remains unclear as clinical trials have led to inconsistent results. Modulation of the tumor-immune microenvironment by chemotherapy is poorly characterized. We aimed to investigate this modulation, focusing on potential clinical implications for immune checkpoint inhibitor response.
Biomarker analyses investigating disease biology and associations with outcomes in the JAVELIN Merkel 200 trial of avelumab in metastatic Merkel cell carcinoma
Authors: Sandra P. D’Angelo, Céleste Lebbé, Paul Nghiem, Andrew S. Brohl, Thomas Mrowiec, Trent Leslie, Sara Georges, Gülseren Güzel, Parantu Shah
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Avelumab (anti–PD-L1) became the first approved treatment for metastatic Merkel cell carcinoma (mMCC) based on results from the phase II JAVELIN Merkel 200 trial. In this study, we report exploratory biomarker analyses from the trial. Patients and Methods: Patients with mMCC (n = 88) with or without prior first-line chemotherapy received avelumab 10 mg/kg every 2 weeks. We conducted analyses on somatic mutations, mutational signatures, and tumor mutational burden using paired whole-exome sequencing. Additionally, we examined gene and gene set expression, immune content from RNA sequencing profiles, as well as tumor PD-L1 and CD8 statuses from IHC and CD8 status from digital pathology. Results: Tumors positive for Merkel cell polyomavirus (MCPyV) were characterized by an absence of driver mutations and a low tumor mutational burden, consistent with previous studies. A novel MCPyV-specific host gene expression signature was identified. MCPyV+ tumors had increased levels of immunosuppressive M2 macrophages in the tumor microenvironment, which seemed to correlate with PD-L1 expression; high CD8+ T-cell density in these tumors did not predict response to avelumab. Conversely, in patients with MCPyV− tumors, higher CD8+ T-cell density seemed to be associated with response to avelumab. Mutations in several genes were associated with treatment outcomes. Compared with tumors sampled before chemotherapy, tumors sampled after chemotherapy had downregulated gene signatures for immune responses, including reduced expression of IFNγ-related pathways. Levels of activated dendritic cells in responding patients were higher in patients assessed after versus before chemotherapy. Conclusions: Exploratory analyses provide insights into mMCC biology and potential associations with response to avelumab. Chemotherapy seems to negatively modulate the immune microenvironment.
SJPedPanel: A pan-cancer gene panel for childhood malignancies to enhance cancer monitoring and early detection
Authors: Pandurang Kolekar, Vidya Balagopal, Li Dong, Yanling Liu, Scott Foy, Quang Tran, Heather Mulder, Anna L.W. Huskey, Emily Plyler, Zhikai Liang, Jingqun Ma, Joy Nakitandwe, Jiali Gu, Maria Namwanje, Jamie Maciaszek, Debbie Payne-Turner, Saradhi Mallampati, Lu Wang, John Easton, Jeffery M. Klco, Xiaotu Ma
Journal: Clinical Cancer Research (2024)

Abstract Purpose: The purpose of the study was to design a pan-cancer gene panel for childhood malignancies and validate it using clinically characterized patient samples. Experimental Design: In addition to 5,275 coding exons, SJPedPanel also covers 297 introns for fusions/structural variations and 7,590 polymorphic sites for copy-number alterations. Capture uniformity and limit of detection are determined by targeted sequencing of cell lines using dilution experiment. We validate its coverage by in silico analysis of an established real-time clinical genomics (RTCG) cohort of 253 patients. We further validate its performance by targeted resequencing of 113 patient samples from the RTCG cohort. We demonstrate its power in analyzing low tumor burden specimens using morphologic remission and monitoring samples. Results: Among the 485 pathogenic variants reported in RTCG cohort, SJPedPanel covered 86% of variants, including 82% of 90 rearrangements responsible for fusion oncoproteins. In our targeted resequencing cohort, 91% of 389 pathogenic variants are detected. The gene panel enabled us to detect ∼95% of variants at allele fraction (AF) 0.5%, whereas the detection rate is ∼80% at AF 0.2%. The panel detected low-frequency driver alterations from morphologic leukemia remission samples and relapse-enriched alterations from monitoring samples, demonstrating its power for cancer monitoring and early detection. Conclusions: SJPedPanel enables the cost-effective detection of clinically relevant genetic alterations including rearrangements responsible for subtype-defining fusions by targeted sequencing of ∼0.15% of human genome for childhood malignancies. It will enhance the analysis of specimens with low tumor burdens for cancer monitoring and early detection.
The Difficulty in Defining the True High-Risk Smoldering Myeloma
Authors: Niels Weinhold, Leo Rasche
Journal: Clinical Cancer Research (2024)

Early intervention trials have been initiated for the precursor disease smoldering myeloma (SMM). A recent study showed that genomic complexity varies widely among patients treated for high-risk SMM and is associated with response to triplet therapy, suggesting that established clinical risk scores often fail to discriminate between stable and aggressive disease. See related article by Kazandjian et al., p. 4482.
Dynamic Risk Estimation of Adverse Events in Ambulatory LVAD Patients
Authors: Palak Shah, Gabriel Sayer, Shashank S Sinha, Manreet K Kanwar, Jennifer A Cowger, Francis D Pagani, Aditi Nayak, Mandeep R Mehra, Joseph C Cleveland, Mitchell A Psotka, Ramesh Singh, Shashank S Desai, Qianhui Lu, Yajing Hu, Allison Connolly, Robert L Kormos, Nir Uriel
Journal: JACC Heart Failure (2024)
Prevalence, Incidence, and Outcomes of Diastolic Dysfunction in Isolated Tricuspid Regurgitation
Authors: Jwan A Naser, Tomonari Harada, Atsushi Tada, Shunichi Doi, Gal Tsaban, Sorin V Pislaru, Vuyisile T Nkomo, Christopher G Scott, Austin M Kennedy, Mackram F Eleid, Yogesh N V Reddy, Grace Lin, Patricia A Pellikka, Barry A Borlaug
Journal: JACC. Cardiovascular imaging (2024)
Older MRD vs. younger MUD in patients older than 50 years with AML in remission using post-transplant cyclophosphamide
Authors: Simona Piemontese, Myriam Labopin, Goda Choi, Annoek E C Broers, Jacopo Peccatori, Ellen Meijer, Gwendolyn Van Gorkom, Montserrat Rovira, Maria Jesús Pascual Cascon, Simona Sica, Jan Vydra, Alexander Kulagin, Alexandros Spyridonidis, Arnon Nagler, Ali Bazarbachi, Bipin Savani, Eolia Brissot, Jaime Sanz, Mohamad Mohty, Fabio Ciceri
Journal: Leukemia (2024)
Reply: Aspirin and GLP-1RAs—The missing confounders of empagliflozin for MASLD without diabetes mellitus?
Authors: Ka Shing Cheung, Wai K. Leung
Journal: Hepatology (2024)

We thank Hu et al1 for their letter commenting on our recent article "Effect of empagliflozin on liver fat in metabolic-dysfunction associated steatotic liver disease patients without diabetes mellitus: A randomized, double-blind, placebo-controlled trial."2 They commented that aspirin3 and glucagon-like peptide-1 receptor agonists4 may act as confounding factors on the causality of empagliflozin reducing hepatic steatosis in patients with metabolic dysfunction–associated steatotic liver disease without diabetes mellitus. As it was a randomized study, all this information was available, and we reviewed the records of the 98 study participants. There were 11 (11.2%) aspirin users with 5 (10.2%) in the empagliflozin group, and 6 (12.2%) in the control group, with no statistically significant difference between the 2 groups (p = 0.749). There was, however, no glucagon-like peptide-1 receptor agonist user as this study only included patients without diabetes, in which glucagon-like peptide-1 receptor agonist was only approved for this indication locally. However, we did not think subgroup analysis based on aspirin use was meaningful as this study was not powered to explore this. In fact, a properly conducted randomized controlled study would be able to eliminate both measured and unmeasured confounders, including what has been proposed by the authors.1
Liver transplantation provides survival benefit at all levels of frailty: From the Multicenter Functional Assessment in Liver Transplantation Study
Authors: Melinda Wang, Sy Han Chiou, Daniel Ganger, Jessica Ruck, Chiung-Yu Huang, Matthew R. Kappus, Elizabeth A. King, Daniela P. Ladner, Robert S. Rahimi, Andres Duarte-Rojo, Michael L. Volk, Amit D. Tevar, Elizabeth C. Verna, Jennifer C. Lai
Journal: Hepatology (2024)

Offering LT to frail patients may reduce waitlist mortality but may increase post-LT mortality. LT survival benefit is the concept of balancing these risks. We sought to quantify the net survival benefit with LT by liver frailty index (LFI).
Ag-driven CD8+ T cell clonal expansion is a prominent feature of MASH in humans and mice
Authors: Abbigayl E.C. Burtis, Destiny M.C. DeNicola, Megan E. Ferguson, Radleigh G. Santos, Clemencia Pinilla, Michael S. Kriss, David J. Orlicky, Beth A. Jirón Tamburini, Austin E. Gillen, Matthew A. Burchill
Journal: Hepatology (2024)

Background and Aims: Chronic liver disease due to metabolic dysfunction–associated steatohepatitis (MASH) is a rapidly increasing global epidemic. MASH progression is a consequence of the complex interplay between inflammatory insults and dysregulated hepatic immune responses. T lymphocytes have been shown to accumulate in the liver during MASH, but the cause and consequence of T cell accumulation in the liver remain unclear. Our study aimed to define the phenotype and T cell receptor diversity of T cells from human cirrhotic livers and an animal model of MASH to begin resolving their function in disease. Approach and Results: In these studies, we evaluated differences in T cell phenotype in the context of liver disease. Accordingly, we isolated liver resident T cell populations from humans with cirrhosis and from mice with diet-induced MASH. Using both 5’ single-cell sequencing and flow cytometry, we defined the phenotype and T cell receptor repertoire of liver resident T cells during health and disease. Conclusions: MASH-induced human cirrhosis and diet-induced MASH in mice resulted in the accumulation of activated and clonally expanded T cells in the liver. The clonally expanded T cells in the liver expressed markers of chronic antigenic stimulation, including PD1 , TIGIT , and TOX . Overall, this study establishes for the first time that T cells undergo Ag-dependent clonal expansion and functional differentiation during the progression of MASH. These studies could lead to the identification of antigenic targets that drive T cell activation, clonal expansion, and recruitment to the liver during MASH.
Improving vaccine equity by increasing vaccine thermostability
Authors: Jonathan Hare, Renske Hesselink, Alexander Bongers, Paul Blakeley, Giovanna Riggall
Journal: Science Translational Medicine (2024)

The development, manufacture, and deployment of new vaccine technologies to combat SARS-CoV-2 enabled an unparalleled rapid response to the emerging health threat. However, the unequal global distribution of these vaccines highlighted a major gap in existing thermotolerance profiles and cold chain infrastructure that needs to be addressed to maximize their global health impact.