Nardi et al. report that eIF4A inhibitors improve the efficacy of KRAS G12C inhibitors in non-small cell lung cancer by suppressing prosurvival BCL-2 family proteins. MYC expression drives dependency and is a biomarker of sensitivity. Image credit: Arif biswas/Shutterstock.
Luke V. Rasmussen, Eric W. Whitley, Leah J. Welty
The pulmonary vasculature has been frequently overlooked in acute and chronic lung diseases, such as acute respiratory distress syndrome (ARDS), pulmonary fibrosis (PF), and chronic obstructive pulmonary disease (COPD). The primary emphasis in the management of these parenchymal disorders has largely revolved around the injury and aberrant repair of epithelial cells. However, there is increasing evidence that the vascular endothelium plays an active role in the development of acute and chronic lung diseases. The endothelial cell network in the capillary bed and the arterial and venous vessels provides a metabolically highly active barrier that controls the migration of immune cells, regulates vascular tone and permeability, and participates in the remodeling processes. Phenotypically and functionally altered endothelial cells, and remodeled vessels, can be found in acute and chronic lung diseases, although to different degrees, likely because of disease-specific mechanisms. Since vascular remodeling is associated with pulmonary hypertension, which worsens patient outcomes and survival, it is crucial to understand the underlying vascular alterations. In this Review, we describe the current knowledge regarding the role of the pulmonary vasculature in the development and progression of ARDS, PF, and COPD; we also outline future research directions with the hope of facilitating the development of mechanism-based therapies.
Izabela Borek, Anna Birnhuber, Norbert F. Voelkel, Leigh M. Marsh, Grazyna Kwapiszewska
Infectious diarrhea is a major cause of morbidity and mortality, particularly for children in low- and middle-income countries. Cryptosporidium is a diarrheal pathogen for which there is no vaccine and current therapies are only partially effective. In this issue of the JCI, Gilchrist, Campo, and colleagues surveyed a large cohort of Bangladeshi children to profile antibody responses against an array of Cryptosporidium proteins. They discovered 233 proteins to which children developed antibodies, identified seven as being associated with protection from reinfection, and provided insights regarding the longevity of Cryptosporidium antibodies and the development of antibody breadth. In this commentary, we discuss the burden of disease caused by Cryptosporidium and how these studies highlight the strategies to better manage this parasite.
Ian S. Cohn, Christopher A. Hunter
Nirmal S. Sharma, Kapil Patel, Ezgi Sari, Shruti Shankar, Maria G. Gastanadui, Diego Moncada-Giraldo, Yixel Soto-Vazquez, Delores Stacks, Louise Hecker, Kevin Dsouza, Mudassir Banday, Edward O’Neill, Paul Benson, Gregory Payne, Camilla Margaroli, Amit Gaggar
Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding transactive response DNA-binding protein 43 kDa (TDP-43), account for less than 1% of all ALS cases, TDP-43–positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS–causing (fALS-causing) mutations. Interestingly, TDP-43 inclusions are also present in subsets of patients with frontotemporal dementia, Alzheimer’s disease, and Parkinson’s disease; therefore, methods of activating intracellular protein quality control machinery capable of clearing toxic cytoplasmic TDP-43 species may alleviate disease-related phenotypes. Here, we identify a function of nemo-like kinase (Nlk) as a negative regulator of lysosome biogenesis. Genetic or pharmacological reduction of Nlk increased lysosome formation and improved clearance of aggregated TDP-43. Furthermore, Nlk reduction ameliorated pathological, behavioral, and life span deficits in 2 distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared through the autophagy/lysosome pathway, targeted reduction of Nlk represents a potential approach to therapy development for multiple neurodegenerative disorders.
Leon Tejwani, Youngseob Jung, Hiroshi Kokubu, Sowmithra Sowmithra, Luhan Ni, Changwoo Lee, Benjamin Sanders, Paul J. Lee, Yangfei Xiang, Kimberly Luttik, Armand Soriano, Jennifer Yoon, Junhyun Park, Hannah H. Ro, Hyoungseok Ju, Clara Liao, Sofia Massaro Tieze, Frank Rigo, Paymaan Jafar-Nejad, Janghoo Lim
There is no vaccine to protect from cryptosporidiosis, a leading cause of diarrhea in infants in low- and middle-income countries. Here, we comprehensively identified parasite antigens associated with protection from reinfection. A Cryptosporidium protein microarray was constructed by in vitro transcription and translation of 1,761 C. parvum, C. hominis, or C. meleagridis antigens, including proteins with a signal peptide and/or a transmembrane domain. Plasma IgG and/or IgA from Bangladeshi children longitudinally followed for cryptosporidiosis from birth to 3 years of age allowed for identification of 233 seroreactive proteins. Seven of these were associated with protection from reinfection. These included Cp23, Cp17, Gp900, and 4 additional antigens — CpSMP1, CpMuc8, CpCorA and CpCCDC1. Infection in the first year of life, however, often resulted in no detectable antigen-specific antibody response, and antibody responses, when detected, were specific to the infecting parasite genotype and decayed in the months after infection. In conclusion, humoral immune responses against specific parasite antigens were associated with acquired immunity. While antibody decay over time and parasite genotype-specificity may limit natural immunity, this work serves as a foundation for antigen selection for vaccine design.
Carol A. Gilchrist, Joseph J. Campo, Jozelyn V. Pablo, Jennie Z. Ma, Andy Teng, Amit Oberai, Adam D. Shandling, Masud Alam, Mamun Kabir, A.S.G. Faruque, Rashidul Haque, William A. Petri Jr.
Despite the success of KRAS G12C inhibitors in non–small cell lung cancer (NSCLC), more effective treatments are needed. One preclinical strategy has been to cotarget RAS and mTOR pathways; however, toxicity due to broad mTOR inhibition has limited its utility. Therefore, we sought to develop a more refined means of targeting cap-dependent translation and identifying the most therapeutically important eukaryotic initiation factor 4F complex–translated (eIF4F-translated) targets. Here, we show that an eIF4A inhibitor, which targets a component of eIF4F, dramatically enhances the effects of KRAS G12C inhibitors in NSCLCs and together these agents induce potent tumor regression in vivo. By screening a broad panel of eIF4F targets, we show that this cooperativity is driven by effects on BCL-2 family proteins. Moreover, because multiple BCL-2 family members are concomitantly suppressed, these agents are broadly efficacious in NSCLCs, irrespective of their dependency on MCL1, BCL-xL, or BCL-2, which is known to be heterogeneous. Finally, we show that MYC overexpression confers sensitivity to this combination because it creates a dependency on eIF4A for BCL-2 family protein expression. Together, these studies identify a promising therapeutic strategy for KRAS-mutant NSCLCs, demonstrate that BCL-2 proteins are the key mediators of the therapeutic response in this tumor type, and uncover a predictive biomarker of sensitivity.
Francesca Nardi, Naiara Perurena, Amy E. Schade, Ze-Hua Li, Kenneth Ngo, Elena V. Ivanova, Aisha Saldanha, Chendi Li, Prafulla C. Gokhale, Aaron N. Hata, David A. Barbie, Cloud P. Paweletz, Pasi A. Jänne, Karen Cichowski
Long-acting antiretroviral agents for preexposure prophylaxis (PrEP) represent a promising new alternative to daily oral regimens for HIV prevention. Lenacapavir (LEN) is a first-in-class long-acting capsid inhibitor approved for the treatment of HIV-1 infection. Here, we assessed the efficacy of LEN for PrEP using a single high-dose simian-human immunodeficiency virus (SHIV) rectal challenge macaque model. In vitro, LEN showed potent antiviral activity against SHIV, as it did for HIV-1. In macaques, a single subcutaneous administration of LEN demonstrated dose proportional increases in and durability of drug plasma levels. A high-dose SHIV inoculum for the PrEP efficacy evaluation was identified via virus titration in untreated macaques. LEN-treated macaques were challenged with high-dose SHIV 7 weeks after drug administration, and the majority remained protected from infection, as confirmed by plasma PCR, cell-associated proviral DNA, and serology testing. Complete protection and superiority to the untreated group was observed among animals whose LEN plasma exposure exceeded its model-adjusted clinical efficacy target at the time of challenge. All infected animals had subprotective LEN concentrations and showed no emergent resistance. These data demonstrate effective SHIV prophylaxis in a stringent macaque model at clinically relevant LEN exposures and support the clinical evaluation of LEN for HIV PrEP in humans.
Elena Bekerman, Stephen R. Yant, Laurie VanderVeen, Derek Hansen, Bing Lu, William Rowe, Kelly Wang, Christian Callebaut
BACKGROUND Food allergy (FA) is a growing health problem requiring physiologic confirmation via the oral food challenge (OFC). Many OFCs result in clinical anaphylaxis, causing discomfort and risk while limiting OFC utility. Transepidermal water loss (TEWL) measurement provides a potential solution to detect food anaphylaxis in real time prior to clinical symptoms. We evaluated whether TEWL changes during an OFC could predict anaphylaxis onset.METHODS Physicians and nurses blinded to the TEWL results conducted and adjudicated the results of all 209 OFCs in this study. A study coordinator measured TEWL throughout the OFC and had no input on the OFC conduct. TEWL was measured 2 ways in 2 separate groups. First, TEWL was measured using static, discrete measurements. Second, TEWL was measured using continuous monitoring. Participants who consented provided blood samples before and after the OFCs for biomarker analyses.RESULTS TEWL rose significantly (2.93 g/m2/h) during reactions and did not rise during nonreacting OFCs (–1.00 g/m2/h). Systemic increases in tryptase and IL-3 were also detected during reactions, providing supporting biochemical evidence of anaphylaxis. The TEWL rise occurred 48 minutes earlier than clinically evident anaphylaxis. Continuous monitoring detected a significant rise in TEWL that presaged positive OFCs, but no rise was seen in the OFCs that resulted in no reaction, providing high predictive specificity (96%) for anaphylaxis against nonreactions 38 minutes prior to anaphylaxis onset.CONCLUSIONS During OFCs, a TEWL rise anticipated a positive clinical challenge. TEWL presents a monitoring modality that may predict food anaphylaxis and facilitate improvements in OFC safety and tolerability.
Charles F. Schuler IV, Kelly M. O’Shea, Jonathan P. Troost, Bridgette Kaul, Christopher M. Launius, Jayme Cannon, David M. Manthei, George E. Freigeh, Georgiana M. Sanders, Simon P. Hogan, Nicholas W. Lukacs, James R. Baker Jr.
BACKGROUND Typhoid fever is caused by the Gram-negative bacterium Salmonella enterica serovar Typhi and poses a substantial public health burden worldwide. Vaccines have been developed based on the surface Vi-capsular polysaccharide of S. Typhi; these include a plain-polysaccharide-based vaccine, ViPS, and a glycoconjugate vaccine, ViTT. To understand immune responses to these vaccines and their vaccine-induced immunological protection, molecular signatures were analyzed using bioinformatic approaches.METHODS Bulk RNA-Seq data were generated from blood samples obtained from adult human volunteers enrolled in a vaccine trial, who were then challenged with S. Typhi in a controlled human infection model (CHIM). These data were used to conduct differential gene expression analyses, gene set and modular analyses, B cell repertoire analyses, and time-course analyses at various post-vaccination and post-challenge time points between participants receiving ViTT, ViPS, or a control meningococcal vaccine.RESULTS Transcriptomic responses revealed strong differential molecular signatures between the 2 typhoid vaccines, mostly driven by the upregulation in humoral immune signatures, including selective usage of immunoglobulin heavy chain variable region (IGHV) genes and more polarized clonal expansions. We describe several molecular correlates of protection against S. Typhi infection, including clusters of B cell receptor (BCR) clonotypes associated with protection, with known binders of Vi-polysaccharide among these.CONCLUSION The study reports a series of contemporary analyses that reveal the transcriptomic signatures after vaccination and infectious challenge, while identifying molecular correlates of protection that may inform future vaccine design and assessment.TRIAL REGISTRATION ClinicalTrials.gov NCT02324751.
Henderson Zhu, Irina Chelysheva, Deborah L. Cross, Luke Blackwell, Celina Jin, Malick M. Gibani, Elizabeth Jones, Jennifer Hill, Johannes Trück, Dominic F. Kelly, Christoph J. Blohmke, Andrew J. Pollard, Daniel O’Connor
BACKGROUND IgE-mediated anaphylaxis is a potentially fatal systemic allergic reaction for which there are no currently FDA-approved preventative therapies. Bruton’s tyrosine kinase (BTK) is an essential enzyme for IgE-mediated signaling pathways and is an ideal pharmacologic target to prevent allergic reactions. In this open-label trial, we evaluated the safety and efficacy of acalabrutinib, a BTK inhibitor that is FDA approved to treat some B cell malignancies, in preventing clinical reactivity to peanut in adults with peanut allergy.METHODS After undergoing graded oral peanut challenge to establish their baseline level of clinical reactivity, 10 patients had a 6-week rest period, then received 4 standard doses of 100 mg acalabrutinib twice daily and underwent repeat food challenge. The primary endpoint was the change in patients’ threshold dose of peanut protein to elicit an objective clinical reaction.RESULTS At baseline, patients tolerated a median of 29 mg of peanut protein before objective clinical reaction. During subsequent food challenge on acalabrutinib, patients’ median tolerated dose significantly increased to 4,044 mg (range 444–4,044 mg). 7 patients tolerated the maximum protocol amount (4,044 mg) of peanut protein with no clinical reaction, and the other 3 patients’ peanut tolerance increased between 32- and 217-fold. 3 patients experienced a total of 4 adverse events that were considered to be possibly related to acalabrutinib; all events were transient and nonserious.CONCLUSION Acalabrutinib pretreatment achieved clinically relevant increases in patients’ tolerance to their food allergen, thereby supporting the need for larger, placebo-controlled trials.TRIAL REGISTRATION ClinicalTrials.gov NCT05038904FUNDING AstraZeneca Pharmaceuticals, the Johns Hopkins Institute for Clinical and Translational Research, the Ludwig Family Foundation, and NIH grants AI143965 and AI106043.
Ragha V. Suresh, Collin Dunnam, Dhananjay Vaidya, Robert A. Wood, Bruce S. Bochner, Donald W. MacGlashan Jr., Melanie C. Dispenza