RATIONALE. 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 blind to 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 OFC conduct. TEWL was measured two ways in two separate groups. First, TEWL was measured using static, discrete measurements. Second, TEWL was measured using continuous monitoring. Participants who consented gave blood before and after OFCs for biomarker analyses. RESULTS. TEWL rose significantly (2.93 g/m2/h) during reactions and did not rise during non-reacting OFCs (-1.00 g/m2/h). Systemic increases in tryptase and interleukin-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 OFCs with no reaction, providing high predictive specificity (96%) for anaphylaxis against non-reactions 38 minutes prior to anaphylaxis. CONCLUSIONS. During OFCs, a TEWL rise anticipates a positive clinical challenge. TEWL presents a novel monitoring modality that may predict food anaphylaxis and facilitate improvements in OFC safety and tolerability.
Charles F. Schuler, Kelly M. O'Shea, Jonathan P. Troost, Bridgette Kaul, Christopher M. Launius, Jayme Cannon, David M. Manthei, George E. Freigeh, Georgiana Sanders, Simon P. Hogan, Nicholas W. Lukacs, James R. Baker Jr
Nirmal S. Sharma, Kapil Patel, Ezgi Sari, Shruti Shankar, Maria G. Gastanadui, Diego Moncada-Giraldo, Yixel M. Soto-Vázquez, Delores A. Stacks, Louise Hecker, Kevin G. Dsouza, Mudassir Banday, Edward O'Neill, Paul Benson, Gregory A. Payne, Camilla Margaroli, Amit Gaggar
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 co-target 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 identify the most therapeutically important 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. Janne, Karen Cichowski
Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding 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 (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 novel 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 lifespan deficits in two distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared along the autophagy-lysosome axis, 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
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 four 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). Seven 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. Three 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 NCT05038904 FUNDING. 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
Long-acting antiretroviral agents for pre-exposure 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, similar to 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 post 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 A. VanderVeen, Derek Hansen, Bing Lu, William Rowe, Kelly Wei Wang, Christian Callebaut
CXCR7 is an atypical chemokine receptor that recruits β-arrestin (ARRB2) and internalizes into clathrin-coated intracellular vesicles where the complex acts as a scaffold for cytoplasmic kinase assembly and signal transduction. Here we report that CXCR7 was elevated in the majority of prostate cancer (PCa) with neuroendocrine features (NEPC). CXCR7 markedly induced mitotic spindle and cell cycle gene expression. Mechanistically, we identified Aurora Kinase A (AURKA), a key regulator of mitosis, as a novel target that was bound and activated by the CXCR7-ARRB2 complex. CXCR7 interacted with proteins associated with microtubules and Golgi, and as such, the CXCR7-ARRB2-containing vesicles trafficked along the microtubules to the pericentrosomal Golgi apparatus, where the complex interacted with AURKA. Accordingly, CXCR7 promoted PCa cell proliferation and tumor growth, which was mitigated by AURKA inhibition. In summary, our study reveals a critical role of CXCR7-ARRB2 in interacting and activating AURKA, which can be targeted by AURKA inhibitors to benefit a subset of patients with NEPC.
Galina Gritsina, Ka-wing Fong, Xiaodong Lu, Zhuoyuan Lin, Wanqing Xie, Shivani Agarwal, Dong Lin, Gary E. Schiltz, Himisha Beltran, Eva Corey, Colm Morrissey, Yuzhuo Wang, Jonathan C. Zhao, Maha Hussain, Jindan Yu
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 1761 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 three years of age, identified 233 seroreactive proteins. Seven of these were associated with protection from reinfection. These included Cp23 and Cp17, Gp900 and four 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 (i) specific to the infecting parasite genotype, and (ii) decayed in the months post-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, Abu S.G. Faruque, Rashidul Haque, William A. Petri Jr.
Increasing studies have demonstrated that disease states of the endocrine or exocrine pancreas aggravate one another, which implies bi-directional blood flow between islets and exocrine cells. However, this is inconsistent with the current model of uni-directional blood flow, which is strictly from islets to exocrine tissues. This conventional model was first proposed in 1932 and it has never been revisited to date. Here, large-scale image capture was used to examine the spatial relationship between islets and blood vessels in the following species; human, monkey, pig, rabbit, ferret, and mouse. While some arterioles passed by or traveled through islets, the majority of islets had no association with them. Islets with direct contact with the arteriole were significantly larger in size and less in number than those without contact. Unique to the pancreas, capillaries directly branched out from the arterioles, and have been labeled as “small arterioles” in the past studies. Overall, the arterioles emerged to feed the pancreas regionally, not specifically targeting individual islets. Vascularizing the pancreas in this way may allow an entire downstream region of islets and acinar cells to be simultaneously exposed to changes in the blood levels of glucose, hormones and other circulating factors.
Adam A. Rizk, Michael P. Dybala, Khalil C. Rodriguez, Marjan Slak Rupnik, Manami Hara
The liver can fully regenerate after partial resection and its underlying mechanisms have been extensively studied. The liver can also rapidly regenerate after injury with most studies focusing on hepatocyte proliferation; however, how hepatic necrotic lesions during acute or chronic liver diseases are eliminated and repaired remains obscure. Here we demonstrated that monocyte-derived macrophages (MoMFs) were rapidly recruited to and encapsulate necrotic areas during immune-mediated liver injury, and this feature was essential in repairing necrotic lesions. At the early stage of injury, infiltrating MoMFs activated the JAG1-NOTCH2 axis to induce cell death-resistant SOX9+ hepatocytes near the necrotic lesions, which acted as a barrier from further injury. Subsequently, necrotic environment (hypoxia and dead cells) induced a cluster of C1q+MoMFs that promoted necrotic removal and liver repair, while Pdgfb+MoMFs activated hepatic stellate cells (HSCs) to express -smooth muscle actin and induce a strong contraction signal (YAP, pMLC) to squeeze and finally eliminate the necrotic lesions. In conclusion, MoMFs play a key role in repairing the necrotic lesions not only by removing necrotic tissues but also by inducing cell death resistant hepatocytes to form a perinecrotic capsule and by activating α-smooth actin expressing HSCs to facilitate necrotic lesion resolution.
Dechun Feng, Xiaogang Xiang, Yukun Guan, Adrien Guillot, Hongkun Lu, Chingwen Chang, Yong He, Hua Wang, Hongna Pan, Cynthia Ju, Sean P. Colgan, Frank Tacke, Xin Wei Wang, George Kunos, Bin Gao
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