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Background: Patients requiring extracorporeal life support (ECLS) support post-Norwood operation constitute an extremely high-risk group. Materials and methods: We retrospectively aimed to evaluate the relationship of hyperoxia with mortality and other clinical outcomes in patients who required ECLS following Norwood operation between January/2010 and December/2020 in a large volume center. Results: During the study period 65 patients required ECLS post-Norwood. Using receiver operating characteristic (ROC) curve analysis, mean PaO2 of 182 mmHg in the first 48-hour on ECLS was determined to have the optimal discriminatory ability for mortality (sensitivity 68%, specificity 70%). Of the 65 patients, 52% had PaO2 > 182 mmHg and were designated as hyperoxia group. Patients in the hyperoxia-group had longer cardiopulmonary bypass time (187 vs. 165 min, p = 0.023), shorter duration from CICU arrival to ECLS-cannulation (13.28 vs. 132.58 h, p = 0.003), higher serum lactate within 2-hours from ECLS-canulation (14.55 vs. 5.80, p = 0.01), higher ECLS flows in the first 4-hours (152.68 vs. 124.14, p = 0.006), and higher mortality (77% vs. 39%, p = 0.005). In the unadjusted-analysis, using a derived cut-point, patients in the hyperoxia-group had 5.15 higher odds of mortality (p = 0.003). However, this association was insignificant when adjusting for confounding variables (p = 0.104). Using a functional status scale, new morbidity (38% vs. 21%), and unfavorable outcomes (13% vs. 5%) were higher in the hyperoxia group. Despite being higher in the hyperoxia group, this did not reach statistical significance. Conclusion: Neonates with hyperoxia (PaO2 > 182 Torr) during the first 48-hour of ECLS post-Norwood operation had 5 times higher odds of mortality in the unadjusted analysis, however, this was insignificant when adjusting for confounding variables. Patients in the hyperoxia group had shorter duration from CICU arrival to ECLS-cannulation, higher serum lactate prior to ECLS-canulation, and higher ECLS flows in the first 4-hours, (p

ObjectiveWe evaluated diagnostic performance of oral swab analysis (OSA) for tuberculosis (TB) in a high HIV/TB burden setting in Kenya.MethodsIn this cross-sectional study, buccal swabs and sputum were collected from 100 participants with suspected TB in outpatient clinics in Kenya at enrollment and subsequent morning visits. Buccal swabs underwent IS6110-targeted qPCR analysis. Sputum was evaluated by Xpert MTB/RIF (Xpert) and culture. Diagnostic performance of OSA for TB diagnosis was evaluated relative to a combined reference of sputum Xpert and culture.ResultsAmong 100 participants, 54% were living with HIV (PLHIV). Twenty percent (20/100) of participants had confirmed TB (19/20 [95%] culture-positive, 17/20 [85%] Xpert-positive). Overall buccal swab sensitivity was 65.0% (95% CI 40.8-84.6%) vs. sputum Xpert/culture and 76.5% (95% CI 50.1-93.2%) vs. sputum Xpert alone. Specificity was 81.3% (95% CI 71.0-89.1%) and 81.9% (95% CI 72.0-89.5%) compared to sputum Xpert/culture and Xpert alone, respectively. Sensitivity among PLHIV (n = 54) with suspected TB was 83.3% (95% CI 35.9-99.6%) vs. sputum Xpert/culture and 100% (95% CI 47.8-100.0%) vs. sputum Xpert alone. Among participants with TB, mean OSA threshold quantitation cycle (Cq) value was lower (stronger signal) at subsequent morning compared to enrolment visit (33.4 SD ± 3.7 vs. 35.2 SD ± 2.9, p = 0.009).ConclusionsIn this pilot study, results confirm M. tuberculosis DNA is detectable in oral swabs including among PLHIV with fair diagnostic performance. Further work is needed to optimize OSA and evaluate its utility in diverse settings.

Background: Flexible bronchoscopy with bronchoalveolar lavage (BAL) is performed widely for the diagnosis of pulmonary infections in patients with cancer, but there is no consensus regarding the technical parameters of the lavage procedure in this setting.Methods: The authors evaluated the mechanics (instilled and recovered volumes), diagnostic yield, and safety of a standardized BAL protocol in 284 patients with cancer who underwent bronchoscopy for the evaluation of new radiologic infiltrates.Results: Physician adherence to the BAL protocol was > 90%. The most common protocol deviations were reductions in the saline volume instilled because of actual or anticipated oxyhemoglobin desaturation during the procedure. The mean volume instilled was 121.5 ± 13.9 mL, the mean volume recovered was 68.7 ± 18.1 mL, and the mean ratio of volume instilled to that recovered was 56.7% ± 14.5%. The overall diagnostic yield of BAL was 33.8% and was higher in the nonhematologic malignancy group (42.3% vs 29.4%; P = .021). The diagnostic yield in neutropenic patients was significantly higher than in non-neutropenic patients (41.5% vs 24.6%; P = .019). No major complications were encountered.Conclusions: In summary, the diagnostic performance of a standardized BAL protocol was comparable to that of nonprotocolized BAL reported in the literature with few complications. Adherence to a standardized BAL protocol may improve clinical and laboratory comparisons between studies, potentially facilitating research into the diagnosis and management of pneumonia in patients with cancer. [ABSTRACT FROM AUTHOR]

Autoimmune progesteron dermatitis (AIPD) is a rare disorder which is characterized by cyclical premenstrual flares of cutaneous or mucocutaneous manifestations. We present a 36-year-old woman with a 2-year history of oral ulcers and a rash which presents a week before every menstruation. She also had a history of recurrent herpes labialis infection; however herpes simplex virus could not be detected by PCR in oral lesions. Routine laboratory investigations, as well as serum complement levels were normal, except for elevated ANA titer (1/160). Histopathological examination of one of the papules was consistent with erythema multiforme and immunobullous diseases were ruled out by negative immunofluorescence studies. Based on the history and the clinical features, AIPD was suspected and the diagnosis was confirmed by flare of the lesions after progesterone challenge test. Subsequently, oral tamoxifen was started which controlled her flares significantly and no major side effects except amenorrhea was observed during treatment. Next she was given spironolactone which did not control her symptoms, therefore oral prednisolone had to be introduced. Due to its rare occurence, clinical features, pathogenesis, diagnostic and treatment alternatives of AIPD are discussed in this study based on the review of the medical literature. [ABSTRACT FROM AUTHOR]

Infantile systemic hyalinosis (ISH) is an autosomal recessive, rare disorder in which hyaline deposition occurs in multiple organ systems, including the skin. It is characterised by painful joint contractures, gingival hypertrophy, generalized osteopenia, small pearly papules on the head, flesh nodules in the perianal region, and usually thickened skin. The onset occurs within the first few weeks of life and death occurs by two years of age as a result of recurrent pulmonary infections and diarrhea. Unfortunately, treatment is primarily palliative as there is no cure currently available. Herein, we report an 8-month-old boy who is diagnosed with ISH with the characteristic clinical presentation and histopathological findings. [ABSTRACT FROM AUTHOR]

Copyright of Turkish Journal of Dermatology / Turk Dermatoloji Dergisis is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Turkish Journal of Dermatology / Turk Dermatoloji Dergisis is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Rationale: The lungs are a common site of serious infection in both healthy and immunocompromised subjects, and the most likely route of delivery of a bioterror agent. Since the airway epithelium shows great structural plasticity in response to inflammatory stimuli, we hypothesized it might also show functional plasticity.Objectives: To test the inducibility of lung defenses against bacterial challenge.Methods: Mice were treated with an aerosolized lysate of ultraviolet-killed nontypeable (unencapsulated) Haemophilus influenzae (NTHi), then challenged with a lethal dose of live Streptococcus pneumoniae (Spn) delivered by aerosol.Measurements and Main Results: Treatment with the NTHi lysate induced complete protection against challenge with a lethal dose of Spn if treatment preceded challenge by 4 to 24 hours. Lesser levels of protection occurred at shorter (83% at 2 h) and longer (83% at 48-72 h) intervals between treatment and challenge. There was also some protection when treatment was given 2 hours after challenge (survival increased from 14 to 57%), but not 24 hours after challenge. Protection did not depend on recruited neutrophils or resident mast cells and alveolar macrophages. Protection was specific to the airway route of infection, correlated in magnitude and time with rapid bacterial killing within the lungs, and was associated with increases of multiple antimicrobial polypeptides in lung lining fluid.Conclusions: We infer that protection derives from stimulation of local innate immune mechanisms, and that activated lung epithelium is the most likely cellular effector of this response. Augmentation of innate antimicrobial defenses of the lungs might have therapeutic value. [ABSTRACT FROM AUTHOR]

More than 30 million Americans have chronic obstructive pulmonary disease (COPD) and asthma, with internists, pediatricians, and family physicians providing most of their medical care. Recent management guidelines for asthma and COPD recommend regular use of spirometry for the diagnosis and management of these disorders. Because of the development of easy-to-use office-based spirometers, an increasing number of physicians have ready access to spirometry. Beyond simple spirometry, various tests are available from many pulmonary function laboratories for more detailed evaluation of patients with respiratory disorders. For these reasons, all physicians who care for patients with pulmonary disease must understand basic pulmonary function testing and have a fundamental understanding of more sophisticated tests. A series of performance standards has been developed for improved accuracy and precision of pulmonary function tests. Physicians responsible for administering and interpreting pulmonary function tests, even simple spirometry, must be aware of relevant guidelines. This concise review addresses current indications for pulmonary function testing, provides an overview of the studies commonly available in modern pulmonary function laboratories, and includes comments on basic interpretation and testing standards. [ABSTRACT FROM AUTHOR]

The aim of this study was to look at the current lifestyle of young adult survivors of childhood cancer between the ages of 16 and 30 years to document their achievements and expose any psychosocial problems. Sixty six young adult survivors were contacted and asked if they and their siblings (16-30 years) would take part in a lifestyle study; 48 patients and 38 sibling controls were interviewed. This took the form of a structured lifestyle questionnaire, a self esteem questionnaire (Oxford Psychologists Press), and an unstructured interview. Fifty five per cent of patients achieved five or more A-C grades at 'O' level/GCSE compared with 62% of siblings and a national average of 30%. Despite that these patients were significantly less likely to go on to higher education than their siblings. The two groups were equally employable and earning similar salaries. There were three cases of known employer prejudice. A slightly higher percentage of patients than siblings had their driving licence. Seventeen patients felt their appearance had changed and eight felt that they had a residual physical mobility problem. Both groups were socially active and equally likely to partake in competitive sports. There was no overall difference in the self esteem of the two groups. In general the survivors of childhood cancer were coping well in their young adult life and achieving the same lifestyle goals as their siblings. However, significant problems have been identified. [ABSTRACT FROM AUTHOR]

Mass spectrometry (MS) is a potentially powerful approach for the diagnostic detection of SARS-CoV-2 and other viruses. However, MS detection is compromised when viral antigens are present at low concentrations, especially in complex biological media. We hypothesized that viral receptors could be used for viral target capture to enable detection by MS under such conditions. This was tested using the extracellular domain of the SARS-CoV-2 receptor ACE2. To maximize recovery of the target protein, directed protein evolution was first used to increase the affinity of ACE2 for spike protein. This generated an evolved ACE2 with increased binding affinity for the spike protein receptor-binding domain (RBD). However, as with other affinity-enhanced evolved forms of ACE2, binding was sensitive to mutations in variant RBDs. As an alternative strategy to maximize capture, the native ACE2 extracellular domain was engineered for increased binding by the addition of an oligomerization scaffold to create pentameric ACE2. This bound extremely tightly to SARS-CoV-2 RBD, with an increase in apparent affinity of several thousand-fold over monomeric ACE2, and RBD retention of more than 8 h. Immobilization of multimeric ACE2 enabled quantitative enrichment of viral spike protein from saliva and increased the sensitivity of detection by MS. These data show that capture by engineered receptors combined with MS can be an effective, rapid method for detection and quantitation of target protein. A similar approach could be used for attachment proteins of other viruses or any target protein for which there are suitable receptors., Competing Interests: The authors declare no competing financial interest., (© 2025 The Authors. Published by American Chemical Society.)

Aims: Disulfiram (Antabuse®) is an oral alcohol sobriety medication that exhibits antimicrobial activity against Gram-positive facultative anaerobes. The aims of this study were to measure the antimicrobial activity against anaerobic bacteria of the gut human microbiome and establish the extent that disulfiram alters the microbial composition of the ileum, cecum, and feces using C57BL/6 mice., Methods and Results: Antimicrobial susceptibility testing by the microdilution method revealed that disulfiram inhibits the in vitro growth of gut anaerobic species of Bacteroides, Clostridium, Peptostreptococcus, and Porphyromonas. Differential sequencing of 16S rRNA isolated from the ileum, cecum, and feces contents of treated vs. untreated mice showed that disulfiram enriches the Gram-negative enteric population. In female mice, the enrichment was greatest in the ileum, whereas the feces composition in male mice was the most heavily altered., Conclusions: Daily administration of oral disulfiram depletes the enteric Gram-positive anaerobe population as predicted by the minimum inhibitory concentration data for isolates from the human gut microbiota., (© The Author(s) 2024. Published by Oxford University Press on behalf of Applied Microbiology International.)

Long-term climate history can influence rates of soil carbon cycling but the microbial traits underlying these legacy effects are not well understood. Legacies may result if historical climate differences alter the traits of soil microbial communities, particularly those associated with carbon cycling and stress tolerance. However, it is also possible that contemporary conditions can overcome the influence of historical climate, particularly under extreme conditions. Using shotgun metagenomics, we assessed the composition of soil microbial functional genes across a mean annual precipitation gradient that previously showed evidence of strong climate legacies in soil carbon flux and extracellular enzyme activity. Sampling coincided with recovery from a regional, multi-year severe drought, allowing us to document how the strength of climate legacies varied with contemporary conditions. We found increased investment in genes associated with resource cycling with historically higher precipitation across the gradient, particularly in traits related to resource transport and complex carbon degradation. This legacy effect was strongest in seasons with the lowest soil moisture, suggesting that contemporary conditions-particularly, resource stress under water limitation-influences the strength of legacy effects. In contrast, investment in stress tolerance did not vary with historical precipitation, likely due to frequent periodic drought throughout the gradient. Differences in the relative abundance of functional genes explained over half of variation in microbial functional capacity-potential enzyme activity-more so than historical precipitation or current moisture conditions. Together, these results suggest that long-term climate can alter the functional potential of soil microbial communities, leading to legacies in carbon cycling., (© The Author(s) 2025. Published by Oxford University Press on behalf of the International Society for Microbial Ecology.)

Background: Prior studies have found no differences in procedural chest discomfort for patients undergoing manual syringe aspiration or drainage with gravity after thoracentesis. However, whether gravity drainage could protect against chest pain due to the larger negative-pressure gradient generated by wall suction has not been investigated., Research Question: Does wall suction drainage result in more chest discomfort compared with gravity drainage in patients undergoing large-volume thoracentesis?, Study Design and Methods: In this multicenter, single-blinded, randomized controlled trial, patients with large free-flowing effusions of ≥ 500 mL were assigned at a 1:1 ratio to wall suction or gravity drainage. Wall suction was performed with a suction system attached to the suction tubing and with vacuum pressure adjusted to full vacuum. Gravity drainage was performed with a drainage bag placed 100 cm below the catheter insertion site and connected via straight tubing. Patients rated chest discomfort on a 100-mm visual analog scale before, during, and after drainage. The primary outcome was postprocedural chest discomfort at 5 minutes. Secondary outcomes included measures of postprocedure chest discomfort, breathlessness, procedure time, volume of fluid drained, and complication rates., Results: Of the 228 patients initially randomized, 221 were included in the final analysis. The primary outcome of procedural chest discomfort did not differ significantly between the groups (P = .08), nor did the secondary outcomes of postprocedural discomfort and dyspnea. Similar volumes were drained in both groups, but the procedure duration was longer in the gravity arm by approximately 3 minutes. No differences in rate of pneumothorax or reexpansion pulmonary edema were noted between the two groups., Interpretation: Thoracentesis via wall suction and gravity drainage results in similar levels of procedural discomfort and dyspnea improvement., Clinical Trial Registry: ClinicalTrials.gov; No.: NCT05131945; URL: www., Clinicaltrials: gov., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: F. M. reports conflicts of interest with Pleural Dynamics, Medtronic, and Rocket Medical. K. K. reports conflicts of interest with Astra Zeneca. L. D. reports conflicts of interest with Intuitive Surgical and Elucent Medical. None declared (S. S., J. Pannu, L. Y., A. F., C. MacR, R. B., L. D., Z. S. DeP., S. A. F., C. A. J., S. K. A., E. V., A. DeM., L. B., T. F., R. A., G. A. E., D. E. O., S. B., A. K., V. S., A. S., R. F. C., S. E. E., K. P., N. C., D. D. B., V. P., R. L., C. P., L. R., J. M., J. Z., J. L., L. V., E. O., G. Y., J. A., C. B., R.-R. A., M. S., J. Pettee, L. Z. M., M. H. A., H. B. G.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The incidence of invasive fungal infections is increasing in immune-competent and immune-compromised patients. An examination of the recent literature related to the treatment of fungal infections was performed to address two clinical questions. First, in patients with proven or probable invasive pulmonary aspergillosis, should combination therapy with a mold-active triazole plus echinocandin be administered vs. mold-active triazole monotherapy? Second, in critically ill patients at risk for invasive candidiasis who are non-neutropenic and are not transplant recipients, should systemic antifungal agents be administered either as prophylaxis or as empiric therapy?, Methods: A multidisciplinary panel reviewed the available data concerning the two questions. The evidence was evaluated, and recommendations were generated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach., Results: A conditional recommendation was made for patients with proven or probable invasive pulmonary aspergillosis to receive either initial combination therapy with a mold-active triazole plus an echinocandin or initial mold-active triazole monotherapy based on low-quality evidence. Further, a conditional weak recommendation was made against routine administration of prophylactic or empiric antifungal agents targeting Candida species for critically ill patients without neutropenia or a history of transplant based on low-quality evidence., Conclusions: The recommendations presented in these Guidelines are the result of an analysis of currently available evidence. Additional research and new clinical data will prompt an update in the future.

Pneumonia is a worldwide threat to public health, demanding novel preventative and therapeutic strategies. The lung epithelium is a critical environmental interface that functions as a physical barrier to pathogen invasion while also actively sensing and responding to pathogens. We have reported that stimulating lung epithelial cells with a combination therapeutic consisting of a diacylated lipopeptide and a synthetic CpG oligodeoxynucleotide (ODN) induces synergistic pneumonia protection against a wide range of pathogens. We report here that mice deficient in TLR9, the previously described receptor for ODN, still displayed partial ODN-induced protection. This prompted us to seek an alternate ODN receptor, and we discovered by mass spectroscopy that the RNA sensor RIG-I could also bind DNA-like ODN. ODN binding by RIG-I resulted in MAVS-dependent pneumonia-protective signaling events. While RIG-I is essential to native defenses against viral infections, we report that therapeutic RIG-I activation with ODN promoted pathogen killing and host survival following both viral and bacterial challenges. These data indicate that maximal ODN-induced pneumonia protection requires activation of both the TLR9/MyD88 and RIG-I/MAVS signaling pathways. These findings not only identify what we believe to be a novel pattern recognition receptor for DNA-like molecules, but reveal a potential therapeutic strategy to protect susceptible individuals against lethal pneumonias during periods of peak vulnerability.

Topic Importance: Since its discovery in 1957, respiratory syncytial virus (RSV) has been widely recognized as a common and deadly pathogen. Although early studies focused on the impact of RSV on the health of children, more recent data show that RSV imposes a significant burden on individuals aged ≥ 70 years. RSV also substantially harms the health of individuals with cardiopulmonary diseases., Review Findings: Early efforts to develop an RSV vaccine were hampered by toxicity due to antibody-enhanced viral pneumonia and a lack of efficacy in vaccines that targeted the postfusion configuration of the F fusion protein, which is crucial to the pathogenesis of RSV-mediated injury. A newer wave of vaccines has targeted a stabilized prefusion F protein, generating effective neutralizing antibodies and reducing the burden of mild and severe RSV lower respiratory tract injury. This review focuses on the burden of RSV in patients with pulmonary diseases, highlights the tumultuous path from the early days of RSV vaccine development to the modern era, and offers insights into key gaps in knowledge that must be addressed to adequately protect the vulnerable population of patients with severe pulmonary diseases., Summary: RSV vaccination with bivalent RSVPreF or RSVPreF3OA, which target the stabilized prefusion F protein, can be broadly recommended to adults aged ≥ 60 years with pulmonary diseases. However, more data are needed to understand how these vaccinations affect key clinical outcomes in individuals with pulmonary disease., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Osteoderms (ODs) are mineralized tissue embedded within the skin and are particularly common in reptiles. They are generally thought to form a protective layer between the soft tissues of the animal and potential external threats, although other functions have been proposed. The aim of this study was to characterize OD variation across the lizard body. Adults of three lizard species were chosen for this study. After whole body CT scanning of each lizard, single ODs were extracted from 10 different anatomical regions, CT scanned, and characterized using sectioning and nanoindentation. Morphological analysis and material characterization revealed considerable diversity in OD structure across the species investigated. The scincid Tiliqua gigas was the only studied species in which ODs had a similar external morphology across the head and body. Greater osteoderm diversity was found in the gerrhosaurid Broadleysaurus major and the scincid Tribolonotus novaeguineae. Dense capping tissue, like that reported for Heloderma, was found in only one of the three species examined, B. major. Osteoderm structure can be surprisingly complex and variable, both among related taxa, and across the body of individual animals. This raises many questions about OD function but also about the genetic and developmental factors controlling OD shape., (© 2024 The Authors. The Anatomical Record published by Wiley Periodicals LLC on behalf of American Association for Anatomy.)

RIBULOSE-1,5-BISPHOSPHATE CARBOXYLASE/OXYGENASE (Rubisco) produces pyruvate in the chloroplast through β-elimination of the aci-carbanion intermediate 1 . Here we show that this side reaction supplies pyruvate for isoprenoid, fatty acid and branched-chain amino acid biosynthesis in photosynthetically active tissue. 13 C labelling studies of intact Arabidopsis plants demonstrate that the total carbon commitment to pyruvate is too large for phosphoenolpyruvate to serve as a precursor. Low oxygen stimulates Rubisco carboxylase activity and increases pyruvate production and flux through the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway, which supplies the precursors for plastidic isoprenoid biosynthesis 2,3 . Metabolome analysis of mutants defective in phosphoenolpyruvate or pyruvate import and biochemical characterization of isolated chloroplasts further support Rubisco as the main source of pyruvate in chloroplasts. Seedlings incorporated exogenous, 13 C-labelled pyruvate into MEP pathway intermediates, while adult plants did not, underscoring the developmental transition in pyruvate sourcing. Rubisco β-elimination leading to pyruvate constituted 0.7% of the product profile in in vitro assays, which translates to 2% of the total carbon leaving the Calvin-Benson-Bassham cycle. These insights solve the "pyruvate paradox" 4 , improve the fit of metabolic models for central metabolism and connect the MEP pathway directly to carbon assimilation., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

We retrospectively reviewed 64 cases of cancer with pulmonary legionellosis ( Legionella pneumophila in 73%). Nearly all patients received Legionella -active antibiotics, yet 30-day mortality was 23%. Independent predictors of 30-day mortality were hyponatremia, bilateral lung involvement, and Sequential Organ Failure Assessment score ≥5. Lung coinfections were common (31%) but did not significantly increase mortality., Competing Interests: Potential conflicts of interest. D. P. K. reports honoraria and research support from Gilead Sciences and Astellas Pharma. He also received consultant fees from Astellas Pharma, Merck, and Gilead Sciences and is a member of the Data Review Committee for Cidara Therapeutics, AbbVie, Scynexis, and the Mycoses Study Group. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Continued improvements in the treatment of pulmonary infections have paradoxically resulted in a growing challenge of individuals with postinfectious pulmonary complications (PIPCs). PIPCs have been long recognized after tuberculosis, but recent experiences such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic have underscored the importance of PIPCs following other lower respiratory tract infections. Independent of the causative pathogen, most available studies of pulmonary infections focus on short-term outcomes rather than long-term morbidity among survivors. In this document, we establish a conceptual scope for PIPCs with discussion of globally significant pulmonary pathogens and an examination of how these pathogens can damage different components of the lung, resulting in a spectrum of PIPCs. We also review potential mechanisms for the transition from acute infection to PIPC, including the interplay between pathogen-mediated injury and aberrant host responses, which together result in PIPCs. Finally, we identify cross-cutting research priorities for the field to facilitate future studies to establish the incidence of PIPCs, define common mechanisms, identify therapeutic strategies, and ultimately reduce the burden of morbidity in survivors of pulmonary infections.

Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion of CEBPD resulted in loss of IL-21 NK cell potency while its overexpression increased NK cell long-term cytotoxicity and metabolic fitness. These results suggest that IL-21, through C/EBP transcription factors, drives epigenetic reprogramming of NK cells, enhancing their anti-tumor efficacy against GBM., Competing Interests: Declaration of interests M.S., M. Daher, R.B., H.R., S.A., Y.L., N.U., E.L., E.J.S., K.R., and The University of Texas MD Anderson Cancer Center have an institutional financial conflict of interest with Takeda Pharmaceutical. R.B., E.J.S., K.R., and The University of Texas MD Anderson Cancer Center have an institutional financial conflict of interest with Affimed GmbH. K.R. participates on the Scientific Advisory Board for Avenge Bio, Virogin Biotech, Navan Technologies, Caribou Biosciences, Bit Bio Limited, Replay Holdings, oNKo Innate, and The Alliance for Cancer Gene Therapy ACGT. K.R. is the Scientific founder of Syena. E.J.S. has served on the Scientific Advisory Board for Adaptimmune, Axio, Celaid, FibroBiologics, Navan Technologies, New York Blood Center and Novartis. M Daher participates on the Scientific Advisory Board for Cellsbin. M.S., H.S., E.J.S., and K.R. have filed for a patent (20230074303); “Cell immunotherapy for the treatment of cancer.”, (Copyright © 2024 Elsevier Inc. All rights reserved.)

The fully aquatic Japanese giant salamander (Andrias japonicus) is a member of the Cryptobranchidae, and is currently distributed in western Japan, with other members of this group restricted to China and North America. Their feeding behaviour is characterized by a form of suction feeding that includes asymmetric movements of the jaw and hyobranchial apparatus. Previous studies on the North American species, Cryptobranchus alleganiensis, have suggested that this specialized jaw movement is produced by a flexible quadrate-articular joint combined with a loosely connected lower jaw symphysis including two small fibrocartilaginous pads. However, little is known about this feeding behaviour in the Asian species, nor have the three-dimensional asymmetric jaw movements been fully investigated in any member of Cryptobranchidae. In this study, we explore the asymmetric jaw movements in A. japonicus using three methods: (1) dissection of musculoskeletal structures; (2) filming of feeding behaviour to understand in which situations asymmetric feeding is used; (3) analysis of 3D movement of jaws and skull. In the third component, fresh (from frozen) specimens of A. japonicus were manipulated to replicate asymmetric and symmetric jaw movements, with the specimens CT scanned after each step to obtain the 3D morphology of the jaws at different positions. These positions were combined and their Euler angles from resting (closed) jaw position were calculated for asymmetric or symmetric jaw positions. Our filming revealed that asymmetric jaw movements are linked to the position of the prey in relation to the snout, with the jaw closest to the prey opening asymmetrically. Moreover, this action allows the salamander to simultaneously grasp prey in one side of the mouth while ejecting water on the other side, if the first suction attempt fails. The asymmetric jaw movements are performed mainly by rotation of the mandible about its long axis, with very limited lateral jaw movements. During asymmetric and symmetric jaw movements, the posterior ends of the maxilla and quadrate move slightly. The asymmetric jaw movements are permitted by a mobile quadrate-articular joint formed by wide, round cartilages, and by two small fibrocartilage pads within the jaw symphysis that act as cushions during jaw rotation. Some of these soft tissue structures leave traces on the jaws and skull, allowing feeding mode to be reconstructed in fossil taxa. Understanding cryptobranchid asymmetric jaw movement thus requires a comprehensive assessment of not only the symphysial morphology but also that of other cranial and hyobranchial elements., (© 2024 Anatomical Society.)

The Entner-Doudoroff (ED) pathway provides an alternative to glycolysis. It converts 6-phosphogluconate (6-PG) to glyceraldehyde-3-phosphate and pyruvate in two steps consisting of a dehydratase (EDD) and an aldolase (EDA). Here, we investigate its distribution and significance in higher plants and determine the ED pathway is restricted to prokaryotes due to the absence of EDD genes in eukaryotes. EDDs share a common origin with dihydroxy-acid dehydratases (DHADs) of the branched chain amino acid pathway (BCAA). Each dehydratase features strict substrate specificity. E. coli EDD dehydrates 6-PG to 2-keto-3-deoxy-6-phosphogluconate, while DHAD only dehydrates substrates from the BCAA pathway. Structural modeling identifies two divergent domains which account for their non-overlapping substrate affinities. Coupled enzyme assays confirm only EDD participates in the ED pathway. Plastid ancestors lacked EDD but transferred metabolically promiscuous EDA, which explains the absence of the ED pathway from the Viridiplantae and sporadic persistence of EDA genes across the plant kingdom., (© 2024. The Author(s).)

Background: Traf2 and Nck-interacting kinase (TNIK) is known for its regulatory role in various processes within cancer cells. However, its role within endothelial cells (ECs) has remained relatively unexplored., Methods: Leveraging RNA-seq data and Ingenuity Pathway Analysis (IPA), we probed the potential impact of TNIK depletion on ECs., Results: Examination of RNA-seq data uncovered more than 450 Differentially Expressed Genes (DEGs) in TNIK-depleted ECs, displaying a fold change exceeding 2 with a false discovery rate (FDR) below 0.05. IPA analysis unveiled that TNIK depletion leads to the inhibition of the interferon (IFN) pathway [-log ( p -value) >11], downregulation of IFN-related genes, and inhibition of Hypercytokinemia/Hyperchemokinemia [-log ( p -value) >8]. The validation process encompassed qRT-PCR to evaluate mRNA expression of crucial IFN-related genes, immunoblotting to gauge STAT1 and STAT2 protein levels, and ELISA for the quantification of IFN and cytokine secretion in siTNIK-depleted ECs. These assessments consistently revealed substantial reductions upon TNIK depletion. When transducing HUVECs with replication incompetent E1-E4 deleted adenovirus expressing green fluorescent protein (Ad-GFP), it was demonstrated that TNIK depletion did not affect the uptake of Ad-GFP. Nonetheless, TNIK depletion induced cytopathic effects (CPE) in ECs transduced with wild-type human adenovirus serotype 5 (Ad-WT)., Summary: Our findings suggest that TNIK plays a crucial role in regulating the EC response to virus infections through modulation of the IFN pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer VD declared a past co-authorship with the author JC to the handling editor., (© 2024 Chau, Dominic, Davis, Kotla, Berrios, Fahim, Arunesh, Li, Zhao, Chen, Davis, Nguyen, Wang, Evans, Wang, Cooke, Abe, Huston and Le.)

Rationale: Pulmonary function testing (PFT) is performed to aid patient selection before surgical resection for non-small cell lung cancer (NSCLC). The interpretation of PFT data relies on normative equations, which vary by race, but the relative strength of association of lung function using race-specific or race-neutral normative equations with postoperative pulmonary complications is unknown. Objectives: To compare the strength of association of lung function, using race-neutral or race-specific equations, with surgical complications after lobectomy for NSCLC. Methods: We studied 3,311 patients who underwent lobectomy for NSCLC and underwent preoperative PFT from 2001 to 2021. We used Global Lung Function Initiative equations to generate race-specific and race-neutral normative equations to calculate percentage predicted forced expiratory volume in 1 second (FEV 1 %). The primary outcome of interest was the occurrence of postoperative pulmonary complications within 30 days of surgery. We used unadjusted and race-adjusted logistic regression models and least absolute shrinkage and selection operator analyses adjusted for relevant comorbidities to measure the association of race-specific and race-neutral FEV 1 % with pulmonary complications. Results: Thirty-one percent of patients who underwent surgery experienced pulmonary complications. Higher FEV 1 , whether measured with race-neutral (odds ratio [OR], 0.98 per 1% change in FEV 1 % [95% confidence interval (CI), 0.98-0.99]; P  < 0.001) or race-specific (OR, 0.98 per 1% change in FEV 1 % [95% CI, 0.98-0.98]; P  < 0.001) normative equations, was associated with fewer postoperative pulmonary complications. The area under the receiver operator curve for pulmonary complications was similar for race-adjusted race-neutral (0.60) and race-specific (0.60) models. Using least absolute shrinkage and selection operator regression, higher FEV 1 % was similarly associated with a lower rate of pulmonary complications in race-neutral (OR, 0.99 per 1% [95% CI, 0.98-0.99]) and race-specific (OR, 0.99 per 1%; 95% CI, 0.98-0.99) models. The marginal effect of race on pulmonary complications was attenuated in all race-specific models compared with all race-neutral models. Conclusions: The choice of race-specific or race-neutral normative PFT equations does not meaningfully affect the association of lung function with pulmonary complications after lobectomy for NSCLC, but the use of race-neutral equations unmasks additional effects of self-identified race on pulmonary complications.

The Toll-like receptor (TLR) adaptor protein MyD88 is integral to airway inflammatory response to microbial-enriched organic dust extract (ODE) exposures. ODE-induced airway neutrophil influx and release of pro-inflammatory cytokines was essentially abrogated in global MyD88-deficient mice, yet these mice demonstrate an increase in airway epithelial cell mucin expression. To further elucidate the role of MyD88-dependent responses specific to lung airway epithelial cells in response to ODE in vivo , the surfactant protein C protein (SPC) Cre + embryologic expressing airway epithelial cells floxed for MyD88 to disrupt MyD88 signaling were utilized. The inducible club cell secretory protein (CCSP) Cre + , MyD88 floxed, were also developed. Using an established protocol, mice were intranasally instilled with ODE or saline once or daily up to 3 weeks. Mice with MyD88-deficient SPC + lung epithelial cells exhibited decreased neutrophil influx following ODE exposure once and repetitively for 1 week without modulation of classic pro-inflammatory mediators including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and neutrophil chemoattractants. This protective response was lost after 3 weeks of repetitive exposure. ODE-induced Muc5ac mucin expression at 1 week was also reduced in MyD88-deficient SPC + cells. Acute ODE-induced IL-33 was reduced in MyD88-deficient SPC + cells whereas serum IgE levels were increased at one week. In contrast, mice with inducible MyD88-deficient CCSP + airway epithelial cells demonstrated no significant difference in experimental indices following ODE exposure. Collectively, these findings suggest that MyD88-dependent signaling targeted to all airway epithelial cells plays an important role in mediating neutrophil influx and mucin production in response to acute organic dust exposures.

Extraskeletal myxoid chondrosarcoma (EMC) is a malignant cartilage neoplasm usually encountered in the proximal extremities. We report the case of a 58-year-old male who presented initially with a 3-month history of cough. Initial staging demonstrated a right upper lobe mass with bilateral pulmonary nodules and moderate tracer uptake in the right lung mass and right groin on positron emission tomography imaging. Endobronchial ultrasound biopsy confirmed a histological diagnosis of EMC for which the patient underwent right upper lobe wedge resection. Pelvic MRI revealed a peripherally enhancing juxta-articular lesion within the region of the right obturator externus bursa, which was thought initially to represent either a ganglion or paralabral cyst. However, ultrasound-guided biopsy yielded identical histology to the resected lung mass leading to the diagnosis of primary EMC in the right groin with pulmonary metastases. The patient underwent surgical excision of the right groin mass with no local recurrence on the surveillance computed tomography at 5, 12, and 18 months but eventual disease recurrence in the right groin and further progression of the pulmonary metastases at 29 months. We emphasize that the contrast enhancement pattern of EMC can mimic a benign cystic lesion, in particular, when in a juxta-articular location, which has the potential to mislead radiologists and delay diagnosis and definitive treatment., (© 2023 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Androgen deprivation therapy-based with or without first-generation anti-androgens, was the standard of care for patients with metastatic hormone-sensitive prostate cancer (mHSPC) for decades. However, the development of docetaxel chemotherapy and new androgen receptor-targeted agents, abiraterone acetate and prednisolone, apalutamide , enzalutamide and darolutamide (in combination with docetaxel chemotherapy) has proven that combination of treatments is more effective. Recently, intensification therapy, so-called "triplets", have emerged in the armamentarium of mHSPC treatment. Metastatic disease is a clinical state that remains poorly understood. The optimal diagnostic and management of patients with mHSPC are changing thanks to the development of new imaging techniques and therapies. The primary objective of this study is to develop and validate a predictive model for the occurrence of symptomatic progression, initiation of new treatments and death amongst patients with mHSPC treated with one of the approved treatment plans, on characteristics present at admission., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Osteoderms (ODs) are calcified organs formed directly within the skin of most major extant tetrapod lineages. Lizards possibly show the greatest diversity in ODs morphology and distribution. ODs are commonly hypothesized to function as a defensive armor. Here we tested the hypothesis that cranial osteoderms also contribute to the mechanics of the skull during biting. A series of in vivo experiments were carried out on three specimens of Tiliqua gigas. Animals were induced to bite a force plate while a single cranial OD was strain gauged. A finite element (FE) model of a related species, Tiliqua scincoides, was developed and used to estimate the level of strain across the same OD as instrumented in the in vivo experiments. FE results were compared to the in vivo data and the FE model was modified to test two hypothetical scenarios in which all ODs were (i) removed from, and (ii) fused to, the skull. In vivo data demonstrated that the ODs were carrying load during biting. The hypothetical FE models showed that when cranial ODs were fused to the skull, the overall strain across the skull arising from biting was reduced. Removing the ODs showed an opposite effect. In summary, our findings suggest that cranial ODs contribute to the mechanics of the skull, even when they are loosely attached., (© 2023 The Authors. The Anatomical Record published by Wiley Periodicals LLC on behalf of American Association for Anatomy.)

Salicylic acid (SA) is produced by plants in response to pathogen infection. SA binds the NONEXPRESSOR OF PATHOGENESIS-RELATED GENES (NPR) family of receptors to regulate both positive (NPR1) and negative (NPR3/4) plant immune responses by interacting with the clade II TGACG (TGA) motif-binding transcription factors (TGA2, TGA5, and TGA6). Here, we report that the principal metabolome-level response to SA treatment in Arabidopsis is a reduction in sucrose and other free sugars. We observed nearly identical effects in the tga256 triple mutant, which lacks all clade II TGA transcription factors. The tga256 mutant presents reduced leaf blade development and elongated hypocotyls, roots, and petioles consistent with sucrose starvation. No changes were detected in auxin levels, and mutant seedling growth could be restored to that of wild-type by sucrose supplementation. Although the retrograde signal 2- C -methyl-D-erythritol-2,4-cyclodiphosphate is known to stimulate SA biosynthesis and defense signaling, we detected no negative feedback by SA on this or any other intermediate of the 2- C -methyl-D-erythritol-4-phosphate pathway. Trehalose, a proxy for the sucrose regulator trehalose-6-phosphate (T6P), was highly reduced in tga256 , suggesting that defense-related reductions in sugar availability may be controlled by changes in T6P levels. We conclude that the negative regulatory roles of TGA2/5/6 include maintaining sucrose levels in healthy plants. Disruption of TGA2/5/6-NPR3/4 inhibitory complexes by mutation or SA triggers sucrose reductions in Arabidopsis leaves, consistent with the 'pathogen starvation' hypothesis. These findings highlight sucrose availability as a mechanism by which TGA2/5/6 balance defense and development.

Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infection an urgent need. Manipulating the lungs' intrinsic host defenses by therapeutic delivery of certain pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODN) with mitochondrial voltage-dependent anion channel 1 (VDAC1). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), increases mitochondrial membrane potential (ΔΨm), differentially modulates ETC complex activities and consequently results in leak of electrons from ETC complex III and superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy to broadly protect against pneumonia without reliance on antibiotics., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: MJT and SEE are authors on U.S. patent 8,883,174, “Stimulation of Innate Resistance of the Lungs to Infection with Synthetic Ligands.” MJT and SEE own stock in Pulmotect, Inc. All other authors declare that no conflicts of interest exist., (Copyright: © 2023 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Survivors of SARS-CoV-2 pneumonia often develop persistent respiratory symptom and interstitial lung abnormalities (ILAs) after infection. Risk factors for ILA development and duration of ILA persistence after SARS-CoV-2 infection are not well described in immunocompromised hosts, such as cancer patients., Methods: We conducted a prospective cohort study of 95 patients at a major cancer center and 45 patients at a tertiary referral center. We collected clinical and radiographic data during the index hospitalization for COVID-19 pneumonia and measured pneumonia severity using a semi-quantitative radiographic score, the Radiologic Severity Index (RSI). Patients were evaluated in post-COVID-19 clinics at 3 and 6 months after discharge and underwent comprehensive pulmonary evaluations (symptom assessment, chest computed tomography, pulmonary function tests, 6-min walk test). The association of clinical and radiological factors with ILAs at 3 and 6 months post-discharge was measured using univariable and multivariable logistic regression., Results: Sixty-six (70%) patients of cancer cohort had ILAs at 3 months, of whom 39 had persistent respiratory symptoms. Twenty-four (26%) patients had persistent ILA at 6 months after hospital discharge. In adjusted models, higher peak RSI at admission was associated with ILAs at 3 (OR 1.5 per 5-point increase, 95% CI 1.1-1.9) and 6 months (OR 1.3 per 5-point increase, 95% CI 1.1-1.6) post-discharge. Fibrotic ILAs (reticulation, traction bronchiectasis, and architectural distortion) were more common at 6 months post-discharge., Conclusions: Post-COVID-19 ILAs are common in cancer patients 3 months after hospital discharge, and peak RSI and older age are strong predictors of persistent ILAs., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

PIONEER is a European network of excellence for big data in prostate cancer consisting of 37 private and public stakeholders from 9 countries across Europe. Many progresses have been done in prostate cancer management, but unanswered questions in the field still exist, and big data could help to answer these questions. The PIONEER consortium conducted a two-round modified Delphi survey aiming at building consensus between two stakeholder groups - health-care professionals and patients with prostate cancer - about the most important questions in the field of prostate cancer to be answered using big data. Respondents were asked to consider what would be the effect of answering the proposed questions on improving diagnosis and treatment outcomes for patients with prostate cancer and to score these questions on a scale of 1 (not important) to 9 (critically important). The mean percentage of participants who scored each of the proposed questions as critically important was calculated across the two stakeholder groups and used to rank the questions and identify the highest scoring questions in the critically important category. The identification of questions in prostate cancer that are important to various stakeholders will help the PIONEER consortium to provide answers to these questions to improve the clinical care of patients with prostate cancer., (© 2023. Springer Nature Limited.)

Background: Root and soil microbial communities constitute the below-ground plant microbiome, are drivers of nutrient cycling, and affect plant productivity. However, our understanding of their spatiotemporal patterns is confounded by exogenous factors that covary spatially, such as changes in host plant species, climate, and edaphic factors. These spatiotemporal patterns likely differ across microbiome domains (bacteria and fungi) and niches (root vs. soil)., Results: To capture spatial patterns at a regional scale, we sampled the below-ground microbiome of switchgrass monocultures of five sites spanning > 3 degrees of latitude within the Great Lakes region. To capture temporal patterns, we sampled the below-ground microbiome across the growing season within a single site. We compared the strength of spatiotemporal factors to nitrogen addition determining the major drivers in our perennial cropping system. All microbial communities were most strongly structured by sampling site, though collection date also had strong effects; in contrast, nitrogen addition had little to no effect on communities. Though all microbial communities were found to have significant spatiotemporal patterns, sampling site and collection date better explained bacterial than fungal community structure, which appeared more defined by stochastic processes. Root communities, especially bacterial, were more temporally structured than soil communities which were more spatially structured, both across and within sampling sites. Finally, we characterized a core set of taxa in the switchgrass microbiome that persists across space and time. These core taxa represented < 6% of total species richness but > 27% of relative abundance, with potential nitrogen fixing bacteria and fungal mutualists dominating the root community and saprotrophs dominating the soil community., Conclusions: Our results highlight the dynamic variability of plant microbiome composition and assembly across space and time, even within a single variety of a plant species. Root and soil fungal community compositions appeared spatiotemporally paired, while root and soil bacterial communities showed a temporal lag in compositional similarity suggesting active recruitment of soil bacteria into the root niche throughout the growing season. A better understanding of the drivers of these differential responses to space and time may improve our ability to predict microbial community structure and function under novel conditions., (© 2023. The Author(s).)

The lung epithelium is dynamic, capable of considerable structural and functional plasticity in response to pathogen challenges. Our laboratory has demonstrated that an inhaled combination of a Toll-like receptor (TLR) 2/6 agonist and a TLR9 agonist (Pam2ODN) results in robust protection against otherwise lethal pneumonias. We have previously shown that intact epithelial TLR signaling and generation of multisource epithelial reactive oxygen species (ROS) are required for inducible protection. Further investigating the mechanisms underlying this phenomenon of inducible resistance, reverse-phase protein array analysis demonstrated robust STAT3 (signal transducer and activator of transcription 3) phosphorylation following treatment of lung epithelial cells. We show here that Pam2ODN-induced STAT3 phosphorylation is IL-6-independent. We further found that therapeutic epithelial STAT3 activation is required for inducible protection against Pseudomonas aeruginosa pneumonia. Additional studies showed that inhibiting epithelial dual oxidases or scavenging ROS significantly reduced the Pam2ODN induction of STAT3 phosphorylation, suggesting a proximal role for ROS in inducible STAT3 activation. Dissecting these mechanisms, we analyzed the contributions of redox-sensitive kinases and found that Pam2ODN activated epithelial growth factor receptor in an ROS-dependent manner that is required for therapeutically inducible STAT3 activation. Taken together, we demonstrate that epithelial STAT3 is imperative for Pam2ODN's function and describe a novel redox-based mechanism for its activation. These key mechanistic insights may facilitate strategies to leverage inducible epithelial resistance to protect susceptible patients during periods of peak vulnerability.

Introduction: Toll-like receptors (TLRs) are an extensive group of proteins involved in host defense processes that express themselves upon the increased production of endogenous damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) due to the constant contact that airway epithelium may have with pathogenic foreign antigens. We have previously shown that COPD-like airway inflammation induced by exposure to an aerosolized lysate of nontypeable Haemophilus influenzae (NTHi) promotes tumorigenesis in a K-ras mutant mouse model of lung cancer, CCSP Cre /LSL-K-ras G12D (CC-LR) mouse., Methods: In the present study, we have dissected the role of TLRs in this process by knocking out TLR2, 4, and 9 and analyzing how these deletions affect the promoting effect of COPD-like airway inflammation on K-ras-driven lung adenocarcinoma., Results: We found that knockout of TLR 2, 4, or 9 results in a lower tumor burden, reduced angiogenesis, and tumor cell proliferation, accompanied by increased tumor cell apoptosis and reprogramming of the tumor microenvironment to one that is antitumorigenic. Additionally, knocking out of downstream signaling pathways, MyD88/NF-κB in the airway epithelial cells further recapitulated this initial finding., Discussion: Our study expands the current knowledge of the roles that TLR signaling plays in lung cancer, which we hope, can pave the way for more reliable and efficacious prevention and treatment modalities for lung cancer., Competing Interests: SM reports funding from Arrowhead Pharma and Boehringer Ingelheim outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Velasco, Khosravi, Castro-Pando, Torres-Garza, Grimaldo, Krishna, Clowers, Umer, Tariq Amir, Del Bosque, Daliri, De La Garza, Ramos-Castaneda, Evans and Moghaddam.)