Search

Abstract Background Particulate matter exposure (PM) is a cause of aerodigestive disease globally. The destruction of the World Trade Center (WTC) exposed first responders and inhabitants of New York City to WTC-PM and caused obstructive airways disease (OAD), gastroesophageal reflux disease (GERD) and Barrett’s Esophagus (BE). GERD not only diminishes health-related quality of life but also gives rise to complications that extend beyond the scope of BE. GERD can incite or exacerbate allergies, sinusitis, bronchitis, and asthma. Disease features of the aerodigestive axis can overlap, often necessitating more invasive diagnostic testing and treatment modalities. This presents a need to develop novel non-invasive biomarkers of GERD, BE, airway hyperreactivity (AHR), treatment efficacy, and severity of symptoms. Methods Our observational case-cohort study will leverage the longitudinally phenotyped Fire Department of New York (FDNY)-WTC exposed cohort to identify Biomarkers of Airway Disease, Barrett’s and Underdiagnosed Reflux Noninvasively (BAD-BURN). Our study population consists of n = 4,192 individuals from which we have randomly selected a sub-cohort control group (n = 837). We will then recruit subgroups of i. AHR only ii. GERD only iii. BE iv. GERD/BE and AHR overlap or v. No GERD or AHR, from the sub-cohort control group. We will then phenotype and examine non-invasive biomarkers of these subgroups to identify under-diagnosis and/or treatment efficacy. The findings may further contribute to the development of future biologically plausible therapies, ultimately enhance patient care and quality of life. Discussion Although many studies have suggested interdependence between airway and digestive diseases, the causative factors and specific mechanisms remain unclear. The detection of the disease is further complicated by the invasiveness of conventional GERD diagnosis procedures and the limited availability of disease-specific biomarkers. The management of reflux is important, as it directly increases risk of cancer and negatively impacts quality of life. Therefore, it is vital to develop novel noninvasive disease markers that can effectively phenotype, facilitate early diagnosis of premalignant disease and identify potential therapeutic targets to improve patient care. Trial registration Name of Primary Registry: “Biomarkers of Airway Disease, Barrett's and Underdiagnosed Reflux Noninvasively (BADBURN)”. Trial Identifying Number: NCT05216133 . Date of Registration: January 31, 2022.

Background and Aims: Gastroesophageal reflux disease (GERD) is a prevalent gastrointestinal disorder that may complicate conditions such as obstructive airway disease. Our group has identified predictive biomarkers of GERD in particulate exposed first responders with obstructive airway disease. In addition, GERD diagnosis and treatment is costly and invasive. In light of these clinical concerns, we aimed to systematically review studies identifying noninvasive, multiOmic, and multicompartmental biomarkers of GERD. Methods: A systematic review of PubMed and Embase was performed using keywords focusing on reflux disease and biomarkers and registered with PROSPERO. We included original human studies in English, articles focusing on noninvasive biomarkers of GERD published after December 31, 2009. GERD subtypes (non-erosive reflux disease and erosive esophagitis) and related conditions (Barrett’s Esophagus [BE] and Esophageal Adenocarcinoma). Predictive measures were synthesized and risk of bias assessed (Newcastle-Ottawa Scale). Results: Initial search identified n = 238 studies and n = 13 articles remained after applying inclusion/exclusion criteria. Salivary pepsin was the most studied biomarker with significant sensitivity and specificity for GERD. Serum assessment showed elevated levels of Tumor Necrosis Factor- alpha in both GERD and Barrett’s. Exhaled breath volatile sulfur compounds and acetic acid were associated with GERD. Oral Microbiome: Models with Lautropia, Streptococcus, and Bacteroidetes showed the greatest discrimination between BE and controls vs Lautropia; ROCAUC 0.94 (95% confidence interval; 0.85–1.00). Conclusion: Prior studies identified significant multiOmic, multicompartmental noninvasive biomarker risks for GERD and BE. However, studies have a high risk of bias and the reliability and accuracy of the biomarkers identified are greatly limited, which further highlights the need to discover and validate clinically relevant noninvasive biomarkers of GERD.

In the original publication [...]

Pulmonary hypertension (PH) has a high mortality and few treatment options. Adaptive immune mediators of PH in mice challenged with antigen/particulate matter (antigen/PM) has been the focus of our prior work. We identified key roles of type-2- and type-17 responses in C57BL/6 mice. Here, we focused on type-2-response-related cytokines, specifically resistin-like molecule (RELM)α, a critical mediator of hypoxia-induced PH. Because of strain differences in the immune responses to type 2 stimuli, we compared C57BL/6J and BALB/c mice. A model of intraperitoneal antigen sensitization with subsequent, intranasal challenges with antigen/PM (ovalbumin and urban ambient PM2.5) or saline was used in C57BL/6 and BALB/c wild-type or RELMα−/− mice. Vascular remodeling was assessed with histology; right ventricular (RV) pressure, RV weights and cytokines were quantified. Upon challenge with antigen/PM, both C57BL/6 and BALB/c mice developed pulmonary vascular remodeling; these changes were much more prominent in the C57BL/6 strain. Compared to wild-type mice, RELMα−/− had significantly reduced pulmonary vascular remodeling in BALB/c, but not in C57BL/6 mice. RV weights, RV IL-33 and RV IL-33-receptor were significantly increased in BALB/c wild-type mice, but not in BALB/c-RELMα−/− or in C57BL/6-wild-type or C57BL/6-RELMα−/− mice in response to antigen/PM2.5. RV systolic pressures (RVSP) were higher in BALB/c compared to C57BL/6J mice, and RELMα−/− mice were not different from their respective wild-type controls. The RELMα−/− animals demonstrated significantly decreased expression of RELMβ and RELMγ, which makes these mice comparable to a situation where human RELMβ levels would be significantly modified, as only humans have this single RELM molecule. In BALB/c mice, RELMα was a key contributor to pulmonary vascular remodeling, increase in RV weight and RV cytokine responses induced by exposure to antigen/PM2.5, highlighting the significance of the genetic background for the biological role of RELMα.

OBJECTIVES/GOALS: Particulate matter (PM) and metabolic syndrome (MetSyn) increase risk of World Trade Center-Lung Injury (WTC-LI). Mediterranean-type diets have also been found to improve lung function. Fire Department of New York 1st-responders with a high PM exposure at WTC and MetSyn may have improved lung function after a Mediterranean dietary intervention. METHODS/STUDY POPULATION: Food Intake REstriction for Health OUtcome Support and Education (FIREHOUSE) randomized clinical trial (RCT) assessed our hypothesis that a low-calorie Mediterranean (LoCalMed) intervention targeting clinically relevant disease modifiers will improve metabolic risk, subclinical indicators of cardiopulmonary disease, quality of life, and lung function in firefighters with WTC-LI. Primary-outcome targeted a LoCalMed loss of BMI(≥1kg/m2). Secondary-outcomes included lung function, quality of life, and cardiovascular health. Male firefighters with WTC-LI and a BMI>27kg/m2 were randomized to: 1. LoCalMed (n=46); or 2. Usual Care (UC; n=43). Clinicaltrials.gov:NCT03581006. RESULTS/ANTICIPATED RESULTS: LoCalMed’s estimated efficacy on BMI reduction crossed the pre-specified significance boundary on interim analysis compared to UC. In addition, improvements were observed in secondary-outcomes of lung health (FEV1 and FVC), inflammation (WBC), vascular disease (DBP), quality of life (SF-36, health perception) and dietary habits (less cholesterol, carbohydrates, fats, and sweets and increased protein) in the LoCalMed arm. DISCUSSION/SIGNIFICANCE: LoCalMed significantly decreased BMI and alleviated adverse health outcomes in our WTC-exposed first responders. A fully powered RCT is required to determine if this approach is efficacious for the treatment of WTC-associated pulmonary disease, as well as LoCalMed’s generalizability to PM associated disease.

Abstract Background Diet is a modifier of metabolic syndrome which in turn is associated with World Trade Center obstructive airways disease (WTC-OAD). We have designed this study to (1) assess the dietary phenotype (food types, physical activity, and dietary habits) of the Fire Department of New York (FDNY) WTC-Health Program (WTC-HP) cohort and (2) quantify the association of dietary quality and its advanced glycation end product (AGE) content with the development of WTC-OAD. Methods WTC-OAD, defined as developing WTC-Lung Injury (WTC-LI; FEV1

Background: Particulate matter (PM) exposure is responsible for seven million deaths annually and has been implicated in the pathogenesis of respiratory infections such as severe acute respiratory syndrome (SARS). Understanding modifiable risk factors of high mortality, resource burdensome C19 and exposure risks such as PM is key to mitigating their devastating effects. This systematic review focuses on the literature available, identifying the spatial and temporal variation in the role of quantified PM exposure in SARS disease outcome and planning our future experimental studies. Methods: The systematic review utilized keywords adhered to the PRISMA guidelines. We included original human research studies in English. Results: Initial search yielded N = 906, application of eligibility criteria yielded N = 46. Upon analysis of risk of bias N = 41 demonstrated high risk. Studies found a positive association between elevated PM2.5, PM10 and SARS-related outcomes. A geographic and temporal variation in both PM and C19’s role was observed. Conclusion: C19 is a high mortality and resource intensive disease which devastated the globe. PM exposure is also a global health crisis. Our systematic review focuses on the intersection of this impactful disease-exposure dyad and understanding the role of PM is important in the development of interventions to prevent future spread of viral infections.

Biomarkers predict World Trade Center-Lung Injury (WTC-LI); however, there remains unaddressed multicollinearity in our serum cytokines, chemokines, and high-throughput platform datasets used to phenotype WTC-disease. To address this concern, we used automated, machine-learning, high-dimensional data pruning, and validated identified biomarkers. The parent cohort consisted of male, never-smoking firefighters with WTC-LI (FEV1, %Pred< lower limit of normal (LLN); n = 100) and controls (n = 127) and had their biomarkers assessed. Cases and controls (n = 15/group) underwent untargeted metabolomics, then feature selection performed on metabolites, cytokines, chemokines, and clinical data. Cytokines, chemokines, and clinical biomarkers were validated in the non-overlapping parent-cohort via binary logistic regression with 5-fold cross validation. Random forests of metabolites (n = 580), clinical biomarkers (n = 5), and previously assayed cytokines, chemokines (n = 106) identified that the top 5% of biomarkers important to class separation included pigment epithelium-derived factor (PEDF), macrophage derived chemokine (MDC), systolic blood pressure, macrophage inflammatory protein-4 (MIP-4), growth-regulated oncogene protein (GRO), monocyte chemoattractant protein-1 (MCP-1), apolipoprotein-AII (Apo-AII), cell membrane metabolites (sphingolipids, phospholipids), and branched-chain amino acids. Validated models via confounder-adjusted (age on 9/11, BMI, exposure, and pre-9/11 FEV1, %Pred) binary logistic regression had AUCROC [0.90(0.84-0.96)]. Decreased PEDF and MIP-4, and increased Apo-AII were associated with increased odds of WTC-LI. Increased GRO, MCP-1, and simultaneously decreased MDC were associated with decreased odds of WTC-LI. In conclusion, automated data pruning identified novel WTC-LI biomarkers; performance was validated in an independent cohort. One biomarker-PEDF, an antiangiogenic agent-is a novel, predictive biomarker of particulate-matter-related lung disease. Other biomarkers-GRO, MCP-1, MDC, MIP-4-reveal immune cell involvement in WTC-LI pathogenesis. Findings of our automated biomarker identification warrant further investigation into these potential pharmacotherapy targets.

Abstract Background Quantifying morphologic changes is critical to our understanding of the pathophysiology of the lung. Mean linear intercept (MLI) measures are important in the assessment of clinically relevant pathology, such as emphysema. However, qualitative measures are prone to error and bias, while quantitative methods such as mean linear intercept (MLI) are manually time consuming. Furthermore, a fully automated, reliable method of assessment is nontrivial and resource-intensive. Methods We propose a semi-automated method to quantify MLI that does not require specialized computer knowledge and uses a free, open-source image-processor (Fiji). We tested the method with a computer-generated, idealized dataset, derived an MLI usage guide, and successfully applied this method to a murine model of particulate matter (PM) exposure. Fields of randomly placed, uniform-radius circles were analyzed. Optimal numbers of chords to assess based on MLI were found via receiver-operator-characteristic (ROC)-area under the curve (AUC) analysis. Intraclass correlation coefficient (ICC) measured reliability. Results We demonstrate high accuracy (AUCROC > 0.8 for MLIactual > 63.83 pixels) and excellent reliability (ICC = 0.9998, p

The prevalence of non-cardiac chest pain (NCCP) ranges from 13–33%. A majority of those presenting with a chief complaint of chest pain are found to have a diagnosis of NCCP. Aerodigestive diseases are a cause of NCCP, and billions of dollars are spent annually on the treatment of NCCP. Furthermore, NCCP can cause significant psychological stress. NCCP is commonly diagnosed when patients have chest pain despite a normal cardiac evaluation. The leading cause of NCCP is gastro-oesophageal reflux disease (GORD). GORD should be suspected in patients who report a history of acid regurgitation, cough, dysphagia, and bloating. Another common cause of NCCP is obstructive airway disease (OAD). A thorough history and review of the symptoms should be performed for those with suspected NCCP, especially because of the contributing end organs. It is known that environmental exposures can commonly cause GORD and OAD; however, NCCP has not been fully explored in the context of environmental exposure. Patients with a history of exposure to particulate matter can develop environmental-exposure-associated GORD and coexisting OAD. This narrative review aims to provide a practical overview of NCCP, its causes, their relation to environmental exposure, and associated biomarkers. The authors used a PubMed search that spanned 2003–2018 to accomplish this. Additionally, this review provides a broad overview of biomarkers of GORD-associated NCCP and OAD-associated NCCP due to environmental exposure.

Abstract Gastroesophageal reflux disease (GERD) and Barrett’s Esophagus (BE), which are prevalent in the World Trade Center (WTC) exposed and general populations, negatively impact quality of life and cost of healthcare. GERD, a risk factor of BE, is linked to obstructive airways disease (OAD). We aim to identify serum biomarkers of GERD/BE, and assess the respiratory and clinical phenotype of a longitudinal cohort of never-smoking, male, WTC-exposed rescue workers presenting with pulmonary symptoms. Biomarkers collected soon after WTC-exposure were evaluated in optimized predictive models of GERD/BE. In the WTC-exposed cohort, the prevalence of BE is at least 6 times higher than in the general population. GERD/BE cases had similar lung function, D LCO , bronchodilator response and long-acting β-agonist use compared to controls. In confounder-adjusted regression models, TNF-α ≥ 6 pg/mL predicted both GERD and BE. GERD was also predicted by C-peptide ≥ 360 pg/mL, while BE was predicted by fractalkine ≥ 250 pg/mL and IP-10 ≥ 290 pg/mL. Finally, participants with GERD had significantly increased use of short-acting β-agonist compared to controls. Overall, biomarkers sampled prior to GERD/BE presentation showed strong predictive abilities of disease development. This study frames future investigations to further our understanding of aerodigestive pathology due to particulate matter exposure.

We present a case of severe symptomatic hyponatremia (94 mEq/L) in a male patient who presented with nausea, vomiting, and multiple falls. The patient was found with symptomatic hypo-osmolar hypovolemic hyponatremia secondary to volume loss from vomiting, diuretic use, and consumption of solute-free water. To manage such a severely hyponatremic patient, concomitant 3% hypertonic saline and DDAVP were initiated with successful slow and sustained correction of sodium without complications of osmotic demyelination syndrome.

OBJECTIVES/GOALS: Metabolic syndrome (MetSyn) is a risk for World Trade Center-Lung Injury (WTC-LI; defined as developing FEV1

Background Our group has identified the receptor for advanced glycation end-products (RAGE) as a predictor of World Trade Center particulate matter associated lung injury. The aim of this systematic review is to assess the relationship between RAGE and obstructive airways disease secondary to environmental exposure. Methods A comprehensive search using PubMed and Embase was performed on January 5, 2018 utilising keywords focusing on environmental exposure, obstructive airways disease and RAGE and was registered with PROSPERO (CRD42018093834). We included original human research studies in English, focusing on pulmonary end-points associated with RAGE and environmental exposure. Results A total of 213 studies were identified by the initial search. After removing the duplicates and applying inclusion and exclusion criteria, we screened the titles and abstracts of 61 studies. Finally, 19 full-text articles were included. The exposures discussed in these articles include particulate matter (n=2) and cigarette smoke (n=17). Conclusion RAGE is a mediator of inflammation associated end-organ dysfunction such as obstructive airways disease. Soluble RAGE, a decoy receptor, may have a protective effect in some pulmonary processes. Overall, RAGE is biologically relevant in environmental exposure associated lung disease. Future investigations should focus on further understanding the role and therapeutic potential of RAGE in particulate matter exposure associated lung disease.

World Trade Center-particulate matter(WTC-PM) exposure and metabolic-risk are associated with WTC-Lung Injury(WTC-LI). The receptor for advanced glycation end-products (RAGE) is most highly expressed in the lung, mediates metabolic risk, and single-nucleotide polymorphisms at the AGER-locus predict forced expiratory volume(FEV). Our objectives were to test the hypotheses that RAGE is a biomarker of WTC-LI in the FDNY-cohort and that loss of RAGE in a murine model would protect against acute PM-induced lung disease. We know from previous work that early intense exposure at the time of the WTC collapse was most predictive of WTC-LI therefore we utilized a murine model of intense acute PM-exposure to determine if loss of RAGE is protective and to identify signaling/cytokine intermediates. This study builds on a continuing effort to identify serum biomarkers that predict the development of WTC-LI. A case-cohort design was used to analyze a focused cohort of male never-smokers with normal pre-9/11 lung function. Odds of developing WTC-LI increased by 1.2, 1.8 and 1.0 in firefighters with soluble RAGE (sRAGE)≥97pg/mL, CRP≥2.4mg/L, and MMP-9≤397ng/mL, respectively, assessed in a multivariate logistic regression model (ROCAUC of 0.72). Wild type(WT) and RAGE-deficient(Ager-/-) mice were exposed to PM or PBS-control by oropharyngeal aspiration. Lung function, airway hyperreactivity, bronchoalveolar lavage, histology, transcription factors and plasma/BAL cytokines were quantified. WT-PM mice had decreased FEV and compliance, and increased airway resistance and methacholine reactivity after 24-hours. Decreased IFN-γ and increased LPA were observed in WT-PM mice; similar findings have been reported for firefighters who eventually develop WTC-LI. In the murine model, lack of RAGE was protective from loss of lung function and airway hyperreactivity and was associated with modulation of MAP kinases. We conclude that in a multivariate adjusted model increased sRAGE is associated with WTC-LI. In our murine model, absence of RAGE mitigated acute deleterious effects of PM and may be a biologically plausible mediator of PM-related lung disease.

Particulate matter (PM) exposure and metabolic syndrome (MetSyn) are both significant global health burdens. PM exposure has been implicated in the pathogenesis of MetSyn and cardiopulmonary diseases. Individuals with pre-existing MetSyn may be more susceptible to the detrimental effects of PM exposure. Our aim was to provide a narrative review of MetSyn/PM-induced systemic inflammation in cardiopulmonary disease, with a focus on prior studies of the World Trade Center (WTC)-exposed Fire Department of New York (FDNY). We included studies (1) published within the last 16-years; (2) described the epidemiology of MetSyn, obstructive airway disease (OAD), and vascular disease in PM-exposed individuals; (3) detailed the known mechanisms of PM-induced inflammation, MetSyn and cardiopulmonary disease; and (4) focused on the effects of PM exposure in WTC-exposed FDNY firefighters. Several investigations support that inhalation of PM elicits pulmonary and systemic inflammation resulting in MetSyn and cardiopulmonary disease. Furthermore, individuals with these preexisting conditions are more sensitive to PM exposure-related inflammation, which can exacerbate their conditions and increase their risk for hospitalization and chronic disease. Mechanistic research is required to elucidate biologically plausible therapeutic targets of MetSyn- and PM-induced cardiopulmonary disease.

OBJECTIVES/SPECIFIC AIMS: In this pilot case-control study, the metabolome was quantified in subjects with previously measured serum and clinical biomarkers. The serum metabolome was then integrated with existing serum and clinical biomarkers of WTC-exposed firefighters to identify pathways significant to loss of lung function following acute PM-exposure. This robust subset of metabolite and serum biomarkers may be clinically relevant to predicting progression to lung disease in a larger cohort. METHODS/STUDY POPULATION: Serum drawn within 6 months of 9/11 was analyzed in this pilot. Clinical measures were obtained from electronic medical records. Never-smoking, male, WTC-exposed firefighters with normal pre-9/11 lung function were segregated based on FEV1 percent predicted (FEV1 %Pred) at symptomatic presentation. Cases of WTC-LI (FEV1 %Pred

OBJECTIVES/SPECIFIC AIMS: Obstructive lung disease following particulate matter (PM) exposure is a major health concern. Coexisting metabolic syndrome (MetSyn) often occurs. Receptor for advanced glycation end products (RAGE) is highly expressed in the lung, is a strong predictor of FEV1, and is a key mediator of MetSyn. To determine if the loss of RAGE protects from the persistence of effects of particulate associated lung injury in a murine model. METHODS/STUDY POPULATION: Wild type (WT) and RAGE knockout (RKO) mice were exposed to 100 μg of PM (WTC-Aggregate, PM53) or PBS control by oropharyngeal aspiration. Lung function, methacholine challenge, and bronchoalveolar lavage (BAL) were quantified 28 days after PM exposure using flexiVent (Scireq Montreal, QC). BAL was obtained and cell differentials, cytokines and transcription factors were assayed. Bio-volume to airspace ratio and mean chord length were measured (Image J and Adobe Photoshop). RESULTS/ANTICIPATED RESULTS: WT mice were hyper-reactive to methacholine compared with their PBS controls 28 days after a single exposure to PM. They recovered from increased neutrophilia, loss of FEV, decreased compliance, and increased resistance, which were previously observed 24-hours after exposure. RKO were not hyper-reactive when compared with their own PBS controls. Lung histology shows persistence of loss of alveolar space in WT mice exposed to PM after 28 days. Area fraction was significantly higher in PM exposed WT mice after 28 days which was not significant after 24 hours. Mean chord length was significantly shorter for PM exposed at both time points for WT mice. The relative expression of phosphorylated to total CREB and ERK1/2 proteins was lower in RKO PM exposed mice compared with WT PM while STAT3 expression was lower in WT PM compared with WT PBS. PM induced a lower fold change of total proteins from the PBS controls in RKO for CREB, p38, ERK1/2, STAT3, and STAT5. JNK and p70S6k total proteins expressed a decreased fold change in WT PM exposed mice compared with WT PBS controls. DISCUSSION/SIGNIFICANCE OF IMPACT: A single dose of PM can produce persistent airway hyper-reactivity after 28 days of exposure. This PM induced injury is alleviated in the absence of RAGE, similar to what was seen at 24 hours. Inhibiting RAGE may be key to limiting the persistent inflammatory effects of high intensity PM exposure.

After 9/11/2001, some Fire Department of New York (FDNY) workers had excessive lung function decline. We hypothesized that early serum matrix metalloproteinases (MMP) expression predicts World Trade Center-Lung Injury (WTC-LI) years later.This is a nested case-control analysis of never-smoking male firefighters with normal pre-exposure Forced Expiratory Volume in one second (FEV1) who had serum drawn up to 155 days post 9/11/2001. Serum MMP-1, 2,3,7,8, 9, 12 and 13 were measured. Cases of WTC-LI (N = 70) were defined as having an FEV1 one standard deviation below the mean (FEV1 ≤ 77%) at subspecialty pulmonary evaluation (SPE) which was performed 32 months (IQR 21-53) post-9/11. Controls (N = 123) were randomly selected. We modeled MMP's ability as a predictor of cases status with logistic regression adjusted for time to blood draw, exposure intensity, weight gain and pre-9/11 FEV1.Each log-increase in MMP-3 and MMP-12 showed reduced odds of developing WTC-LI by 73% and 54% respectively. MMP-3 and MMP-12 consistently clustered together in cases, controls, and the cohort. Increasing time to blood draw significantly and independently increased the risk of WTC-LI.Elevated serum levels of MMP-3 and MMP-12 reduce the risk of developing WTC-LI. At any level of MMP-3 or 12, increased time to blood draw is associated with a diminished protective effect.

The WTC collapse exposed over 300,000 people to high concentrations of WTC-PM; particulates up to ∼50 mm were recovered from rescue workers' lungs. Elevated MDC and GM-CSF independently predicted subsequent lung injury in WTC-PM-exposed workers. Our hypotheses are that components of WTC dust strongly induce GM-CSF and MDC in AM; and that these two risk factors are in separate inflammatory pathways.Normal adherent AM from 15 subjects without WTC-exposure were incubated in media alone, LPS 40 ng/mL, or suspensions of WTC-PM(10-53) or WTC-PM(2.5) at concentrations of 10, 50 or 100 µg/mL for 24 hours; supernatants assayed for 39 chemokines/cytokines. In addition, sera from WTC-exposed subjects who developed lung injury were assayed for the same cytokines. In the in vitro studies, cytokines formed two clusters with GM-CSF and MDC as a result of PM(10-53) and PM(2.5). GM-CSF clustered with IL-6 and IL-12(p70) at baseline, after exposure to WTC-PM(10-53) and in sera of WTC dust-exposed subjects (n = 70) with WTC lung injury. Similarly, MDC clustered with GRO and MCP-1. WTC-PM(10-53) consistently induced more cytokine release than WTC-PM(2.5) at 100 µg/mL. Individual baseline expression correlated with WTC-PM-induced GM-CSF and MDC.WTC-PM(10-53) induced a stronger inflammatory response by human AM than WTC-PM(2.5). This large particle exposure may have contributed to the high incidence of lung injury in those exposed to particles at the WTC site. GM-CSF and MDC consistently cluster separately, suggesting a role for differential cytokine release in WTC-PM injury. Subject-specific response to WTC-PM may underlie individual susceptibility to lung injury after irritant dust exposure.

RET-fusions are a known cause of acquired osimertinib resistance in patients with advanced NSCLC. Herein we describe the case of a patient who developed resistance to osimertinib, via acquisition of a novel CGN-RET fusion mutation. She had a favorable response to treatment with RET-targeting TKI selpercatinib, in combination with osimertinib.

Dissemination of tuberculosis (TB) is known as miliary tuberculosis. When miliary tuberculosis lacks classic radiographic and clinical features, it can be labeled cryptic miliary tuberculosis and may mimic metastatic cancer. This unusual presentation of an already atypical form of TB often delays diagnosis. We present a case of a 58-year-old female who presented with presumed metastatic carcinoma, who was ultimately diagnosed with both primary breast cancer and disseminated TB. This case emphasizes the need for a high index of suspicion for miliary tuberculosis in patients with presumed or proven malignancy.