Pro-regenerative biomaterials recruit immunoregulatory dendritic cells after traumatic injury.

During wound healing and surgical implantation, the body establishes a delicate balance between immune activation to fight off infection and clear debris and immune tolerance to control reactivity against self-tissue. Nonetheless, how such a balance is achieved is not well understood. Here we describe that pro-regenerative biomaterials for muscle injury treatment promote the proliferation of a BATF3-dependent CD103+XCR1+CD206+CD301b+ dendritic cell population associated with cross-presentation and self-tolerance. Upregulation of E-cadherin, the ligand for CD103, and XCL-1 in injured tissue suggests a mechanism for cell recruitment to trauma. Muscle injury recruited natural killer cells that produced Xcl1 when stimulated with fragmented extracellular matrix. Without cross-presenting cells, T-cell activation increases, pro-regenerative macrophage polarization decreases and there are alterations in myogenesis, adipogenesis, fibrosis and increased muscle calcification. These results, previously observed in cancer progression, suggest a fundamental mechanism of immune regulation in trauma and material implantation with implications for both short- and long-term injury recovery.

Sulfur radical formation from the tropospheric irradiation of aqueous sulfate aerosols.

The sulfate anion radical (SO4•-) is known to be formed in the autoxidation chain of sulfur dioxide and from minor reactions when sulfate or bisulfate ions are activated by OH radicals, NO3 radicals, or iron. Here, we report a source of SO4•-, from the irradiation of the liquid water of sulfate-containing organic aerosol particles under natural sunlight and laboratory UV radiation. Irradiation of aqueous sulfate mixed with a variety of atmospherically relevant organic compounds degrades the organics well within the typical lifetime of aerosols in the atmosphere. Products of the SO4•- + organic reaction include surface-active organosulfates and small organic acids, alongside other products. Scavenging and deoxygenated experiments indicate that SO4•- radicals, instead of OH, drive the reaction. Ion substitution experiments confirm that sulfate ions are necessary for organic reactivity, while the cation identity is of low importance. The reaction proceeds at pH 1-6, implicating both bisulfate and sulfate in the formation of photoinduced SO4•-. Certain aromatic species may further accelerate the reaction through synergy. This reaction may impact our understanding of atmospheric sulfur reactions, aerosol properties, and organic aerosol lifetimes when inserted into aqueous chemistry model mechanisms.

Erdafitinib in BCG-treated high-risk non-muscle-invasive bladder cancer.

BACKGROUND: Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) with disease recurrence after bacillus Calmette-Guérin (BCG) treatment and who are ineligible for/refuse radical cystectomy. FGFR alterations are commonly detected in NMIBC. We evaluated the activity of oral erdafitinib, a selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, versus intravesical chemotherapy in patients with high-risk NMIBC and select FGFR3/2 alterations following recurrence after BCG treatment. PATIENTS AND METHODS: Patients aged ≥18 years with recurrent, BCG-treated, papillary-only high-risk NMIBC (high-grade Ta/T1) and select FGFR alterations refusing or ineligible for radical cystectomy were randomized to 6 mg daily oral erdafitinib or investigator's choice of intravesical chemotherapy (mitomycin C or gemcitabine). The primary endpoint was recurrence-free survival (RFS). The key secondary endpoint was safety. RESULTS: Study enrollment was discontinued due to slow accrual. Seventy-three patients were randomized 2 : 1 to erdafitinib (n = 49) and chemotherapy (n = 24). Median follow-up for RFS was 13.4 months for both groups. Median RFS was not reached for erdafitinib [95% confidence interval (CI) 16.9 months-not estimable] and was 11.6 months (95% CI 6.4-20.1 months) for chemotherapy, with an estimated hazard ratio of 0.28 (95% CI 0.1-0.6; nominal P value = 0.0008). In this population, safety results were generally consistent with known profiles for erdafitinib and chemotherapy. CONCLUSIONS: Erdafitinib prolonged RFS compared with intravesical chemotherapy in patients with papillary-only, high-risk NMIBC harboring FGFR alterations who had disease recurrence after BCG therapy and refused or were ineligible for radical cystectomy.

Clonal germinal center B cells function as a niche for T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is proposed to be initiated by age-related clonal hematopoiesis (ACH) with TET2 mutations, whereas the G17V RHOA mutation in immature cells with TET2 mutations promotes the development of T follicular helper (TFH)-like tumor cells. Here, we investigated the mechanism by which TET2-mutant immune cells enable AITL development using mouse models and human samples. Among the 2 mouse models, mice lacking Tet2 in all the blood cells (Mx-Cre × Tet2flox/flox × G17V RHOA transgenic mice) spontaneously developed AITL for approximately up to a year, while mice lacking Tet2 only in the T cells (Cd4-Cre × Tet2flox/flox × G17V RHOA transgenic mice) did not. Therefore, Tet2-deficient immune cells function as a niche for AITL development. Single-cell RNA-sequencing (scRNA-seq) of >50 000 cells from mouse and human AITL samples revealed significant expansion of aberrant B cells, exhibiting properties of activating light zone (LZ)-like and proliferative dark zone (DZ)-like germinal center B (GCB) cells. The GCB cells in AITL clonally evolved with recurrent mutations in genes related to core histones. In silico network analysis using scRNA-seq data identified Cd40-Cd40lg as a possible mediator of GCB and tumor cell cluster interactions. Treatment of AITL model mice with anti-Cd40lg inhibitory antibody prolonged survival. The genes expressed in aberrantly expanded GCB cells in murine tumors were also broadly expressed in the B-lineage cells of TET2-mutant human AITL. Therefore, ACH-derived GCB cells could undergo independent clonal evolution and support the tumorigenesis in AITL via the CD40-CD40LG axis.

Quantification of Free Radicals from Vaping Electronic Cigarettes Containing Nicotine Salt Solutions with Different Organic Acid Types and Concentrations.

Electronic (e-) cigarette formulations containing nicotine salts from a range of organic acid conjugates and pH values have dominated the commercial market. The acids in the nicotine salt formulations may alter the redox environment in e-cigarettes, impacting free radical formation in e-cigarette aerosol. Here, the generation of aerosol mass and free radicals from a fourth-generation e-cigarette device was evaluated at 2 wt % nicotine salts (pH 7, 30:70 mixture propylene glycol to vegetable glycerin) across eight organic acids used in e-liquids: benzoic acid (BA), salicylic acid (SLA), lactic acid (LA), levulinic acid (LVA), succinic acid (SA), malic acid (MA), tartaric acid (TA), and citric acid (CA). Furthermore, 2 wt % BA nicotine salts were studied at the following nicotine to acid ratios: 1:2 (pH 4), 1:1 (pH 7), and 2:1 (pH 8), in comparison with freebase nicotine (pH 10). Radical yields were quantified by spin-trapping and electron paramagnetic resonance (EPR) spectroscopy. The EPR spectra of free radicals in the nicotine salt aerosol matched those generated from the Fenton reaction, which are primarily hydroxyl (OH) radicals and other reactive oxygen species (ROS). Although the aerosol mass formation was not significantly different for most of the tested nicotine salts and acid concentrations, notable ROS yields were observed only from BA, CA, and TA under the study conditions. The e-liquids with SLA, LA, LVA, SA, and MA produced less ROS than the 2 wt % freebase nicotine e-liquid, suggesting that organic acids may play dual roles in the production and scavenging of ROS. For BA nicotine salts, it was found that the ROS yield increased with a higher acid concentration (or a lower nicotine to acid ratio). The observation that BA nicotine salts produce the highest ROS yield in aerosol generated from a fourth-generation vape device, which increases with acid concentration, has important implications for ROS-mediated health outcomes that may be relevant to consumers, manufacturers, and regulatory agencies.

Endovascular Repair of Juxtarenal and Pararenal Abdominal Aortic Aneurysms Using a Novel Low-Profile Fenestrated Custom-Made Endograft: Technical Details and Short-Term Outcomes.

INTRODUCTION: The aim of this study is to share preliminary experiences and outcomes with a novel custom-made fenestrated TREO® Abdominal Stent-Graft System to treat juxtarenal and pararenal abdominal aortic aneurysms (AAAs). METHODS: Juxtarenal and pararenal AAA patients treated with the custom-made fenestrated TREO® Abdominal Stent-Graft System were included from 4 high-volume European academic medical centers from June 2021 to September 2023. Technical success and 30-day/in-hospital mortality and complications were analyzed. Technical success was defined as successful endovascular implantation of the stent graft with preservation of antegrade flow to the target vessels, and absence of type 1 or 2 endoleak (EL) at the first postoperative computed tomography angiography (CTA). RESULTS: Forty-two consecutive patients were included. The majority of the devices were constructed with 2 (N=4; 9.5%), 3 (N=9; 21.4%), or 4 (N=27; 64%) fenestrations. In 1 case, the device was constructed with a single fenestration (2.4%) and 1 device contained 5 fenestrations (2.4%); 17% had previous AAA repair. Target vessel cannulation with placement of a bridging stent was successful in all but 1 vessel (99, 3%). One aneurysm-related death occurred in the direct postoperative period and 2 limb occlusions necessitated reintervention during admission. In the median follow-up period of 101 (2-620) days, 3 more patients died due to non-aneurysm-related causes. Technical success was achieved in 90% of the cases. Nineteen ELs were seen on the first postoperative CT scan: 1 type 1b EL (N=1; 2%), 15 type 2 ELs (N=15; 36%), and 3 type 3 ELs (N=3%). Eleven patients received more than 1 CT scan during a median follow-up of 361 days (82-620): 3 type 2 ELs resolved and 1 type 3 EL was treated in this period. In the follow-up, 1 patient had a coagulation disorder that caused occlusions of the branches. CONCLUSION: The results of the first experiences using the custom-made fenestrated TREO® Abdominal Stent-Graft System in Europe are promising. There was a low short-term mortality and morbidity rate in these patients of which 17% had previous AAA repair. Mid-term and long-term follow-up data are needed to evaluate endograft durability and performance. CLINICAL IMPACT: This study shows the first experiences and short-term results of a novel low-profile custom-made device: the custom-made fenestrated TREO® Abdominal Stent-Graft System. Showing these results and experiences can help the physicians in clinical decision-making for their patients.

Perceived Benefits and Barriers to Implementing Occupational Health Recommendations Among Immigrant-Owned Nail Salons in the Greater Philadelphia Region.

Introduction. Immigrant nail salon owners and employees face multiple barriers to accessing occupational health training and services. We formed an academic-community-based organization-business owner partnership-unique in that all partners were culturally congruent-to develop a pilot intervention program for the nail salon community. Methods. Eighteen individuals (nine salon owners and nine employees) from the Greater Philadelphia region received the training in their native language and provided feedback through in-depth qualitative interviews. Interview guide was developed using the Consolidated Framework for Implementation Research (CFIR). Themes of perceived benefits and barriers were identified and aligned with relevant CFIR constructs to gain better understanding of the implementation challenges. Results. Reported benefits of program were improved knowledge of the workplace hazards and safety practices, and the potential to attract more customers and retain employees. Perceived barriers to implementing recommended practices were limited availability of safer products and high cost, challenges communicating with customers, lack of engagement from some owners, organizational management practices affecting employees' motivation, and limited partnership with local government to assist small immigrant-owned businesses. Conclusions. Our study revealed multiple factors that pit long-term health protection of nail salon workers against the economic viability of the businesses that employ them. Our research highlights the need to (1) advocate for federal policies making safer products to be more accessible to the masses, (2) establish local policy and culturally appropriate technical support programs that engage community-based organizations, and (3) develop economic opportunities and mentorship for immigrant entrepreneurs to operate profitable healthy salons.

Carbonyls and Aerosol Mass Generation from Vaping Nicotine Salt Solutions Using Fourth- and Third-Generation E-Cigarette Devices: Effects of Coil Resistance, Coil Age, and Coil Metal Material.

Aerosol formation and production yields from 11 carbonyls (carbonyl concentration per aerosol mass unit) were investigated (1) from a fourth-generation (4th gen) e-cigarette device at different coil resistances and coil age (0-5000 puffs) using unflavored e-liquid with 2% benzoic acid nicotine salt, (2) between a sub-ohm third-generation (3rd gen) tank mod at 0.12 Ω and a 4th gen pod at 1.2 Ω using e-liquid with nicotine salt, together with nicotine yield, and (3) from 3rd gen coils of different metals (stainless steel, kanthal, nichrome) using e-liquid with freebase nicotine. Coil resistance had an inverse relationship with coil temperature, and coil temperature was directly proportional to aerosol mass formation. Trends in carbonyl yields depended on carbonyl formation mechanisms. Carbonyls produced primarily from thermal degradation chemistry (e.g., formaldehyde, acetaldehyde, acrolein, propionaldehyde) increased per aerosol mass with higher coil resistances, despite lower coil temperature. Carbonyls produced primarily from chemistry initiated by reactive oxygen species (ROS) (e.g., hydroxyacetone, dihydroxyacetone, methylglyoxal, glycolaldehyde, lactaldehyde) showed the opposite trend. Coil age did not alter coil temperature nor aerosol mass formation but had a significant effect on carbonyl formation. Thermal carbonyls were formed optimally at 500 puffs in our study and then declined to a baseline, whereas ROS-derived carbonyls showed a slow rise to a maximum trend with coil aging. The 3rd gen versus 4th gen device comparison mirrored the trends in coil resistance. Nicotine yields per aerosol mass were consistent between 3rd and 4th gen devices. Coil material did not significantly alter aerosol formation nor carbonyl yield when adjusted for wattage. This work shows that sub-ohm coils may not necessarily produce higher carbonyl yields even when they produce more aerosol mass. Furthermore, carbonyl formation is dynamic and not generalizable during the coil's lifetime. Finally, studies that compare data across different e-cigarette devices, coil age, and coil anatomy should account for the aerosol chemistry trends that depend on these parameters.

Development of a High-Color Flow Cytometry Panel for Immunologic Analysis of Tissue Injury and Reconstruction in a Rat Model.

The rat model is an important resource in biomedical research due to its similarities to the human immune system and its use for functional studies. However, because of the preponderance of mouse models in foundational and mechanistic immunological studies, there is a relative lack of diverse, commercially available flow cytometry antibodies for immunological profiling in the rat model. Available antibodies are often conjugated to common fluorophores with similar peak emission wavelengths, making them hard to distinguish on conventional flow cytometers and restricting more comprehensive immune analysis. This can become a limitation when designing immunological studies in rat injury models to investigate the immune response to tissue injury. In addition, this lack of available antibodies limits the number of studies that can be done on the immune populations in lymphoid organs in other research areas. To address this critical unmet need, we designed a spectral flow cytometry panel for rat models. Spectral cytometry distinguishes between different fluorophores by capturing their full emission spectra instead of their peak emission wavelengths. This flow cytometry panel includes 24 distinct immune cell markers to analyze the innate and adaptive immune response. Importantly, this panel identifies different immune phenotypes, including tolerogenic, Type 1, and Type 2 immune responses. We show that this panel can identify unique immune populations and phenotypes in a rat muscle trauma model. We further validated that the panel can identify distinct adaptive and innate immune populations and their unique phenotypes in lymphoid organs. This panel expands the scope of previous rat panels providing a tool for scientists to examine the immune system in homeostasis and injury while pairing mechanistic immunological studies with functional studies.

Fine particulate matter and incident coronary heart disease events up to 10 years of follow-up among Deepwater Horizon oil spill workers.

BACKGROUND: During the 2010 Deepwater Horizon (DWH) disaster, in-situ burning and flaring were conducted to remove oil from the water. Workers near combustion sites were potentially exposed to burning-related fine particulate matter (PM2.5). Exposure to PM2.5 has been linked to increased risk of coronary heart disease (CHD), but no study has examined the relationship among oil spill workers. OBJECTIVES: To investigate the association between estimated PM2.5 from burning/flaring of oil/gas and CHD risk among the DWH oil spill workers. METHODS: We included workers who participated in response and cleanup activities on the water during the DWH disaster (N = 9091). PM2.5 exposures were estimated using a job-exposure matrix that linked modelled PM2.5 concentrations to detailed DWH spill work histories provided by participants. We ascertained CHD events as the first self-reported physician-diagnosed CHD or a fatal CHD event that occurred after each worker's last day of burning exposure. We estimated hazard ratios (HR) and 95% confidence intervals (95%CI) for the associations between categories of average or cumulative daily maximum PM2.5 exposure (versus a referent category of water workers not near controlled burning) and subsequent CHD. We assessed exposure-response trends by examining continuous exposure parameters in models. RESULTS: We observed increased CHD hazard among workers with higher levels of average daily maximum exposure (low vs. referent: HR = 1.26, 95% CI: 0.93, 1.70; high vs. referent: HR = 2.11, 95% CI: 1.08, 4.12; per 10 µg/m3 increase: HR = 1.10, 95% CI: 1.02, 1.19). We also observed suggestively elevated HRs among workers with higher cumulative daily maximum exposure (low vs. referent: HR = 1.19, 95% CI: 0.68, 2.08; medium vs. referent: HR = 1.38, 95% CI: 0.88, 2.16; high vs. referent: HR = 1.44, 95% CI: 0.96, 2.14; per 100 µg/m3-d increase: HR = 1.03, 95% CI: 1.00, 1.05). CONCLUSIONS: Among oil spill workers, exposure to PM2.5 from flaring/burning of oil/gas was associated with increased risk of CHD.

Exposure to volatile hydrocarbons and neurologic function among oil spill workers up to 6 years after the Deepwater Horizon disaster.

BACKGROUND: During the 2010 Deepwater Horizon (DWH) disaster, oil spill response and cleanup (OSRC) workers were exposed to toxic volatile components of crude oil. Few studies have examined exposure to individual volatile hydrocarbon chemicals below occupational exposure limits in relation to neurologic function among OSRC workers. OBJECTIVES: To investigate the association of several spill-related chemicals (benzene, toluene, ethylbenzene, xylene, n-hexane, i.e., BTEX-H) and total petroleum hydrocarbons (THC) with neurologic function among DWH spill workers enrolled in the Gulf Long-term Follow-up Study. METHODS: Cumulative exposure to THC and BTEX-H across the oil spill cleanup period were estimated using a job-exposure matrix that linked air measurement data to detailed self-reported DWH OSRC work histories. We ascertained quantitative neurologic function data via a comprehensive test battery at a clinical examination that occurred 4-6 years after the DWH disaster. We used multivariable linear regression and modified Poisson regression to evaluate relationships of exposures (quartiles (Q)) with 4 neurologic function measures. We examined modification of the associations by age at enrollment (<50 vs. ≥50 years). RESULTS: We did not find evidence of adverse neurologic effects from crude oil exposures among the overall study population. However, among workers ≥50 years of age, several individual chemical exposures were associated with poorer vibrotactile acuity of the great toe, with statistically significant effects observed in Q3 or Q4 of exposures (range of log mean difference in Q4 across exposures: 0.13-0.26 µm). We also observed suggestive adverse associations among those ≥ age 50 years for tests of postural stability and single-leg stance, although most effect estimates did not reach thresholds of statistical significance (p < 0.05). CONCLUSIONS: Higher exposures to volatile components of crude oil were associated with modest deficits in neurologic function among OSRC workers who were age 50 years or older at study enrollment.

Duration of employment within occupations and incident stroke in a US general population cohort 45 years of age or older (REGARDS study).

BACKGROUND: The work environment can contribute to the risk of cardiovascular diseases (CVD) including stroke. Our objective was to identify occupations with elevated risk of stroke within the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. METHODS: We analyzed incident stroke outcomes (ischemic and hemorrhagic strokes) from 2003 to 2020 and employment characteristics of 13,659 adults aged ≥45 years enrolled in a national population-based cohort study. Using a modified Poisson regression approach, we estimated the relative risks (RRs) and the associated 95% confidence intervals (CI) of stroke in relation to years of employment within each occupation coded using the US Census two-digit Standard Occupation Code. Models were adjusted for Framingham Stroke Risk Score, region, race, age, and body mass index. We conducted stratified analysis by sex, employment time period (pre-1975 vs. post-1975), and region. RESULTS: Workers in the following occupations had a greater risk of stroke with longer duration of employment (per decade): protective service (RR: 2.35, 95% CI: 1.11, 4.97), food preparation and service (RR: 1.51, 95% CI: 1.05, 2.19), and transportation and material moving (RR: 1.30, 95% CI: 1.00, 1.69). The stroke risk in these occupations was disproportionately elevated in men, and differed by region and employment time period. CONCLUSIONS: Longer employment in protective service, food preparation and serving, and transportation and materials moving occupations may increase the risk of stroke. Surveillance may uncover specific work-related risk factors in these occupations, leading to interventions to reduce the burden of stroke among US workers.

The need for a multi-level approach to occupational safety and health among Asian and Asian American beauty service workers.

Asian and Asian Americans (A/AA) are a group overlooked in general health outcomes but especially occupational safety and health outcomes. In the United States, the beauty service microbusiness industry (e.g., nail salons) predominantly employs immigrant Asian women who regularly encounter a plethora of occupational hazards (e.g., harmful chemical exposures -toluene, formaldehyde, bloodborne pathogens, fungi. However, due to the precariousness of beauty service jobs, cultural and linguistic barriers, and social determinants of health, A/AA beauty service workers face complex occupational safety and health challenges that require interdisciplinary collaboration and cultural competency to address. This commentary will discuss a multi-level approach including specific outreach partners that will offer the required diverse skillsets necessary for improving the occupational safety and health for this worker population in this microbusiness industry. Implications and suggestions for interventions and policy changes are also recommended utilizing the National Institute on Minority Health and Health Disparities' Research Framework.

Healing of particulate allografts mixed with platelet concentrates in ridge preservation and sinus lift: a prospective histomorphometric study.

The objective of the present study was to evaluate the bone quality of sinus and alveolar grafts following filling with particulate allogenous bone (DFDBA 300-500µm) and platelet concentrate (platelet-rich fibrin, PRF). A prospective interventional clinical study was carried out. A total of 40 bone cores, 2mm in diameter, were taken from 21 patients: 22 from grafted alveoli, 7 from grafted sinus sites, and 11 from native bone used as a control. Fixed, paraffin-embedded samples were subjected to histological staining with hematoxylin-eosin and Masson's trichrome. Bone maturity of the samples was evaluated by two independent operators using histomorphometric analysis. There existed a greater proportion of lamellar neoformed bone than woven neoformed bone as the healing time increased. Moreover, there was also an increasing proportion of newly formed bone in the grafted sockets as a function of healing time (average: 41.22% ≤ 5 months, 55.89% Ëƒ 5 months). Resorption of DFDBA particles also appears to be correlated with healing time in the grafted socket (average: 15.43 ≤ 5 months, 13.72% Ëƒ 5 months). In conclusion, performing sinus lift and alveolar socket preservation techniques using DFDBA and PRF results in high quality, mature bone tissue according to histological criteria.

VAV1 mutations contribute to development of T-cell neoplasms in mice.

Activating mutations in the Vav guanine nucleotide exchange factor 1 (VAV1) gene are reported in various subtypes of mature T-cell neoplasms (TCNs). However, oncogenic activities associated with VAV1 mutations in TCNs remain unclear. To define them, we established transgenic mice expressing VAV1 mutants cloned from human TCNs. Although we observed no tumors in these mice for up to a year, tumors did develop in comparably aged mice on a p53-null background (p53-/-VAV1-Tg), and p53-/-VAV1-Tg mice died with shorter latencies than did p53-null (p53-/-) mice. Notably, various TCNs with tendency of maturation developed in p53-/-VAV1-Tg mice, whereas p53-/- mice exhibited only immature TCNs. Mature TCNs in p53-/-VAV1-Tg mice mimicked a subtype of human peripheral T-cell lymphoma (PTCL-GATA3) and exhibited features of type 2 T helper (Th2) cells. Phenotypes seen following transplantation of either p53-/-VAV1 or p53-/- tumor cells into nude mice were comparable, indicating cell-autonomous tumor-initiating capacity. Whole-transcriptome analysis showed enrichment of multiple Myc-related pathways in TCNs from p53-/-VAV1-Tg mice relative to p53-/- or wild-type T cells. Remarkably, amplification of the Myc locus was found recurrently in TCNs of p53-/-VAV1-Tg mice. Finally, treatment of nude mice transplanted with p53-/-VAV1-Tg tumor cells with JQ1, a bromodomain inhibitor that targets the Myc pathway, prolonged survival of mice. We conclude that VAV1 mutations function in malignant transformation of T cells in vivo and that VAV1-mutant-expressing mice could provide an efficient tool for screening new therapeutic targets in TCNs harboring these mutations.

Vaping Aerosols from Vitamin E Acetate and Tetrahydrocannabinol Oil: Chemistry and Composition.

The popularity of vaping cannabis products has increased sharply in recent years. In 2019, a sudden onset of electronic cigarette/vaping-associated lung injury (EVALI) was reported, leading to thousands of cases of lung illness and dozens of deaths due to the vaping of tetrahydrocannabinol (THC)-containing e-liquids that were obtained on the black market. A potential cause of EVALI has been hypothesized due to the illicit use of vitamin E acetate (VEA) in cannabis vape cartridges. However, the chemistry that modifies VEA and THC oil, to potentially produce toxic byproducts, is not well understood under different scenarios of use. In this work, we quantified carbonyls, organic acids, cannabinoids, and terpenes in the vaping aerosol of pure VEA, purified THC oil, and an equal volume mixture of VEA and THC oil at various coil temperatures (100-300 °C). It was found under the conditions of our study that degradation of VEA and cannabinoids, including Δ9-THC and cannabigerol (CBG), occurred via radical oxidation and direct thermal decomposition pathways. Evidence of terpene degradation was also observed. The bond cleavage of aliphatic side chains in both VEA and cannabinoids formed a variety of smaller carbonyls. Oxidation at the ring positions of cannabinoids formed various functionalized products. We show that THC oil has a stronger tendency to aerosolize and degrade compared to VEA at a given temperature. The addition of VEA to the e-liquid nonlinearly suppressed the formation of vape aerosol compared to THC oil. At the same time, toxic carbonyls including formaldehyde, 4-methylpentanal, glyoxal, or diacetyl and its isomers were highly enhanced in VEA e-liquid when normalized to particle mass.

Second-Order Kinetic Rate Coefficients for the Aqueous-Phase Sulfate Radical (SO4•-) Oxidation of Some Atmospherically Relevant Organic Compounds.

The sulfate anion radical (SO4•-) is a reactive oxidant formed in the autoxidation chain of sulfur dioxide, among other sources. Recently, new formation pathways toward SO4•- and other reactive sulfur species have been reported. This work investigated the second-order rate coefficients for the aqueous SO4•- oxidation of the following important organic aerosol compounds (kSO4): 2-methyltetrol, 2-methyl-1,2,3-trihydroxy-4-sulfate, 2-methyl-1,2-dihydroxy-3-sulfate, 1,2-dihydroxyisoprene, 2-methyl-2,3-dihydroxy-1,4-dinitrate, 2-methyl-1,2,4-trihydroxy-3-nitrate, 2-methylglyceric acid, 2-methylglycerate, lactic acid, lactate, pyruvic acid, pyruvate. The rate coefficients of the unknowns were determined against that of a reference in pure water in a temperature range of 298-322 K. The decays of each reagent were measured with nuclear magnetic resonance (NMR) and high-performance liquid chromatography-high-resolution mass spectrometry (HPLC-HRMS). Incorporating additional SO4•- reactions into models may aid in the understanding of organosulfate formation, radical propagation, and aerosol mass sinks.

Tet2 deficiency in immune cells exacerbates tumor progression by increasing angiogenesis in a lung cancer model.

Immune cells harboring somatic mutations reportedly infiltrate cancer tissues in patients with solid cancers and accompanying clonal hematopoiesis. Loss-of-function TET2 mutations are frequently observed in clonal hematopoiesis in solid cancers. Here, using a mouse lung cancer model, we evaluated the activity of Tet2-deficient immune cells in tumor tissues. Myeloid-specific Tet2 deficiency enhanced tumor growth in mice relative to that seen in controls. Single-cell sequencing analysis of immune cells infiltrating tumors showed relatively high expression of S100a8/S100a9 in Tet2-deficient myeloid subclusters. In turn, treatment with S100a8/S100a9 promoted Vegfa production by cancer cells, leading to a marked increase in the tumor vasculature in Tet2-deficient mice relative to controls. Finally, treatment of Tet2-deficient mice with an antibody against Emmprin, a known S100a8/S100a9 receptor, suppressed tumor growth. These data suggest that immune cells derived from TET2-mutated clonal hematopoiesis exacerbate lung cancer progression by promoting tumor angiogenesis and may provide a novel therapeutic target for lung cancer patients with TET2-mutated clonal hematopoiesis.

Cabazitaxel versus abiraterone or enzalutamide in poor prognosis metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase II trial.

BACKGROUND: Treatment of poor prognosis metastatic castration-resistant prostate cancer (mCRPC) includes taxane chemotherapy and androgen receptor pathway inhibitors (ARPI). We sought to determine optimal treatment in this setting. PATIENTS AND METHODS: This multicentre, randomised, open-label, phase II trial recruited patients with ARPI-naive mCRPC and poor prognosis features (presence of liver metastases, progression to mCRPC after <12 months of androgen deprivation therapy, or ≥4 of 6 clinical criteria). Patients were randomly assigned 1 : 1 to receive cabazitaxel plus prednisone (group A) or physician's choice of enzalutamide or abiraterone plus prednisone (group B) at standard doses. Patients could cross over at progression. The primary endpoint was clinical benefit rate for first-line treatment (defined as prostate-specific antigen response ≥50%, radiographic response, or stable disease ≥12 weeks). RESULTS: Ninety-five patients were accrued (median follow-up 21.9 months). First-line clinical benefit rate was greater in group A versus group B (80% versus 62%, P = 0.039). Overall survival was not different between groups A and B (median 37.0 versus 15.5 months, hazard ratio (HR) = 0.58, P = 0.073) nor was time to progression (median 5.3 versus 2.8 months, HR = 0.87, P = 0.52). The most common first-line treatment-related grade ≥3 adverse events were neutropenia (cabazitaxel 32% versus ARPI 0%), diarrhoea (9% versus 0%), infection (9% versus 0%), and fatigue (7% versus 5%). Baseline circulating tumour DNA (ctDNA) fraction above the cohort median and on-treatment ctDNA increase were associated with shorter time to progression (HR = 2.38, P < 0.001; HR = 4.03, P < 0.001). Patients with >30% ctDNA fraction at baseline had markedly shorter overall survival than those with undetectable ctDNA (HR = 38.22, P < 0.001). CONCLUSIONS: Cabazitaxel was associated with a higher clinical benefit rate in patients with ARPI-naive poor prognosis mCRPC. ctDNA abundance was prognostic independent of clinical features, and holds promise as a stratification biomarker.

Impact of e-Liquid Composition, Coil Temperature, and Puff Topography on the Aerosol Chemistry of Electronic Cigarettes.

E-cigarette aerosol is a complex mixture of gases and particles with a composition that is dependent on the e-liquid formulation, puffing regimen, and device operational parameters. This work investigated mainstream aerosols from a third generation device, as a function of coil temperature (315-510 °F, or 157-266 °C), puff duration (2-4 s), and the ratio of propylene glycol (PG) to vegetable glycerin (VG) in e-liquid (100:0-0:100). Targeted and untargeted analyses using liquid chromatography high-resolution mass spectrometry, gas chromatography, in situ chemical ionization mass spectrometry, and gravimetry were used for chemical characterizations. PG and VG were found to be the major constituents (>99%) in both phases of the aerosol. Most e-cigarette components were observed to be volatile or semivolatile under the conditions tested. PG was found almost entirely in the gas phase, while VG had a sizable particle component. Nicotine was only observed in the particle phase. The production of aerosol mass and carbonyl degradation products dramatically increased with higher coil temperature and puff duration, but decreased with increasing VG fraction in the e-liquid. An exception is acrolein, which increased with increasing VG. The formation of carbonyls was dominated by the heat-induced dehydration mechanism in the temperature range studied, yet radical reactions also played an important role. The findings from this study identified open questions regarding both pathways. The vaping process consumed PG significantly faster than VG under all tested conditions, suggesting that e-liquids become more enriched in VG and the exposure to acrolein significantly increases as vaping continues. It can be estimated that a 30:70 initial ratio of PG:VG in the e-liquid becomes almost entirely VG when 60-70% of e-liquid remains during the vaping process at 375 °F (191 °C). This work underscores the need for further research on the puffing lifecycle of e-cigarettes.