Background: Peroxisome proliferator-activated receptor agonists such as fibrates restore oxidative metabolism in cytotoxic T-lymphocytes, thereby enhancing response to immune checkpoint inhibitors (ICI) in preclinical models. However, there is no evidence in humans on the clinical impact of fibrates as an adjunct to ICI. Methods: In this cohort study of Veterans with non-small cell lung cancer (NSCLC) receiving ICI, fibrate exposure was defined as a prescription filled within 90 days of an ICI infusion. Overall survival (OS), measured from the start of ICI, was compared between exposed and unexposed Veterans. Cox multivariable analysis (MVA) was used to identify factors associated with OS. A sensitivity analysis of Veterans with stage IV NSCLC who received docetaxel without ICI was similarly performed. Results: The ICI cohort included 3593 Veterans, of whom 301 (8.5%) coincidentally received a fibrate. Veterans receiving fibrates were more likely to be older, white, male, and married, and to have greater comorbidity burden, but less likely to receive chemotherapy. Coincidental fibrates were associated with improved OS both on MVA (HR 0.86, 95%CI 0.75–0.99) and in a matched subset (HR 0.75, 95%CI 0.63–0.90). In contrast, among the cohort of 968 Veterans treated with chemotherapy, fibrates did not have a significant impact on OS by MVA (HR 0.99, 95%CI 0.79–1.25) or in a matched subset (HR 1.02, 95%CI CI 0.75–1.39). Conclusions: Concomitant fibrates are associated with improved OS among NSCLC patients receiving ICI but not among those receiving chemotherapy. This hypothesis-generating observation supports a potential role for fibrates as an adjunct to immunotherapy.
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Nicholas Giovannone;
Aristotelis Antonopoulos;
Jennifer Liang;
Jenna Geddes Sweeney;
Matthew R. Kudelka;
Sandra L. King;
Gi Soo Lee;
Richard Cummings;
Anne Dell;
Steven R. Barthel;
Hans R. Widlund;
Stuart M. Haslam;
Charles J. Dimitroff
Germinal centers (GC) are microanatomical niches where B cells proliferate, undergo antibody affinity maturation, and differentiate to long-lived memory B cells and antibody-secreting plasma cells. For decades, GC B cells have been defined by their reactivity to the plant lectin peanut agglutinin (PNA), which binds serine/threonine (O-linked) glycans containing the asialylated disaccharide Gal-β1,3-GalNAc-Ser/Thr (also called T-antigen). In T cells, acquisition of PNA binding by activated T cells and thymocytes has been linked with altered tissue homing patterns, cell signaling, and survival. Yet, in GC B cells, the glycobiological basis and significance of PNA binding remains surprisingly unresolved. Here, we investigated the basis for PNA reactivity of GC B cells. We found that GC B cell binding to PNA is associated with downregulation of the α2,3 sialyltransferase, ST3GAL1 (ST3Gal1), and overexpression of ST3Gal1 was sufficient to reverse PNA binding in B cell lines. Moreover, we found that the primary scaffold for PNA-reactive O-glycans in B cells is the B cell receptor-associated receptor-type tyrosine phosphatase CD45, suggesting a role for altered O-glycosylation in antigen receptor signaling. Consistent with similar reports in T cells, ST3Gal1 overexpression in B cells in vitro induced drastic shortening in O-glycans, which we confirmed by both antibody staining and mass spectrometric O-glycomic analysis. Unexpectedly, ST3Gal1-induced changes in O-glycan length also correlated with altered binding of two glycosylation-sensitive CD45 antibodies, RA3-6B2 (more commonly called B220) and MEM55, which (in humans) have previously been reported to favor binding to naïve/GC subsets and memory/plasmablast subsets, respectively. Analysis of primary B cell binding to B220, MEM55, and several plant lectins suggested that B cell differentiation is accompanied by significant loss of O-glycan complexity, including loss of extended Core 2 O-glycans. To our surprise, decreased O-glycan length from naïve to post-GC fates best correlated not with ST3Gal1, but rather downregulation of the Core 2 branching enzyme GCNT1. Thus, our data suggest that O-glycan remodeling is a feature of B cell differentiation, dually regulated by ST3Gal1 and GCNT1, that ultimately results in expression of distinct O-glycosylation states/CD45 glycoforms at each stage of B cell differentiation.
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Beau Batton;
Lei Li;
Nancy S. Newman;
Abhik Das;
Kristi L. Watterberg;
Bradley A. Yoder;
Roger G. Faix;
Matthew M. Laughon;
Barbara Stoll;
Rosemary D. Higgins;
Michele C. Walsh
Objective:To examine changes in arterial blood pressure (ABP) after birth in extremely preterm infants.
Study Design:Prospective observational study of infants 23 0/7 to 26 6/7 weeks gestational age (GA). Antihypotensive therapy use and ABP measurements were recorded for the first 24 h.
Result:A cohort of 367 infants had 18 709 ABP measurements recorded. ABP decreased for the first 3 h, reached a nadir at 4 to 5 h and then increased at an average rate of 0.2 mm Hg h -1. The rise in ABP from hour 4 to 24 was similar for untreated infants (n=164) and infants given any antihypotensive therapy (n=203), a fluid bolus (n=135) or dopamine (n=92). GA-specific trends were similar. ABP tended to be lower as GA decreased, but varied widely at each GA.
Conclusion:ABP increased spontaneously over the first 24 postnatal hours for extremely preterm infants. The rate of rise in ABP did not change with antihypotensive therapy.
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Sara Auld;
Hardy Kornfeld;
Pholo Maenetje;
Mandla Mlotshwa;
William Chase;
Mboyo di-Tamba Vangu;
Drew A. Torigian;
Robert S. Wallis;
Gavin Churchyard;
Gregory P. Bisson
Background: While tuberculosis is considered a risk factor for chronic obstructive pulmonary disease, a restrictive pattern of pulmonary impairment may actually be more common among tuberculosis survivors. We aimed to determine the nature of pulmonary impairment before and after treatment among people with HIV and tuberculosis and identify risk factors for long-term impairment. Methods: In this prospective cohort study conducted in South Africa, we enrolled adults newly diagnosed with HIV and tuberculosis who were initiating antiretroviral therapy and tuberculosis treatment. We measured lung function and symptoms at baseline, 6, and 12 months. We compared participants with and without pulmonary impairment and constructed logistic regression models to identify characteristics associated with pulmonary impairment. Results: Among 134 participants with a median CD4 count of 110 cells/μl, 112 (83%) completed baseline spirometry at which time 32 (29%) had restriction, 13 (12%) had obstruction, and 9 (7%) had a mixed pattern. Lung function was dynamic over time and 30 (33%) participants had impaired lung function at 12 months. Baseline restriction was associated with greater symptoms and with long-term pulmonary impairment (adjusted odds ratio 5.44, 95% confidence interval 1.16–25.45), while baseline obstruction was not (adjusted odds ratio 1.95, 95% confidence interval 0.28–13.78). Conclusions: In this cohort of people with HIV and tuberculosis, restriction was the most common, symptomatic, and persistent pattern of pulmonary impairment. These data can help to raise awareness among clinicians about the heterogeneity of post-tuberculosis pulmonary impairment, and highlight the need for further research into mediators of lung injury in this vulnerable population.
Objectives: Several studies suggest that adolescent marijuana use predicts earlier age at onset of schizophrenia, which is a crucial prognostic indicator. Yet, many investigations have not adequately established a clear temporal relationship between the use and onset. Methods: We enrolled 247 first-episode psychosis patients from six psychiatric units and collected data on lifetime marijuana/alcohol/tobacco use, and ages at onset of prodrome and psychosis in 210 of these patients. Cox regression (survival analysis) was employed to quantify hazard ratios (HRs) for effects of diverse premorbid use variables on psychosis onset. Results: Escalation of premorbid use in the 5 years prior to onset was highly predictive of an increased risk for onset (e.g., increasing from no use to daily use, HR = 3.6, p < 0.0005). Through the analysis of time-specific measures, we determined that daily use approximately doubled the rate of onset (HR = 2.2, p < 0.0005), even after controlling for simultaneous alcohol/tobacco use. Building on previous studies, we were able to determine that cumulative marijuana exposure was associated with an increased rate of onset of psychosis (= 0.007), independent of gender and family history, and this is possibly the reason for age at initiation of marijuana use also being associated with rate of onset in this cohort. Conclusions: These data provide evidence of a clear temporal relationship between escalations in use in the five years pre-onset and an increased rate of onset, demonstrate that the strength of the association is similar pre- and post-onset of prodromal symptoms, and determine that early adult use may be just as important as adolescent use in these associations.
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Corinne Loughlin;
Jennifer L. Reimche;
Jacqueline T. Balthazar;
Vijaya Dhulipala;
Kim M. Gernert;
Ellen N. Kersh;
Cau D. Pham;
Kevin Pettus;
A. Jeanine Abrams;
David L. Trees;
Sancta St Cyr;
William M Shafer
Recent reports suggest that mosaic-like sequences within the mtr (mul-tiple transferable resistance) efflux pump locus of Neisseria gonorrhoeae, likely originating from commensal Neisseria sp. by transformation, can increase the ability of gonococci to resist structurally diverse antimicrobials. Thus, acquisition of numerous nucleotide changes within the mtrR gene encoding the transcriptional repressor (MtrR) of the mtrCDE efflux pump-encoding operon or overlapping promoter region for both along with those that cause amino acid changes in the MtrD transporter protein were recently reported to decrease gonococcal susceptibility to numerous antimicrobials, including azithromycin (Azi) (C. B. Wadsworth, B. J. Arnold, M. R. A. Satar, and Y. H. Grad, mBio 9:e01419-18, 2018, https://doi.org/10.1128/mBio.01419-18). We performed detailed genetic and molecular studies to define the mechanistic basis for why such strains can exhibit decreased susceptibility to MtrCDE antimicrobial substrates, including Azi. We report that a strong cis-acting transcriptional impact of a single nucleotide change within the –35 hexamer of the mtrCDE promoter as well gain-of-function amino acid changes at the C-terminal region of MtrD can mechanis-tically account for the decreased antimicrobial susceptibility of gonococci with a mosaic-like mtr locus. IMPORTANCE Historically, after introduction of an antibiotic for treatment of gonorrhea, strains of N. gonorrhoeae emerge that display clinical resistance due to spontaneous mutation or acquisition of resistance genes. Genetic exchange between members of the Neisseria genus occurring by transformation can cause significant changes in gonococci that impact the structure of an antibiotic target or expression of genes involved in resistance. The results presented here provide a framework for understanding how mosaic-like DNA sequences from commensal Neisseria that recombine within the gonococcal mtr efflux pump locus function to decrease bacterial susceptibility to antimicrobials, including antibiotics used in therapy of gonorrhea.
Small cell lung cancer (SCLC) remains a fatal disease due to limited therapeutic options. Systemic chemotherapy is the bedrock of treatment for both the limited and extensive stages of the disease. However, the established management paradigm of platinum-based chemotherapy has reached an efficacy plateau. A modest survival improvement, approximately 5%, was witnessed with the addition of cranial or thoracic radiation to systemic chemotherapy. Other strategies to improve outcome of platinum-based chemotherapy in the last two decades have met with minimal success. The substitution of irinotecan for etoposide in the frontline treatment of SCLC achieved significant efficacy benefit in Japanese patients, but similar benefit could not be reproduced in other patient populations. Salvage treatment for recurrent or progressive SCLC is particularly challenging, where topotecan remains the only agent with regulatory approval to date. Ongoing evaluation of biologic agents targeting angiogenesis, sonic hedgehog pathway, DNA repair pathway, and immune checkpoint modulators hold some promise for improved outcome in SCLC. It is hoped that the coming decade will witness the application of new molecular biology and genomic research techniques to improve our understanding of SCLC biology and identification of molecular subsets that can be targeted appropriately using established and emerging biological agents similar to the accomplishments of the last decade with non-small cell lung cancer (NSCLC).
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Sergio Ramírez-Pérez;
Luis Alexis Hernández-Palma;
Edith Oregon-Romero;
Brian Uriel Anaya-Macías;
Samuel García-Arellano;
Guillermo González-Estevez;
José Francisco Muñoz-Valle
The inflammatory process implicates homeostasis disruption and increased production of inflammatory mediators. Myeloid differentiation primary response 88 (MyD88) is an essential protein recruited after lipopolysaccharide (LPS) and interleukin (IL)-1β stimulation, a process that converges in nuclear factor kappa B (NF-κB) activation, as well as a transcription of several genes of both pro- and anti-inflammatory cytokines. The inhibition of MyD88 has shown efficacy by decrease inflammatory response, and has demonstrated potential application as a therapeutic target in chronic diseases. In this study, we investigate the effect of MyD88 dimerisation inhibitor ST2825 on cytokine production from rhIL-1β and LPS-stimulated peripheral blood mononuclear cells (PBMC) from healthy blood donors (HBD). ST2825 significantly downregulates the production of IFN-γ, IL-6, IL-12, IL-2, IL-15, IL-7, VEGF, IL-1Ra, IL-4, IL-5, IL-13 and IL-9 (p < 0.05) in LPS-stimulated PBMC. Moreover, ST2825 had a relatively low impact on IL-1β signalling pathway inhibition, showing that only a few specific cytokines, such as IFN-γ and IL-1Ra, are inhibited in rhIL-1β-stimulated PBMC (p < 0.01). In conclusion, MyD88 dimerisation inhibitor ST2825 showed high efficacy by inhibiting pro- and anti-inflammatory cytokine production in LPS-stimulated PBMC. Moreover, although rhIL-1β induced a sustained cytokine production (p < 0.05), ST2825 did not show a significant effect in the secretion of neither pro- nor anti-inflammatory cytokines in rhIL-1β-stimulated PBMC.
We evaluated the relationship of drinking water salinity to neonatal and infant mortality using Bangladesh Demographic Health Surveys of 2000, 2004, 2007, 2011, and 2014. Point data of groundwater electrical conductivity (EC)— a measure of salinity—were collated from the Bangladesh Water Development Board and digitizing salinity contour map. Data for groundwater dissolved elements (sodium, calcium, magnesium, and potassium) data came from a national hydrochemistry survey in Bangladesh. Point EC and dissolved minerals data were then interpolated over entire Bangladesh and extracted to each cluster location, the primary sampling unit of Bangladesh Demographic Health Surveys. We used restricted cubic splines and survey design-specific logistic regression models to determine the relationship of water salinity to neonatal and infant mortality. A U-shaped association between drinking water salinity and neonatal and infant mortality was found, suggesting higher mortality when salinity was very low and high. Compared to mildly saline (EC ≥0.7 and < 2 mS/cm) water drinkers, freshwater (EC < 0.7 mS/cm) drinkers had 1.37 (95% CI: 1.01, 1.84) times higher neonatal mortality and 1.43 (95% CI: 1.08, 1.89) times higher infant mortality. Compared to mildly saline water drinkers, severe-saline (EC ≥10 mS/cm) water drinkers had 1.77 (95% CI: 1.17, 2.68) times higher neonatal mortality and 1.93 (95% CI: 1.35, 2.76) times higher infant mortality. We found that mild-salinity water had a high concentration of calcium and magnesium, whereas severe-salinity water had a high concentration of sodium. Freshwater had the least concentrations of salubrious calcium and magnesium.
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Kristie Blum;
Mei-Yin Polley;
Sin-Ho Jung;
Travis J. Dockter;
Sarah Anderson;
Eric D. Hsi;
Nina Wagner-Johnston;
Beth Christian;
Jim Atkins;
Bruce D. Cheson;
John P. Leonard;
Nancy L. Bartlett
Background: This multicenter, randomized phase 2 trial evaluated complete responses (CRs), efficacy, and safety with ofatumumab and bendamustine and with ofatumumab, bendamustine, and bortezomib in patients with untreated, high-risk follicular lymphoma (FL). Methods: Patients with grade 1 to 3a FL and either a Follicular Lymphoma International Prognostic Index (FLIPI) score of 2 with 1 lymph node >6 cm or an FLIPI score of 3 to 5 were randomized to arm A (ofatumumab, bendamustine, and maintenance ofatumumab) or to arm B (ofatumumab, bendamustine, bortezomib, and maintenance ofatumumab and bortezomib). Results: One hundred twenty-eight patients (66 in arm A and 62 in arm B) received treatment. The median age was 61 years, and 61% had disease >6 cm; 29% had an FLIPI score of 2, and 71% had an FLIPI score of 3 to 5. In arm A, 86% completed induction, and 64% completed maintenance. In arm B, 66% and 52% completed induction and maintenance, respectively. Dose modifications were required in 65% and 89% in arms A and B, respectively. Clinically significant grade 3 to 4 toxicities included neutropenia (A, 36%; B, 31%), nausea/vomiting (A, 0%; B, 8%), diarrhea (A, 5%; B, 11%), and sensory neuropathy (A, 0%; B, 5%). The estimated CR rates were 62% (95% confidence interval [CI], 50%-74%) and 60% (95% CI, 47%-72%) in arms A and B, respectively (P =.68). With a median follow-up of 3.3 years, the estimated 2-year progression-free survival (PFS) and overall survival (OS) rates were 80% and 97%, respectively, for arm A and 76% and 91%, respectively, for arm B. Conclusions: The CR rates, PFS, and OS were not improved with the addition of bortezomib to ofatumumab and bendamustine in patients with high-risk FL. Although grade 3 to 4 toxicities were similar, more patients treated with bortezomib required dose modifications and early discontinuation.