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The Journal of Clinical Investigation Jul 2024Cystic fibrosis is a debilitating disease characterized by a poor medical prognosis due to devastating lung injury. Recent medical advances targeting the major genetic...
Cystic fibrosis is a debilitating disease characterized by a poor medical prognosis due to devastating lung injury. Recent medical advances targeting the major genetic mutation ΔF508 of the cystic fibrosis transmembrane conductance regulator (CFTR) protein have dramatically increased the lifespan of patients with this mutation. This development has led to major changes in the field and has pushed research beyond the ion transport nature of cystic fibrosis and toward multiorgan physiological reprogramming. In this issue of the JCI, Bae, Kim, and colleagues utilized a large animal pig model prior to the onset of disease. They revealed metabolic reprogramming and organ crosstalk that occurred prior to disease progression. These findings provide paradigm-shifting insight into this complex disease.
Topics: Cystic Fibrosis; Animals; Humans; Cystic Fibrosis Transmembrane Conductance Regulator; Swine; Disease Models, Animal
PubMed: 38949023
DOI: 10.1172/JCI182329 -
JPMA. the Journal of the Pakistan... Jun 2024To determine the predisposing factors for lengthy intensive care unit stay of chronic obstructive pulmonary disease patients with acute exacerbation.
OBJECTIVES
To determine the predisposing factors for lengthy intensive care unit stay of chronic obstructive pulmonary disease patients with acute exacerbation.
METHODS
The retrospective study was conducted after approval from the ethics review committee of Atatürk Sanatorium Training and Research Hospital, Turkey, and comprised data from January 1, 2017, to August 31, 2022, related to acute exacerbation chronic obstructive pulmonary disease patients receiving intensive care unit treatment. Demographics, comorbidities, treatment, length of stay in hospital and in intensive care unit, and nutritional status were evaluated. Data of patients who spent <10 days in intensive care unit formed Group 1, while those having spent 10 days or more formed Group 2 for comparison purposes. Data was analysed using SPSS 22.
RESULTS
Of the 460 patients, 366(79.6%) were in Group 1; 224(61.2%) males and 64(38.8%) females with mean age 70.81±11.57 years. There were 94(20.4%) patients in Group 2; 62(66%) males and 32(34%) females with mean age 72.38±10.88 years (p>0.05). Inotropic agent support, need for haemodialysis, timeframe of invasive mechanical ventilation, length of stay in hospital, 1-month mortality, antibiotic use, use of diuretic agent, acute physiology and chronic health evaluation-ii score, nutrition risk in the critically ill score, history of lung malignancy, and pneumonic infiltration on chest radiograph were significantly more frequenttly observed in Group 2 patients (p<0.05). Age, timeframe of invasive mechanical ventilation, and length of stay in hospital were the factors prolonging intensive care unit stay (p<0.05).
CONCLUSIONS
Higher age, longer invasive mechanical ventilation timeframe and hospital stay with acute exacerbation chronic obstructive pulmonary disease caused a prolonged stay in intensive care unit.
Topics: Humans; Male; Pulmonary Disease, Chronic Obstructive; Female; Aged; Length of Stay; Retrospective Studies; Middle Aged; Aged, 80 and over; Risk Factors; Disease Progression; Intensive Care Units; Critical Care; Respiration, Artificial; Turkey; Nutritional Status; Anti-Bacterial Agents; Renal Dialysis
PubMed: 38948972
DOI: 10.47391/JPMA.9418 -
HemaSphere Jul 2024Bridging therapy (BT) after leukapheresis is required in most relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients receiving chimeric antigen receptor (CAR) T...
Bridging therapy (BT) after leukapheresis is required in most relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients receiving chimeric antigen receptor (CAR) T cells. Bendamustine-containing regimens are a potential BT option. We aimed to assess if this agent had a negative impact on CAR-T outcomes when it was administered as BT. We included R/R LBCL patients from six centers who received systemic BT after leukapheresis from February 2019 to September 2022; patients who only received steroids or had pre-apheresis bendamustine exposure were excluded. Patients were divided into two BT groups, with and without bendamustine. Separate safety and efficacy analyses were carried out for axi-cel and tisa-cel. Of 243 patients who received BT, bendamustine (benda) was included in 62 (26%). There was a higher rate of BT progressors in the non-benda group (62% vs. 45%, = 0.02). Concerning CAR-T efficacy, complete responses were comparable for benda versus non-benda BT cohorts with axi-cel (70% vs. 53%, = 0.12) and tisa-cel (44% vs. 36%, = 0.70). Also, 12-month progression-free and overall survival were not significantly different between BT groups with axi-cel (56% vs. 43% and 71% vs. 63%) and tisa-cel (25% vs. 26% and 52% vs. 48%); there were no differences when BT response was considered. CAR T-cell expansion for each construct was similar between BT groups. Regarding safety, CRS G ≥3 (6% vs. 6%, = 0.79), ICANS G ≥3 (15% vs. 17%, = 0.68), severe infections, and neutropenia post-infusion were comparable among BT regimens. BT with bendamustine-containing regimens is safe for patients requiring disease control during CAR T-cell manufacturing.
PubMed: 38948924
DOI: 10.1002/hem3.86 -
International Journal of Chronic... 2024Vitamin D deficiency (VDD, 25-hydroxyvitamin D < 20 ng/mL) has been reported associated with exacerbation of chronic obstructive pulmonary disease (COPD) but sometimes... (Observational Study)
Observational Study
PURPOSE
Vitamin D deficiency (VDD, 25-hydroxyvitamin D < 20 ng/mL) has been reported associated with exacerbation of chronic obstructive pulmonary disease (COPD) but sometimes controversial. Research on severe vitamin D deficiency (SVDD, 25-hydroxyvitamin D < 10 ng/mL) in exacerbation of COPD is limited.
PATIENTS AND METHODS
We performed a retrospective observational study in 134 hospitalized exacerbated COPD patients. 25-hydroxyvitamin D was modeled as a continuous or dichotomized (cutoff value: 10 or 20 ng/mL) variable to evaluate the association of SVDD with hospitalization in the previous year. Receiver operator characteristic (ROC) analysis was performed to find the optimal cut-off value of 25-hydroxyvitamin D.
RESULTS
In total 23% of the patients had SVDD. SVDD was more prevalent in women, and SVDD group tended to have lower blood eosinophils counts. 25-hydroxyvitamin D level was significantly lower in patients who were hospitalized in the previous year (13.6 vs 16.7 ng/mL, = 0.044), and the prevalence of SVDD was higher (38.0% vs 14.3%, = 0.002). SVDD was independently associated with hospitalization in the previous year [odds ratio (OR) 4.34, 95% CI 1.61-11.72, = 0.004] in hospitalized exacerbated COPD patients, whereas continuous 25-hydroxyvitamin D and VDD were not ( = 0.1, = 0.9, separately). The ROC curve yielded an area under the curve of 0.60 (95% CI 0.50-0.71) with an optimal 25-hydroxyvitamin D cutoff of 10.4 ng/mL.
CONCLUSION
SVDD probably showed a more stable association with hospitalization in the previous year in hospitalized exacerbated COPD patients. Reasons for lower eosinophil counts in SVDD group needed further exploration.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Vitamin D Deficiency; Female; Male; Retrospective Studies; Vitamin D; Aged; Prevalence; Disease Progression; Risk Factors; Middle Aged; Severity of Illness Index; Biomarkers; ROC Curve; Hospitalization; Time Factors; Odds Ratio; Aged, 80 and over; Area Under Curve; Logistic Models; Chi-Square Distribution; Patient Admission; Multivariate Analysis
PubMed: 38948911
DOI: 10.2147/COPD.S461029 -
International Journal of Chronic... 2024Exacerbations of chronic obstructive pulmonary disease (COPD) were reported less frequently during the COVID-19 pandemic. We report real-world data on COPD exacerbation...
BACKGROUND
Exacerbations of chronic obstructive pulmonary disease (COPD) were reported less frequently during the COVID-19 pandemic. We report real-world data on COPD exacerbation rates before and during this pandemic.
METHODS
Exacerbation patterns were analysed using electronic medical records or claims data of patients with COPD before (2017-2019) and during the COVID-19 pandemic (2020 through early 2022) in France, Germany, Italy, the United Kingdom and the United States. Data from each country were analysed separately. The proportions of patients with COPD receiving maintenance treatment were also estimated.
RESULTS
The proportion of patients with exacerbations fell 45-78% across five countries in 2020 versus 2019. Exacerbation rates in most countries were reduced by >50% in 2020 compared with 2019. The proportions of patients with an exacerbation increased in most countries in 2021. Across each country, seasonal exacerbation increases seen during autumn and winter in pre-pandemic years were absent during the first year of the pandemic. The percentage of patients filling COPD prescriptions across each country increased by 4.53-22.13% in 2019 to 9.94-34.17% in 2021.
CONCLUSION
Early, steep declines in exacerbation rates occurred in 2020 versus 2019 across all five countries and were accompanied by a loss of the seasonal pattern of exacerbation.
Topics: Humans; COVID-19; Pulmonary Disease, Chronic Obstructive; Disease Progression; Male; Female; Aged; Middle Aged; SARS-CoV-2; United States; France; United Kingdom; Pandemics; Italy; Time Factors; Seasons
PubMed: 38948907
DOI: 10.2147/COPD.S451009 -
BioRxiv : the Preprint Server For... Jun 2024It is not clear whether human progression to active tuberculosis disease (TB) risk signatures are viable endpoint criteria for evaluations of treatments in clinical or...
UNLABELLED
It is not clear whether human progression to active tuberculosis disease (TB) risk signatures are viable endpoint criteria for evaluations of treatments in clinical or preclinical development. TB is the deadliest infectious disease globally and more efficacious vaccines are needed to reduce this mortality. However, the immune correlates of protection for either preventing infection with or preventing TB disease have yet to be completely defined, making the advancement of candidate vaccines through the pipeline slow, costly, and fraught with risk. Human-derived correlate of risk (COR) gene signatures, which identify an individual's risk to progressing to active TB disease, provide an opportunity for evaluating new therapies for TB with clear and defined endpoints. Though prospective clinical trials with longitudinal sampling are prohibitively expensive, characterization of COR gene signatures is practical with preclinical models. Using a 3Rs (Replacement, Reduction and Refinement) approach we reanalyzed heterogeneous publicly available transcriptional datasets to determine whether a specific set of COR signatures are viable endpoints in the preclinical pipeline. We selected RISK6, Sweeney3 and BATF2 human-derived blood-based RNA biosignatures because they require relatively few genes to assign a score and have been carefully evaluated across several clinical cohorts. Excitingly, these data provide proof-of-concept that human COR signatures seem to have high fidelity across several tissue types in the preclinical TB model pipeline and show best performance when the model most closely reflected human infection or disease conditions. Human-derived COR signatures offer an opportunity for high-throughput preclinical endpoint criteria of vaccine and drug therapy evaluations.
ONE SENTENCE SUMMARY
Human-derived biosignatures of tuberculosis disease progression were evaluated for their predictive fidelity across preclinical species and derived tissues using available public data sets.
PubMed: 38948876
DOI: 10.1101/2024.06.21.600067 -
BioRxiv : the Preprint Server For... Jun 2024Endothelial tissues are essential mechanosensors in the vasculature and facilitate adaptation to various blood flow-induced mechanical cues. Defects in endothelial...
Endothelial tissues are essential mechanosensors in the vasculature and facilitate adaptation to various blood flow-induced mechanical cues. Defects in endothelial mechanoresponses can perturb tissue remodelling and functions leading to cardiovascular disease progression. In this context, the precise mechanisms of endothelial mechanoresponses contributing to normal and diseased tissue functioning remain elusive. Here, we sought to uncover how flow-mediated transcriptional regulation drives endothelial mechanoresponses in healthy and atherosclerotic-prone tissues. Using bulk RNA sequencing, we identify novel mechanosensitive genes in response to healthy unidirectional flow (UF) and athero-prone disturbed flow (DF). We find that the transcription as well as protein expression of Four-and-a-half LIM protein 2 (FHL2) are enriched in athero-prone DF both and . We then demonstrate that the exogenous expression of FHL2 is necessary and sufficient to drive discontinuous adherens junction morphology and increased tissue permeability. This athero-prone phenotype requires the force-sensitive binding of FHL2 to actin. In turn, the force-dependent localisation of FHL2 to stress fibres promotes microtubule dynamics to release the RhoGEF, GEF-H1, and activate the Rho-ROCK pathway. Thus, we unravelled a novel mechanochemical feedback wherein force-dependent FHL2 localisation promotes hypercontractility. This misregulated mechanoresponse creates highly permeable tissues, depicting classic hallmarks of atherosclerosis progression. Overall, we highlight crucial functions for the FHL2 force-sensitivity in tuning multi-scale endothelial mechanoresponses.
PubMed: 38948838
DOI: 10.1101/2024.06.16.599227 -
BioRxiv : the Preprint Server For... Jun 2024Cirrhosis, advanced liver disease, affects 2-5 million Americans. While most patients have compensated cirrhosis and may be fairly asymptomatic, many decompensate and...
UNLABELLED
Cirrhosis, advanced liver disease, affects 2-5 million Americans. While most patients have compensated cirrhosis and may be fairly asymptomatic, many decompensate and experience life-threatening complications such as gastrointestinal bleeding, confusion (hepatic encephalopathy), and ascites, reducing life expectancy from 12 to less than 2 years. Among patients with compensated cirrhosis, identifying patients at high risk of decompensation is critical to optimize care and reduce morbidity and mortality. Therefore, it is important to preferentially direct them towards specialty care which cannot be provided to all patients with cirrhosis. We used discovery Top-down Proteomics (TDP) to identify differentially expressed proteoforms (DEPs) in the plasma of patients with progressive stages of liver cirrhosis with the ultimate goal to identify candidate biomarkers of disease progression. In this pilot study, we identified 209 DEPs across three stages of cirrhosis (compensated, compensated with portal hypertension, and decompensated), of which 115 derived from proteins enriched in the liver at a transcriptional level and discriminated the three stages of cirrhosis. Enrichment analyses demonstrated DEPs are involved in several metabolic and immunological processes known to be impacted by cirrhosis progression. We have preliminarily defined the plasma proteoform signatures of cirrhosis patients, setting the stage for ongoing discovery and validation of biomarkers for early diagnosis, risk stratification, and disease monitoring.
HIGHLIGHTS
Performed a pilot top-down LC-MS/MS analysis to identify proteoforms (PFRs) in the plasma of patients with 3 progressive stages of liver cirrhosis.Identified 2867 proteoforms (PFRs) and 209 differentially regulated proteoforms (DRPs) in the different stages of the disease.Identified DRP profiles able to potentially distinguish early from late stages of the disease, including 115 liver-derived DRPs.Fibrinogen alpha chain, haptoglobin, and Apo A-I are the proteins with the highest number of DRPs and represent potential candidate biomarkers of liver cirrhosis progression.
PubMed: 38948836
DOI: 10.1101/2024.06.19.599662 -
BioRxiv : the Preprint Server For... Jun 2024is an opportunistic fungal pathogen responsible for >150,000 deaths every year with a mortality rate as high as 81%. This high medical burden is due, in part, to an...
UNLABELLED
is an opportunistic fungal pathogen responsible for >150,000 deaths every year with a mortality rate as high as 81%. This high medical burden is due, in part, to an incomplete understanding of its pathogenesis. In a previous study, we identified a cryptococcal atypical pleiotropic drug resistance (PDR) transporter, , that regulated antifungal resistance and host interactions. Here, we follow-up on the role of in cryptococcal virulence. , mice infected with the Δ strain display altered symptomatology and disease progression. Specifically, we observed a significant increase in the innate immune cell populations in the Δ-infected mice when compared to their WT-infected littermates. Furthermore, quantification of pulmonary cytokines/chemokines revealed a robust increase of pro-inflammatory cytokines in mice infected with the Δ mutant strain. Whereas antifungal treatment of Δ-infected animals did not affect survival, treatment with a corticosteroid significantly extended survival, highlighting the importance of a balanced/controlled host immune response. We determined that the hyper-inflammatory immune response occurs, in part, because the loss of the Pdr6 transporter indirectly alters the cryptococcal cell wall architecture and results in the increased exposure of chitin, β-glucan, and other cryptococcal-specific pathogen associated molecular patterns. Taken together, this study provides clinical insights regarding cryptococcal pathogenesis while also providing additional functions of PDR-type ATP-binding cassette (ABC) transporters in pathogenic fungi.
IMPORTANCE
Yeasts of the genus, especially , can cause disease with unacceptably high mortality. This is due to delays in diagnostics, ineffective treatments, and an incomplete understanding of the interactions between this fungus and our immune system. In this study, we expand our knowledge of the biological function of the gene, particularly its effect on modulating the host's immune response. Normally, 's infections are characterized by an anti-inflammatory response that is unable to control the yeast. In the absence of , the response to the infection is a dysregulated pro-inflammatory response that initially controls the fungi but eventually results in death of the host due to too much tissue damage. This is due, in part, to an altered fungal surface. Given the dual role of in modulating antifungal sensitivity and immune responses, this work provides important insights that may lead to new or improved therapeutics.
PubMed: 38948814
DOI: 10.1101/2024.06.17.599354 -
BioRxiv : the Preprint Server For... Jun 2024Non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is the most common liver disease worldwide. The progression...
Non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is the most common liver disease worldwide. The progression to fibrosis, occurring against a backdrop of hepatic steatosis and inflammation, critically determines liver-related morbidity and mortality. Inflammatory processes contribute to various stages of MAFLD and thought to instigate hepatic fibrosis. For this reason, targeting inflammation has been heavily nominated as a strategy to mitigate liver fibrosis. Lipopolysaccharide binding protein (LBP) is a secreted protein that plays an established role in innate immune responses. Here, using adoptive transfer studies and tissue-specific deletion models we show that hepatocytes are the dominant contributors to circulating LBP. In a murine model of MAFLD, hepatocyte-specific deletion of LBP restrained hepatic inflammation and improved liver function abnormalities, but not measures of fibrosis. Human studies, including genetic evidence, corroborate an important role for LBP in hepatic inflammation with minimal impact on fibrosis. Collectively, our data argues against the idea that targeting hepatic inflammation is a viable approach to reducing fibrosis.
PubMed: 38948798
DOI: 10.1101/2024.06.17.599212