-
Journal of Colloid and Interface Science Jun 2024The recent coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spurred intense research efforts...
The recent coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spurred intense research efforts to develop new materials with antiviral activity. In this study, we genetically engineered amyloid-based nanofibrils for capturing and neutralizing SARS-CoV-2. Building upon the amyloid properties of a short Sup35 yeast prion sequence, we fused it to SARS-CoV-2 receptor-binding domain (RBD) capturing proteins, LCB1 and LCB3. By tuning the reaction conditions, we achieved the spontaneous self-assembly of the Sup35-LCB1 fusion protein into a highly homogeneous and well-dispersed amyloid-like fibrillar material. These nanofibrils exhibited high affinity for the SARS-CoV-2 RBD, effectively inhibiting its interaction with the angiotensin-converting enzyme 2 (ACE2) receptor, the primary entry point for the virus into host cells. We further demonstrate that this functional nanomaterial entraps and neutralizes SARS-CoV-2 virus-like particles (VLPs), with a potency comparable to that of therapeutic antibodies. As a proof of concept, we successfully fabricated patterned surfaces that selectively capture SARS-CoV-2 RBD protein on wet environments. Collectively, these findings suggest that these protein-only nanofibrils hold promise as disinfecting coatings endowed with selective SARS-CoV-2 neutralizing properties to combat viral spread or in the development of sensitive viral sampling and diagnostic tools.
PubMed: 38955007
DOI: 10.1016/j.jcis.2024.06.175 -
Gynecologic Oncology Jul 2024Peritoneal carcinomatosis (PC) is common in patients with advanced gynecologic and gastrointestinal cancers. Frequently, patients with PC undergo palliative surgery or...
BACKGROUND
Peritoneal carcinomatosis (PC) is common in patients with advanced gynecologic and gastrointestinal cancers. Frequently, patients with PC undergo palliative surgery or procedures to manage disease-related complications and side effects. However, there are limited data regarding patients' and family caregivers' decision-making processes about these procedures. Thus, we sought to describe the decision-making experiences of patients with PC who elect to pursue palliative surgical procedures and their family caregivers.
METHODS
We conducted a secondary analysis of qualitative data collected during a pilot randomized controlled trial of BOLSTER, a nurse-led telehealth intervention for patients with PC and their caregivers after an acute hospitalization and palliative procedure. Participants in both study arms described their experiences in semi-structured interviews. We re-analyzed coded qualitative data with a focus on understanding decision-making experiences surrounding palliative surgery and procedures using conventional content analysis.
RESULTS
Interviews from 32 participants, 23 patients and 9 caregivers, were analyzed. Participants reported their decision-making was complicated by illness uncertainty and a desire for clear, effective communication with surgical and medical oncology teams. Participants requested more information about the impact of palliative procedures on their daily life. Several also noted that, without improved understanding, a misalignment between patient and family caregiver goals and palliative procedures may inadvertently increase suffering.
CONCLUSION
Discussions related to patients' goals and preferences can improve the quality of treatment decision-making in patients with PC and their caregivers. Future research should test interventions to improve advanced cancer patients' illness understanding and decision-making surrounding palliative surgery and procedures.
PubMed: 38954989
DOI: 10.1016/j.ygyno.2024.06.014 -
Molecular Immunology Jul 2024Acute lung injury is one of the most serious complications of sepsis, which is a common critical illness in clinic. This study aims to investigate the role of caspase-3/...
Acute lung injury is one of the most serious complications of sepsis, which is a common critical illness in clinic. This study aims to investigate the role of caspase-3/ gasdermin-E (GSDME)-mediated pyroptosis in sepsis-induced lung injury in mice model. Cecal ligation (CLP) operation was used to establish mice sepsis-induced lung injury model. Lung coefficient, hematoxylin and eosin staining and transmission electron microscopy were used to observe the lung injury degree. In addition, caspase-3-specific inhibitor Z-DEVD-FMK and GSDME-derived inhibitor AC-DMLD-CMK were used in CLP model, caspase-3 activity, GSDME immunofluorescence, serum lactate dehydrogenase (LDH) and interleukin-6 (IL-6) levels, TUNEL staining, and the expression levels of GSDME related proteins were detected. The mice in CLP group showed the increased expressions of cleaved-caspase-3 and GSDME-N terminal, destruction of lung structure, and the increases of LDH, IL-6, IL-18 and IL-1β levels, which were improved in mice treated with Z-DEVD-FMK or AC-DMLD-CMK. In conclusion, caspase-3/GSDME mediated pyroptosis is involved in the occurrence of sepsis-induced lung injury in mice model, inhibiting caspase-3 or GSDME can both alleviate lung injury.
PubMed: 38954890
DOI: 10.1016/j.molimm.2024.06.007 -
Blood Advances Jul 2024The leukemic stem cell (LSC) score LSC-17 based on a stemness-related gene expression signature is an indicator of poor disease outcome in acute myeloid leukemia (AML)....
The leukemic stem cell (LSC) score LSC-17 based on a stemness-related gene expression signature is an indicator of poor disease outcome in acute myeloid leukemia (AML). However, our understanding of the relationships between LSC and pre-leukemic cells is still incomplete. In particular, it is not known whether "niche-anchoring" of pre-leukemic cell affects disease evolution. To address this issue, we conditionally inactivated the adhesion molecule JAM-C expressed by haematopoietic stem cells (HSC) and LSC in an inducible iMLL-AF9-driven AML mouse model. Deletion of Jam3 (encoding JAM-C) before induction of the leukemia-initiating iMLL-AF9 fusion resulted in a shift from long term to short term-HSC expansion, without affecting disease initiation and progression. In vitro experiments showed that JAM-C controlled leukemic cell nesting irrespective of the bone marrow stromal cells used. RNA sequencing performed on leukemic HSC isolated from diseased mice revealed that genes upregulated in Jam3-deficient animals belonged to Activation Protein-1 (AP-1) and TNF-/NFB pathways. Human orthologs of dysregulated genes allowed to identify a score based on AP-1/TNF-a gene expression that was distinct and complementary from LSC-17 score. Sub-stratification of AML patients with LSC-17 and AP-1/TNF-genes signature defined four groups with median survival ranging from below one year to a median not reached after 8 years. Finally, coculture experiments showed that AP-1 activation in leukemic cells was dependent on the nature of stromal cells. Altogether, our results identify the AP-1/TNF- gene signature as a proxy of LSC anchoring in specific bone marrow niches which improves the prognosis value of the LSC-17 score. NCT02320656.
PubMed: 38954834
DOI: 10.1182/bloodadvances.2023011747 -
PloS One 2024A number of seroprevalence studies in Zambia document the extent of spread of acute SARS-CoV-2 infection, yet knowledge gaps still exist on symptoms and conditions that...
Clinical characteristics and factors associated with long COVID among post-acute COVID-19 clinic patients in Zambia, August 2020 to January 2023: A cross-sectional and longitudinal study design.
INTRODUCTION
A number of seroprevalence studies in Zambia document the extent of spread of acute SARS-CoV-2 infection, yet knowledge gaps still exist on symptoms and conditions that continue or develop after acute COVID-19 (long COVID). This is an important gap given the estimated prevalence of long COVID in other African countries. We assessed factors associated with long COVID at the initial visit to a post-acute COVID-19 (PAC-19) clinic and longitudinally among a cohort of patients with ≥2 review visits.
METHODS
We implemented a cross-sectional and longitudinal analysis of PAC-19 clinic patients from Aug-2020 to Jan-2023. The study outcome was long COVID; defined as the presence of new, relapsing, or persistent COVID-19 symptoms that interfere with the ability to function at home or work. Explanatory variables were demographic and clinical characteristics of patients which included sex, age group, presence of new onset medical conditions, presence of pre-existing comorbidities, vaccination status and acute COVID-19 episode details. We fitted logistic and mixed effects regression models to assess for associated factors and considered statistical significance at p<0.05.
RESULTS
Out of a total 1,359 PAC-19 clinic patients in the cross-sectional analysis, 548 (40.3%) patients with ≥2 PAC-19 clinic visits were in the longitudinal analysis. Patients' median age was 53 (interquartile range [IQR]: 41-63) years, 919 (67.6%) were hospitalized for acute COVID-19, and of whom 686 (74.6%) had severe acute COVID-19. Overall, 377 (27.7%) PAC-19 clinic patients had long COVID. Patients with hospital length of stay ≥15 days (adjusted odds ratio [aOR]: 5.37; 95% confidence interval [95% CI]: 2.99-10.0), severe acute COVID-19 (aOR: 3.22; 95% CI: 1.68-6.73), and comorbidities (aOR:1.50; 95% CI: 1.02-2.21) had significantly higher chance of long COVID. Longitudinally, long COVID prevalence significantly (p<0.001) declined from 75.4% at the initial PAC-19 visit to 26.0% by the final visit. The median follow-up time was 7 (IQR: 4-12) weeks.
CONCLUSION
Factors associated with long COVID in Zambia were consistent both cross-sectionally at the initial visit to PAC-19 clinics and longitudinally across subsequent review visits. This highlights the importance of ongoing monitoring and tailored interventions for patients with comorbidities and severe COVID-19 to mitigate the long-term impacts of COVID-19.
Topics: Humans; Zambia; COVID-19; Male; Female; Cross-Sectional Studies; Longitudinal Studies; Adult; Middle Aged; SARS-CoV-2; Post-Acute COVID-19 Syndrome; Aged; Young Adult; Adolescent; Comorbidity; Risk Factors; Prevalence
PubMed: 38954717
DOI: 10.1371/journal.pone.0306131 -
European Heart Journal. Acute... Jul 2024Diagnosing myocardial infarction (MI) in patients with chronic kidney disease (CKD) is difficult as they often have increased high-sensitivity cardiac troponin T...
BACKGROUND
Diagnosing myocardial infarction (MI) in patients with chronic kidney disease (CKD) is difficult as they often have increased high-sensitivity cardiac troponin T (hs-cTnT) concentrations.
METHODS
Observational U.S. cohort study of emergency department (ED) patients undergoing hs-cTnT measurement. Cases with >1 hs-cTnT increase >99th percentile were adjudicated following the Fourth Universal Definition of MI. Diagnostic performance of baseline and serial 2-hour hs-cTnT thresholds for ruling-in acute MI was compared between those without and with CKD (eGFR <60 ml/min/1.73m2).
RESULTS
The study cohort included 1992 patients, amongst whom 501 (25%) had CKD. There were 75 (15%) and 350 (70%) patients with CKD and 80 (5%) and 351 (24%) without CKD who had acute MI and myocardial injury. In CKD patients with baseline hs-cTnT thresholds of >52, >100, >200 or >300 ng/L, PPVs for MI were 36% (95% CI 28-45), 53% (95% CI 39-67), 73% (95% CI 50-89) and 80% (95% CI 44-98), and in those without CKD, 61% (95% CI 47-73), 69% (95% CI 49-85), 59% (95% CI 33-82) and 54% (95% CI 25-81). In CKD patients with a 2-hour hs-cTnT delta of >10, >20 or >30 ng/L, PPVs were 66% (95% CI 51-79), 86% (95% CI 68-96) and 88% (95% CI 68-97), and in those without CKD, 64% (95% CI 50-76), 73% (95% CI 57-86) and 75% (95% CI 58-88).
CONCLUSION
Diagnostic performance of standard baseline and serial 2-hour hs-cTnT thresholds to rule-in MI is suboptimal in CKD patients. It significantly improves when using higher baseline thresholds and delta values.
PubMed: 38954535
DOI: 10.1093/ehjacc/zuae079 -
Inflammation primes the murine kidney for recovery by activating AZIN1 adenosine-to-inosine editing.The Journal of Clinical Investigation Jul 2024The progression of kidney disease varies among individuals, but a general methodology to quantify disease timelines is lacking. Particularly challenging is the task of...
The progression of kidney disease varies among individuals, but a general methodology to quantify disease timelines is lacking. Particularly challenging is the task of determining the potential for recovery from acute kidney injury following various insults. Here, we report that quantitation of post-transcriptional adenosine-to-inosine (A-to-I) RNA editing offers a distinct genome-wide signature, enabling the delineation of disease trajectories in the kidney. A well-defined murine model of endotoxemia permitted the identification of the origin and extent of A-to-I editing, along with temporally discrete signatures of double-stranded RNA stress and Adenosine Deaminase isoform switching. We found that A-to-I editing of Antizyme Inhibitor 1 (AZIN1), a positive regulator of polyamine biosynthesis, serves as a particularly useful temporal landmark during endotoxemia. Our data indicate that AZIN1 A-to-I editing, triggered by preceding inflammation, primes the kidney and activates endogenous recovery mechanisms. By comparing genetically modified human cell lines and mice locked in either A-to-I edited or uneditable states, we uncovered that AZIN1 A-to-I editing not only enhances polyamine biosynthesis but also engages glycolysis and nicotinamide biosynthesis to drive the recovery phenotype. Our findings implicate that quantifying AZIN1 A-to-I editing could potentially identify individuals who have transitioned to an endogenous recovery phase. This phase would reflect their past inflammation and indicate their potential for future recovery.
PubMed: 38954486
DOI: 10.1172/JCI180117 -
JCI Insight Jul 2024Upon infection, naïve CD8+ T cells differentiate into cytotoxic effector cells to eliminate the pathogen-infected cells. Although many mechanisms underlying this...
Upon infection, naïve CD8+ T cells differentiate into cytotoxic effector cells to eliminate the pathogen-infected cells. Although many mechanisms underlying this process have been demonstrated, the regulatory role of chromatin remodel system in this process remains largely unknown. Here we showed that BRD7, a component of the polybromo-associated BRG1-associated factor complex (PBAF), was required for naïve CD8+ T cells to differentiate into functional short-lived effector cells (SLECs) in response to acute infections caused by influenza virus or lymphocytic choriomeningitis virus (LCMV). BRD7-deficiency in CD8+ T cells resulted in profound defects in effector population and functions, thereby impairing viral clearance and host recovery. Further mechanical studies indicated that the expression of BRD7 significantly turned to high from naïve CD8+ T cells to effector cells, bridged BRG1 and PBRM1 to the core module of PBAF complex, consequently facilitating the assembly of PBAF complex rather than BAF complex in the effector cells. The PBAF complex changed the chromatin accessibility at the loci of Tbx21 gene and up-regulated its expression, leading to the maturation of effector T cells. Our research confirms BRD7 and the PBAF complex are key in CD8+ T cell development and present a significant target for advancing immune therapies.
PubMed: 38954484
DOI: 10.1172/jci.insight.171605 -
JCI Insight Jul 2024Solid organ transplantation remains the life-saving treatment for end-stage organ failure, but chronic rejection remains a major obstacle to long-term allograft outcomes...
Solid organ transplantation remains the life-saving treatment for end-stage organ failure, but chronic rejection remains a major obstacle to long-term allograft outcomes and has not improved substantially. Tertiary lymphoid organs (TLO) are ectopic lymphoid structures that form under conditions of chronic inflammation, and evidence from human transplantation suggests that TLO regularly form in allografts undergoing chronic rejection. In this study, we utilized a mouse renal transplantation model and manipulation of the lymphotoxin alpha (LTα) - lymphotoxin beta receptor (LTβR) pathway, which is essential for TLO formation, to define the role of TLO in transplantation. We showed that intragraft TLO are sufficient to activate the alloimmune response and mediate graft rejection in a model where the only lymphoid organs are TLO in the allograft. When transplanted to recipients with a normal set of secondary lymphoid organs, the presence of graft TLO or LTα overexpression accelerated rejection. If the LTβR pathway was disrupted in the donor graft, TLO formation was abrogated, and graft survival prolonged. Intravital microscopy of renal TLO demonstrated that local T and B cell activation in TLOs is similar to that observed in secondary lymphoid organs. In summary, we demonstrated that immune activation in TLO contributes to local immune responses, leading to earlier allograft failure. TLO and the LTαβ-LTβR pathway are therefore prime targets to limit local immune responses and prevent allograft rejection. These findings are applicable to other diseases such as autoimmunity or tumors, where either limiting or boosting local immune responses is beneficial and improves disease outcomes.
PubMed: 38954463
DOI: 10.1172/jci.insight.177555 -
Europace : European Pacing,... Jul 2024Prior case series showed promising results for cardioneuroablation in patients with vagally induced atrioventricular blocks (VAVBs). We aimed to examine the acute...
Procedural and Intermediate-term Results of the Electroanatomical-guided Cardioneuroablation for the Treatment of Supra-Hisian Second- or Advanced-degree Atrioventricular Block: the PIRECNA multicentre registry.
AIMS
Prior case series showed promising results for cardioneuroablation in patients with vagally induced atrioventricular blocks (VAVBs). We aimed to examine the acute procedural characteristics and intermediate-term outcomes of electroanatomical-guided cardioneuroablation (EACNA) in patients with VAVB.
METHODS AND RESULTS
This international multicentre retrospective registry included data collected from 20 centres. Patients presenting with symptomatic paroxysmal or persistent VAVB were included in the study. All patients underwent EACNA. Procedural success was defined by the acute reversal of atrioventricular blocks (AVBs) and complete abolition of atropine response. The primary outcome was occurrence of syncope and daytime second- or advanced-degree AVB on serial prolonged electrocardiogram monitoring during follow-up. A total of 130 patients underwent EACNA. Acute procedural success was achieved in 96.2% of the cases. During a median follow-up of 300 days (150, 496), the primary outcome occurred in 17/125 (14%) cases with acute procedural success (recurrence of AVB in 9 and new syncope in 8 cases). Operator experience and use of extracardiac vagal stimulation were similar for patients with and without primary outcomes. A history of atrial fibrillation, hypertension, and coronary artery disease was associated with a higher primary outcome occurrence. Only four patients with primary outcome required pacemaker placement during follow-up.
CONCLUSION
This is the largest multicentre study demonstrating the feasibility of EACNA with encouraging intermediate-term outcomes in selected patients with VAVB. Studies investigating the effect on burden of daytime symptoms caused by the AVB are required to confirm these findings.
Topics: Humans; Male; Female; Registries; Retrospective Studies; Aged; Middle Aged; Treatment Outcome; Atrioventricular Block; Catheter Ablation; Time Factors; Vagus Nerve Stimulation; Electrophysiologic Techniques, Cardiac; Syncope; Recurrence; Atrioventricular Node
PubMed: 38954426
DOI: 10.1093/europace/euae164