Epithelial cell death is a major contributor to fibrogenesis in the lung. In this study, we sought to determine the function of mitochondria and their clearance (mitophagy) in alveolar epithelial ...cell death and fibrosis.
We studied markers of mitochondrial injury and the mitophagy marker, PTEN-induced putative kinase 1 (PINK1), in IPF lung tissues by Western blotting, transmission electron microscopy (TEM), and immunofluorescence. In vitro experiments were carried out in lung epithelial cells stimulated with transforming growth factor-β1 (TGF-β1). Changes in cell function were measured by Western blotting, flow cytometry and immunofluorescence. In vivo experiments were performed using the murine bleomycin model of lung fibrosis.
Evaluation of IPF lung tissue demonstrated increased PINK1 expression by Western blotting and immunofluorescence and increased numbers of damaged mitochondria by TEM. In lung epithelial cells, TGF-β1 induced mitochondrial depolarization, mitochondrial ROS, and PINK1 expression; all were abrogated by mitochondrial ROS scavenging. Finally, Pink1-/- mice were more susceptible than control mice to bleomycin induced lung fibrosis.
TGF-β1 induces lung epithelial cell mitochondrial ROS and depolarization and stabilizes the key mitophagy initiating protein, PINK1. PINK1 ameliorates epithelial cell death and may be necessary to limit fibrogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Cardioneuroablation (CNA) is a novel therapeutic approach for functional bradyarrhythmias, specifically neurocardiogenic syncope or atrial fibrillation, achieved through endocardial ...radiofrequency catheter ablation of vagal innervation, obviating the need for pacemaker implantation. Originating in the nineties, the first series of CNA procedures was published in 2005. Extra‐cardiac vagal stimulation (ECVS) is employed as a direct method for stepwise denervation control during CNA.
Objective
This study aimed to compare the long‐term follow‐up outcomes of patients with severe cardioinhibitory syncope undergoing CNA with and without denervation confirmation via ECVS.
Method
A cohort of 48 patients, predominantly female (56.3%), suffering from recurrent syncope (5.1 ± 2.5 episodes annually) that remained unresponsive to clinical and pharmacological interventions, underwent CNA, divided into two groups: ECVS and NoECVS, consisting of 34 and 14 cases, respectively. ECVS procedures were conducted with and without atrial pacing.
Results
Demographic characteristics, left atrial size, and ejection fraction displayed no statistically significant differences between the groups. Follow‐up duration was comparable, with 29.1 ± 15 months for the ECVS group and 31.9 ± 20 months for the NoECVS group (p = .24). Notably, syncope recurrence was significantly lower in the ECVS group (two cases vs. four cases, Log Rank p = .04). Moreover, the Hazard ratio revealed a fivefold higher risk of syncope recurrence in the NoECVS group.
Conclusion
This study demonstrates that concluding CNA with denervation confirmation via ECVS yields a higher success rate and a substantially reduced risk of syncope recurrence compared to procedures without ECVS confirmation.
While T cells are established major players in antitumor immunity, tumor-associated B cells and antibodies have recently emerged as critical components in modulating immunity in the tumor ...microenvironment. In the current issue of Cancer Research, Mandal and colleagues show that tumor-infiltrating B cells are associated with improved outcomes in endometrial cancers. Mechanistically, the investigators demonstrate that the immune response is mediated by class-switched IgA binding to the polymeric immunoglobulin receptor in tumor cells, resulting in tumor cell-intrinsic activation of inflammatory pathways. These findings highlight that coordinated B-cell and T-cell responses may predict improved outcomes in patients with endometrial cancer and set the groundwork to further investigate the mechanisms by which humoral immunity could be exploited for cancer immunotherapy. See related article by Mandal et al., p. 859.
It has been reported that treatment of DENV-infected cultures with Lovastatin (LOV), can affect viral assembly. The objective of this study was to evaluate the effect of LOV on the survival rate and ...viremia levels of DENV-2-infected AG129 mice.
Mice were inoculated with 1 × 10(6) plaque-forming units (PFU/ml) of DENV-2 and treated with LOV (200 mg/kg/day). Pre-treatment with one or three doses of LOV increased the survival rate compared to untreated mice (7.3 and 7.1 days, respectively, compared to 4.8 days). Viremia levels also decreased by 21.8% compared to untreated mice, but only in the group administered three doses prior to inoculation. When LOV was administered after viral inoculation, the survival rate increased (7.3 days in the group treated at 24 hpi, 6.8 days in the group treated at 48 hpi and 6.5 days in the group treated with two doses) compared to the untreated group (4.8 days). Interestingly, the serum viral titer increased by 24.6% in mice treated at 48 hpi with a single dose of LOV and by 21.7% in mice treated with two doses (at 24 and 48 hpi) of LOV compared to untreated mice. Finally histopathological changes in the liver and spleen in infected and untreated mice included massive extramedullary erythropoiesis foci and inflammatory filtration, and these characteristics were decreased or absent in LOV-treated mice.
Our results suggest that the effect of LOV on viremia depends on the timing of treatment and on the number of doses administered. We observed a significant increase in the survival rate in both schemes due to a delay in the progression of the disease. However, the results obtained in the post-treatment scheme must be handled carefully because this treatment scheme increases viremia and we do not know how this increase could affect disease progression in humans.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: The present study aims to perform an epidemiological and molecular characterization of Blastocystis infection in a child population attending daycare centers of Medellín, Colombia. ...Methods: A total of 265 children aged 0–5 years were enrolled in five children’s centers in urban sectors of Medellín, northwestern Colombia. Stool samples were taken to identify intestinal parasites by direct examination, Ritchie–Frick concentration, and molecular identification of Blastocystis by conventional PCR and subtype (ST) identification by PCR barcoding with subsequent phylogenetic reconstruction. Kappa index was calculated to evaluate the agreement between microscopy and PCR for the diagnosis of Blastocystis. Results: The prevalence of intestinal protozoa was 36.6% (97/265), with Blastocystis as the most frequent parasitic protozoan at 15.8% (42/265), followed by Giardia intestinalis at 15.5% (41/265) and Endolimax nana at 15.1% (40/265). The prevalence of Blastocystis by PCR was 53.2% (141/265), the subtypes identified were ST3 at 30.5% (18/59), ST2 at 23.7% (14/59), ST1 at 20.3% (12/59), and with less frequency, ST4 at 5.1% (3/59), ST6 at 1.7% (1/59) and ST16 at 15.3% (9/59) allele 162. Conclusion: This study provides the first genetic characterization of Blastocystis subtypes circulating in a population of Medellín, Colombia, and also updates the epidemiology of Blastocystis subtypes in the world with the first identification of ST16 in humans.
This cross-sectional study explores the different conditions related to the infestation of ticks in households and the potential risks for rickettsial transmission in Urabá, Colombia. The main ...outcome of interest was villagers' perception of tick infestation. The data were analyzed using a clog-log mixed regression model. Ticks were collected from infested humans to diagnose infection by spotted fever group rickettsiae (SFGR). In addition, a thematic analysis of qualitative data from key informants concerning knowledge about ticks was conducted. The prevalence of infestation of ticks in households was estimated at 60.99% (95% CI: 51.58–93.51). The multivariate model suggested that households with palm leaf roofs (PR = 1.95; 95% CI: 1.19–2.95), canines (PR = 1.76; 95% CI: 1.21–2.46), rats (PR = 2.19; 95% CI: 1.45–3.08), and with the presence of opossums in areas surrounding the households (PR = 1.51; 95% CI: 1.05–2.10) had a higher prevalence of tick infestation. Two samples of the tick species Amblyomma patinoi were found infected with Rickettsia amblyommatis and Candidatus Rickettsia colombianensi. A thematic analysis provided the names that local community members give to ticks, areas where ticks are common, and the individuals at risk of infestation.The presence of domestic, synanthropic, and wild animals suggests a high risk of the dissemination of ticks inside dwellings and close to them in these rural areas.
•Dynamic modeling of a central receiver sCO2 Brayton CSP system is presented.•Effects of design and operating parameters on the system performance are studied.•Seasonal conditions have a strong ...impact in the system efficiency and power output.•Efficiencies found are comparable with efficiencies of high performance PV panels.
In this study, the dynamic behavior of a concentrated solar power (CSP) supercritical CO2 cycle is studied under different seasonal conditions. The system analyzed is composed of a central receiver, hot and cold thermal energy storage units, a heat exchanger, a recuperator, and multi-stage compression–expansion subsystems with intercoolers and reheaters between compressors and turbines respectively. Energy models for each component of the system are developed in order to optimize operating and design parameters such as mass flow rate, intermediate pressures and the effective area of the recuperator to lead to maximum efficiency. The results show that the parametric optimization leads the system to a process efficiency of about 21% and a maximum power output around 1.6 MW. The thermal energy storage allows the system to operate for several hours after sunset. This operating time is approximately increased from 220 to 480 minutes after optimization. The hot and cold thermal energy storage also lessen the temperature fluctuations by providing smooth changes of temperatures at the turbine and compressor inlets. The results obtained in this paper indicate that concentrated solar systems using supercritical CO2 could be a viable alternative to satisfying energy needs in desert areas with scarce water and fossil fuel resources.
The understanding of physical processes over submerged reefs represents an important ongoing research topic when considering wave energy dissipation and coastal protection that these environments ...provide. Detailed analyses are required to assess wave damping based on the contribution of reef roughness and wave breaking. For this purpose, the CFD (computational fluid dynamics) toolbox OpenFOAM
®
is applied to simulate the wave energy dissipation process over reefs with explicit accounting for the complexities of coral shape instead of commonly applied parameterized approaches for bottom roughness and wave breaking. Model validation was performed through comparison with field measurements over a reef profile of Tesoro Island in the Colombian Caribbean. Quantitative analysis of wave damping caused by wave breaking and reef roughness was conducted for (1) moderate and extreme wave conditions, (2) smooth and rough seabed configurations and (3) changes in the water depth over the reef crest. Wave height attenuation is found to vary along the reef profile reaching differences of up to 55% between smooth and rough reef surface scenarios, particularly for moderate wave conditions. Wave breaking, high turbulent flows and detachment of undertow currents are among the reef roughness effects on hydrodynamics. The fore-reef terrace and the reef crest are identified as the most critical zones where dissipation takes place. Wave breaking from rough seabeds provides a global wave attenuation of 75.4–94.8%, with the reef roughness alone accounting for ~ 4–14%. Under extreme wave height scenarios, the wave damping from reef roughness is not significant. Further predictions regarding roughness effects on the reef hydrodynamics, wave set-up and undertow currents for moderate and extreme wave climate conditions are also shown. Directions for future research using CFD are presented to address limitations that arise from the limited span-wise domain in our approach that prevents development of large lateral coherent structures.
Response to programmed cell death protein 1 (PD-1) blockade is often conceptualized as resulting from reinvigoration of tumor-infiltrating lymphocytes. However, recruited antitumor immunity from the ...periphery may also be an important contributor to response. A detailed assessment of the response dynamics of individual metastasis could provide insight to the systemic and local features that mediate response and resistance to immunotherapy.
Patients with metastatic non-small-cell lung cancer (NSCLC) or mismatch repair deficiency (MMRD) carcinoma treated with PD-1 monotherapy were evaluated independently. Absolute and percent change of each target lesion were quantified at each computed tomography scan using RECIST. Patterns of progression were predefined as systemic or mixed and were correlated with clinical outcomes.
A total of 761 individual lesions from 214 patients with NSCLC and 290 lesions from 78 patients with MMRD carcinoma were examined. Individual target lesion responses aligned with best overall response of each patient (85% NSCLC and 93% MMRD lesions responded in patients with partial response/complete response). In responding patients, timing of response was uniform (73% NSCLC and 76% MMRD lesions responded synchronously), and deeper responses were associated with prolonged progression-free survival and overall survival. By contrast, at progression, mixed progression was common (45% of NSCLC and 53% of MMRD) and associated with improved survival compared with those who experienced systemic progression (NSCLC hazard ratio HR, 0.58;
= .001; MMRD HR, 0.40;
= .07). Organ sites had differential responses, with lymph node and liver metastasis among the most and least responsive, respectively.
Temporal-spatial patterns of response across individual metastases tend to be uniform, favoring the role of peripheral, clonally directed antitumor immunity as a key mediator of response to PD-1 blockade. In contrast, progression is more heterogeneous, potentially revealing the clinical importance of local features and intertumoral heterogeneity.
While anti-CD47 antibodies hold promise for cancer immunotherapy, early-phase clinical trials have shown limited clinical benefit, suggesting that CD47 blockade alone might be insufficient for ...effective tumor control. Here, we investigate the contributions of the Fc domain of anti-CD47 antibodies required for optimal in vivo antitumor activity across multiple species-matched models, providing insights into the mechanisms behind the efficacy of this emerging class of therapeutic antibodies. Using a mouse model humanized for CD47, SIRPα, and FcγRs, we demonstrate that local administration of Fc-engineered anti-CD47 antibodies with enhanced binding to activating FcγRs promotes tumor infiltration of macrophages and antigen-specific T cells, while depleting regulatory T cells. These effects result in improved long-term systemic antitumor immunity and minimal on-target off-tumor toxicity. Our results highlight the importance of Fc optimization in the development of effective anti-CD47 therapies and provide an attractive strategy to enhance the activity of this promising immunotherapy.
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