Cytotoxic T Lymphocytes Research Articles

Admission diagnoses and outcomes among hospitalized people living with HIV during pre-COVID-19, COVID-19 and post-COVID-19 pandemic periods.

Data on the impact of coronavirus disease 2019 (COVID-19) on hospitalization and outcomes among people living with HIV (PLHIV) are limited. A retrospective cohort study was conducted among PLHIV hospitalized during the pre-COVID-19, COVID-19, and post-COVID-19 periods. Of the 310 PLHIV included, 117, 125 and 68 were admitted during the three periods, respectively and 115 (37%) were newly diagnosed with HIV. Median CD4 cell counts and proportions of those with antiretroviral therapy (ART) adherence rates ≥95% at admission were different between the three periods [(206, 97 and 138 cells/mm3 (p = .02) and 97%, 89% and 100% (p = .06), respectively]. Of the 310 PLHIV, admission diagnoses were non-AIDS-related (62%) and AIDS-related (38%). Most of the non-AIDS-related diagnoses were infections other than opportunistic infections (OIs) (40%) while OIs were the most common for AIDS-related diagnoses (88%). The types of admission diagnoses were comparable between the three periods. Hospital mortality rates were 10%, 13% and 16% during pre-COVID-19, COVID-19 and post-COVID-19 periods, respectively (p = .80). By multivariable analysis, intensive care unit admission, underlying malignancy, monthly income less than $USD 400, and admission CD4 less than 50 cells/mm3 were independently associated with hospital mortality. Although admission during COVID-19 pandemic period was not associated with increased mortality, we observed the impact of the pandemic on the lower CD4 cell count and ART adherence at admission among hospitalized PLHIV. Interventions to improve early care engagement, ART adherence, and close monitoring for those with identified mortality risks are needed for better HIV care, especially during pandemics.

Interleukin 15-Presenting Nanovesicles with Doxorubicin-Loaded Ferritin Cores for Cancer Immunochemotherapy.

Interleukin 15 (IL15) is crucial for fostering the survival and proliferation of nature killer (NK) cells and cytotoxic T lymphocytes (CTLs), playing a pivotal role in tumor control. However, IL15 supplementary therapy encounters challenges such as systemic inflammation and non-specific stimulation of cancer cells. Herein, a nanovesicle termed DoxFILN, comprising a membrane presenting IL15/IL15 receptor α complexes (IL15c) and a core of doxorubicin-loaded ferritin (Dox-Fn) are reported. The DoxFILN significantly enhances the densities and activities of intratumoral CTLs and NK cells. Mechanistically, DoxFILN undergoes deshelling in the acidic tumor microenvironment, releasing Dox-Fn and membrane-bound IL15c. Dox-Fn selectively target transferrin receptors on cancerous cells, facilitating intracellular Dox release and inducing immunogenic cell death. Concurrently, membrane-bound IL15c recognizes and activates IL15 receptor β/γc heterodimers, leading to a remarkable increase in the proliferation and activation of CTLs (16-fold and 28-fold) and NK cells (37-fold and 50-fold). The IL15-displaying nanovesicle introduced here holds promise as a potential platform for immunochemotherapy in the treatment of cancer.

The novel quinoline derivative SKA-346 as a KCa3.1 channel selective activator.

The calcium-activated KCa3.1 channel plays a crucial role in T-cell immune response. Genetic manipulation of T-cells to upregulate the expression of K+ channels has been shown to boost T-cell cytotoxicity in cancer. Here, we aimed to identify and characterize an activator that would augment KCa3.1 currents without affecting other channels. We synthesized five quinoline derivatives and used electrophysiology to screen them on KCa3.1 and a panel of 14 other ion channels. One quinoline derivative, SKA-346, activated KCa3.1 with an EC50 of 1.9 μM and showed selectivity against the other channels. In silico analysis using RosettaLigand and GLIDE demonstrated a well-converged pose of SKA-346 in a binding pocket at the interface between the calmodulin N-lobe and the S45A helix in the S4-S5 linker of the KCa3.1 channel. SKA-346 (30 mg kg-1), tolerated by mice after intra-peritoneal administration, exhibited a peak plasma concentration of 6.29 μg mL-1 (29.2 μM) at 15 min and a circulating half-life (t 1/2) of 2.8 h. SKA-346 could serve as a template for the development of more potent KCa3.1 activators to enhance T-cell cytotoxicity in cancer.

Concurrent intratumoural Treg cell depletion and CD8+ T cell expansion via a cleavable anti-4-1BB-interleukin-15 fusion protein.

Potent agonists of the inducible co-stimulatory receptor 4-1BB are too toxic for patients with advanced cancer. Here, on the basis of observations of a weak agonist of 4-1BB depleting regulatory T (Treg) cells within the tumour microenvironment without leading to substantial restoration of dysfunctional cytotoxic T cells (CTLs), we show that effective tumour control can be achieved via concurrent Treg cell depletion and CTL expansion through an anti-4-1BB antibody fused to interleukin-15 (IL-15) via a peptide sensitive to tumour proteases. In mouse models of advanced cancers, intraperitoneal injection of the bifunctional protein attenuated the activity of the interleukin mostly in the periphery of the primary tumour while allowing for the expansion of CTLs within the tumour microenvironment, led to more effective tumour inhibition and to lower systemic toxicity than treating the cancers with combinatorial treatment with unlinked anti-4-1BB antibody and IL-15, and reduced the resistance of tumours to checkpoint blockade. Concurrent eradication of Treg cells and activation of tumour-infiltrating lymphocytes may represent a general strategy for the effective control of advanced metastatic tumours.

Designing and immunomolecular analysis of a new broad-spectrum multiepitope vaccine against divergent human papillomavirus types.

Human papillomavirus (HPV), which is transmitted through sexual activity, is the primary cause of cervical cancer and the fourth most common type of cancer in women. In this study, an immunoinformatics approach was employed to predict immunodominant epitopes from a diverse array of antigens with the ultimate objective of designing a potent multiepitope vaccine against multiple HPV types. Immunodominant B cell, cytotoxic T cell (CTL), and helper T cell (HTL) epitopes were predicted using bioinformatics tools These epitopes were subsequently analyzed using various immunoinformatics tools, and those that exhibited high antigenicity, immunogenicity, non-allergenicity, non-toxicity, and excellent conservation were selected. The selected epitopes were linked with appropriate linkers and adjuvants to formulate a broad-spectrum multiepitope vaccine candidate against HPV. The stability of the multiepitope vaccine candidate was confirmed through structural analysis, and docking results indicated a high affinity for Toll-like receptors (TLR2 and TLR4). Molecular dynamics simulations demonstrated a persistent interaction of TLR2 and TLR4 with the multiepitope vaccine candidate. In silico immunological simulations showed that three injections of the multiepitope vaccine candidate resulted in high levels of B- and T-cell immune responses. Moreover, the in silico cloning results indicated that the multiepitope vaccine candidate could be expressed in substantial amounts in E. coli. The results of this study imply that designing a broad-spectrum vaccine against various HPV types using computational methods is plausible; however, experimental validation and safety testing to confirm the findings is essential.

Depletion of adipose stroma-like cancer-associated fibroblasts potentiates pancreatic cancer immunotherapy

Abstract Immune checkpoint blockade therapy, transformative in some cancer types, has remained ineffective for patients with pancreatic cancer. The effects of sub-populations of cancer-associated fibroblasts (CAFs) on cancer progression and therapy resistance are incompletely understood. Here, the roles of CAFs expressing platelet-derived growth factor receptor beta (Pdgfrb) and of CAFs expressing markers of adipose stromal cells (ASCs) were analyzed in mice with pancreatic ductal adenocarcinoma. Ablation of Pdgfrb+ cells resulted in suppression of primary pancreatic tumor growth, reduction of extracellular matrix (ECM) deposition, and increased cancer cell metastasis to the liver. A peptide D-CAN, which induces apoptosis in ASC-like CAFs, also reduced pancreatic tumor growth and ECM deposition while promoting metastases. Single cell RNA sequencing demonstrated that depletion of either Pdgfrb+ or ASC-like CAFs decreased frequencies of tumor endothelial cells and viable cancer cells. However, while depletion of Pdgfrb+ CAFs led to stronger induction of cancer cell aggressiveness markers, depletion of ASC-like CAFs had an opposite effect on remaining CAFs. Depletion of ASC-like CAFs using D-CAN also led to higher infiltration of cytotoxic T-lymphocytes and B-lymphocytes. Administration of anti-PD-L1 antibody (aPDL1), which inhibits the immune checkpoint, had a stronger suppressive effect on tumor growth when combined with D-CAN in both female and male mice. Liver metastases were also reduced by the D-CAN / aPDL1 combination more effectively than by aPDL1 alone in female mice. We conclude that improved approaches to target ASC-like CAFs may be effective in combination with immunotherapy.

Elective Surgery for People With HIV With Low CD4 Cell Count.

This case report describes a man in his 60s with hypertension, deep vein thrombosis, and a recent diagnosis of HIV presented with low CD4 cell count after starting antiretroviral therapy with tenofovir alafenamide-emtricitabine-bictegravir.

Anti-CTLA-4 antibody self-presented dendritic cell nanovesicles boost the immunotherapy of hepatocellular carcinoma after microwave ablation

Microwave ablation (MWA) is a frequently adopted regional therapy for treating hepatocellular carcinoma (HCC) in clinic. However, incomplete microwave ablation (IMWA) is often inevitable due to the restraint of ablating large tumors or tumors in special locations, resulting in a high recurrence rate of HCC. Moreover, the most promising immune checkpoint blockade (ICB)-based immunotherapy is raising hindered by the toxicity and insufficient immune response. To overcome these barriers, we conjugate small nanovesicle (smDV)-derived from matured dendritic cells (mDCs) with anti-CTLA-4 antibody (smDV-aCTLA-4) using a metabolic tagging technology, which could trigger the infiltration of cytotoxic T cells (CTLs) and adopted tumor-infiltrating lymphocytes (TILs) in residual HCC after IMWA. In HCC microenvironment, the administration of smDV-aCTLA-4 could promote antigen presentation and immune checkpoint suppression to activate CTLs and improve the safety of anti-CTLA-4 antibody. Moreover, the anti-tumor efficacy of CTLs elicited by smDV-aCTLA-4 could also be further enhanced by anti-programmed death 1 (aPD-1) antibody. In addition, compared to the adoptive TILs therapy, the treatment using smDV-aCTLA-4-bonded TILs (smDV-aCTLA-4@TILs) could promote the proliferation and infiltration of cytotoxic TILs in residual HCC after IMWA. Our results clearly evidences the potency of a new type of engineered DC nanovesicles in reducing HCC recurrence after IMWA.

Designing a multi-epitope subunit vaccine against Toxoplasma gondii through reverse vaccinology approach

The parasite Toxoplasma gondii, or T. gondii, is zoonotic that both individuals as well as animals can contract resulting in toxoplasmosis, a life-threatening illness. We used an immunoinformatic technique in our research to construct a vaccine with multi-epitopes so that it can decrease the devastating impact caused by this dangerous parasite. In order to construct the vaccine, GRA6 and MIC3 proteins were targeted, which are engaged in T. gondii identification, infection, and immune response. Novel epitopes for linear B lymphocytes (LBL), cytotoxic T lymphocytes (CTL), and helper T lymphocytes (HTL) were found by epitope mapping, every anticipated epitope was assessed through rigorous screening to determine the top choices for epitopes which were entirely preserved, very antigenic in nature, nonallergenic, and nontoxic. 4 CTLs, 3 HTLs and 4 LBL epitopes were chosen and combined along with proper linkers and adjuvants to design a vaccine with several epitopes. Linkers as well as adjuvants were provided to make the vaccine more immunogenic, antigenic, and stable. The proposed vaccination was identified to possess the necessary biophysical properties, be soluble, extremely antigenic, and non-allergic. Reliability of the vaccine design was demonstrated by secondary along with tertiary structure prediction. It was anticipated that the vaccine's three-dimensional structure would likely link up with TLR-2 and TLR-4 via the investigation of molecular docking. TLR-2 and TLR-4 are crucial for the parasite's invasion and the body's response. In our docking investigation, both TLRs demonstrated strong binding affinities utilizing the vaccine structure. After that, the vaccine construct's elevated expression rate, which was observed in Escherichia coli strain K12, was confirmed by an investigation using in silico cloning and codon adaptation. The results of the research are really encouraging and some properties of the vaccine were found to be significantly better than existing the T. gondii multi-epitope vaccination based on the same proteins. Nonetheless, in vivo trials are strongly suggested for potential future studies.

CaCO3-complexed pH-responsive nanoparticles encapsulating mitoxantrone and celastrol enhance tumor chemoimmunotherapy

Modulating the immunosuppressive tumor microenvironment (TME) while enhancing antitumor immune responses is a promising strategy. In this study, we designed an acid-sensitive nanosystem (MCCaNPs) to demonstrate effective immunotherapy against cancer through the systemic delivery of immune-stimulating chemotherapy combinations. A pH-responsive nanoplatform containing CaCO3 was prepared by the double emulsion method, and mitoxantrone (MIT) and celastrol (CEL) were simultaneously encapsulated as immunogenic cell death (ICD) inducers. Due to the acid responsiveness of CaCO3, the nanoparticles rapidly consume H+ to relieve the acidic tumor microenvironment and explosively release CEL and MIT, showing inherent immunomodulatory activity in collaborative tumor chemoimmunotherapy. MIT and CEL synergistically trigger stronger ICD by inducing tumor cells to release calreticulin (CRT), high mobility group box 1 protein (HMGB1). Following the intravenous administration of MCCaNPs, the local tumor microenvironment(TME) was reprogrammed in mice-bearing tumors. This reprogramming was characterized by a significant increase in the density of tumor-infiltrating cytotoxic T lymphocytes(CTLs), ultimately prolonging survival. Therefore, this research proposes a promising approach to trigger immunogenic cell death collaboratively, aiming to boost the tumor CTLs infiltration for anticancer immunotherapy.

In silico Designing of a Multi-epitope-based Subunit Vaccine against SARS-CoV-2 (Delta Variant) by Exploiting Its Structural Proteins: A Reverse Vaccinomics and Immunoinformatics Approach

Background: The continuously emerging novel strains of SARS-CoV-2 remain a menace to the global population. The vicious delta variant (originated in India) is considered one of the most infectious/contagious variants of SARS-CoV-2. The transmission frequency of this variant is 225% higher than other variants, extending its prevalence and causing a massive surge in the COVID-19 pandemic. It is also the most ravenous variant among others. Objective: Though the delta variant has already disappeared, it could re-emerge/come out at any time with a more powerful strike than earlier. Therefore, to tackle such ferocity, this research is undertaken with a next-generation vaccine development strategy to design a multi-epitope-based subunit vaccine against the delta variant of SARS-CoV-2, which might boost the body's immunity. Materials and Methods: In the present investigation, reverse vaccinomics and immunoinformatics approaches were adopted to create an immune-stimulating prospective vaccine candidate having B cell, helper T cell (Th)/helper T lymphocyte (HTL), cytotoxic T cell (Tc)/cytotoxic T lymphocyte (CTL), and interferon-gamma (IFN-γ) inducing epitopes by exploiting the SARS-CoV-2 (delta variant) (GenBank: MZ724536.1) structural proteins: envelope glycoprotein (E), nucleocapsid phosphoprotein (N), surface glycoprotein (S), and membrane glycoprotein (M). The established vaccine construct was then completed by combining antigenic epitopes with adjuvants and linkers. Subsequently, the 3D model of the suggested vaccine was created and docked with an immune receptor (Toll-Like Receptor-4). A molecular dynamics (MD) simulation study was performed to confirm the binding stability between the vaccine conjugate and TLR4. Later, an immune simulation study was carried out to predict the in silico immune response of the vaccine candidate. To effectively express the developed vaccine in a bacterial system (E. coli), in silico codon optimization and cloning were done in an expression vector to manufacture it on a large scale. Results: According to the computational analysis, the vaccine candidate was found to be highly antigenic while maintaining favorable properties for the human body. Molecular docking and dynamics simulation study between the suggested vaccine construct and TLR4 immune receptor depicted it as extremely efficient and stable, ensuring a proper immunological response within the host cell. Eventually, an in silico immune simulation study of the vaccine candidate demonstrated a robust immune response to vaccine administration. Conclusion: We have hypothesized that the constructed vaccine model is benign, stable, and immunogenic, making it a promising/potent candidate for immune system stimulation against SARSCOV- 2 (DV). Hereof, wet lab-based investigations are needed to justify the competence of the novel vaccine candidate towards the delta variant along with other variants of SARS-CoV-2.

384 Sodium chloride in the tumor microenvironment enhances T-cell metabolic fitness and cytotoxicity

384 Sodium chloride in the tumor microenvironment enhances T-cell metabolic fitness and cytotoxicity

Enhancing preventive and therapeutic cancer vaccine efficacy through biotherapeutic ligand-associated extracellular vesicles

Extracellular vesicles (EVs), secreted by almost all living cells, have gained significant attention for their role in intercellular communication and their potential as versatile carriers for biotherapeutics. However, the clinical translation of EV-based therapies faces significant challenges, primarily due to the lack of efficient methods for loading biotherapeutic agents into EVs. This study introduces a simple, reproducible strategy for the simultaneous incorporation of various biotherapeutics within EVs. The process is gentle and preserves the essential physicochemical and biological characteristics of EVs, thereby protecting labile ligands from premature degradation and elimination. The binding and uptake efficiency of EVs by target cells reached approximately 97 % within 24 h of incubation. Administration of EVs loaded with oligodeoxynucleotides (ODN) resulted in a 4-fold increase in IFNγ+ CD4+ T cells and a 5-fold increase in IFNγ+ CD8+ T cells in the spleens and lymph nodes. Additionally, the co-administration of EVs with ODN and ovalbumin (OVA) induced elevated Th1-biased antibody responses and antigen-specific cytotoxic T-cell responses, providing long-lasting complete protection in 60 % of mice against T-cell thymoma challenge. Furthermore, EVs associated with three different ligands (OVA, CpG-ODN, and α-GalCer) effectively regressed established murine melanoma and significantly improved survival rates in mice. This study presents a powerful and promising approach to overcoming the limitations of EV-based cancer vaccines, advancing the development of effective cancer immunotherapies. SummaryImmunization with EVs that are co-associated with antigen and biotherapeutic cargo through a lyophilization-based technique elicits potent anti-cancer immunity.

HepB-CpG vs HepB-Alum Vaccine in People With HIV and Prior Vaccine Nonresponse: The BEe-HIVe Randomized Clinical Trial.

Nonresponse to hepatitis B vaccine is common among people with HIV, resulting in vulnerability to infection with hepatitis B virus (HBV). To compare the seroprotection response achieved with a 2-dose (noninferiority, 10% margin) and a 3-dose hepatitis B vaccine with a cytosine phosphoguanine adjuvant (HepB-CpG vaccine) vs a conventional 3-dose hepatitis B vaccine with an aluminum hydroxide adjuvant (HepB-alum vaccine) in people with HIV and prior nonresponse to HepB-alum vaccine. This phase 3, open-label, randomized clinical trial included people with HIV receiving antiretroviral therapy (CD4 cell count ≥100 cells/μL and HIV RNA <1000 copies/mL) without past or present serological evidence of having HBV or a response to hepatitis B vaccine. From December 2020 to February 2023, 561 adults were enrolled in the study at 41 sites in 10 countries in Africa, Asia, North America, and South America with follow-up for the primary outcome analysis through September 4, 2023. Participants were randomly assigned to receive 2 doses of HepB-CpG vaccine administered intramuscularly at weeks 0 and 4; 3 doses of HepB-CpG vaccine administered intramuscularly at weeks 0, 4, and 24; or 3 doses of HepB-alum vaccine administered intramuscularly at weeks 0, 4, and 24. The primary outcome was a seroprotection response to hepatitis B vaccine (defined as level of antibody titer against hepatitis B surface antigen [HBsAg] ≥10 mIU/mL) at week 12 for the 2-dose regimen (8 weeks after dose 2) and at week 28 for 3-dose regimens (4 weeks after dose 3). Key secondary outcomes included seroprotection response at additional time points, antibody titer against HBsAg, and adverse events within 4 weeks of hepatitis B vaccination. Of 561 participants included in the analysis (median age, 46 years [IQR, 31-56 years]); 64% were male; 17% of participants were Asian, 42% were Black, and 35% were White), a seroprotection response was achieved in 93.1% who received 2 doses of HepB-CpG vaccine (n = 174), in 99.4% who received 3 doses of HepB-CpG vaccine (n = 169), and in 80.6% who received 3 doses of HepB-alum vaccine (n = 165). The stratified difference in seroprotection response between the 2-dose HepB-CpG vaccine group and the 3-dose HepB-alum vaccine group was 12.5% (97.5% CI, 4.1%-20.9%), achieving noninferiority and indicating superiority. The 3-dose HepB-CpG vaccine regimen was superior to the 3-dose HepB-alum vaccine regimen (stratified difference in seroprotection response, 18.4% [repeated 97.5% CI, 10.4%-26.2%]). By week 12, more than 90% of participants who received HepB-CpG vaccine achieved a seroprotection response. The 3-dose regimen of HepB-CpG vaccine achieved a higher proportion of participants with antibody titer against HBsAg greater than 1000 mIU/mL (78.1%) vs the other 2 regimen groups (26.4% for 2 doses of HepB-CpG vaccine and 35.2% for 3 doses of HepB-alum vaccine). No unexpected safety issues were observed. Among people with HIV and nonresponse to prior hepatitis B vaccination, both the 2-dose and 3-dose regimens of HepB-CpG vaccine achieved a superior seroprotection response compared with 3 doses of HepB-alum vaccine. ClinicalTrials.gov Identifier: NCT04193189.

Cutting-edge Bioinformatics strategies for synthesizing Cyclotriazadisulfonamide (CADA) analogs in next-Generation HIV therapies

Cyclotriazadisulfonamide (CADA) is a macrocyclic compound known for its unique mechanism in inhibiting HIV infection by downregulating the CD4 T-cell receptor, a crucial entry point for the virus. Unlike other antiretrovirals, CADA exhibits activity against a wide range of HIV strains, as all HIV variants require CD4 binding for infection. Furthermore, CADA has shown a synergistic effect with clinically approved anti-HIV drugs, offering potential for enhanced therapeutic strategies (Vermeire & Schols, [65]). One proposed mechanism for CADA’s inhibition of the CD4 receptor involves blocking the gates of the Sec61 channel, thereby preventing its translocation. However, CADA suffers from poor solubility and bioavailability. To address this, the study aimed to design CADA analogs with improved binding to the Sec61 channel, enhanced bioavailability, and reduced toxicity. The analogs were designed using SeeSAR, with Avogadro and Meeko used for 3D configuration and pseudoatom placement, respectively. AutoDock Vina version 1.2.4 was employed to predict the binding energies of these analogs. Of the 113 analogs designed, 93 demonstrated a more negative binding energy to the Sec61 channel compared to CADA. Structure-binding energy analyses were done to the top-binding analogs to show favorable structural modifications. Enzyme-ligand interactions were analyzed to elucidate the forces contributing to these binding energies. Additionally, 33 of the 113 analogs were deemed bioavailable using a bioavailability criteria specific for macrocycles. Toxicity predictions using PASS Online and StopTox identified analogs JGL023, JGL024, JGL032, and JGL047 as potential drug candidates. Molecular dynamics simulations using Gromacs-2020.4 revealed that JGL023 and JGL032 exhibited the most favorable binding to the Sec61 channel, as determined by evaluating ligand and residue flexibility, compactness, contact frequency, motion pathways, free energy, and other relevant parameters. Synthetic routes for these four analogs were proposed for future studies. The results of this study offer a new perspective on developing drugs to inhibit HIV entry.

Pathologic differences between systemic sclerosis-associated and idiopathic pulmonary arterial hypertension.

Advances in pulmonary arterial hypertension therapies have led to improvements in the quality of life and survival for patients with idiopathic pulmonary arterial hypertension, but these trends have not uniformly translated to patients with systemic sclerosis-associated pulmonary arterial hypertension. In order to better understand the heterogeneity in treatment response and survival, we aimed to examine the histological and immunophenotypic differences between the systemic sclerosis-associated pulmonary arterial hypertension and idiopathic pulmonary arterial hypertension pulmonary vasculopathies. We performed a semi-quantitative lung morphometry-based analysis comparing sections obtained from systemic sclerosis-associated pulmonary arterial hypertension (n = 24), idiopathic pulmonary arterial hypertension (n = 9), and control (n = 13) bio-banked lung tissue specimens. H&E (Hematoxylin and Eosin) and VVG (Verhoeff-Van Gieson)-stained lung sections were analyzed for interstitial and vascular pathology. Immunohistochemistry was used to stain for an array of inflammatory and fibrosis mediators. Baseline demographic and hemodynamic data for each patient were collected via chart review at the time of lung explantation. Plexiform lesions were present in 5/9 (55%) of idiopathic pulmonary arterial hypertension samples, but absent in all systemic sclerosis-associated pulmonary arterial hypertension samples (0/24). Systemic sclerosis-associated pulmonary arterial hypertension lungs demonstrated significantly worse interstitial fibrosis (p = 0.0001) and interstitial cellularity (p = 0.0002) compared to idiopathic pulmonary arterial hypertension lungs. The degree of smooth muscle hypertrophy and pulmonary artery intimal proliferation were not different between systemic sclerosis-associated pulmonary arterial hypertension and idiopathic pulmonary arterial hypertension lungs. Immunohistochemistry analysis revealed that systemic sclerosis-associated pulmonary arterial hypertension lungs exhibited increased interstitial infiltration of CD3 T-cells (p = 0.009), CD20 B-cells (p = 0.01), and CD163 macrophages (p = 0.048) when compared to idiopathic pulmonary arterial hypertension and control lungs. Systemic sclerosis-associated pulmonary arterial hypertension lungs display a distinct pulmonary vascular pathology as well as significant interstitial fibrosis when compared to idiopathic pulmonary arterial hypertension lungs.

Differential immunophenotype and proviral composition in young adults with perinatally acquired HIV: Are special cure strategies needed?

To characterize the immune functionality and phenotype and the proviral composition of a cohort of young adults with perinatally-acquired HIV (p-YA) from Argentina. Cross-sectional study of 18 p-YA, 15 young adults with non-perinatally acquired HIV matched by age with p-YA and 14 adults with non-perinatally acquired HIV, matched by time from HIV diagnosis with p-YA, all from Argentina. Immune memory/effector phenotype, exhaustion, activation, PTK-7 and Ki-67 expression were evaluated by flow cytometry on NK and T-cells. Total, intact and defective proviral (TP, IP and DP) HIV-DNA were measured in CD4 T-cells by IPDA. Soluble markers were determined by ELISA. p-YA displayed lower expression of PD-1, higher levels of CD38+ CD4 T-cells and increased levels of naïve T-cells than control groups. Also, a trend of lower levels of IP HIV-DNA normalized to CD4 T-cell counts and to the proportion of naïve T-cells was found in p-YA. The higher frequency of naïve CD4 T-cells in p-YA cannot be explained by elevated thymic activity nor by a higher T-cell proliferation rate. This imbalance could have been generated early in life and persisted during adulthood. Naïve CD4 T-cells may not serve as a major viral reservoir in p-YA. Also, the lower PD-1+ CD4 T-cell count suggests that p-YA did not present higher levels of exhaustion. These findings suggest that acquiring HIV perinatally may imply different challenges for proviral eradication.

Photothermal-Triggered Extracellular Matrix Clearance and Dendritic Cell Maturation for Enhanced Osteosarcoma Immunotherapy.

Osteosarcoma, a predominant malignant tumor among adolescents, exhibits high mortality and suboptimal immunotherapy efficacy due to a collagen-dense extracellular matrix (ECM) that hinders cytotoxic T lymphocyte (CTL) infiltration. Herein, we developed mesoporous polydopamine (MPDA) nanoparticles encapsulating bromelain and the immune adjuvant R848 (M@B/R), aimed at enhancing photothermal immunotherapy. These nanoparticles efficiently accumulate at the tumor site following injection. Upon near-infrared (NIR) light irradiation, photothermal therapy (PTT) induces immunogenic cell death in tumor cells and, with the aid of R848, efficiently promotes dendritic cell maturation, activating antitumor immunity and leading to CTL infiltration into the tumor. Concurrently, NIR-induced heating activates bromelain, resulting in ECM degradation and improved CTL penetration into the tumor. Our in vivo evaluations demonstrate potent antitumor effects in osteosarcoma-bearing mice. This integrated approach offers a promising strategy for overcoming physical barriers in ECM-rich tumors, marking a significant advancement in the treatment of osteosarcoma.

Ubiquitin-Activating Enzyme E1 (UBA1) as a Prognostic Biomarker and Therapeutic Target in Breast Cancer: Insights into Immune Infiltration and Functional Implications

Ubiquitin-Activating Enzyme E1 (UBA1), an E1 enzyme involved in the activation of ubiquitin enzymes, has been involved in the onset and progression of different cancers in humans. Nevertheless, the precise contribution of UBA1 in breast cancer (BC) is still poorly characterized. In this study, a thorough investigation was carried out to elucidate the significance of UBA1 and validate its functionality in BC. Through the analysis of mRNA sequencing data of BC patients, the mRNA expression of UBA1 was observed to be notably enhanced in cancer tissues relative to controls, and high UBA1 expression was linked to worse overall survival (OS), disease-specific survival (DSS), and progress-free survival (PFS). Moreover, UBA1 exhibited potential as an independent prognostic and diagnostic biomarker for individuals with BC. Additionally, functional enrichment analysis revealed the involvement of UBA1 in inflammation-linked pathways, like the TNF-α signaling pathway, the IL-6 signaling pathway, and various immune-related biological processes. Notably, single-sample gene set enrichment analysis (ssGSEA) aided in the identification of a negative link between UBA1 expression and the levels of infiltrating mast cells, Th1 cells, iDC cells, B cells, DC cells, Tem cells, Cytotoxic cells, T cells, CD8T cells, and pDC cells. Finally, this study demonstrated that silencing UBA1 significantly impeded the growth and development of BC cell lines. These findings highlight UBA1 as a potential prognostic biomarker linked to immune infiltration in BC, thereby depicting its potential as a new therapeutic target for individuals with BC.

Impact of Yoga and Meditation on Immune System – A Systematic Review and Meta-Analysis

Background: Yoga and Meditation is a mind body technique which has various positive effects on immune system and helps in bring down the inflammatory markers. Therefore, therapies based on Yoga and Meditation showed promising effects on immuno-compromised condition like HIV, Aim: To examine the effects of Yoga and Meditation on immune system functioning in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for conducting systematic reviews.Methods: Four electronic databases (MEDLINE/PubMed, Scopus, the Cochrane Central Register of Controlled Trials, and IndMED) were searched and the extraction of the applicable variables and assessing the risk of bias from the gathered studies was noted. The data analysis was done using, Review Manager software (RevMan; version 5.3.5) and R statistical software (version 3.6.1). Mean differences (MD), and standardize mean difference (SMD) were measured for continuous outcomes. Heterogeneity with the help of I2 statistic was used for the assessment of inconsistency across studies with the level of significance at P&lt; 0.10. Publication bias was assessed using funnel plots, Egger’s test for the selected studies.Results:From a total of 141 papers, duplicates and other filtrations like languages other than English, non- clinical trials and non-RCT papers were excluded and finally 91 papers were selected for the present study. After the complete review of the selected papers, articles were grouped based on each immune parameters like Nuclear factor-kB , Interleukin-1b, Interleukin-6 , Tumor necrosis factor , CD4 T-cells, CD8-cells and NK cells. According to the inclusion and exclusion criteria, a total of nineteen RCTs were included in the meta-analysis. Conclusion: Yoga may have potential for the supplemental treatment and prevention of inflammation-related disorders, according to current studies. Yoga practice may be beneficial as it combines the positive effects of physical activity with those of mindfulness; consequently, more research into the advantages of yoga-based therapies is especially important.Systematic review registration: PROSPERO registration number- CRD42020187532