CD4 Lymphocyte Research Articles

Analysis of central pontine myelinolysis in HIV-infected patients

Aim: to conduct a clinical and epidemiological analysis of cases of central pontine myelinolysis (CPM) in HIV-infected patients. Materials and methods. Four patients hospitalized in the infectious diseases department of No. 1 Clinic of the South Ural State Medical University were under dynamic observation. Results and its discussion. Four patients hospitalized in the infectious diseases department of Clinic No. 1 of the South Ural State Medical University were under dynamic observation. Patient management was carried out in accordance with current clinical recommendations for the provision of medical care to patients with HIV infection with a set of clinical and laboratory methods, including examination of lumbar puncture, its cytological and biochemical composition, determination of DNA of cytomegalovirus (CMV) and Epstein-Barr viruses (EBV) herpes simplex types 1 and 2, T. gondii, Cr. Neoformans, M. Tuberculosis, Cryptococcus neoformans, the presence of pathogens of bacterial infections. All patients underwent magnetic resonance imaging (MRI) of the brain. Conclusion. The process of demyelination of the central nervous system develops regardless of the level of CD4 lymphocytes and HIV viral load. The main method for verifying the diagnosis is MRI of the brain

The effectiveness of treatment depending on an adherence to dispensary observation and antiretroviral therapy in patients with HIV infection

Aim. Determination of the causes of deaths and analysis of the survival of people living with HIV, depending on an adherence to dispensary observation and treatment. Materials and methods. The analysis of socio-demographic characteristics and clinical and laboratory data of 284 adult HIV patients observed in 1999–2011 at the Lomonosov Interdistrict Hospital named after I. N. Yudchenko was carried out. Patients who followed the prescribed monitoring regimen (at least 2 times a doctor’s visit during the year) were considered committed to dispensary supervision. Patients who observed the regularity and continuity of monitoring and receiving antiretroviral therapy (ART) were considered committed to treatment. Among the patients included in the study, 115 people were committed to treatment or follow-up and 169 patients were non-committed. Objective (biological) indicators of adherence and effectiveness of treatmentwere the number of CD4 lymphocytes and the level of HIV viral load. Based on the method of comparing survival curves, factors related to the life expectancy of HIV patients were assessed, taking into account the gender of patients, their adherence to monitoring and treatment, indicators of HIV viral load and the number of CD4 lymphocytes and the outcome of the disease from the moment of registration at the dispensary and over the next 120 months (after 3 months, 6 months, 1.5 years, 2 years, 5, 7 and 10 years). Results and discussion. Significant differences were found in the survival curves of patients who received and did not receive ART (117.9 and 91.4 months, p<0.005) and patients who were committed and non-committed to therapy (116.9 and 83.8 months, p<0.005). Regardless of adherence to outpatient follow-up and therapy, the survival time of women compared to men for the entire follow-up period was longer (105.0 and 92.4 months, respectively, p<0.005). Among those committed to treatment, 21% of patients died due to concomitant somatic pathology, 5% from injuries incompatible with life. In the group of those committedto follow–up, the causes of deaths in 12% were various somatic pathology, brain lymphoma — in 1% and injuries incompatible with life — in 3% of cases. The highest mortality rates were recorded among patients who were not exposed to ART (71%) and the routine of follow-up (52%). Almost half of these patients (49%) died from secondary HIV infections, of which 85% of cases were posthumously diagnosed with tuberculosis, mainly the pulmonary form of the disease. The second most common cause of death was violent death, including drug poisoning. Conclusion. Regular dispensary observation, timely initiation of ART and adherence to therapy make it possible to control the disease, prevent the development of opportunistic pathology, and improve the quality and life expectancy of patients with HIV infection. Despite the increased availability of ART and strategies for active involvement and retention of patients in dispensary care, issues of patient adherence to therapy remain key in the management of HIV patients.

Pathogenetic parallels and clinical relationships of HIV infection and Hodgkin’s lymphoma

Aim: to show the importance of the features of the development of Hodgkin’s lymphoma (HL) against the background of HIV infection, possible clinical relationships and consequences of simultaneous diseases in patients, as well as complex therapy. Material and methods. The article presents an analytical review of the problem and retrospective data on 63 patients with HIV[1]associated HL (HIV-HL) who were diagnosed with HL in St. Petersburg hospitals in the period 2000–2017. For the diagnosis of HIV-HL, regulated morphological, immunohistochemical, instrumental and laboratory research methods were used, the tumor stage was determined based on the Cotswolds-modified Ann Arbor classification. The diagnosis of HIV infection was confirmed by the detection of specific antibodies to HIV (and the p24 antigen) during serological and enzyme immunoassay of blood, by immune blotting. The number of copies of HIV RNA and the number of CD4 lymphocytes in the blood of patients were determined using commercial test systems approved for use in the territory of the Russian Federation. The analysis of overall survival was performed using the Kaplan–Meyer method. Statistical processing of the research results was performed using statistical programs MS Excel 2010, GraphPad Prism 8 (GraphPad Software, Inc., USA), SPSS version 22.Results. The study group was dominated by men (73%), the median age was 32 years, in 16 (25.4%) patients HIV and HL were detected simultaneously. The number of CD4 lymphocytes > 500 cl/μl at the HL debut was noted in 33.3% of patients, patients with severe immunosuppression prevailed (50–250 cl/μl in 20 (31.7%), 250–500 cl/μl in 11 (17.5%), less than 50 cl/μl in 11 (17.5%). The amount of HIV RNA>400 kop/ml was noted in 82.5%, HIV infection at stages 4B-5 was detected in 89% of cases, at the time of detection of HL ART was performed in 16 patients. EBV coinfection (77.8%), cytomegalovirus (60%), viral hepatitis (55.6%) with a predominance of viral hepatitis C, common opportunistic infections (tuberculosis, pneumocystis pneumonia, toxoplasmosis of the brain, common candidiasis), simultaneously occurring from 1 to 3 infections were observed in 77.8%. Stage IV HL was established in 54%, III — in 22%, II — in 24% of patients, the presence of B-symptoms was confirmed in 73% of cases. The predominant histological variant of HIV-HL was nodular sclerosis (58 patients), mixed[1]cell sclerosis in 4 patients, with lymphoid predominance in 1 case. Extranodal lesions were observed in 34 (54%), complications of the tumor process in 33 (37.5%) patients. 42 (66.7%) patients received antitumor treatment for HL: line 1 according to the ABVD scheme — 85.7% (80% achieved PET-negative complete remission (CR), according to the VEASORR esc or VEASORR schemes — 33.3%; line 2 — according to the ICE or DHAP schemes (n=10). An objective response was noted in 4 patients, PET-negative response in 2 of them, partial PET-positive regression in 2 patients. Progression was observed in 2 people. Autologous bone marrow transplantation was performed in 2 patients (in partial PET-positive regression); line 3 (n=3) — chemoimmunotherapy with bendamustine, gemcitabine (2 patients underwent autologous bone marrow transplantation). The cumulative life expectancy of patients for 1 year and 2 years was 44% and 37%, respectively, 1-year overall survival was 75%, 2-year — 60%. The factors negatively affecting survival and life expectancy were tumor progression and complications, ECOG≥2 (p=0.0001), candidiasis, pneumonia (p=0.001), viral hepatitis B and C (p=0.045), lack of antitumor treatment and ART (p=0.0001), age younger than 40 years, central nervous system damage, the presence of 1 or more concomitant infections (p=0.024). Conclusion. HIV-HL is one of the most common hematological malignancies, characterized by heterogeneity in its manifestations, polymorphism of pathogenetic and clinical features and relationships. During the dispensary supervision of PLHIV, special attention should be paid to the factors of an unfavorable prognosis of the disease, the timeliness of the appointment of ART and the assessment of the risks of developing lymphoproliferative diseases within the framework of the immune system restoration syndrome (IRIS) in order to increase their survival and quality of life. Further research is needed on the pathogenesis, early diagnosis and effective treatment of lymphomas associated with the human immunodeficiency virus

Immunotherapy with an antibody against CD1d modulates neuroinflammation in an α-synuclein transgenic model of Lewy body like disease.

The neuroinflammatory process in synucleinopathies of the aging population such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB) involves microglial activation as well as infiltration of the CNS by T cells and natural killer T cells (NKTs). To evaluate the potential of targeting NKT cells to modulate neuroinflammation, we treated α-syn transgenic (tg) mice (e.g.: Thy1 promoter line 61) with an antibody against CD1d, which is a glycoprotein expressed in antigen presenting cells (APCs). CD1d-presented lipid antigens activate NKT cells through the interaction with T cell receptor in NKTs, resulting in the production of cytokines. Thus, we hypothesized that blocking the APC-NKT interaction with an anti-CD1d antibody might reduce neuroinflammation and neurodegeneration in models of DLB/PD. Treatment with the anti-CD1d antibody did not have effects on CD3 (T cells), slightly decreased CD4 and increased CD8 lymphocytes in the mice. Moreover, double labeling studies showed that compared to control (IgG) treated α-syn tg mice, treatment with anti-CD1d decreased numbers of CD3/interferon γ (IFN γ)-positive cells, consistent with NKTs. Further double labeling studies showed that CD1d-positive cells co-localized with the astrocytes marker GFAP and that anti-CD1d antibody reduced this effect. While in control α-syn tg mice CD3 positive cells were near astrocytes, this was modified by the treatment with the CD1d antibody. By qPCR, levels of IFN γ, CCL4, and interleukin-6 were increased in the IgG treated α-syn tg mice. Treatment with CD1d antibody blunted this cytokine response that was associated with reduced astrocytosis and microgliosis in the CNS of the α-syn tg mice treated with CD1d antibody. Flow cytometric analysis of immune cells in α-syn tg mice revealed that CD1d-tet + T cells were also increased in the spleen of α-syn tg mice, which treatment with the CD1d antibody reduced. Reduced neuroinflammation in the anti-CD1d-treated α-syn tg mice was associated with amelioration of neurodegenerative pathology. These results suggest that reducing infiltration of NKT cells with an antibody against CD1d might be a potential therapeutical approach for DLB/PD.

Assessment of CD4, CD8 and White Cell Parameters Amongst HIV Seronegative Pregnant Subjects in Port Harcourt, Nigeria

Pregnancy involves maternal immunological adjustments to accommodate the fetus and maintain a strong immune defense against potential pathogens. The present study evaluated the changes in CD4, CD8, white blood cell (WBC) and total lymphocyte count (TLC) amongst HIV seronegative pregnant subjects in Port Harcourt, Nigeria. A total of 302 female subjects (18-39 years) were recruited for the study. They consisted of 205 pregnant subjects and 97 non-pregnant subjects which served as the control. All subjects were screened for HIV type 1 and type 2 using standard test kits. Total and differential white blood cell counts were determined using a haematology auto analyzer while the total lymphocyte count (TLC) was obtained by multiplying total white blood cell count (TWC) with percentage lymphocyte count. The CD4 and CD8 cell counts were analyzed using the automated flow cytometry analyzer while the CD4:CD8 cell count ratio was obtained by dividing the CD4 cell count value by that of CD8. The result of the study shows a statistically significant decrease in CD4 and CD8 cell counts, lymphocyte and total lymphocyte counts and an increase in neutrophil count in all the trimesters of pregnancy when compared to the non-pregnant control (p<0.05). Also, there was a significant increase in WBC during the third trimester and a similar decrease in monocyte count in the first and third trimesters of pregnancy. The evidence from the present study concludes that pregnancy modifies the maternal immune response to ensure fetal survival and the protection of the mother from invading pathogens as reported in the increase in total WBC, neutrophil and monocyte counts and a reduction in TLC, CD4 and CD8 counts. The study recommends routine assessments of these crucial cellular immune markers for pregnant women during antenatal visits.

Therapeutic Effect of Music Therapy on Patients with End-stage Cancer: A Retrospective Study.

The aim of this study was to retrospectively analyze the effect of music therapy on patients with end-stage cancer in hospice care. This retrospective cohort study included 195 patients with end-stage cancer from January 2021 to December 2023. The conventional group comprised patients who received routine hospice care, whereas the combination group comprised those who received routine hospice care and music therapy. The immune indicators, anxiety and depression scores, quality of life scores, and sleep quality scores of both groups were compared before and after management. Before management, no significant differences were observed in the immune indicators, anxiety and depression scores, quality of life scores, and sleep quality scores between both groups (P > 0.05). However, after management, the immune indicators lymphocytes CD3+ and CD4+ were significantly higher in the combination group than in the conventional group (P < 0.05); in contrast, anxiety and depression and the Pittsburgh Sleep Quality Index scores were lower in the combination group than in the conventional group (P < 0.05). Lastly, the World Health Organization Quality of Life Brief Version scores were significantly higher in all domains in the combination group than in those in the conventional group; furthermore, the degree of decline in the physical, psychological, and social relationship domain scores was smaller in the combination group than in the conventional group (P < 0.05). For patients with end-stage cancer, music therapy can improve their immune status, quality of life, and sleep and ameliorate their anxiety and depression.

Trends of pre-treatment drug resistance in antiretroviral-naïve people with HIV-1 in the era of second-generation integrase strand-transfer inhibitors in Taiwan.

Monitoring the trends of pre-treatment drug resistance (PDR) and resistance-associated mutations (RAMs) among antiretroviral-naïve people with HIV (PWH) is important for the implementation of HIV treatment and control programmes. We analysed the trends of HIV-1 PDR after the introduction of second-generation integrase strand-transfer inhibitors (INSTIs) in 2016 in Taiwan, when single-tablet regimens of non-nucleoside reverse-transcriptase inhibitor (NNRTI-) and INSTI-based antiretroviral therapy became the preferred treatments. In this multicentre study, we included newly diagnosed, antiretroviral-naïve PWH who underwent tests for RAMs between 2016 and 2022. Pre-treatment genotypic resistance testing was performed, along with HIV-1 subtyping and determinations of plasma HIV RNA load and CD4 lymphocyte counts. RAMs were analysed using the Stanford University HIV Drug Resistance Database and only RAMs conferring at least low-level resistance were included. From 2016 to 2022, pre-treatment blood samples from 3001 newly diagnosed PWH, which constituted 24.3% of newly diagnosed PWH in Taiwan during the study period, were tested. Of the PWH with analysable gene sequences, the HIV-1 PDR prevalence to NNRTIs, nucleoside reverse-transcriptase inhibitors (NRTIs), first- and second-generation INSTIs and PIs was 10.0%, 2.1%, 2.5%, 0.6% and 0.4%, respectively. While the trends of PDR remained stable for NRTIs, INSTIs and PIs, there was a significantly increasing trend of PDR to NNRTIs from 6.0% in 2016% to 13.1% in 2022 (P = 0.001). After the introduction of second-generation INSTIs in Taiwan, the trends of HIV-1 PDR to NRTIs and INSTIs remained low. Furthermore, there was no significant decrease of the prevalence of PDR toward NNRTIs between 2016 and 2022.

Abstract 1048: Loss of MTAP expression is strongly linked to homozygous 9p21 deletion, unfavorable tumor phenotype and non-inflamed microenvironment in urothelial bladder cancer

Abstract 9p21 deletions are common in urothelial carcinoma and mostly include S-methyl-5′-thioadenosine phosphorylase (MTAP) a critical enzyme for DNA and RNA synthesis. Homozygous MTAP deletions result in a complete loss of expression which can be visualized by immunohistochemistry (IHC). Evidence is emerging that MTAP deficiency results in a critical vulnerability of cancer cells towards drugs targeting multiple different pathways that depend on a functional MTAP gene and causes resistance to immune checkpoint inhibitors. To determine the prevalence and clinical significance of MTAP deficiency and its relationship with the tumor microenvironment in urothelial bladder carcinomas, more than 2,500 tumors were analyzed by fluorescence in-situ hybridization (FISH) and IHC in a tissue microarray format, and the data were compared with existing data on intratumoral lymphocyte subsets and PD-L1 expression. The cohort included 1,826 patients that underwent radical cystectomy for muscle-invasive disease (pT2-4). 9p21 deletion was homozygous in 364 (21.3%) and heterozygous in 334 (19.5%) of 1,711 analyzable tumors. The rate of 9p21 deleted tumors increased from pTa G2 low (9.2% homozygous, 25.8% heterozygous) to pTa G2 high (32.6%, 20.9%; p&amp;lt;0.0001) but was slightly lower in pTa G3 (16.7% each). In pT2-pT4 carcinomas, 9p21 deletions were homozygous in 23.3% and heterozygous in 17.9%. Within muscle-invasive cancers, 9p21 deletions were tied to high pT (p=0.0014) and poor overall survival (p=0.0461). MTAP expression loss was strongly linked to homozygous 9p21 deletions. Complete absence of MTAP staining was seen in 96.1% of homozygous deleted cancers while only 4 of 249 MTAP negative cancers had retained at least one 9p21 copy (p&amp;lt;0.0001). Accordingly, absence of MTAP staining was also linked to advanced pT status and poor overall survival (p&amp;lt;0.05 each). Tumors with heterozygous 9p21 deletion did often show preserved but low-level expression of MTAP. 9p21 deletions were associated with low numbers of PD-L1 positive tumor cells (p&amp;lt;0.0001), CD8 (p=0.01) and CD4 positive lymphocytes (p=0.009), M2-macrophages (p&amp;lt;0.0001), and dendritic cells (p=0.0007). A similar tendency was observed for MTAP expression loss, but the level of significance was only reached for PD-L1 positive tumor cells (p&amp;lt;0.0001), M2 macrophages (p=0.001) and dendritic cells (p=0.012). Complete MTAP expression loss is common in urinary bladder cancer and strongly tied to homozygous 9p21 loss, aggressive disease, and non-inflamed microenvironment. Drugs targeting MTAP-deficiency may be highly useful in bladder cancer. MTAP IHC is an excellent surrogate for the detection of MTAP deficiency in this tumor entity. Citation Format: Natalia Gorbokon, Niklas Wößner, Viktoria Ahlburg, Simon Schallenberg, Henning Plage, Sebastian Hofbauer, Kira Furlano, Sarah Weinberger, Paul G. Bruch, Florian Roßner, Sefer Elezkurtaj, Maximilian Lennartz, Niclas C. Blessin, Andreas H. Marx, Henrik Samtleben, Margit Fisch, Michael Rink, Marcin Slojewski, Krystian Kaczmarek, Thorsten Ecke, Steffen Hallmann, Stefan Koch, Nico Adamini, Sarah Minner, Ronald Simon, Guido Sauter, Henrik Zecha, David Horst, Tobias Klatte, Thorsten Schlomm, Martina Kluth. Loss of MTAP expression is strongly linked to homozygous 9p21 deletion, unfavorable tumor phenotype and non-inflamed microenvironment in urothelial bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1048.

Abstract 4037: Optimizing the efficacy of anti-VEGF/cytotoxics/anti-PD-1 scheduling in a lung cancer mice model through B and T cells monitoring

Abstract The exact modalities of combinatorial regimens associating Immune Checkpoint Inhibitors (ICI) with other treatments are yet to be defined. Understanding how and when cytotoxics best reshape tumor immunity could help optimizing the scheduling of ICI’s. In vivo studies were performed on C57BL/6 mice grafted with LL/2lung cancer cells. A longitudinal immunomonitoring study on tumor, spleen and blood after multiple treatments including Cisplatin, Pemetrexed and anti-VEGF as single agents and in combination was performed for up to 21 days to determine the best time-window during which immune checkpoint inhibitors should be added. Finally, an efficacy study was conducted comparing the antiproliferative performance of various schedules of anti-VEGF, Pemetrexed-Cisplatin doublet, plus anti-PD-1 (i.e., immunomonitoring-guided scheduling, concurrent dosing or a random sequence). Immunomonitoring showed marked differences between treatments, organs and time-points. However, harnessing tumor immunity (i.e., promoting CD8 lymphocytes or increasing the CD8/Treg ratio) started on D7 and peaked on D14 with the anti-VEGF followed by cytotoxics combination. Therefore, a two-week delay between anti-VEGF/cytotoxic and anti-PD1 administration was considered the best sequence to test. Efficacy studies then confirmed that this sequence achieved higher anti-proliferative efficacy compared to other treatment modalities (i.e. -71% in tumor volume compared to control at the end of the study). Anti-VEGF and cytotoxic agents show time-dependent immunomodulatory effects, suggesting that sequencing is a critical feature when combining these agents with immune checkpoint inhibitors. Our efficacy study confirmed that sequencing treatments further enhances anti-proliferative effects in lung cancer models compared to concurrent dosing. Citation Format: Guillaume Sicard, Dorian Protzenko, Sarah Giacometti, Raphaelle Fanciullino, Fabrice Barlesi, Joseph Ciccolini. Optimizing the efficacy of anti-VEGF/cytotoxics/anti-PD-1 scheduling in a lung cancer mice model through B and T cells monitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4037.

The trajectories of CD4 T lymphocytes over time in patients who have defaulted on treatment for tuberculosis in a cohort of people living with HIV, Recife/PE.

The CD4 T lymphocyte count in people living with HIV (PLHIV) is a predictor for the progression of the disease (AIDS), survival and response to antiretroviral treatment (ART). A CD4 T lymphocyte count of less than 200 cells/mm3 is indicative of a greater risk for the onset of opportunistic diseases and death. Defaulting on treatment for tuberculosis (TB) may impact immune recovery in PLHIV who are taking ART. The aim of this study was to investigate an association of the CD4 lymphocyte with TB treatment Trajectory and with death. A cohort of PLHIV over eighteen years of age and who were taking ART and who had defaulted on pulmonary TB treatment. Latent Class analysis was used to identify different trajectories of CD4 T lymphocyte counts over time. Latent class 1 (High CD4 trajectory) grouped individuals together who were characterized as maintaining a low probability (0 to 29%) of a CD4 count ≤ 200 cells/mm3over time, while latent class 2 (Low CD4 trajectory) grouped individuals together with a high probability (93% to 60%), and latent class 3 (Fluctuating CD4 trajectory), grouped individuals with a fluctuating probability (66% to 0%). The chance of defaulting on treatment earlier (≤ 90 days) was four times higher in latent class 2 (Low CD4 trajectory). Although there was no statistical significance, there was a higher frequency of deaths in this same latent class. Individuals with a high probability of a CD4 count ≤ 200 cells/ mm3 should be monitored in order to avoid treatment default and thereby prevent death. New studies should be conducted with a larger sample size and a longer follow-up time in PLHIV who initiated ART treatment early so as to support clinical decisions for a better understanding of immune behavior.

Neutrophil-to-lymphocyte and Platelet-to-lymphocyte Ratio as Predictors of CD4 Count among People Living with HIV

Human Immunodeficiency Virus (HIV) infection remains a global health concern characterized by the reduction of CD4 lymphocyte cells and weakened immune systems. Knowing the CD4 count and the factors affecting it is crucial for assessing the immune status of HIV patients. Hematological markers, including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), have been recognized as prognostic tools that were associated with CD4 Count. The goal of this study was to determine the impact of NLR and PLR on CD4 count among people living with HIV (PLHIV). This study used analytic observational method with a cross-sectional on HIV-positive individuals who were treated at Moewardi Hospital, Surakarta, Indonesia. The Chi-Square and Pearson correlation tests were performed to identify the correlation between variables and the linear regression test was done to investigate the association between NLR and PLR with CD4 count. A total of 80 PLHIV were identified for this study, with the median CD4 count of 103 cells/mm3. NLR and PLR were found to be 3.06 and 181.03, respectively. This study found that opportunistic infection, duration on ARV treatment, body mass index, total lymphocyte count, and hemoglobin were significantly associated with CD4 count. The Pearson correlation test revealed a strong correlation between NLR and PLR to CD4 count. Linear regression analyses showed that NLR and PLR could predict the CD4 count. These findings indicate that NLR and PLR could serve as alternative prognostic parameters for monitoring treatment outcomes in PLHIV, particularly in health facilities where access to CD4 count testing is limited.

Immunity in the Progeroid Model of Cockayne Syndrome: Biomarkers of Pathological Aging.

Cockayne syndrome (CS) is a rare autosomal recessive disorder that affects the DNA repair process. It is a progeroid syndrome predisposing patients to accelerated aging and to increased susceptibility to respiratory infections. Here, we studied the immune status of CS patients to determine potential biomarkers associated with pathological aging. CS patients, as well as elderly and young, healthy donors, were enrolled in this study. Complete blood counts for patients and donors were assessed, immune cell subsets were analyzed using flow cytometry, and candidate cytokines were analyzed via multi-analyte ELISArray kits. In CS patients, we noticed a high percentage of lymphocytes, an increased rate of intermediate and non-classical monocytes, and a high level of pro-inflammatory cytokine IL-8. In addition, we identified an increased rate of particular subtypes of T Lymphocyte CD8+ CD28- CD27-, which are senescent T cells. Thus, an inflammatory state was found in CS patients that is similar to that observed in the elderly donors and is associated with an immunosenescence status in both groups. This could explain the CS patients' increased susceptibility to infections, which is partly due to an aging-associated inflammation process.

Low-intensity pulsed ultrasound activated the anti-tumor immunity by irradiating the spleen of mice in 4 T-1 breast cancer

Tumor immunotherapy is booming around the world. However, strategies to activate the immune system and alleviate the immunosuppression still need to be refined. Here, we demonstrate for the first time that low-intensity pulsed ultrasound (LIPUS, spatial average time average intensity (Isata) is 200 mW/cm2, frequency is 0.3 MHz, repetition frequency is 1 kHz, and duty cycle is 20%) triggers the immune system and further reverses the immunosuppressive state in the mouse models of breast cancer by irradiating the spleen of mice. LIPUS inhibited tumor growth and extended survival in mice with 4 T-1 tumors. Further studies had previously shown that LIPUS enhanced the activation of CD4+ and CD8+ T cells in the spleen and led to significant changes in cytokines, as well as induced upregulation of mRNA levels involved in multiple immune regulatory pathways in the spleen. In addition, LIPUS promoted tumor-infiltrating lymphocyte accumulation and CD8+ T cell activation and improved the dynamics of cytokines/chemokines in the tumor microenvironment, resulting in a reversal of the immunosuppressive state of the tumor microenvironment. These results suggest a novel approach to activate the immune response by irradiating the spleen with LIPUS.

DOLAMA 200: Effectiveness and Safety of a Dual Therapy with Dolutegravir Plus Lamivudine in Treatment-Experienced HIV-1 Infected Real World Participants in Spain.

The continuous pharmacological advances in antiretroviral treatment (ART) and the increasing understanding of HIV drug resistance has led to a change in the paradigm of ART optimization in the setting of the viral suppression of treatment-experienced patients with the emerging evidence of the effectiveness and safety of dual therapies. The aim of this study is to determine the antiviral efficacy and safety of switching to Dolutegravir + Lamivudine in people living with HIV, and to analyze the rate of patients with virologic failure (VF). A total of 200 patients were included with a median age of 51 years, 189 cells/µL of nadir CD4+, 13 years on ART and four previous ART regimens. Among the 168 patients who completed a follow-up at 48 weeks, a total of five VFs occurred, resulting in a 2.98% (5/168) VF rate. The results of the intention-to-treat analysis were a VF rate of 2.54% (5/197), and the rate of patients/year with viral suppression was 98.3% (298/303) in the observed data analysis. We observed a significant improvement in mean CD4 lymphocytes, the CD4/CD8 ratio and lipid profiles. The optimization of ART to DTG plus 3TC is a cost-effective switch option for treatment-experienced HIV patients, and also improves their lipid profiles.

The impact of the tumor immune microenvironment and tumor-infiltrating lymphocyte subgroups on laryngeal cancer prognosis.

The absence of improvement in survival rates across various cancers, including laryngeal cancer, has led to an increasing interest in understanding the immune response to cancer. In head and neck cancers, immune modulatory mechanisms such as immune microenvironment and immune infiltration are important in cancer pathogenesis. This study aims to explore the distribution of tumor-infiltrating lymphocyte (TIL) subgroups in the immune microenvironment and evaluate their impact on tumor histopathological characteristics and prognosis. The study included 50 patients who underwent laryngectomy for laryngeal squamous cell carcinoma, in Istanbul University - Cerrahpaşa, Faculty of Medicine Department of Otorhinolaryngology, between January 2016 and January 2018. Pathology specimens were evaluated using immunohistochemistry to assess the expressions of the CD3, CD20, CD8, CD4, CD25, and FoxP3 markers, identifying subgroups of TILs. The investigation aimed to uncover how these subgroups influence tumor histopathological features and survival outcomes. The high infiltration of CD3, CD20, and CD4 had a positive impact on disease-specific survival, disease-free survival, and recurrence-free survival. In addition, overall survival was positively affected by high CD3 and CD4 infiltrations. However, no significant relationship was observed between the expressions of CD8, FoxP3, and CD25 and any of the survival parameters. The infiltration of CD3, CD20, and CD4 positive cells indicative of a robust antitumoral immune response-emerged as favorable prognostic factors in laryngeal cancer. These findings suggest that enhancing the infiltration of CD3, CD20, and CD4 lymphocytes could be a therapeutic strategy worth exploring in clinical trials.

Construction and Validation of a Nomogram Model to Predict the Severity of Mycoplasma pneumoniae Pneumonia in Children.

This study aimed to develop a nomogram model for early prediction of the severe Mycoplasma pneumoniae pneumonia (MPP) in children. A retrospective analysis was conducted on children with MPP, classifying them into severe and general MPP groups. The risk factors for severe MPP were identified using Logistic Stepwise Regression Analysis, followed by Multivariate Regression Analysis to construct the nomogram model. The model's discrimination was evaluated using a receiver operating characteristic curve, its calibration with a calibration curve, and the results were visualized using the Hosmer-Lemeshow goodness-of-fit test. Univariate analysis revealed that age, duration of fever, length of hospital-stay, decreased sounds of breathing, respiratory rate, hypokalemia, and incidence of co-infection were significantly different between severe and general MPP. Significant differences (p < 0.05) were also observed in C-reactive protein, procalcitonin, peripheral blood lymphocyte count, neutrophil-to-lymphocyte ratio, ferritin, lactate dehydrogenase, alanine aminotransferase, interleukin-6, immunoglobulin A, and CD4+ T cells between the two groups. Logistic Stepwise Regression Analysis showed that age, decreased sounds of breathing, respiratory rate, duration of fever (OR = 1.131; 95% CI: 1.060-1.207), length of hospital-stay (OR = 1.415; 95% CI: 1.287-1.555), incidence of co-infection (OR = 1.480; 95% CI: 1.001-2.189), ferritin level (OR = 1.003; 95% CI: 1.001-1.006), and LDH level (OR = 1.003; 95% CI: 1.001-1.005) were identified as risk factors for the development of severe MPP (p < 0.05 in all). The above factors were applied in constructing a nomogram model that was subsequently tested with 0.862 of the area under the ROC curve. Age, decreased sound of breathing, respiratory rate, duration of fever, length of hospital-stay, co-infection with other pathogen(s), ferritin level, and LDH level were the significant contributors for the establishment of a nomogram model to predict the severity of MPP in children.

Analysis of Differences in Lymphocyte Subsets and CD4+ T Cells Immune Activation Between Re-detectable Positive and Non-re-detectable Positive COVID-19 Convalescent Patients

Background: When coronavirus disease 2019 (COVID-19) first broke out, much literature was reported on the re-detectable positive phenomenon of COVID-19 patients during recovery; however, there were few studies on the lymphocyte subsets, T-lymphocyte activation indicators, and levels of specific antibodies between the re-detectable positive (RP) and non-re-detectable positive (NRP) patients. Objectives: This study aimed to analyze the immunological characteristics of RP and NRP patients among convalescent patients from post-discharge COVID-19 patients and to explore immunological factors related to RP. Methods: Anticoagulated whole blood samples were collected from 11 healthy controls (HCs) and 66 COVID-19 convalescent patients. Then, the percentage of lymphocyte subsets and CD4+CD38+/HLA-DR+ T cells were tested with flow cytometry, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) anti-spike protein receptor-binding domain immunoglobulin G (S-RBD-IgG) antibody was detected by chemiluminescence. Results: B cells (%) in the RP group were significantly lower than that in the HC group (P = 0.014), and B cells (%) decreased successively in HC, NRP, and RP groups, with significant differences among the three groups (P = 0.016). CD3+ and CD8+ T cells (%) in the RP group were noticeably higher than that in the NRP group (P = 0.004 and 0.019, respectively); nevertheless, there was no difference in CD4+ T cells (%) and natural killer (NK) cells (%) among the three groups. The CD4+CD38+ and CD4+HLA-DR+ T cells (%) in the RP group were noticeably higher than that in the HC group (P = 0.013 and 0.025). The analysis of differences among the three groups showed that CD4+CD38+ and HLA-DR+ T cells (%) were also significantly different (P = 0.037 and 0.015), and CD4+HLA-DR+ T cells (%) in the three groups increased in turn. Meanwhile, there was a positive correlation between RBD-IgG titer and CD4+HLA-DR+ (%) (P = 0.003, r = 0.517), and the RBD-IgG titer of HLA-DR+ high group was higher than that of HLA-DR+ Low group (P = 0.005) in the COVID-19 convalescent patients. Conclusions: In this study, the immunological characteristics of the RP patients of COVID-19 convalescent patients were analyzed based on the lymphocyte subsets and the relationship between S-RBD-IgG and activated CD4+ T cells. The results showed that the low B cells (%) and the increased CD4+HLA-DR+ T cells (%) in the convalescent patients of COVID-19 might be related to the RP phenomenon, and the activated CD4+ T cells might play a crucial role in specific antibody responses.

Spatial and temporal heterogeneity of tumor immune microenvironment between primary tumor and brain metastases in NSCLC

BackgroundBrain metastasis is a common outcome in non-small cell lung cancer, and despite aggressive treatment, its clinical outcome is still frustrating. In recent years, immunotherapy has been developing rapidly, however, its therapeutic outcomes for primary lung cancer and brain metastases are not the same, suggesting that there may be differences in the immune microenvironment of primary lung cancer and brain metastases, however, we currently know little about these differences.MethodsSeventeen paired samples of NSCLC and their brain metastases and 45 other unpaired brain metastases samples were collected for the current study. Immunohistochemical staining was performed on all samples for the following markers: immune checkpoints CTLA-4, PD-1, PD-L1, B7-H3, B7-H4, IDO1, and EphA2; tumor-infiltrating lymphocytes (TILs) CD3, CD4, CD8, and CD20; tumor-associated microglia/macrophages (TAMs) CD68 and CD163; and tumor proliferation index Ki-67. The differences in expression of these markers were compared in 17 paired samples, and the effect of the expression level of these markers on the prognosis of patients was analyzed in lung adenocarcinoma brain metastases samples. Subsequently, multiplex immunofluorescence staining was performed in a typical lung-brain paired sample based on the aforementioned results. The multiplex immunofluorescence staining results revealed the difference in tumor immune microenvironment between primary NSCLC and brain metastases.ResultsIn 17 paired lesions, the infiltration of CTLA-4+ (P = 0.461), PD-1+ (P = 0.106), CD3+ (P = 0.045), CD4+ (P = 0.037), CD8+ (P = 0.008), and CD20+ (P = 0.029) TILs in brain metastases were significantly decreased compared with primary tumors. No statistically significant difference was observed in the CD68 (P = 0.954) and CD163 (P = 0.654) TAM infiltration between primary NSCLC and paired brain metastases. In all the brain metastases lesions, the expression of PD-L1 is related to the time interval of brain metastases in NSCLC. In addition, the Cox proportional hazards regression models showed high expression of B7-H4 (hazard ratio [HR] = 3.276, 95% confidence interval [CI] 1.335–8.041, P = 0.010) and CD68 TAM infiltration (HR = 3.775, 95% CI 1.419–10.044, P = 0.008) were independent prognosis factors for lung adenocarcinoma brain metastases patients.ConclusionsBoth temporal and spatial heterogeneity is present between the primary tumor and brain metastases of NCSLC. Brain metastases lesions exhibit a more immunosuppressive tumor immune microenvironment. B7-H4 and CD68+ TAMs may have potential therapeutic value for lung adenocarcinoma brain metastases patients.

The causes of TB development in a child with HIV infection

The article represents a clinical observation of the development of disseminated TB in a 12-year-old child with HIV infection, a high CD4 lymphocyte count (1315 cells/μl), and undetectable viral load (&lt;20 copies per ml of blood). Perinatal transmission occurred, HIV infection was diagnosed immediately after birth, ART was administered from the first days of life. The girl has lived in a foster family since the age of 12 months. Poor adherence to treatment resulted in raised viral load. At the same time, the girl got ill with severe measles. ART was corrected with a rapid positive immunological and virological effect. One year later, TB manifested under the guise of acute bronchopulmonary disease. The examination revealed traces of infancy intrathoracic lymph node TB in the form of small calcinates. The patient had not been previously examined for TB infection and never received preventive TB treatment. The development of acute progressive TB in the child with HIV infection and satisfactory immunological and virological indicators was caused by: lack of due interdisciplinary (pediatricians, infectiologists, phthisiologists) and interdepartmental (medical services, children’s services) interactions; poor adherence to treatment; past measles.

Analisis Hasil Pemeriksaan Viral Load Dan CD4 Pada Penderita HIV Di RSUD Pandan Arang Boyolali Periode Tahun 2022

Acquired Immunodeficiency Syndrome disease cause HIV. This disease damages the body's immune system known as CD4. CD4 lymphocyte count is associated with disease progression, increased opportunism, and mortality. Laboratory examination required to determine the CD4 count using this method flowcytometry, and test viralload PCR method. The of research is analyze results of viralload and CD4 in HIV sufferers at RSUD Boyolali . Quantitative research method with analytical descriptive design. Data univariate and bivariate with the chi-square test to see the magnitude of relationship between the independent variables and HIV infection. total of 94 patients in 2022 showed several normal and abnormal results, where values ​​were normal viralload &lt;10,000copy/ml low, &gt;100,000copy/ml high, and &lt;40copy/ml not detected. Normal CD4 results 410 – 1,600 cells/ml and low &lt;500 cells/ml. CD4 research results and viralload normal 43 (46%) patients, CD4 results and viralload abnormal in about 9 (9%), and 1% of patients with normal CD4 countsviral load abnormal patient has not received treatment. CD4 examination uses the method flowcytometry whereas viral load using the PCR method and blood plasma samples. There is relationship viralload method PCR dan CD4 method flowcytrometry with significance value of 0.013. Further research needs to be carried out using experimental methods.