Molecular and immunological origins of catatonia.

Catatonia occurs secondary to both primary psychiatric and neuromedical etiologies. Emerging evidence suggests possible linkages between causes of catatonia and neuroinflammation. These include obvious infectious and inflammatory etiologies, common neuromedical illnesses such as delirium, and psychiatric entities such as depression and autism-spectrum disorders. Symptoms of sickness behavior, thought to be a downstream effect of the cytokine response, are common in many of these etiologies and overlap significantly with symptoms of catatonia. Furthermore, there are syndromes that overlap with catatonia that some would consider variants, including neuroleptic malignant syndrome (NMS) and akinetic mutism, which may also have neuroinflammatory underpinnings. Low serum iron, a common finding in NMS and malignant catatonia, may be caused by the acute phase response. Cellular hits involving either pathogen-associated molecular patterns (PAMP) danger signals or the damage-associated molecular patterns (DAMP) danger signals of severe psychosocial stress may set the stage for a common pathway immunoactivation state that could lower the threshold for a catatonic state in susceptible individuals. Immunoactivation leading to dysfunction in the anterior cingulate cortex (ACC)/mid-cingulate cortex (MCC)/medial prefrontal cortex (mPFC)/paralimbic cortico-striato-thalamo-cortical (CSTC) circuit, involved in motivation and movement, may be particularly important in generating the motor and behavioral symptoms of catatonia.

Dual-Antigen-Displaying Nanovaccines Elicit Synergistic Immunoactivation for Treating Cancer and Preventing Infectious Complications.

As one of the most common complications, infection causes the majority of mortality in cancer patients. However, therapeutic strategies that can simultaneously suppress tumors and protect patients from infection have been rarely reported. Here, the use of dual-antigen-displaying nanovaccines (DADNs) is described to elicit synergistic immunoactivation for treating cancer and preventing infectious complications. DADNs are prepared by wrapping immunoadjuvant-loaded nanoparticles with a hybrid coating, which is fused from cell membranes that are separately genetically engineered to express tumor and infectious pathogenic antigens. Due to the presence of a dual-antigen combination, DADNs are able to promote the maturation of dendritic cells and more importantly to trigger cross-presentation of both combined antigens. During in vivo investigations, we find that DADNs can reverse immunosuppression by stimulating tumor-associated antigen-specific T-cell responses, resulting in significantly delayed tumor growth in mice. These nanovaccines also elicit effective protective immunity against tumor challenges and induce robust production of pathogenic antigen-specific immunoglobulin G antibody in a prophylactic study. This work offers a unique approach to develop dual-mode vaccines, which are promising for synchronously treating cancer and preventing infection.

The antagonist of ß-adrenergic receptor propranolol inhibits T cell lymphoma growth and enhances antitumor efficacy of cisplatin in vivo: A role of modulated apoptosis, glucose metabolism, pH regulation, and antitumor immune response.

Accumulating evidence has shown a vital role of stress-regulatory hormones, including epinephrine, in the progression of numerous cancers, including T cell lymphoma. Further, the antitumor and chemosensitizing potential of propranolol, an inexpensive ß-adrenergic receptor antagonist has also been reported against breast, colon, ovarian, and pancreatic cancers. However, in vivo antitumor and chemopotentiating activity of propranolol have not yet been examined against malignancies of hematological origin, including T cell lymphoma. Therefore, the present study is designed to evaluate the antitumor and chemopotentiating action of propranolol in a T cell lymphoma murine model. In this study, T cell lymphoma-bearing mice were treated with vehicle alone (PBS) or containing propranolol followed by administration of with or without cisplatin. The progression of the tumor was assessed along with analysis of tumor cell apoptosis, glucose metabolism, pH regulation, and antitumor immune response. The apoptosis was estimated by cellular and nuclear morphology analysis through Wright-Giemsa, annexin-V, and DAPI staining. ELISA was used to detect the epinephrine level in serum. The glucose, lactate, and NO levels were measured in the tumor ascitic fluid by calorimetric methods. RT-PCR and Western blot were used to assess the levels of various crucial regulators at gene and protein levels, respectively. Our results showed that propranolol exerts antitumor as well as chemopotentiating ability in DL-bearing mice by altering apoptosis, glycolysis, acidification of TME, and immunosuppression.

Reactive oxygen species in biological media are they friend or foe? Major In vivo and In vitro sensing challenges.

The role of Reactive Oxygen Species (ROS) on biological media has been shifting over the years, as the knowledge on the complex mechanism that lies in underneath their production and overall results has been growing. It has been known for some time that these species are associated with a number of health conditions. However, they also participate in the immunoactivation cascade process, and can have an active role in theranostics. Macrophages, for example, react to the presence of pathogens through ROS production, potentially allowing the development of new therapeutic strategies. However, their short lifetime and limited spatial distribution of ROS have been limiting factors to the development and understanding of this phenomenon. Even though, ROS have shown successful theranostic applications, e.g., photodynamic therapy, their wide applicability has been hampered by the lack of effective tools for monitoring these processes in real time. Thus the development of innovative sensing strategies for in vivo monitoring of the balance between ROS concentration and the resultant immune response is of the utmost relevance. Such knowledge could lead to major breakthroughs towards the development of more effective treatments for neurodegenerative diseases. Within this review we will present the current understanding on the interaction mechanisms of ROS with biological systems and their overall effect. Additionally, the most promising sensing tools developed so far, for both in vivo and in vitro tracking will be presented along with their main limitations and advantages. This review focuses on the four main ROS that have been studied these are: singlet oxygen species, hydrogen peroxide, hydroxyl radical and superoxide anion.

Targeting intracellular and extracellular receptors with nano-to-macroscale biomaterials to activate immune cells.

Activation of immune cells is an essential process in innate and adaptive immunity. A high number of immune cell activation pathways have been discovered, which are stimulated via various intra- and extracellular receptors. Small-molecule and macromolecular agonists have been identified to target immune receptors in preclinical research and clinical practice. However, current immunostimulants are often associated with undesired side effects and/or low potency in vivo. These two issues have been addressed with multiscale biomaterials. In this review, we summarize and discuss the most explored intra/extracellular immune receptors which have been targeted with immunoactivating biomaterials. To target intracellular immune receptors, nano/microscale materials have been employed to deliver agonists into the endo/lysosomes or the cytoplasm. To target surface immune receptors, nano-to-macroscale biomaterials have been engineered to engage with them to activate immune cells. In this context, biomaterials are not only the drug carriers, but also function as part of the immunostimulants. The biomaterials-based modalities have shown clearly enhanced immunoactivation potency and decreased side effects compared to native immunostimulants. It is envisaged that nano-to-macroscale biomaterials will greatly contribute to the development of more effective strategies for immunoactivation, which have the potential to reshape future vaccination and immunotherapy.

Magnetic-Acoustic Sequentially Actuated CAR T Cell Microrobots for Precision Navigation and In Situ Antitumor Immunoactivation.

Despite its clinical success, chimeric antigen receptor T (CAR T)-cell immunotherapy remains limited in solid tumors, owing to the harsh physical barriers and immunosuppressive microenvironment. Here a CAR-T-cell-based live microrobot (M-CAR T) is created by decorating CAR T with immunomagnetic beads using click conjugation. M-CAR Ts are capable of magnetic-acoustic actuation for precision targeting and in situ activation of antitumor immune responses. Sequential actuation endows M-CAR Ts with magnetically actuated anti-flow and obstacle avoidance as well as tissue penetration driven by acoustic propulsion, enabling efficient migration and accumulation in artificial tumor models. In vivo, sequentially actuated M-CAR Ts achieves long-distance targeting and accumulate at the peritumoural area under programmable magnetic guidance, and subsequently acoustic tweezers actuate M-CAR Ts to migrate into deep tumor tissues, resulting in a 6.6-fold increase in accumulated exogenous CD8+ CAR T cells compared with that without actuation. Anti-CD3/CD28 immunomagnetic beads stimulate infiltrated CAR T proliferation and activation in situ, significantly enhancing their antitumor efficacy. Thus, this sequential-actuation-guided cell microrobot combines the merits of autonomous targeting and penetration of intelligent robots with in situ T-cell immunoactivation, and holds considerable promise for precision navigation and cancer immunotherapies.

Chiral polypeptide nanoparticles as nanoadjuvants of nanovaccines for efficient cancer prevention and therapy.

The chirality of bioactive molecules is closely related to their functions. D-amino acids commonly distributed in the bacterial cell walls trigger a robust anti-infective immune response. Inspired by that, two kinds of chiral polypeptides, poly(L-phenylalanine)-block-poly(L-lysine) (PL-K) and poly(L-phenylalanine)-block-poly(D-lysine) (PD-K), were synthesized and used as nanoadjuvants of nanovaccines for cancer prevention and therapy. The amphiphilic polypeptides self-assembled into nanoparticles with a diameter of about 30 nm during ultrasonic-assisted dissolution in phosphate-buffered saline. The nanovaccines PL-K-OVA and PD-K-OVA were easily prepared by mixing solutions of PL-K or PD-K and the model antigen chicken ovalbumin (OVA), respectively, with loading efficiencies of almost 100%. Compared to PL-K-OVA, PD-K-OVA more robustly induced dendritic cell maturation, antigen cross-presentation, and adaptive immune response. More importantly, it effectively prevented and treated the OVA-expressed B16-OVA melanoma model. PD-K-OVA achieved a tumor inhibition rate of 94.9% and even 97.0% by combining with anti-PD-1 antibody. Therefore, the chiral polypeptide nanoparticles represent simple, efficient, and extensively applicable nanoadjuvants for various nanovaccines.

Direct immunoactivation by chemotherapeutic drugs in cancer treatment.

The immune system plays a crucial role in recognizing and eliminating pathogenic substances and malignant cells in the body. For cancer treatment, immunotherapy is becoming the standard treatment for many types of cancer and is often combined with chemotherapy. Although chemotherapeutic agents are often reported to have adverse effects, including immunosuppression, they can also play a positive role in immunotherapy by directly stimulating the immune system. This has been demonstrated in preclinical and clinical studies in the past decades. Chemotherapeutics can activate immune cells through different immune receptors and signaling pathways depending on their chemical structure and formulation. In this review, we summarize and discuss the direct immunoactivation effects of chemotherapeutics and possible mechanisms behind these effects. Finally, we prospect chemo-immunotherapeutic combinations for the more effective and safer treatment of cancer.

Nutritional Supplementation to Increase Influenza Vaccine Response in Children Living With HIV: A Pilot Clinical Trial.

Aims: Vaccine response is poor among children living with HIV. The gut microbiota has been identified as a potential target to improve vaccine immunogenicity, but data are scarce in the context of HIV infection. Methods: Pilot, double-blind, randomized placebo-controlled trial in which 24 HIV-infected children were randomized to receive a mixture of symbiotics, omega-3/6 fatty acids, and amino acids or placebo for 4 weeks, each in combination with ART, and were then immunized against influenza. Vaccine response and safety of the nutritional supplementation were the primary outcomes. Results: Eighteen HIV-infected children completed the follow-up period (mean age 11.5 ± 4.14 years, 61% female). The nutritional supplement was safe but did not enhance the response to the influenza vaccine. A 4-fold rise in antibody titers was obtained in only 37.5% of participants in the intervention arm vs. 40% in the placebo. No immunological or inflammatory predictors of vaccine response were identified. Conclusions: In this exploratory study, a 4-week course of symbiotics did not increase influenza vaccine immunogenicity in HIV-infected children. Larger studies are warranted to address the potential of modulating the microbiome in children living with HIV.

An Abnormal Inflammatory Pattern Associated with Long-Term Non-Progression of HIV Infection Impacts Negatively on Bone Quality.

Introduction. Long-term non-progressors (LTNPs) are HIV-infected individuals (HIV+) whose viral replication is controlled. However, these individuals experience complications associated with HIV, among them, bone remodeling impairment. This study aims to perform a comprehensive bone health assessment and its association with the inflammatory status of HIV+ LTNPs. A cross-sectional study was conducted comparing bone strength components (bone mineral density and bone tissue quality) between age-, sex-, and comorbidities-matched groups of HIV+ LTNPs, HIV+ progressors, and HIV-negative individuals. A panel of bone turnover and inflammatory biomarkers was measured in fasting plasma using ELISA. Bone tissue quality was assessed by bone microindentation, a technique that directly measures the bone resistance to fracture and yields a dimensionless quantifiable parameter called bone material strength (BMSi). Thirty patients were included: ten LTNPs, ten HIV+ progressors, and ten HIV-negative individuals. LTNPs showed an abnormal pattern of immune activation that was represented by significantly lower levels of anti-inflammatory cytokine IL-10 (p = 0.03), pro-inflammatory cytokine IL-8 (p = 0.01), and TNF-α (p < 0.001) with respect to the other groups. Regarding bone health, LTNPs presented lower BMSi, and thus, worse bone tissue quality than HIV-negative individuals (83 (78−85) vs. 90 (89−93), respectively; p = 0.003), and also lower BMSi than HIV+ progressors (83 (78−85) vs. 86 (85−89), respectively; p = 0.022). A trend was found of lower BMSi in HIV+ progressors with respect to the HIV-negative individuals (86 (85−89) vs. 90 (89−93), respectively; p = 0.083). No differences were detected in bone mineral density between groups. In conclusion, LTNPs showed a different inflammatory profile, along with worse bone tissue quality, when compared to HIV+ progressors and HIV-negative individuals. This may contribute to increasing evidence that HIV infection itself has a deleterious effect on bone tissue, likely through a persistent altered inflammation status.

Targeting the Gut Microbiota of Vertically HIV-Infected Children to Decrease Inflammation and Immunoactivation: A Pilot Clinical Trial.

Aims: Children with HIV exhibit chronic inflammation and immune dysfunction despite antiretroviral therapy (ART). Strategies targeting persistent inflammation are needed to improve health in people living with HIV. The gut microbiota likely interacts with the immune system, but the clinical implications of modulating the dysbiosis by nutritional supplementation are unclear. Methods: Pilot, double-blind, randomized placebo-controlled trial in which 24 HIV-infected on ART were randomized to supplementation with a daily mixture of symbiotics, omega-3/6 fatty acids and amino acids, or placebo four weeks, in combination with ART. We analyzed inflammatory markers and T-cell activation changes and their correlations with shifts in fecal microbiota. Results: Twenty-four HIV-infected children were recruited and randomized to receive a symbiotic nutritional supplement or placebo. Mean age was 12 ± 3.9 years, 62.5% were female. All were on ART and had HIV RNA < 50/mL. We did not detect changes in inflammatory (IL-6, IL-7, IP-10), microbial translocation (sCD14), mucosal integrity markers (IFABP, zonulin) or the kynurenine to tryptophan ratio, or changes in markers of the adaptive immune response in relation to the intervention. However, we found correlations between several key bacteria and the assessed inflammatory and immunological parameters, supporting a role of the microbiota in immune modulation in children with HIV. Conclusions: In this exploratory study, a four-week nutritional supplementation had no significant effects in terms of decreasing inflammation, microbial translocation, or T-cell activation in HIV-infected children. However, the correlations found support the interaction between gut microbiota and the immune system.

Moderate to Intense Physical Activity Is Associated With Improved Clinical, CD4/CD8 Ratio, and Immune Activation Status in HIV-Infected Patients on ART.

BACKGROUND: Physical activity has anti-inflammatory effects and reduces morbidity and mortality in the general population, but its role in the clinical, CD4/CD8 ratio, and immune activation status of HIV-infected patients has been poorly studied. METHODS: A cross-sectional study was carried out in a cohort of 155 HIV-infected patients on stable antiretroviral therapy (ART) to compare clinical, biochemical, CD4/CD8 ratio, and immune activation status according to their physical activity in the last 2 years (sedentary/low vs moderate/intense) assessed by the iPAQ. A binary logistic regression and mixed analysis of variance were performed to evaluate the impact of levels of physical activity on CD4/CD8 ratio. RESULTS: In our series, 77 (49.7%) out of 155 patients were sedentary, and 78 (50.3%) practiced moderate/intense physical activity. Moderate/intense physical activity was associated with better metabolic control (lower body mass index, P = .024; glucose, P = .024; and triglyceride, P = .002) and CDC HIV stage (P = .046), lower CD8+ (P =  .018), CD4+CD8+ (P = .026), CD4+CD86+ (P = .045), CD4+HLA-DR+ (P = .011), CD8+HLA-DR+ (P = .048) T lymphocytes and CD16+HLA-DR+ natural killer cells (P = .026), and higher CD3+CD4+ T lymphocytes (P = .016) and CD4/CD8 ratio (P = .001). Sedentary lifestyle (odds ratio [OR], 2.12; P = .042), CD4 nadir (OR, 1.005; P < .001), and CD8+CD38+ T cells (OR, 1.27; P = .006) were independently associated with low CD4/CD8 ratio (<0.8). Earlier and more intense CD4/CD8 ratio recovery was observed in patients with higher physical activity in the 2-year follow-up with a significant interaction between these variables: F(2, 124) = 3.31; P = .049; partial η2 = 0.042. CONCLUSIONS: Moderate to high physical activity is associated with beneficial health effects, improvement in metabolic profile, and reduction of chronic inflammation in patients with HIV. Although more studies and clinical trials are needed to confirm these findings, a healthy lifestyle including at least moderate physical activity should be recommended to HIV patients on stable ART.

Epigenetic Age Acceleration of Stomach Adenocarcinoma Associated With Tumor Stemness Features, Immunoactivation, and Favorable Prognosis.

Background: Abnormal DNA methylation (DNAm) age has been assumed to be an indicator for canceration and all-cause mortality. However, associations between DNAm age and molecular features of stomach adenocarcinoma (STAD), and its prognosis have not been systematically studied. Method: We calculated the DNAm age of 591 STAD samples and 115 normal stomach samples from The Cancer Genome Atlas (TCGA) and gene expression omnibus (GEO) database using the Horvath's clock model. Meanwhile, we utilized survival analysis to evaluate the prognostic value of DNAm age and epigenetic age acceleration shift. In addition, we performed weighted gene co-expression network analysis (WGCNA) to identify DNAm age-associated gene modules and pathways. Finally, the association between DNAm age and molecular features was performed by correlation analysis. Results: DNA methylation age was significantly correlated with chronological age in normal gastric tissues (r = 0.85, p < 0.0001), but it was not associated with chronological age in STAD samples (r = 0.060, p = 0.2369). Compared with tumor adjacent normal tissue, the DNAm age of STAD tissues was significantly decreased. Meanwhile, chronological age in STAD samples was higher than its DNAm age. Both DNAm age and epigenetic acceleration shift were associated with the prognosis of STAD patients. By using correlation analysis, we also found that DNAm age was associated with immunoactivation and stemness in STAD samples. Conclusion: In summary, epigenetic age acceleration of STAD was associated with tumor stemness, immunoactivation, and favorable prognosis.

Blood Bacterial Profiles Associated With Human Immunodeficiency Virus Infection and Immune Recovery.

Human immunodeficiency virus (HIV) infection impairs mucosal immunity and leads to bacterial translocation, fueling chronic inflammation and disease progression. While this is well established, questions remain about the compositional profile of the translocated bacteria, and to what extent it is influenced by antiretroviral therapy (ART). Using 16S ribosomal DNA targeted sequencing and shotgun proteomics, we showed that HIV increases bacterial translocation from the gut to the blood. HIV increased alpha diversity in the blood, which was dominated by aerobic bacteria belonging to Micrococcaceae (Actinobacteria) and Pseudomonadaceae (Proteobacteria) families, and the number of circulating bacterial proteins was also increased. Forty-eight weeks of ART attenuated this phenomenon. We found that enrichment with Lactobacillales order, and depletion of Actinobacteria class and Moraxellaceae and Corynebacteriacae families, were significantly associated with greater immune recovery and correlated with several inflammatory markers. Our findings suggest that the molecular cross talk between the host and the translocated bacterial products could influence ART-mediated immune recovery.

Regulation of the tumor immune microenvironment and vascular normalization in TNBC murine models by a novel peptide.

Triple-negative breast cancer (TNBC) is a highly metastatic and aggressive disease with limited treatment options. Recently, the combination of the immune checkpoint inhibitor (ICI) atezolizumab (anti-PD-L1) with nab-paclitaxel was approved following a clinical trial that showed response rates in at least 43% of patients. While this approval marks a major advance in the treatment of TNBC it may be possible to improve the efficacy of ICI therapies through further modulation of the suppressive tumor immune microenvironment (TIME). Several factors may limit immune response in TNBC including aberrant growth factor signaling, such as VEGFR2 and cMet signaling, inefficient vascularization, poor delivery of drugs and immune cells, and the skewing of immune cell populations toward immunosuppressive phenotypes. Here we investigate the immune-modulating properties of AXT201, a novel 20 amino-acid integrin-binding peptide in two syngeneic mouse TNBC models: 4T1-BALB/c and NT4-FVB. AXT201 treatment improved survival in the NT4 model by 20% and inhibited the growth of 4T1 tumors by 47% over 22 days post-inoculation. Subsequent immunohistochemical analyses of 4T1 tumors also showed a 53% reduction in vascular density and a 184% increase in pericyte coverage following peptide treatment. Flow cytometry analyses demonstrated evidence of a more favorable anti-tumor immune microenvironment following treatment with AXT201, including significant decreases in the populations of T regulatory cells, monocytic myeloid-derived suppressor cells, and PD-L1 expressing cells and increased expression of T cell functional markers. Together, these findings demonstrate immune-activating properties of AXT201 that could be developed in combination with other immunomodulatory agents in the treatment of TNBC.

Epigenetic age acceleration of early stage hepatocellular carcinoma tightly associated with hepatitis B virus load, immunoactivation, and improved survival.

Properly stratifying high-risk individuals with early stage hepatocellular carcinoma (HCC) is essential to identify patients in which the potentially therapies can be offered. To this context, we systematically investigated the prognostic value of epigenetic clock with early stage HCC as well as the association with other molecular characteristics.We computed DNA methylation (DNAm) age of 256 early stage HCC patients and 50 normal samples from TCGA by Horvath clock model. The characteristics of two DNAm age subgroups were differentiated regarding HBV expression, pathway activity, epigenomic, and genomic alteration. Cox regression and restricted cubic spline (RCS) analysis were utilized to evaluate the prognostic value of epigenetic acceleration.DNAm age was significantly associated with chronological age in normal tissue but largely disrupted in tumors (P< .001), and showed significant negative correlation with HBV expression (P< .05). We identified two DNAm age groups (DNAmAge-ACC and DNAmAge-DEC), and the former presented with an immunoactive phenotype (all FDRs<0.05 in enrichment analysis), CpG island hypermethylation (P< .001), and lower mutation burden (P= .018). Every 10-year increase in DNAm age was associated with a 18% decrease in fatality after adjustment for major clinical variables; DNAmAge-ACC had 50% lower mortality risk than DNAmAge-DEC (HR: 0.50, 95% CI: 0.27-0.94, P= .03). RCS revealed the fatality risk significantly decreased as epigenetic age accelerated (P = .04). Conclusions.In summary, we highlighted the prognostic value of epigenetic age acceleration for early stage HCC; better prognosis, relatively lower HBV load, and higher enrichment of immune signatures were tightly associated with epigenetic age accelerated tumors.

Epigenetic age acceleration of cervical squamous cell carcinoma converged to human papillomavirus 16/18 expression, immunoactivation, and favourable prognosis.

BACKGROUND: Ageing-associated molecular changes have been assumed to trigger malignant transformations and the epigenetic clock, and the DNA methylation age has been shown to be highly correlated with chronological age. However, the associations between the epigenetic clock and cervical squamous cell carcinoma (CSCC) prognosis, other molecular characteristics, and clinicopathological features have not been systematically investigated. To this end, we computed the DNA methylation (DNAm) age of 252 CSCC patients and 200 normal samples from TCGA and three external cohorts by using the Horvath clock model. We characterized the differences in human papillomavirus (HPV) 16/18 expression, pathway activity, genomic alteration, and chemosensitivity between two DNAm age subgroups. We then used Cox proportional hazards regression and restricted cubic spline (RCS) analysis to assess the prognostic value of epigenetic acceleration. RESULTS: DNAm age was significantly associated with chronological age, but it was differentiated between tumour and normal tissue (P < 0.001). Two DNAm age groups, i.e. DNAmAge-ACC and DNAmAge-DEC, were identified; the former had high expression of the E6/E7 oncoproteins of HPV16/18 (P < 0.05), an immunoactive phenotype (all FDRs < 0.05 in enrichment analysis), CpG island hypermethylation (P < 0.001), and lower mutation load (P = 0.011), including for TP53 (P = 0.002). When adjusted for chronological age and tumour stage, every 10-year increase in DNAm age was associated with a 12% decrease in fatality (HR 0.88, 95% CI 0.78-0.99, P = 0.03); DNAmAge-ACC had a 41% lower mortality risk and 47% lower progression rate than DNAmAge-DEC and was more likely to benefit from chemotherapy. RCS revealed a positive non-linear association between DNAm age and both mortality and progression risk (both, P < 0.05). CONCLUSIONS: DNAm age is an independent predictor of CSCC prognosis. Better prognosis, overexpression of HPV E6/E7 oncoproteins, and higher enrichment of immune signatures were observed in DNAmAge-ACC tumours.

Cognitive impairment and CSF proteome modification after oral bacteriotherapy in HIV patients.

OBJECTIVE: To investigate whether a probiotic supplementation to cART patients modifies the cerebrospinal fluid (CSF) proteome and improves neurocognitive impairment. METHODS: 26 CSF samples from 13 HIV-positive patients [six patients living with HIV (PLHIV) and seven patients with a history of AIDS (PHAIDS)] were analyzed. All patients underwent to neurocognitive evaluation and blood sampling at baseline and after 6 months of oral bacteriotherapy. Immune phenotyping and activation markers (CD38 and HLA-DR) were evaluated on peripheral blood mononuclear cells (PBMC). Plasma levels of IL-6, sCD14, and MIP-1ß were detected, by enzyme-linked immunosorbent assay (ELISA). Functional proteomic analysis of CSF sample was conducted by two-dimensional electrophoresis; a multivariate analysis was performed by principal component analysis (PCA) and data were enriched by STRING software. RESULTS: Oral bacteriotherapy leads to an improvement on several cognitive test and neurocognitive performance in both groups of HIV-positive subjects. A reduction in the percentage of CD4+CD38+HLA-DR+ T cells was also observed at peripheral level after the probiotic intake (p = 0.008). In addition, the probiotic supplementation to cART significantly modifies protein species composition and abundance at the CSF level, especially those related to inflammation (ß2-microglobulin p = 0.03; haptoglobin p = 0.06; albumin p = 0.003; hemoglobin p = 0.003; immunoglobulin heavy chains constant region p = 0.02, transthyretin p = 0.02) in PLHIV and PHAIDS. CONCLUSIONS: Our results suggest that oral bacteriotherapy as a supplement to cART could exert a role in the amelioration of inflammation state at peripheral and CNS level.

Retinol-binding protein 4 (RBP4), a potential biomarker of frailty in HIV-infected people on stable antiretroviral therapy.

OBJECTIVES: A quantitative biomarker for identification of pre-frail and frail persons is still lacking. This study aimed to identify biomarker predictors of frailty in HIV-infected patients. METHODS: A cross-sectional study of HIV-infected patients who had been on antiretroviral therapy (ART) for at least 1 year and who presented an undetectable viral load (< 50 HIV-1 RNA copies/mL) at baseline was carried out. For each frail patient, up to four pre-frail and robust patients were randomly selected. The frailty status assessment was based on the five-item criteria described by Fried et al. Sociodemographic, anthropometric, biochemical and HIV-related characteristics were evaluated. Multiple potential biomarkers of frailty and a biological age biomarker were analysed. RESULTS: A total of 73 HIV-infected patients on ART for at least 1 year were evaluated. The patients were categorized as robust (n = 33), pre-frail (n = 32) and frail (n = 8) using the Fried criteria. All patients were on ART, with 100% undetectable viral load (< 50 copies/mL) at baseline. No significant differences in demographic, clinical or analytical characteristics were observed among patients in the different categories based on Fried criteria, with the exception of the veterans aging cohort study index (VACS). Similarly, no differences were observed in HIV-related characteristics, although nucleoside reverse transcriptase inhibitor (NRTI) use was less common in frail persons. The distribution of biomarker values varied according to frailty status, with frail persons having higher levels of interleukin (IL)-8, IL-18, CXC chemokine ligand 10 (CXCL10) and retinol-binding protein 4 (RBP4). In multivariable analysis, the assocation of frailty with RBP4 showed a tendency to statistical significance (odds ratio 1.0; 95% confidence interval 0.99-1.00; P < 0.05). CONCLUSIONS: Differential biomarker expression was present according to Fried status. Longitudinal studies will clarify the utility of these biomarkers as targets for diagnostic or therapeutic intervention.

Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes.

Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short-term survival (STS) and long-term survival (LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas-Streptomyces-Saccharopolyspora-Bacillus clausii) highly predictive of long-term survivorship in both discovery and validation cohorts. Through human-into-mice fecal microbiota transplantation (FMT) experiments from STS, LTS, or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease.