Interplay between the Glymphatic System and the Endocannabinoid System: Implications for Brain Health and Disease.

The intricate mechanisms governing brain health and function have long been subjects of extensive investigation. Recent research has shed light on two pivotal systems, the glymphatic system and the endocannabinoid system, and their profound role within the central nervous system. The glymphatic system is a recently discovered waste clearance system within the brain that facilitates the efficient removal of toxic waste products and metabolites from the central nervous system. It relies on the unique properties of the brain's extracellular space and is primarily driven by cerebrospinal fluid and glial cells. Conversely, the endocannabinoid system, a multifaceted signaling network, is intricately involved in diverse physiological processes and has been associated with modulating synaptic plasticity, nociception, affective states, appetite regulation, and immune responses. This scientific review delves into the intricate interconnections between these two systems, exploring their combined influence on brain health and disease. By elucidating the synergistic effects of glymphatic function and endocannabinoid signaling, this review aims to deepen our understanding of their implications for neurological disorders, immune responses, and cognitive well-being.

Nanoceria as Safe Contrast Agents for X-ray CT Imaging.

Cerium oxide nanoparticles (CeO2NPs) have exceptional catalytic properties, rendering them highly effective in removing excessive reactive oxygen species (ROS) from biological environments, which is crucial in safeguarding these environments against radiation-induced damage. Additionally, the Ce atom's high Z number makes it an ideal candidate for utilisation as an X-ray imaging contrast agent. We herein show how the injection of albumin-stabilised 5 nm CeO2NPs into mice revealed substantial enhancement in X-ray contrast, reaching up to a tenfold increase at significantly lower concentrations than commercial or other proposed contrast agents. Remarkably, these NPs exhibited prolonged residence time within the target organs. Thus, upon injection into the tail vein, they exhibited efficient uptake by the liver and spleen, with 85% of the injected dose (%ID) recovered after 7 days. In the case of intratumoral administration, 99% ID of CeO2NPs remained within the tumour throughout the 7-day observation period, allowing for observation of disease dynamics. Mass spectrometry (ICP-MS) elemental analysis confirmed X-ray CT imaging observations.

Epigenetic targets in B- and T-cell lymphomas: latest developments.

Non-Hodgkin's lymphomas (NHLs) comprise a diverse group of diseases, either of mature B-cell or of T-cell derivation, characterized by heterogeneous molecular features and clinical manifestations. While most of the patients are responsive to standard chemotherapy, immunotherapy, radiation and/or stem cell transplantation, relapsed and/or refractory cases still have a dismal outcome. Deep sequencing analysis have pointed out that epigenetic dysregulations, including mutations in epigenetic enzymes, such as chromatin modifiers and DNA methyltransferases (DNMTs), are prevalent in both B- cell and T-cell lymphomas. Accordingly, over the past decade, a large number of epigenetic-modifying agents have been developed and introduced into the clinical management of these entities, and a few specific inhibitors have already been approved for clinical use. Here we summarize the main epigenetic alterations described in B- and T-NHL, that further supported the clinical development of a selected set of epidrugs in determined diseases, including inhibitors of DNMTs, histone deacetylases (HDACs), and extra-terminal domain proteins (bromodomain and extra-terminal motif; BETs). Finally, we highlight the most promising future directions of research in this area, explaining how bioinformatics approaches can help to identify new epigenetic targets in B- and T-cell lymphoid neoplasms.

Exploring the Long-Term Tissue Accumulation and Excretion of 3 nm Cerium Oxide Nanoparticles after Single Dose Administration.

Nanoparticle (NP) pharmacokinetics significantly differ from traditional small molecule principles. From this emerges the need to create new tools and concepts to harness their full potential and avoid unnecessary risks. Nanoparticle pharmacokinetics strongly depend on size, shape, surface functionalisation, and aggregation state, influencing their biodistribution, accumulation, transformations, and excretion profile, and hence their efficacy and safety. Today, while NP biodistribution and nanoceria biodistribution have been studied often at short times, their long-term accumulation and excretion have rarely been studied. In this work, 3 nm nanoceria at 5.7 mg/kg of body weight was intravenously administrated in a single dose to healthy mice. Biodistribution was measured in the liver, spleen, kidney, lung, brain, lymph nodes, ovary, bone marrow, urine, and faeces at different time points (1, 9, 30, and 100 days). Biodistribution and urinary and faecal excretion were also studied in rats placed in metabolic cages at shorter times. The similarity of results of different NPs in different models is shown as the heterogeneous nanoceria distribution in organs. After the expectable accumulation in the liver and spleen, the concentration of cerium decays exponentially, accounting for about a 50% excretion of cerium from the body in 100 days. Cerium ions, coming from NP dissolution, are most likely excreted via the urinary tract, and ceria nanoparticles accumulated in the liver are most likely excreted via the hepatobiliary route. In addition, nanoceria looks safe and does not damage the target organs. No weight loss or apathy was observed during the course of the experiments.

Relationship between Dynamic and Isometric Strength, Power, Speed, and Average Propulsive Speed of Recreational Athletes.

The purpose of this study was to examine the type of relationship between measures of maximal force (dynamic and isometric), maximal power, and mean propulsive velocity. In total, 355 recreational athletes, 96 women (age 20.5 ± 2.5 years; height 158.2 ± 17.3 cm; weight 61.8 ± 48.4 kg) and 259 men (age 21.0 ± 2.6 years; height 170.5 ± 12.6 cm; weight 65.9 ± 9.2 kg) were evaluated in three sessions separated by 72 h each in isometric midthigh pull exercise (ISOS) (kg), bench press maximum strength (1RM MSBP) (kg), jump height (CMJ) (m), and maximum pedaling power (WT) the maximum squat strength (1RM MSS) (kg), the mean propulsive velocity in the bench press (MPVBP) (m·s-1), and the peak power (PPBP) (w), mean propulsive squat velocity (MPVS) (m·s-1), peak power (PP) (w), maximum handgrip force (ISOHG) (kg), and 30 m movement speed (V30) (s). Significant correlations (p ≤ 0.01) were identified between 95% of the various manifestations of force, and only 5% presented a significance of p ≤ 0.05; however, when the magnitude of these correlations is observed, there is great heterogeneity. In this sense, the dynamic strength tests present the best correlations with the other strength and power tests used in the present study, followed by PPBP and PP. The results of this study complement what is reported in the literature regarding the correlation between different types of force manifestations being heterogeneous and contradictory.

Role of Common Cell Culture Media Supplements on Citrate-Stabilized Gold Nanoparticle Protein Corona Formation, Aggregation State, and the Consequent Impact on Cellular Uptake.

Sodium citrate-stabilized gold nanoparticles (AuNPs) are destabilized when dispersed in cell culture media (CCMs). This may promote their aggregation and subsequent sedimentation, or under the proper conditions, their interaction with dispersed proteins can lead to the formation of a NP-stabilizing protein corona. CCMs are ionic solutions that contain growth substances which are typically supplemented, in addition to serum, with different substances such as dyes, antioxidants, and antibiotics. In this study, the impact of phenol red, penicillin-streptomycin, l-glutamine, and ß-mercaptoethanol on the formation of the NP-protein corona in CCMs was investigated. Similar protein coronas were obtained except in the presence of antibiotics. Under these conditions, the protein corona took more time to be formed, and its density and composition were altered, as indicated by UV-vis spectroscopy, Z potential, dynamic light scattering, and liquid chromatography-mass spectrometry analyses. As a consequence of these modifications, a significantly different AuNP cellular uptake was measured, showing that NP uptake increased as did the NP aggregate formation. AuNP uptake studies performed in the presence of clathrin- and caveolin-mediated endocytosis inhibitors showed that neither clathrin receptors nor lipid rafts were significantly involved in the internalization mechanism. These results suggest that in these conditions, NP aggregation is the main mechanism responsible for their cellular uptake.

Bar Load-Velocity Profile of Full Squat and Bench Press Exercises in Young Recreational Athletes.

The purpose of this study was to determine the mean propulsive velocity (MVP) at various percentages of one repetition maximum (1RM) in the full squat and chest press exercises. A total of 96 young women and 256 young men (recreational athletes) performed an incremental test (50−60−70−80% 1RM) comprising the bench press and full squat exercises in two different sessions. The individual load and velocity ratios were established through the MPV. Data were analyzed using SPSS software version 25.0, with the significance level set at 5%. The following findings were revealed: highly linear load-velocity relationships in the group of women (r = 0.806 in the squat, and r = 0.872 in the bench press) and in the group of men (r = 0.832 and r = 0.880, respectively); significant differences (p < 0.001) in the MPV at 50−70−80% 1RM between the bench press and the full squat in men and at 70−80% 1RM in women; and a high variability in the MPV (11.49% to 22.63) in the bench press and full squat (11.58% to 25.15%) was observed in women and men (11.31% to 21.06%, and 9.26% to 24.2%) at the different percentages of 1RM evaluated. These results suggest that the load-velocity ratio in non-strength-trained subjects should be determined individually to more precisely establish the relative load to be used in a full squat and bench press training program.

Multifaceted modes of action of the anticancer probiotic Enterococcus hirae.

A deviated repertoire of the gut microbiome predicts resistance to cancer immunotherapy. Enterococcus hirae compensated cancer-associated dysbiosis in various tumor models. However, the mechanisms by which E. hirae restored the efficacy of cyclophosphamide administered with concomitant antibiotics remain ill defined. Here, we analyzed the multifaceted modes of action of this anticancer probiotic. Firstly, E. hirae elicited emigration of thymocytes and triggered systemic and intratumoral IFNγ-producing and CD137-expressing effector memory T cell responses. Secondly, E. hirae activated the autophagy machinery in enterocytes and mediated ATG4B-dependent anticancer effects, likely as a consequence of its ability to increase local delivery of polyamines. Thirdly, E. hirae shifted the host microbiome toward a Bifidobacteria-enriched ecosystem. In contrast to the live bacterium, its pasteurized cells or membrane vesicles were devoid of anticancer properties. These pleiotropic functions allow the design of optimal immunotherapies combining E. hirae with CD137 agonistic antibodies, spermidine, or Bifidobacterium animalis. We surmise that immunological, metabolic, epithelial, and microbial modes of action of the live E. hirae cooperate to circumvent primary resistance to therapy.

Bone mineral density and low bone mass in severely burned patients: A retrospective cohort study.

INTRODUCTION: Severe burns can alter bone metabolism through different mechanisms. Despite prior published studies describing the association between burns and a decrease in bone mineral density (BMD), no clinical guidelines currently exist recommending the systematic evaluation of bone health in patients after severe burns. This study aims to describe the BMD of individuals with severe burn injuries and healthy controls and determine the frequency of low-to-normal bone mass (LNBM) and BMD below the expected range for age (BEA). MATERIALS AND METHODS: We conducted a retrospective cohort of patients with either severe thermal or electrical burns and healthy controls paired by gender and age. We performed a dual-energy X-ray absorptiometry at least 90 days after the burn and collected data from each patient's clinical evaluation and clinical file. RESULTS: A total of 77 patients (64 men and 13 women) and their paired controls were included in the study (age [mean ± standard deviation, SD]: 30.37 ± 8.66 years). Patients participated in the study an average of 315 ± 438 days after their burn. The BMD (grs/cm2) in total hip burned vs controls was: 0.998 ± 0.135 vs 1.059 ± 0.12 (p = 0.004); femoral neck 0.876 ± 0.121 vs 0.915 ± 0.097 (p = 0.031), spine 0.977 ± 0.127 vs 1.003 ± 0.076 (p = 0.132).The Z-scores for total hip were - 0.06 ± 1.05 vs 0.41 ± 0.80 (p = 0.002); for neck -0.39 ± 0.89 vs -0.01 ± 0.77 (p = 0.005); and for spine -0.75 ± 1.11 vs -0.32 ± 0.73 (p = 0.005). The proportion of subjects with BMD BEA in burns vs controls was 5.2 vs 1.2% (p = 0.05) in total hip, 3.9 vs 0% (p = 0.045) in the neck, and 18.2 vs 1.2% (p = 0.001) in the spine. The logistic regression model found-in burn patients vs controls-an OR of 9.83 for BMD BEA (CI 95%: 2.17-44.45, p = 003), OR = 4.05 for electrical burns (CI 95%: 1.72-20.89, p = 004) and OR = 15.16 for thermal burns (CI 95%: 2.91-79.00, p = 001). The model also found an OR = 2.48 for LNBM (CI 95%: 1.25-4.93, p = 0.009). The burn variables associated with BMD BEA at any site in the patients were BMI >25 Kg/m2 with an OR = 0.180 (CI 95%: 0.046-0.710, p = 0.014); and the lower limb amputation with an OR = 7.33 (CI 95%; 1.12-48.33, p = 0.038). Five burn patients had a fragility fracture. CONCLUSION: BMD was significantly lower in severely burned patients than in controls, and the proportion BMD BEA cases was significantly higher in the burn patient sample. Severe burns are a strong independent predictor of bone loss, and this risk is maintained for an extended period after the burn.

Publisher Correction: Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer.

Hormone receptor (HR)+ breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR+ BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HR+HER2- BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR+ BC.

Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients.

BACKGROUND: The development of immune checkpoint blockade (ICB) has revolutionized the clinical outcome of renal cell carcinoma (RCC). Nevertheless, improvement of durability and prediction of responses remain unmet medical needs. While it has been recognized that antibiotics (ATBs) decrease the clinical activity of ICB across various malignancies, little is known about the direct impact of distinct intestinal nonpathogenic bacteria (commensals) on therapeutic outcomes of ICB in RCC. OBJECTIVE: To evaluate the predictive value of stool bacteria composition for ICB efficacy in a cohort of advanced RCC patients. DESIGN, SETTING, AND PARTICIPANTS: We prospectively collected fecal samples from 69 advanced RCC patients treated with nivolumab and enrolled in the GETUG-AFU 26 NIVOREN microbiota translational substudy phase 2 trial (NCT03013335) at Gustave Roussy. We recorded patient characteristics including ATB use, prior systemic therapies, and response criteria. We analyzed 2994 samples of feces from healthy volunteers (HVs). In parallel, preclinical studies performed in RCC-bearing mice that received fecal transplant (FMT) from RCC patients resistant to ICB (NR-FMT) allowed us to draw a cause-effect relationship between gut bacteria composition and clinical outcomes for ICB. The influence of tyrosine kinase inhibitors (TKIs) taken before starting nivolumab on the microbiota composition has also been assessed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Metagenomic data (MG) from whole genome sequencing (WGS) were analyzed by multivariate and pairwise comparisons/fold ratio to identify bacterial fingerprints related to ATB or prior TKI exposure and patients' therapeutic response (overall response and progression-free survival), and compared with the data from cancer-free donors. RESULTS AND LIMITATIONS: Recent ATB use (n = 11; 16%) reduced objective response rates (from 28% to 9%, p < 0.03) and markedly affected the composition of the microbiota, facilitating the dominance of distinct species such as Clostridium hathewayi, which were also preferentially over-represented in stools from RCC patients compared with HVs. Importantly, TKIs taken prior to nivolumab had implications in shifting the microbiota composition. To establish a cause-effect relationship between gut bacteria composition and ICB efficacy, NR-FMT mice were successfully compensated with either FMT from responding RCC patients or beneficial commensals identified by WGS-MG (Akkermansia muciniphila and Bacteroides salyersiae). CONCLUSIONS: The composition of the microbiota is influenced by TKIs and ATBs, and impacts the success of immunotherapy. Future studies will help sharpen the role of these specific bacteria and their potential as new biomarkers. PATIENT SUMMARY: We used quantitative shotgun DNA sequencing of fecal microbes as well as preclinical models of fecal or bacterial transfer to study the association between stool composition and (pre)clinical outcome to immune checkpoint blockade. Novel insights into the pathophysiological relevance of intestinal dysbiosis in the prognosis of kidney cancer may lead to innovative therapeutic solutions, such as supplementation with probiotics to prevent primary resistance to therapy.

Fitness for health assessment in unilateral lower limb amputation: The Evam1 battery.

BACKGROUND: During the rehabilitation phase, physical exercise is a key element that requires an assessment of the best alternatives for application since the pre-prosthetic phase (PPF) for an accurate prescription. Therefore, the assessment of fitness for health (FFH) shall be included in the initial rehabilitation process. OBJECTIVE: To develop a FFH evaluation battery (Evam1) for pre-prosthetic unilateral lower-limb amputees (PPULLA). METHOD: A descriptive study of the theoretical construction and validation of a FFH evaluation battery based on a review of international literature for tests that measure amputee physical capability. RESULTS: During the scientific literature review, no batteries designed with this goal were found. We therefore designed a battery that was assembled of five tests for anthropometry, aerobic capacity, strength and flexibility. Combined leg and arm cycloergometrics, isokinetic dynamometry, and flexi test are the most reliable tests for the corresponding assessment of each component. CONCLUSIONS: PPF is of great importance, since the basic physical capabilities are altered due to long immobilization and hospitalization periods, inadequate postures, alteration of basic daily activities, and decrease in participation in sports, recreational, and work activities. This is a fundamental proposal, given that the procedures for FFH assessment of PPULLA have been rarely addressed, thus limiting the information on assessment methods, processes and/or tests established for these procedures.

GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism.

GAPDH is emerging as a key player in T cell development and function. To investigate the role of GAPDH in T cells, we generated a transgenic mouse model overexpressing GAPDH in the T cell lineage. Aged mice developed a peripheral Tfh-like lymphoma that recapitulated key molecular, pathological, and immunophenotypic features of human angioimmunoblastic T cell lymphoma (AITL). GAPDH induced non-canonical NF-κB pathway activation in mouse T cells, which was strongly activated in human AITL. We developed a NIK inhibitor to reveal that targeting the NF-κB pathway prolonged AITL-bearing mouse survival alone and in combination with anti-PD-1. These findings suggest the therapeutic potential of targeting NF-κB signaling in AITL and provide a model for future AITL therapeutic investigations.

AIF-regulated oxidative phosphorylation supports lung cancer development.

Cancer is a major and still increasing cause of death in humans. Most cancer cells have a fundamentally different metabolic profile from that of normal tissue. This shift away from mitochondrial ATP synthesis via oxidative phosphorylation towards a high rate of glycolysis, termed Warburg effect, has long been recognized as a paradigmatic hallmark of cancer, supporting the increased biosynthetic demands of tumor cells. Here we show that deletion of apoptosis-inducing factor (AIF) in a KrasG12D-driven mouse lung cancer model resulted in a marked survival advantage, with delayed tumor onset and decreased malignant progression. Mechanistically, Aif deletion leads to oxidative phosphorylation (OXPHOS) deficiency and a switch in cellular metabolism towards glycolysis in non-transformed pneumocytes and at early stages of tumor development. Paradoxically, although Aif-deficient cells exhibited a metabolic Warburg profile, this bioenergetic change resulted in a growth disadvantage of KrasG12D-driven as well as Kras wild-type lung cancer cells. Cell-autonomous re-expression of both wild-type and mutant AIF (displaying an intact mitochondrial, but abrogated apoptotic function) in Aif-knockout KrasG12D mice restored OXPHOS and reduced animal survival to the same level as AIF wild-type mice. In patients with non-small cell lung cancer, high AIF expression was associated with poor prognosis. These data show that AIF-regulated mitochondrial respiration and OXPHOS drive the progression of lung cancer.

Tumor lysis with LTX-401 creates anticancer immunity.

Local immunotherapies such as the intratumoral injection of oncolytic compounds aim at reinstating and enhancing systemic anticancer immune responses. LTX-315 is a first-in-class, clinically evaluated oncolytic peptide-based local immunotherapy that meets these criteria. Here, we show that LTX-401, yet another oncolytic compound designed for local immunotherapy, depicts a similar safety profile and that sequential local inoculation of LTX-401 was able to cure immunocompetent host from subcutaneous MCA205 and TC-1 cancers. Cured animals exhibited long-term immune memory effects that rendered them resistant to rechallenge with syngeneic tumors. Nevertheless, the local treatment with LTX-401 alone had only limited abscopal effects on secondary contralateral lesions. Anticancer effects resulting from single as well as sequential injections of LTX-401 were boosted in combination with PD-1 and CTLA-4 immune checkpoint blockade (ICB), and sequential LTX-401 treatment combined with double ICB exhibited strong abscopal antineoplastic effects on contralateral tumors underlining the potency of this combination therapy.

Lethal Poisoning of Cancer Cells by Respiratory Chain Inhibition plus Dimethyl α-Ketoglutarate.

Inhibition of oxidative phosphorylation (OXPHOS) by 1-cyclopropyl-4-(4-[(5-methyl-3-(3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl]pyridin-2-yl)piperazine (BAY87-2243, abbreviated as B87), a complex I inhibitor, fails to kill human cancer cells in vitro. Driven by this consideration, we attempted to identify agents that engage in synthetically lethal interactions with B87. Here, we report that dimethyl α-ketoglutarate (DMKG), a cell-permeable precursor of α-ketoglutarate that lacks toxicity on its own, kills cancer cells when combined with B87 or other inhibitors of OXPHOS. DMKG improved the antineoplastic effect of B87, both in vitro and in vivo. This combination caused MDM2-dependent, tumor suppressor protein p53 (TP53)-independent transcriptional reprogramming and alternative exon usage affecting multiple glycolytic enzymes, completely blocking glycolysis. Simultaneous inhibition of OXPHOS and glycolysis provoked a bioenergetic catastrophe culminating in the activation of a cell death program that involved disruption of the mitochondrial network and activation of PARP1, AIFM1, and APEX1. These results unveil a metabolic liability of human cancer cells that may be harnessed for the development of therapeutic regimens.

Anticancer effects of anti-CD47 immunotherapy in vivo.

The treatment of breast cancer largely depends on the utilization of immunogenic chemotherapeutics, which, as a common leitmotif, stimulate the exposure of calreticulin (CALR) on the surface of cancer cells, thereby facilitating their recognition by dendritic cells for the uptake of tumor-associated antigens and subsequent antigen cross-presentation to cytotoxic T cells. Breast cancer cells also express the calreticulin antagonist CD47, which inhibits tumor cell phagocytosis and consequently subverts anticancer immune responses. Here, we treated carcinogen-induced or transplantable mouse models of cancer by a CD47 blocking antibody that was at least as efficient as chemotherapy and that could be favorably combined with the anthracycline mitoxantrone in the context of carcinogen-induced orthotopic breast cancers. Monotherapy by CD47 blockade led to a reduction in tumor growth and an increase in overall survival. Of note, this treatment lead to a moderate depletion of M2 macrophages as well as close-to-complete elimination of regulatory T cells from the tumor bed, suggesting a strong favorable impact of CD47 blockade on the tumor microenvironment.

Caspase 1/11 Deficiency or Pharmacological Inhibition Mitigates Psoriasis-Like Phenotype in Mice.

Inflammatory caspases, activated within the inflammasome, are responsible for the maturation and secretion of IL-1ß/IL-18. Although their expression in psoriasis was shown several years ago, little is known about the role of inflammatory caspases in the context of psoriasis. Here, we confirmed that caspases 1, 4, and 5 are activated in lesional skin from psoriasis patients. We showed in three psoriasis-like models that inflammatory caspases are activated, and accordingly, caspase 1/11 invalidation or pharmacological inhibition by Ac-YVAD-CMK (i.e., Ac-Tyr-Val-Ala-Asp-chloromethylketone) injection induced a decrease in ear thickness, erythema, scaling, inflammatory cytokine expression, and immune cell infiltration in mice. We observed that keratinocytes were primed to secrete IL-1ß when cultured in conditions mimicking psoriasis. Generation of chimeric mice by bone marrow transplantation was carried out to decipher the respective contribution of keratinocytes and/or immune cells in the activation of inflammatory caspases during psoriasis-like inflammatory response. Our data showed that the presence of caspase 1/11 in the immune system is sufficient for a fully inflammatory response, whereas the absence of caspase 1/11 in keratinocytes/fibroblasts had no impact. In summary, our study indicates that inflammatory caspases activated in immune cells are implicated in psoriasis pathogenesis.

Oncolysis with DTT-205 and DTT-304 generates immunological memory in cured animals.

Oncolytic peptides and peptidomimetics are being optimized for the treatment of cancer by selecting agents with high cytotoxic potential to kill a maximum of tumor cells as well as the capacity to trigger anticancer immune responses and hence to achieve long-term effects beyond therapeutic discontinuation. Here, we report on the characterization of two novel oncolytic peptides, DTT-205 and DTT-304 that both selectively enrich in the lysosomal compartment of cancer cells yet differ to some extent in their cytotoxic mode of action. While DTT-304 can trigger the aggregation of RIP3 in ripoptosomes, coupled to the phosphorylation of MLKL by RIP3, DTT-205 fails to activate RIP3. Accordingly, knockout of either RIP3 or MLKL caused partial resistance against cell killing by DTT-304 but not DTT-205. In contrast, both agents shared common features in other aspects of pro-death signaling in the sense that their cytotoxic effects were strongly inhibited by both serum and antioxidants, partially reduced by lysosomal inhibition with bafilomycin A1 or double knockout of Bax and Bak, yet totally refractory to caspase inhibition. Both DTT-304 and DTT-205 caused the exposure of calreticulin at the cell surface, as well as the release of HMGB1 from the cells. Mice bearing established subcutaneous cancers could be cured by local injection of DTT-205 or DTT-304, and this effect depended on T lymphocytes, as it led to the establishment of a long-term memory response against tumor-associated antigens. Thus, mice that had been cured from cancer by the administration of DTT compounds were refractory against rechallenge with the same cancer type several months after the disappearance of the primary lesion. In summary, DTT-205 and DTT-304 both have the capacity to induce immunotherapeutic oncolysis.