A phase I safety and efficacy clinical trial of plocabulin and gemcitabine in patients with advanced solid tumors.

Plocabulin (Plo) induces depolymerization of tubulin fibers with disorganization and fragmentation of the microtubule network leading to mitosis. Plo combined with gemcitabine (Gem) showed synergistic anti-tumor activity in preclinical studies. This phase I trial evaluated the safety, pharmacokinetics (PK) and efficacy of Plo 10-min infusion plus Gem on Day 1 and 8 every 3-week in patients with advanced solid tumors. Fifty-seven patients were enrolled into 8 dose levels (DLs); 74%: females; 74%: ECOG performance status 1; median age: 62 years; median number of prior lines of therapy:3. Dose-limiting toxicities (DLT) in Cycle 1 were grade (G) 3 intestinal obstruction at the maximum tolerated dose (MTD), G3 peripheral sensory neuropathy (PSN), G3 abdominal pain, and G4 thrombocytopenia (1 patient each). The highest DL (DL8: Plo 10.5 mg/m2/Gem 1000 mg/m2) was the MTD. Accrual into DL7 (Plo 10.0 mg/m2/Gem 1000 mg/m2) was stopped before it was formally defined as the recommended dose (RD). Most common treatment-related adverse events (AEs) were fatigue (56%), nausea (55%), diarrhea (31%); G3/4 hematologic toxicities comprised anemia (35%), neutropenia (27%) and thrombocytopenia (17%). No treatment-related deaths occurred. PK parameters for Gem or dFdU at all DLs were in line with reference values from the literature. Six of 46 evaluable pts were responders (overall response rate:13%). Of note, 2 partial responses (PR) and 2 stable disease (SD) ≥ 4 months occurred among 13 pts with ovarian cancer. The combination of Plo and Gem is well tolerated. The MTD was Plo 10.5 mg/m2/Gem 1000 mg/m2. No PK drug-drug interaction was found. The most encouraging outcome occurred in ovarian cancer patients.

Canalicular obstructions after monkeypox infection.

We report two cases of lacrimal obstruction after ocular infection with monkeypox virus (MPX) in the 2022 outbreak. One of them was a distal canalicular obstruction and the other was a proximal canalicular obstruction. In the first days of MPX they presented with conjunctivitis and periocular skin vesicles. Several months after the ophthalmic condition was cured, they showed persistence of epiphora, and the lacrimal problem was diagnosed. The photographs taken during the inflammation of the anterior pole were reviewed and vesicles located in the same area as the canalicular damage were observed. One patient underwent a canaliculodacryorhinostomy and the other an exploratory punctoplasty. Both surgical operations failed to restore normal tear flow. Lacrimal drainage disorders related to ocular MPX have not yet been described. And, in addition, these cases are the first relation of viral vesicular skin lesions and canalicular obstructions.

ATP-dependent citrate lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling of the Heart.

Background: Metabolic remodeling is a hallmark of the failing heart. Oncometabolic stress during cancer increases the activity and abundance of the ATP-dependent citrate lyase (ACL, Acly ), which promotes histone acetylation and cardiac adaptation. ACL is critical for the de novo synthesis of lipids, but how these metabolic alterations contribute to cardiac structural and functional changes remains unclear. Methods: We utilized human heart tissue samples from healthy donor hearts and patients with hypertrophic cardiomyopathy. Further, we used CRISPR/Cas9 gene editing to inactivate Acly in cardiomyocytes of MyH6-Cas9 mice. In vivo, positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to the loss of ACL. We conducted a multi-omics analysis using RNA-sequencing and mass spectrometry-based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level. Results: Here, we show that in mice, ACL drives metabolic adaptation in the heart to sustain contractile function, histone acetylation, and lipid modulation. Notably, we show that loss of ACL increases glucose oxidation while maintaining fatty acid oxidation. Ex vivo isotope tracing experiments revealed a reduced efflux of glucose-derived citrate from the mitochondria into the cytosol, confirming that citrate is required for reductive metabolism in the heart. We demonstrate that YAP inactivation facilitates ACL deficiency. Computational flux analysis and integrative multi-omics analysis indicate that loss of ACL induces alternative isocitrate dehydrogenase 1 flux to compensate. Conclusions: This study mechanistically delineates how cardiac metabolism compensates for suppressed citrate metabolism in response to ACL loss and uncovers metabolic vulnerabilities in the heart.

rhIL-7-hyFc, a long-acting interleukin-7, improves efficacy of CAR-T cell therapy in solid tumors.

BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) therapy has achieved remarkable remission in patients with B-cell malignancies. However, its efficacy in treating solid tumors remains limited. Here, we investigated a combination therapy approach using an engineered long-acting interleukin (IL)-7 (rhIL-7-hyFc or NT-I7) and CAR-T cells targeting three antigens, glypican-2 (GPC2), glypican-3 (GPC3), and mesothelin (MSLN), against multiple solid tumor types including liver cancer, neuroblastoma, ovarian cancer, and pancreatic cancer in mice. METHODS: CAR-T cells targeting GPC2, GPC3, and MSLN were used in combination with NT-I7 to assess the anticancer activity. Xenograft tumor models, including the liver cancer orthotopic model, were established using NOD scid gamma mice engrafted with cell lines derived from hepatocellular carcinoma, neuroblastoma, ovarian cancer, and pancreatic cancer. The mice were monitored by bioluminescence in vivo tumor imaging and tumor volume measurement using a caliper. Immunophenotyping of CAR-T cells on NT-I7 stimulation was evaluated for memory markers, exhaust markers, and T-cell signaling molecules by flow cytometry and western blotting. RESULTS: Compared with the IL-2 combination, preclinical evaluation of NT-I7 exhibited regression of solid tumors via enhanced occupancy of CD4+ CAR-T, improved T-cell expansion, reduced exhaustion markers (programmed cell death protein 1 or PD-1 and lymphocyte-activation gene 3 or LAG-3) expression, and increased generation of stem cell-like memory CAR-T cells. The STAT5 pathway was demonstrated to be downstream of NT-I7 signaling, mediated by increased expression of the IL-7 receptor expression in CAR-T cells. Furthermore, CAR-T cells improved efficacy against tumors with low antigen density when combined with NT-I7 in mice, presenting an avenue for patients with heterogeneous antigenic profiles. CONCLUSION: This study provides a rationale for NT-I7 plus CAR-T cell combination therapy for solid tumors in humans.

Creating Expressive Social Robots That Convey Symbolic and Spontaneous Communication.

Robots are becoming an increasingly important part of our society and have started to be used in tasks that require communicating with humans. Communication can be decoupled in two dimensions: symbolic (information aimed to achieve a particular goal) and spontaneous (displaying the speaker's emotional and motivational state) communication. Thus, to enhance human-robot interactions, the expressions that are used have to convey both dimensions. This paper presents a method for modelling a robot's expressiveness as a combination of these two dimensions, where each of them can be generated independently. This is the first contribution of our work. The second contribution is the development of an expressiveness architecture that uses predefined multimodal expressions to convey the symbolic dimension and integrates a series of modulation strategies for conveying the robot's mood and emotions. In order to validate the performance of the proposed architecture, the last contribution is a series of experiments that aim to study the effect that the addition of the spontaneous dimension of communication and its fusion with the symbolic dimension has on how people perceive a social robot. Our results show that the modulation strategies improve the users' perception and can convey a recognizable affective state.

Effectiveness of early and intensive intervention on suicide prevention: CARS programme.

The aim of this study was to evaluate the outcomes of the Programme for Management of Suicidal Behaviour and Suicide Prevention (CARS). Individuals treated in the emergency department of University Hospital Marqués de Valdecilla for suicidal thoughts or attempts (N = 401) between 1-March-2016 and 31-December-2018 were considered. No randomization by patients or groups was performed. Student's t-test, chi-square and repeated measure analysis of variance were used. Kaplan-Meier survival function and Cox proportional hazard regression models were employed to estimate the risks of relapse. Outcome of those who voluntary enrol CARS were compared with treatment as usual (TAU) at 6- and 12-months follow-up. The results indicate a significant reduction and delayed occurrence of suicidal behaviour over a 12-month follow-up period with the CARS programme compared to TAU, along with a decreased frequency of hospital admissions. CARS programme demonstrates a substantial impact, significantly reducing the risk of recurrent suicidal behaviour by 35.5 % and the risk of repeated suicidal attempts by 47.2 % at the 12-month follow-up. The programme exhibits a dual protective effect, diminishing suicidal behaviour and fostering improved long-term outcomes. In conclusion, CARS effectively reduced suicidal behaviour recurrence, achieving significant decreases in suicidal thoughts, plans and attempts.

Exosomes isolated from IMMUNEPOTENT CRP, a hemoderivative, to accelerate diabetic wound healing.

The increasing risk of amputation due to diabetic foot ulcer calls for new therapeutic options; for that, we determined the role of IMMUNEPOTENT CRP (ICRP) and its parts in the wound healing process of superficial wounds in diabetic BALB/c mice. A potency test was performed to confirm the batch of ICRP, and then its parts were separated into pellets, supernatants, and exosomes, and another group of exosomes loaded with insulin was added. Viability and scratch healing were assessed in NIH-3T3, HUVEC, and HACAT cell lines. Diabetes was induced with streptozotocin, and wounds were made by dissecting the back skin. Treatments were topically applied, and closure was monitored; inflammatory cytokines in sera were also evaluated by flow cytometry, and histological analysis was performed by Masson's staining and immunohistochemistry for p-AKT, p-FOXO, p-P21, and p-TSC2. ICRP pellets and exosomes increased cellular viability, and exosomes and exosome-insulin accelerated scratch healing in vitro. Exosome-insulin releases insulin constantly over time in vitro. In vivo, treatments accelerated wound closure, and better performance was observed in pellet, exosome, and exosome-insulin treatments. Best collagen expression was induced by ICRP. P-AKT and p-FOXO were overexpressed in healing tissues. Inflammatory cytokines were downregulated by all treatments. In conclusion, IMMUNEPOTENT CRP components, especially exosomes, and the process of encapsulation of exosome-insulin accelerate diabetic wound healing and enhance cellular proliferation, collagen production, and inflammation modulation through the phosphorylation of components of the AKT pathway.

Osteopontin as a Biomarker in Interstitial Lung Diseases.

Osteopontin (OPN) is a glycoprotein involved in Th1 and Th17 differentiation, and inflammation and tissue remodeling. OPN is a biomarker of disease activity in patients with autoimmune inflammatory conditions. This study aimed to assess the diagnostic and prognostic value of OPN in interstitial lung diseases (ILDs). Between May 2016 and October 2019, 344 patients with ILD were recruited at the Hospital Universitario Marqués de Valdecilla (Spain) and were prospectively followed-up. This study involved the determination of OPN serum levels by ELISA and OPN RNA expression quantified using qPCR. Six genetic polymorphisms in OPN (rs28357094, rs2853749, rs2853750, rs11728697, rs7695531, and rs1126616) were genotyped using TaqMan assays. OPN serum levels were also assessed in 140 healthy controls. OPN serum levels (median [interquartile range]) were significantly higher in ILD patients than in controls (1.05 [0.75-1.51] ng/mL versus 0.81 [0.65-0.98] ng/mL in healthy controls; p < 0.01). OPN serum levels were inversely correlated with the forced vital capacity. OPN serum levels were also higher in ILD patients who died or underwent lung transplantation when compared with the remaining ILD patients (1.15 [0.80-1.72] ng/mL versus 0.99 [0.66-1.32] ng/mL; p = 0.05). Survival worsened in ILD patients with OPN > 1.03 ng/mL at 1, 3, and 5 years. No statistically significant differences in the genetic frequencies of OPN polymorphisms or the RNA expression were found among the different ILD groups. Elevated levels of OPN in the serum may be a useful indicator in identifying patients with ILD who are more likely to experience poor outcomes.

Patterns of cognitive-emotional change after cognitive-behavioural treatment in emotional disorders: A 12-month longitudinal cluster analysis.

INTRODUCTION: The aim of this study was to use cluster analysis based on the trajectory of five cognitive-emotional processes (worry, rumination, metacognition, cognitive reappraisal and expressive suppression) over time to explore differences in clinical and performance variables in primary care patients with emotional symptoms. METHODS: We compared the effect of adding transdiagnostic cognitive-behavioural therapy (TD-CBT) to treatment as usual (TAU) according to cluster membership and sought to determine the variables that predicted cluster membership. 732 participants completed scales about cognitive-emotional processes, anxiety and depressive symptoms, functioning, and quality of life (QoL) at baseline, posttreatment, and at 12 months. Longitudinal cluster analysis and logistic regression analyses were carried out. RESULTS: A two-cluster solution was chosen as the best fit, named as "less" or "more" improvement in cognitive-emotional processes. Individuals who achieved more improvement in cognitive-emotional processes showed lower emotional symptoms and better QoL and functioning at all three time points. TAU+TD-CBT, income level, QoL and anxiety symptoms were significant predictors of cluster membership. CONCLUSIONS: These results underscore the value of adding TD-CBT to reduce maladaptive cognitive-emotional regulation strategies. These findings highlight the importance of the processes of change in therapy and demonstrate the relevance of the patient's cognitive-emotional profile in improving treatment outcomes.

Effect of Reliable Recovery on Health Care Costs and Productivity Losses in Emotional Disorders.

Despite the high economic costs associated with emotional disorders, relatively few studies have examined the variation in costs according to whether the patient has achieved a reliable recovery. The aim of this study was to explore differences in health care costs and productivity losses between primary care patients from a previous randomized controlled trial (RCT)-PsicAP-with emotional symptoms who achieved a reliable recovery and those who did not after transdiagnostic cognitive-behavioral therapy (TD-CBT) plus treatment as usual (TAU) or TAU alone. Sociodemographic and cost data were obtained for 134 participants treated at five primary care centers in Madrid for the 12-month posttreatment period. Reliable recovery rates were higher in the patients who received TD-CBT + TAU versus TAU alone (66% vs. 34%, respectively; chi-square = 13.78, df = 1, p < .001). Patients who did not achieve reliable recovery incurred more costs, especially associated with general practitioner consultations (t = 3.01, df = 132, p = .003), use of emergency departments (t = 2.20, df = 132, p = .030), total health care costs (t = 2.01, df = 132, p = .040), and sick leaves (t = 1.97, df = 132, p = .048). These findings underscore the societal importance of achieving a reliable recovery in patients with emotional disorders, and further support the value of adding TD-CBT to TAU in the primary care setting.

Effect of Operational Variables on Supercritical Foaming of Caffeic Acid-Loaded Poly(lactic acid)/Poly(butylene adipate-co-terephthalate) Blends for the Development of Sustainable Materials.

Expanded polystyrene will account for 5.3% of total global plastic production in 2021 and is widely used for food packaging due to its excellent moisture resistance and thermal insulation. However, some of these packages are often used only once before being discarded, generating large amounts of environmentally harmful plastic waste. A very attractive alternative to the conventional methods used for polymer processing is the use of supercritical carbon dioxide (scCO2) since it has mass-transfer properties adapted to the foam morphology, generating different path lengths for the diffusion of active compounds within its structure and can dissolve a wide range of organic molecules under supercritical conditions. The objective of this research was to evaluate the effect of operational variables on the process of caffeic acid (CA) impregnation and subsequent foaming of polylactic acid (PLA) as well as two PLA/poly(butylene-co-terephthalate-adipate) (PBAT) blends using scCO2. The results showed an increase in the degree of crystallinity of the CA-impregnated samples due to the nucleation effect of the active compound. On the other hand, SEM micrographs of both films and foams showed significant differences due to the presence of PBAT and its low miscibility with PLA. Finally, the results obtained in this work contribute to the knowledge of the important parameters to consider for the implementation of the impregnation and foaming process of PLA and PLA/PBAT blends with potential use in food packaging.

Inflammasome-Related Genetic Polymorphisms as Severity Biomarkers of COVID-19.

The most critical forms of coronavirus disease 2019 (COVID-19) are associated with excessive activation of the inflammasome. Despite the COVID-19 impact on public health, we still do not fully understand the mechanisms by which the inflammatory response influences disease prognosis. Accordingly, we aimed to elucidate the role of polymorphisms in the key genes of the formation and signaling of the inflammasome as biomarkers of COVID-19 severity. For this purpose, a large and well-defined cohort of 377 COVID-19 patients with mild (n = 72), moderate (n = 84), severe (n = 100), and critical (n = 121) infections were included. A total of 24 polymorphisms located in inflammasome-related genes (NLRP3, NLRC4, NLRP1, CARD8, CASP1, IL1B, IL18, NFKB1, ATG16L1, and MIF) were genotyped in all of the patients and in the 192 healthy controls (HCs) (who were without COVID-19 at the time of and before the study) by RT-qPCR. Our results showed that patients with mild, moderate, severe, and critical COVID-19 presented similar allelic and genotypic distribution in all the variants studied. No statistically significant differences in the haplotypic distribution of NLRP3, NLRC4, NLRP1, CARD8, CASP1, IL1B, and ATG16L1 were observed between COVID-19 patients, who were stratified by disease severity. Each stratified group of patients presented a similar genetic distribution to the HCs. In conclusion, our results suggest that the inflammasome polymorphisms studied are not associated with the worsening of COVID-19.

Pharmacokinetics and Safety of Lurbinectedin Administrated with Itraconazole in Cancer Patients: A Drug-Drug Interaction Study.

This open-label, two-part, phase Ib drug-drug interaction study investigated whether the pharmacokinetic (PK) and safety profiles of lurbinectedin (LRB), a marine-derived drug, are affected by co-administration of itraconazole (ITZ), a strong CYP3A4 inhibitor, in adult patients with advanced solid tumors. In Part A, three patients were sequentially assigned to Sequence 1 (LRB 0.8 mg/m2, 1-h intravenous [IV] + ITZ 200 mg/day oral in Cycle 1 [C1] and LRB alone 3.2 mg/m2, 1 h, IV in Cycle 2 [C2]). In Part B, 11 patients were randomized (1:1) to receive either Sequence 1 (LRB at 0.9 mg/m2 + ITZ in C1 and LRB alone in C2) or Sequence 2 (LRB alone in C1 and LRB + ITZ in C2). Eleven patients were evaluable for PK analysis: three in Part A and eight in Part B (four per sequence). The systemic total exposure of LRB increased with ITZ co-administration: 15% for Cmax, area under the curve (AUC) 2.4-fold for AUC0-t and 2.7-fold for AUC0-∞. Co-administration with ITZ produced statistically significant modifications in the unbound plasma LRB PK parameters. The LRB safety profile was consistent with the toxicities described in previous studies. Co-administration with multiple doses of ITZ significantly altered LRB systemic exposure. Hence, to avoid LRB overexposure when co-administered with strong CYP3A4 inhibitors, an LRB dose reduction proportional to CL reduction should be applied.

Reinforcing the Evidence of Mitochondrial Dysfunction in Long COVID Patients Using a Multiplatform Mass Spectrometry-Based Metabolomics Approach.

Despite the recent and increasing knowledge surrounding COVID-19 infection, the underlying mechanisms of the persistence of symptoms for a long time after the acute infection are still not completely understood. Here, a multiplatform mass spectrometry-based approach was used for metabolomic and lipidomic profiling of human plasma samples from Long COVID patients (n = 40) to reveal mitochondrial dysfunction when compared with individuals fully recovered from acute mild COVID-19 (n = 40). Untargeted metabolomic analysis using CE-ESI(+/-)-TOF-MS and GC-Q-MS was performed. Additionally, a lipidomic analysis using LC-ESI(+/-)-QTOF-MS based on an in-house library revealed 447 lipid species identified with a high confidence annotation level. The integration of complementary analytical platforms has allowed a comprehensive metabolic and lipidomic characterization of plasma alterations in Long COVID disease that found 46 relevant metabolites which allowed to discriminate between Long COVID and fully recovered patients. We report specific metabolites altered in Long COVID, mainly related to a decrease in the amino acid metabolism and ceramide plasma levels and an increase in the tricarboxylic acid (TCA) cycle, reinforcing the evidence of an impaired mitochondrial function. The most relevant alterations shown in this study will help to better understand the insights of Long COVID syndrome by providing a deeper knowledge of the metabolomic basis of the pathology.

Long-term depressive symptom trajectories and related baseline characteristics in primary care patients: Analysis of the PsicAP clinical trial.

BACKGROUND: There is heterogeneity in the long-term trajectories of depressive symptoms among patients. To date, there has been little effort to inform the long-term trajectory of symptom change and the factors associated with different trajectories. Such knowledge is key to treatment decision-making in primary care, where depression is a common reason for consultation. We aimed to identify distinct long-term trajectories of depressive symptoms and explore pre-treatment characteristics associated with them. METHODS: A total of 483 patients from the PsicAP clinical trial were included. Growth mixture modeling was used to identify long-term distinct trajectories of depressive symptoms, and multinomial logistic regression models to explore associations between pre-treatment characteristics and trajectories. RESULTS: Four trajectories were identified that best explained the observed response patterns: "recovery" (64.18%), "late recovery" (10.15%), "relapse" (13.67%), and "chronicity" (12%). There was a higher likelihood of following the recovery trajectory for patients who had received psychological treatment in addition to the treatment as usual. Chronicity was associated with higher depressive severity, comorbidity (generalized anxiety, panic, and somatic symptoms), taking antidepressants, higher emotional suppression, lower levels on life quality, and being older. Relapse was associated with higher depressive severity, somatic symptoms, and having basic education, and late recovery was associated with higher depressive severity, generalized anxiety symptoms, greater disability, and rumination. CONCLUSIONS: There were different trajectories of depressive course and related prognostic factors among the patients. However, further research is needed before these findings can significantly influence care decisions.

Foaming of 3D-Printed PLA/CaCO3 Composites by Supercritical CO2 Process for Sustainable Food Contact Materials.

In the last decade, among the emerging technologies in the area of bioplastics, additive manufacturing (AM), commonly referred to as 3D printing, stands out. This technology has gained great interest in the development of new products, mainly due to its capability to easily produce customized and low-cost plastic products. This work aims to evaluate the effect of supercritical foaming of 3D-printed parts based on a commercial PLA matrix loaded with calcium carbonate, for single-use sustainable food contact materials. 3D-printed PLA/CaCO3 parts were obtained by 3D printing with a 20% and 80% infill, and two infill patterns, rectilinear and triangular, were set for each of the infill percentages selected. Supercritical fluid foaming of PLA/CaCO3 composite printed parts was performed using a pressure of 25 MPa, a temperature of 130 °C for 23 min, with a fast depressurization rate (1 s). Closed-cell foams were achieved and the presence of CaCO3 did not influence the surface of the foams or the cell walls, and no agglomerations were observed. Foam samples with 80% infill showed subtle temperature fluctuations, and thermogravimetric analysis showed that samples were thermally stable up to ~300 °C, while the maximum degradation temperature was around 365 °C. Finally, tensile test analysis showed that for lower infill contents, the foams showed lower mechanical performance, while the 80% infill and triangular pattern produced foams with good mechanical performance. These results emphasize the interest in using the supercritical CO2 process to easily produce foams from 3D-printed parts. These materials represent a sustainable alternative for replacing non-biodegradable materials such as Expanded Polystyrene, and they are a promising option for use in many industrial applications, such as contact materials.

rhIL-7-hyFc and hIL-2/TCB2c combination promotes an immune-stimulatory tumor microenvironment that improves antitumor efficacy of checkpoint inhibitors.

BACKGROUND: Recombinant human interleukin (rhIL)-7-hyFc (efineptakin alfa; NT-I7) is a potent T-cell amplifier, with two IL-7 molecules fused to IgD/IgG4 elements. rhIL-7-hyFc promotes extensive infiltration of CD8+ T cells into the tumor, concurrently increasing the numbers of intratumoral PD-1+CD8+ T cells. The hIL-2/TCB2 complex (SLC-3010) inhibits tumor growth by preferential activation of CD122 (IL-2Rß)high CD8+ T cells and natural killer cells, over regulatory T cells (Tregs). We investigated the underlying mechanisms of rhIL-7-hyFc and hIL-2/TCB2c antitumor activity and the potential synergistic efficacy, specifically focusing on tumor-specific CD8+ cells within the tumor and the tumor-draining lymph nodes (tdLN). METHODS: MC38 and CT26 tumor-bearing mice were administered with 10 mg/kg rhIL-7-hyFc intramuscularly and 0.9 mg/kg hIL-2/TCB2c intravenously. Anti-PD-1 monoclonal antibody was administered intraperitoneally three times at 3-day intervals at a dose of 5 mg/kg. Tumor volume was measured to assess efficacy. To compare the composition of immune cells between each monotherapy and the combination therapy, we analyzed tumors and tdLNs by flow cytometry. RESULTS: Our data demonstrate that the combination of rhIL-7-hyFc and hIL-2/TCB2c increases efficacy and generates an immune-stimulatory tumor microenvironment (TME). The TME is characterized by an increased infiltration of tumor-specific CD8+ T cells, and a decreased frequency of CD39highTIM-3+ Treg cells. Most importantly, rhIL-7-hyFc increases infiltration of a CD62L+Ly108+ early progenitor population of exhausted CD8+ T cells (TPEX), which may retain long-term proliferation capacity and replenish functional effector CD8+ T cells. hIL-2/TCB2c induces differentiation of CD62L+Ly108+ TPEX rapidly into CD101+ terminally differentiated subsets (terminally exhausted T cell (TEX term)). Our study also demonstrates that rhIL-7-hyFc significantly enhances the proliferation rate of TPEX in the tdLNs, positively correlating with their abundance within the tumor. Moreover, rhIL-7-hyFc and hIL-2/TCB2c can overcome the limited therapeutic effectiveness of PD-1 blockade, culminating in the complete regression of tumors. CONCLUSIONS: rhIL-7-hyFc can expand and maintain the progenitor pool of exhausted CD8+ T cells, whereas hIL-2/TCB2c promotes their differentiation into TEX term. Together, this induces an immune-stimulatory TME that improves the efficacy of checkpoint blockade.

Retinal vessel volume reference database derived from volume-rendered optical coherence tomography angiography.

Optical coherence tomography angiography (OCTA) enables three-dimensional reconstruction of the functional blood vessels in the retina. Therefore, it enables the quantification of 3D retinal vessel parameters such as surface area and vessel volume. In spite of the widespread use of OCTA, no representative volume-rendered vessel volume (VV) data are published to date. In this study, OCTA 3 × 3 mm macular cubes were processed with volume-rendering techniques to measure VV in 203 eyes from 107 healthy volunteers. Generalized linear models (GLM) were constructed to assess the impact of age, gender, visual acuity (VA), spherical equivalent (SE), and axial length (AL) on VV. Overall mean VV was 0.23 ± 0.05mm3. Age and axial length showed a negative correlation with VV. However, GLM model analysis found that AL exerted the most pronounced influence on VV. No statistically significant associations were identified between gender or between left and right eyes. This is the first study to assess 3D OCTA VV and its naturally occurring variations in a large series of healthy subjects. It offers novel insights into the characterization of normal retinal vascular anatomy in healthy individuals, contributing to a valuable reference for future research in this field.

An IROA Workflow for correction and normalization of ion suppression in mass spectrometry-based metabolomic profiling data.

Ion suppression is a major problem in mass spectrometry (MS)-based metabolomics; it can dramatically decrease measurement accuracy, precision, and signal-to-noise sensitivity. Here we report a new method, the IROA TruQuant Workflow, that uses a stable isotope-labeled internal standard (IROA-IS) plus novel companion algorithms to 1) measure and correct for ion suppression, and 2) perform Dual MSTUS normalization of MS metabolomic data. We have evaluated the method across ion chromatography (IC), hydrophilic interaction liquid chromatography (HILIC), and reverse phase liquid chromatography (RPLC)-MS systems in both positive and negative ionization modes, with clean and unclean ion sources, and across different biological matrices. Across the broad range of conditions tested, all detected metabolites exhibited ion suppression ranging from 1% to 90+% and coefficient of variations ranging from 1% to 20%, but the Workflow and companion algorithms were highly effective at nulling out that suppression and error. Overall, the Workflow corrects ion suppression across diverse analytical conditions and produces robust normalization of non-targeted metabolomic data.

Short physical performance battery is not associated with falls and injurious falls in older persons: longitudinal data of the SCOPE project.

INTRODUCTION: Falls and fall-related injuries in older persons are a major public health problem. Our objective was to study the predictive value of the Short Physical Performance Battery (SPPB) in the cohort of the SCOPE project on falls, injurious falls, and possible difference of prediction between indoors and outdoors falls. METHODS: For this sub-study of the SCOPE project participants reporting no falls at baseline, and survey data on falls at the 12-month and 24-month follow-up were included. Participant´s characteristics were assessed during the baseline interview and medical examinations. Falls as well as injurious falls and fall circumstances were obtained self-reported. SPPB and its association with fallers vs. no fallers at 12 and at 24 months were studied with logistic regression models. RESULTS: The 1198 participants had a median age of 79 years (77-82), and a median SPPB of 10 (8-11), with a 52.5% of female. A total of 227 and 277 falls (12- and 24- month visits, respectively) were reported. In the crude model, the SPPB sum scores (p < 0.001) as well as most single item scores were significant different between fallers and non-fallers over time. However, the association was attenuated in models adjusted for age, sex, marital status, number of medications, quality of life, handgrip strength, and muscle mass [e.g., 12 months; OR 0.94 (0.87-1.02)]. While SPPB fails to differentiate between injurious and non-injurious falls (p = 0.48), a lower SPPB score was associated with falls at home (p < 0.01) after 24 months. CONCLUSION: SBPP was not able to significantly predict the risk of falling as well as experiencing an injurious fall. TRIAL REGISTRATION: This study was registered prospectively on 25th February 2016 at clinicaltrials.gov (NCT02691546).