STPP-UP: An alternative method for drug target identification using protein thermal stability.

Thermal proteome profiling (TPP) has significantly advanced the field of drug discovery by facilitating proteome-wide identification of drug targets and off-targets. However, TPP has not been widely applied for high-throughput drug screenings, since the method is labor intensive and requires a lot of measurement time on a mass spectrometer. Here, we present Single-tube TPP with Uniform Progression (STPP-UP), which significantly reduces both the amount of required input material and measurement time, while retaining the ability to identify drug targets for compounds of interest.

Myeloid-derived suppressor cells and tolerogenic dendritic cells are distinctively induced by PI3K and Wnt signaling pathways.

Imbalanced immune responses are a prominent hallmark of cancer and autoimmunity. Myeloid cells can be overly suppressive, inhibiting protective immune responses or inactive not controlling autoreactive immune cells. Understanding the mechanisms that induce suppressive myeloid cells, such as myeloid-derived suppressor cells (MDSCs) and tolerogenic dendritic cells (TolDCs), can facilitate the development of immune-restoring therapeutic approaches.

Longitudinal analysis on the ecological dynamics of the cervicovaginal microbiome in hrHPV infection.

The cervicovaginal microbiome (CVM) is a dynamic continuous microenvironment that can be clustered in microbial community state types (CSTs) and is associated with women's cervical health. -depleted communities particularly associate with an increased susceptibility for persistence of high-risk human papillomavirus (hrHPV) infections and progression of disease, but the long-term ecological dynamics of CSTs after hrHPV infection diagnosis remain poorly understood. To determine such dynamics, we examined the CVM of our longitudinal cohort of 141 women diagnosed with hrHPV infection at baseline with collected cervical smears at two timepoints six-months apart.

Human CD34-derived complete plasmacytoid and conventional dendritic cell vaccine effectively induces antigen-specific CD8 T cell and NK cell responses in vitro and in vivo.

Allogeneic stem cell transplantation (alloSCT) can be curative for hemato-oncology patients due to effective graft-versus-tumor immunity. However, relapse remains the major cause of treatment failure, emphasizing the need for adjuvant immunotherapies. In this regard, post-transplantation dendritic cell (DC) vaccination is a highly interesting strategy to boost graft-versus-tumor responses.

Longitudinal clinical phenotyping of post COVID condition in Mexican adults recovering from severe COVID-19: a prospective cohort study.

Introduction: Few studies have evaluated the presence of Post COVID-19 conditions (PCC) in people from Latin America, a region that has been heavily afflicted by the COVID-19 pandemic. In this study, we describe the frequency, co-occurrence, predictors, and duration of 23 symptoms in a cohort of Mexican patients with PCC.

Methods: We prospectively enrolled and followed adult patients hospitalized for severe COVID-19 at a tertiary care centre in Mexico City.

Live cell transcription-coupled nucleotide excision repair dynamics revisited.

Transcription-blocking lesions are specifically targeted by transcription-coupled nucleotide excision repair (TC-NER), which prevents DNA damage-induced cellular toxicity and maintains proper transcriptional processes. TC-NER is initiated by the stalling of RNA polymerase II (RNAPII), which triggers the assembly of TC-NER-specific proteins, namely CSB, CSA and UVSSA, which collectively control and drive TC-NER progression. Previous research has revealed molecular functions for these proteins, however, exact mechanisms governing the initiation and regulation of TC-NER, particularly at low UV doses have remained elusive, partly due to technical constraints.

AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival.

Background: AUTO1 is a fast off-rate CD19-targeting chimeric antigen receptor (CAR), which has been successfully tested in adult lymphoblastic leukemia. Tscm/Tcm-enriched CAR-T populations confer the best expansion and persistence, but Tscm/Tcm numbers are poor in heavily pretreated adult patients. To improve this, we evaluate the use of AKT inhibitor (VIII) with the aim of uncoupling T-cell expansion from differentiation, to enrich Tscm/Tcm subsets.

Plasma glycoproteomics delivers high-specificity disease biomarkers by detecting site-specific glycosylation abnormalities.

Introduction: The human plasma glycoproteome holds enormous potential to identify personalized biomarkers for diagnostics. Glycoproteomics has matured into a technology for plasma N-glycoproteome analysis but further evolution towards clinical applications depends on the clinical validity and understanding of protein- and site-specific glycosylation changes in disease.

Objectives: Here, we exploited the uniqueness of a patient cohort of genetic defects in well-defined glycosylation pathways to assess the clinical applicability of plasma N-glycoproteomics.

mRNA-based generation of marmoset PGCLCs capable of differentiation into gonocyte-like cells.

Primate germ cell development remains largely unexplored due to limitations in sample collection and the long duration of development. In mice, primordial germ cell-like cells (PGCLCs) derived from pluripotent stem cells (PSCs) can develop into functional gametes by in vitro culture or in vivo transplantation. Such PGCLC-mediated induction of mature gametes in primates is highly useful for understanding human germ cell development.

The impact of BNT162b2 mRNA vaccine on adaptive and innate immune responses.

The mRNA-based BNT162b2 protects against severe disease and mortality caused by SARS-CoV-2 via induction of specific antibody and T-cell responses. Much less is known about its broad effects on immune responses against other pathogens. Here, we investigated the adaptive immune responses induced by BNT162b2 vaccination against various SARS-CoV-2 variants and its effects on the responsiveness of immune cells upon stimulation with heterologous stimuli.

Cumulative thiopurine dosing and keratinocyte skin cancer in inflammatory bowel disease: a case-control study.

Background And Aim: Patients with inflammatory bowel disease (IBD) treated with thiopurines are at increased risk of keratinocyte skin cancer (KSC). Most international guidelines recommend yearly dermatological screening of thiopurine-treated patients. Whether the association between the development of KSC and the use of thiopurines is dose-dependent remains unclear.

Evaluation of the safety and immunological effects of Bacillus Calmette-Guérin in combination with checkpoint inhibitor therapy in a patient with neuroendocrine carcinoma: a case report.

Background: Immune checkpoint inhibitors have revolutionized therapy of advanced and metastatic cancers. However, a significant proportion of patients do not respond to immune checkpoint inhibitors or develop resistance. Therefore, novel therapies or combinations of therapies that may act synergistically are needed.

Separating friend from foe: Inhibition of TGF-β-induced detrimental SMAD1/5/9 phosphorylation while maintaining protective SMAD2/3 signaling in OA chondrocytes.

Objective: Transforming growth factor-β (TGF-β) signaling via SMAD2/3 is crucial to control cartilage homeostasis. However, TGF-β can also have detrimental effects by signaling via SMAD1/5/9 and thereby contribute to diseases like osteoarthritis (OA). In this study, we aimed to block TGF-β-induced SMAD1/5/9 signaling in primary human OA chondrocytes, while maintaining functional SMAD2/3 signaling.

Fatigue behaviour of a self-healing dental composite.

Objective: Novel self-healing resin-based composites containing microcapsules have been developed to improve the mechanical performance of dental restorations. However, the long-term fatigue behaviour of these self-healing composites has still been hardly investigated. Therefore, this manuscript studied the fatigue behaviour of self-healing composites containing microcapsules by subjecting the specimens to traditional staircase tests and ageing in a custom-designed chewing simulator (Rub&Roll) to simulate oral ageing physiologically relevant conditions.

Clonal Hematopoiesis Has Prognostic Value in Dilated Cardiomyopathy Independent of Age and Clone Size.

Background: Clonal hematopoiesis (CH) gives rise to mutated leukocyte clones that induce cardiovascular inflammation and thereby impact the disease course in atherosclerosis and ischemic heart failure. CH of indeterminate potential refers to a variant allele frequency (VAF) (a marker for clone size) in blood of ≥2%. The impact of CH clones-including small clone sizes (VAF <0.

Change in adiposity is associated with change in glycoprotein acetyls but not hsCRP in adolescents with severe obesity.

Background: Obesity-associated chronic inflammation mediates the development of adverse cardiometabolic outcomes. There are sparse data on associations between severe obesity and inflammatory biomarkers in adolescence; most are cross-sectional and limited to acute phase reactants. Here, we investigate associations between adiposity measures and inflammatory biomarkers in children and adolescents with severe obesity both cross-sectionally and longitudinally.

The Transcriptome Response to Azole Compounds in Shows Differential Gene Expression across Pathways Essential for Azole Resistance and Cell Survival.

The opportunistic pathogen is found on all continents and thrives in soil and agricultural environments. Its ability to readily adapt to novel environments and to produce billions of spores led to the spread of azole-resistant across the globe, posing a threat to many immunocompromised patients, including critically ill patients with severe influenza or COVID-19. In our study, we sought to compare the adaptational response to azoles from isolates that differ in azole susceptibility and genetic background.

Saponin-based adjuvants enhance antigen cross-presentation in human CD11c CD1c CD5 CD163 conventional type 2 dendritic cells.

Background: Adjuvants are key for effective vaccination against cancer and chronic infectious diseases. Saponin-based adjuvants (SBAs) are unique among adjuvants in their ability to induce robust cell-mediated immune responses in addition to antibody responses. Recent preclinical studies revealed that SBAs induced cross-presentation and lipid bodies in otherwise poorly cross-presenting CD11b murine dendritic cells (DCs).

Diagnosis of childhood febrile illness using a multi-class blood RNA molecular signature.

Background: Appropriate treatment and management of children presenting with fever depend on accurate and timely diagnosis, but current diagnostic tests lack sensitivity and specificity and are frequently too slow to inform initial treatment. As an alternative to pathogen detection, host gene expression signatures in blood have shown promise in discriminating several infectious and inflammatory diseases in a dichotomous manner. However, differential diagnosis requires simultaneous consideration of multiple diseases.

A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance.

Cancer cells make extensive use of the folate cycle to sustain increased anabolic metabolism. Multiple chemotherapeutic drugs interfere with the folate cycle, including methotrexate and 5-fluorouracil that are commonly applied for the treatment of leukemia and colorectal cancer (CRC), respectively. Despite high success rates, therapy-induced resistance causes relapse at later disease stages.

Vaginal Fibroblast Behavior as a Function of Stiffness Changes in a Polyisocyanide Hydrogel for Prolapse Repair.

There is an urgent need for improved outcomes in the treatment of pelvic organ prolapse (POP). Success of primary surgery relies on the load bearing capacity of plicated connective tissue underneath the vaginal wall, which is compromised due to an altered vaginal fibroblast function and collagen composition. There is an important factor in connective tissue repair that relates to changes in stiffness of the vaginal fibroblast microenvironment, which influences cell activity through cellular mechanosensing.

Pathologists' first opinions on barriers and facilitators of computational pathology adoption in oncological pathology: an international study.

Computational pathology (CPath) algorithms detect, segment or classify cancer in whole slide images, approaching or even exceeding the accuracy of pathologists. Challenges have to be overcome before these algorithms can be used in practice. We therefore aim to explore international perspectives on the future role of CPath in oncological pathology by focusing on opinions and first experiences regarding barriers and facilitators.

Effects of COVID-19 vaccination and previous infection on Omicron SARS-CoV-2 infection and relation with serology.

An increasing proportion of the population has acquired immunity through COVID-19 vaccination and previous SARS-CoV-2 infection, i.e., hybrid immunity, possibly affecting the risk of new infection.

Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study.

Background: The PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice.

Methods: Febrile children and controls were recruited on presentation to hospital in 9 European countries 2016-2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data.