Model-Based Optimization of Solid-Supported Micro-Hotplates for Microfluidic Cryofixation.

Cryofixation by ultra-rapid freezing is widely regarded as the gold standard for preserving cell structure without artefacts for electron microscopy. However, conventional cryofixation technologies are not compatible with live imaging, making it difficult to capture dynamic cellular processes at a precise time. To overcome this limitation, we recently introduced a new technology, called microfluidic cryofixation.

"Numbers call for action, personalized narratives provide support and recognition": a qualitative assessment of cancer patients' perspectives on patient-reported outcome measures (PROMs) feedback with narratives.

Purpose: Patient-reported outcome measures (PROMs) are questionnaires completed by patients to gain insight in their health-related quality of life. However, patients often find the interpretation of PROMS challenging. A personalized narrative, i.

Vigorous Exercise in Patients With Congenital Long QT Syndrome: Results of the Prospective, Observational, Multinational LIVE-LQTS Study.

Background: Whether vigorous exercise increases risk of ventricular arrhythmias for individuals diagnosed and treated for congenital long QT syndrome (LQTS) remains unknown.

Methods: The National Institutes of Health-funded LIVE-LQTS study (Lifestyle and Exercise in the Long QT Syndrome) prospectively enrolled individuals 8 to 60 years of age with phenotypic and/or genotypic LQTS from 37 sites in 5 countries from May 2015 to February 2019. Participants (or parents) answered physical activity and clinical events surveys every 6 months for 3 years with follow-up completed in February 2022.

The SK4 channel allosteric blocker, BA6b9, reduces atrial fibrillation substrate in rats with reduced ejection fraction.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is strongly associated with several comorbidities including heart failure (HF). AF in general, and specifically in the context of HF, is progressive in nature and associated with poor clinical outcomes. Current therapies for AF are limited in number and efficacy and do not target the underlying causes of atrial remodeling such as inflammation or fibrosis.

Immunotherapy-activated T cells recruit and skew late-stage activated M1-like macrophages that are critical for therapeutic efficacy.

Total tumor clearance through immunotherapy is associated with a fully coordinated innate and adaptive immune response, but knowledge on the exact contribution of each immune cell subset is limited. We show that therapy-induced intratumoral CD8 T cells recruited and skewed late-stage activated M1-like macrophages, which were critical for effective tumor control in two different murine models of cancer immunotherapy. The activated CD8 T cells summon these macrophages into the tumor and their close vicinity via CCR5 signaling.

Unique activity of a Keggin POM for efficient heterogeneous electrocatalytic OER.

Polyoxometalates (POMs) have been well studied and explored in electro/photochemical water oxidation catalysis for over a decade. The high solubility of POMs in water has limited its use in homogeneous conditions. Over the last decade, different approaches have been used for the heterogenization of POMs to exploit their catalytic properties.

T-cell stimulating vaccines empower CD3 bispecific antibody therapy in solid tumors.

CD3 bispecific antibody (CD3 bsAb) therapy is clinically approved for refractory hematological malignancies, but responses in solid tumors have been limited so far. One of the main hurdles in solid tumors is the lack of sufficient T-cell infiltrate. Here, we show that pre-treatment vaccination, even when composed of tumor-unrelated antigens, induces CXCR3-mediated T-cell influx in immunologically 'cold' tumor models in male mice.

Heterogeneous Electrocatalytic Oxygen Evolution Reaction by a Sol-Gel Electrode with Entrapped Na [Ru (μ-CO ) ]: The Effect of NaHCO.

The Na [Ru (μ-CO ) ] complex is acting as a water oxidation catalyst in a homogeneous system. Due to the significance of heterogeneous systems and the effect of bicarbonate on the kinetic, we studied the bicarbonate effect on the heterogeneous electrocatalyst by entrapping the Na [Ru (μ-CO ) ] complex in a sol-gel matrix. We have developed two types of sol-gel electrodes, which differ by the precursor, and are demonstrating their stability over a minimum of 200 electrochemical cycles.

Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment.

Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don't respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy.

Is There a Role for Vitamin K Antagonist in the Management of Atrial Fibrillation in 2023?

Purpose Of Review: To address the following question: Are vitamin K antagonists (VKA) obsolete as stroke prevention therapy for patients with atrial fibrillation (AF) and thromboembolic risk factors?

Recent Findings: A patient-level meta-analysis of the pivotal phase III randomized trials confirmed the favorable treatment effect of direct oral anticoagulants (DOAC) over VKA in multiple key patient subgroups. Among patients with AF and rheumatic heart disease (85% of whom had mitral stenosis), a randomized trial showed that rivaroxaban was not superior to VKA for stroke prevention. Caution should be exercised when prescribing DOAC for AF-related stroke prevention for patients with elevated body mass indices or history of bariatric surgery, patients with bioprosthetic heart valves, and those who require treatment with drugs that interact with cytochrome P450 and P-glycoprotein.

Rapid pathogen identification and phenotypic antimicrobial susceptibility directly from urine specimens.

Implementing effective antimicrobial therapy close to the onset of infection lowers morbidity and mortality and attenuates the spread of antimicrobial resistance. Current antimicrobial susceptibility testing (AST) methods, however, require several days to determine optimal therapies. We present technology and an automated platform that identify (ID) Urinary Tract Infection pathogens in 45 min and provide phenotypic AST results in less than 5 h from urine specimens without colony isolation.

Challenges in neoantigen-directed therapeutics.

A fundamental prerequisite for the efficacy of cancer immunotherapy is the presence of functional, antigen-specific T cells within the tumor. Neoantigen-directed therapy is a promising strategy that aims at targeting the host's immune response against tumor-specific antigens, thereby eradicating cancer cells. Initial forays have been made in clinical environments utilizing vaccines and adoptive cell therapy; however, many challenges lie ahead.

MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling.

The limited efficacy of immune checkpoint inhibitor treatment in triple-negative breast cancer (TNBC) patients is attributed to sparse or unresponsive tumor-infiltrating lymphocytes, but the mechanisms that lead to a therapy resistant tumor immune microenvironment are incompletely known. Here we show a strong correlation between MYC expression and loss of immune signatures in human TNBC. In mouse models of TNBC proficient or deficient of breast cancer type 1 susceptibility gene (BRCA1), MYC overexpression dramatically decreases lymphocyte infiltration in tumors, along with immune signature remodelling.

Allosteric inhibitors targeting the calmodulin-PIP2 interface of SK4 K channels for atrial fibrillation treatment.

The Ca-activated SK4 K channel is gated by Ca-calmodulin (CaM) and is expressed in immune cells, brain, and heart. A cryoelectron microscopy (cryo-EM) structure of the human SK4 K channel recently revealed four CaM molecules per channel tetramer, where the apo CaM C-lobe and the holo CaM -lobe interact with the proximal carboxyl terminus and the linker S4-S5, respectively, to gate the channel. Here, we show that phosphatidylinositol 4-5 bisphosphate (PIP2) potently activates SK4 channels by docking to the boundary of the CaM-binding domain.

Truncated FGFR2 is a clinically actionable oncogene in multiple cancers.

Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer. However, clinical responses to FGFR inhibitors have remained variable, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening and tumour modelling in mice, and find that the truncation of exon 18 (E18) of Fgfr2 is a potent driver mutation.

[Non-bacterial thrombotic endocarditis].

Non-bacterial thrombotic endocarditis (NBTE), also known as non-infective endocarditis, is a rare condition characterised by formation of sterile fibrin and platelet depositions on heart valves. NBTE is commonly seen in advanced malignancies, auto-immune disorders and conditions associated with a hypercoagulable state. Patients are often asymptomatic.

PROTECT: Prospective Phase-II-Trial Evaluating Adaptive Proton Therapy for Cervical Cancer to Reduce the Impact on Morbidity and the Immune System.

External beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy is a very effective treatment for locally advanced cervical cancer (LACC). However, treatment-related toxicity is common and reduces the patient's quality of life (QoL) and ability to complete treatment or undergo adjuvant therapies. Intensity modulated proton therapy (IMPT) enables a significant dose reduction in organs at risk (OAR), when compared to that of standard intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT).

Chemometric approach to characterization of the selected grape seed oils based on their fatty acids composition and FTIR spectroscopy.

Addressing the issues arising from the production and trade of low-quality foods necessitates developing new quality control methods. Cooking oils, especially those produced from the grape seeds, are an example of food products that often suffer from questionable quality due to various adulterations and low-quality fruits used for their production. Among many methods allowing for fast and efficient food quality control, the combination of experimental and advanced mathematical approaches seems most reliable.

Co-Stimulatory versus Cell Death Aspects of Agonistic CD40 Monoclonal Antibody Selicrelumab in Chronic Lymphocytic Leukemia.

Objectives: Chronic lymphocytic leukemia (CLL) is a common form of leukemia with a heterogeneous clinical course that remains incurable due to the development of therapy resistance. In lymph node proliferation centers, signals from the microenvironment such as CD40 ligation through interaction with follicular T helper cells shield CLL cells from apoptosis. Previous observations have shown that, despite CD40-induced changes in apoptotic mediators resulting in cell survival, CD40 activation also increases sensitivity to cell death by CD20 mAbs rituximab and obinutuzumab.

Targeting of Potassium Channels in Cardiac Arrhythmias.

Cardiomyocytes are endowed with a complex repertoire of ion channels, responsible for the generation of action potentials (APs), travelling waves of electrical excitation, propagating throughout the heart and leading to cardiac contractions. Cardiac AP waveforms are shaped by a striking diversity of K channels. The pivotal role of K channels in cardiac health and disease is underscored by the dramatic impact that K channel dysfunction has on cardiac arrhythmias.

Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy.

Background: T-cell-engaging CD3-bispecific antibodies (CD3-bsAbs) are promising modalities for cancer immunotherapy. Although this therapy has reached clinical practice for hematological malignancies, the absence of sufficient infiltrating T cells is a major barrier for efficacy in solid tumors. In this study, we exploited oncolytic reovirus as a strategy to enhance the efficacy of CD3-bsAbs in immune-silent solid tumors.

Vulvar cancer subclassification by HPV and p53 status results in three clinically distinct subtypes.

Objective: There is great need for better risk stratification in vulvar squamous cell carcinoma (VSCC). Our aim was to define the prognostic significance of stratifying VSCC based on p16 and p53 immunohistochemistry (IHC) as surrogate markers for HPV and TP53 mutations.

Methods: A large retrospective cohort of surgically treated women with primary VSCC was used.

Specific targeting of IL-1β activity to CD8 T cells allows for safe use as a vaccine adjuvant.

Annual administration and reformulation of influenza vaccines is required for protection against seasonal infections. However, the induction of strong and long-lasting T cells is critical to reach broad and potentially lifelong antiviral immunity. The NLRP3 inflammasome and its product interleukin-1β (IL-1β) are pivotal mediators of cellular immune responses to influenza, yet, overactivation of these systems leads to side effects, which hamper clinical applications.