[Combination drug therapy in pulmonary hypertension: switch from selexipaq to intravenous trepostinil].

A wide range of substances is currently available for the treatment of patients with pulmonary arterial hypertension. The current recommendations for initial drug therapy are based on the patient's risk profile. For patients at high risk, an initial triple combination therapy with different substances including prostanoids is recommended.

Prognostic relevance of exercise pulmonary hypertension: results of the multicentre PEX-NET Clinical Research Collaboration.

Background: Exercise pulmonary hypertension (PH) was defined by a mean pulmonary arterial pressure (mPAP)/cardiac output (CO) slope >3 mmHg·min·L between rest and exercise in the 2022 European Society of Cardiology/European Respiratory Society PH guidelines. However, large, multicentre studies on the prognostic relevance of exercise haemodynamics and its added value to resting haemodynamics are missing.

Patients And Methods: The PEX-NET (Pulmonary Haemodynamics during Exercise Network) registry enrolled patients who underwent clinically indicated right heart catheterisations both at rest and ergometer exercise from 23 PH centres worldwide.

The Immunomodulatory Effect of Different FLT3 Inhibitors on Dendritic Cells.

Background: FMS-like tyrosine kinase 3 (FLT3) mutations or internal tandem duplication occur in 30% of acute myeloid leukemia (AML) cases. In these cases, FLT3 inhibitors (FLT3i) are approved for induction treatment and relapse. Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the recommended post-induction therapy for suitable patients.

Anti-MDA5 autoantibodies predict clinical dynamics of dermatomyositis following SARS-CoV-2 mRNA vaccination: a retrospective statistical analysis of case reports.

Since the introduction of mRNA vaccines against SARS-CoV-2, the induction of autoimmunity by mRNA vaccination has been discussed. Several cases of dermatomyositis (DM) associated with mRNA vaccination against SARS-CoV-2 infection have been reported. The question is whether there is a common pathomechanism for the induction of DM by this mRNA vaccination.

[Prolonged weaning after long-term ventilation due to SARS-CoV-2 infection: a multicenter retrospective analysis].

Unlabelled: Some of the patients with SARS-CoV-2 infection (COVID-19) received invasive ventilation during inpatient care. Weaning from ventilation was difficult for some patients (so-called prolonged weaning).

Patients: Patients (n=751) with prolonged weaning (reason for ventilation "pneumonia" and "acute respiratory failure") from four centers for the period 2011-23 from the "WeanNet" registry were used as a matched group.

Development of a Crystallographic Screening to Identify Sudan Virus VP40 Ligands.

The matrix protein VP40 of the highly pathogenic Sudan virus (genus ) is a multifunctional protein responsible for the recruitment of viral nucleocapsids to the plasma membrane and the budding of infectious virions. In addition to its role in assembly, VP40 also downregulates viral genome replication and transcription. VP40's existence in various homo-oligomeric states is presumed to underpin its diverse functional capabilities during the viral life cycle.

Next-generation cancer vaccines and emerging immunotherapy combinations.

Therapeutic cancer vaccines have been a subject of research for several decades as potential new weapons to tackle malignancies. Their goal is to induce a long-lasting and efficient antitumour-directed immune response, capable of mediating tumour regression, preventing tumour progression, and eradicating minimal residual disease, while avoiding major adverse effects. Development of new vaccine technologies and antigen prediction methods has led to significant improvements in cancer vaccine efficacy.

Potent anti-coronaviral activity of pateamines and new insights into their mode of action.

Pateamines, derived from the sponge , function as inhibitors of the RNA helicase eIF4A and exhibit promising antiviral and anticancer properties. eIF4A plays a pivotal role in unwinding stable RNA structures within the 5'-UTR of selected mRNAs, facilitating the binding of the 43S preinitiation complex during translation initiation. Pateamines function by clamping RNA substrates onto the eIF4A surface, effectively preventing eIF4A from carrying out the unwinding step.

Case report: Ipilimumab and nivolumab in metastatic adrenocortical cancer with high tumor mutational burden.

In the setting of metastatic adrenocortical cancer, there are limited therapy options such as mitotane and platinum-based chemotherapy with only low response rates. Ipilimumab and nivolumab are approved for several solid cancer types. Tumor mutational burden is one established marker to predict treatment success of immunotherapy and has been associated with improved response rates to immune checkpoint inhibitors.

Alpha2 Agonist Use in Critically Ill Adults: A Focus on Sedation and Withdrawal Prevention.

The management of sedation in critically ill adults poses a unique challenge to clinicians. Dexmedetomidine, an α agonist, has a unique mechanism and favorable pharmacokinetics, making it an attractive intravenous option for sedation and delirium in the intensive care unit. However, patients may be at risk for withdrawal with prolonged use, adding to the complexity of sedation and agitation management in this patient population.

Cardiopulmonary exercise testing and the 2022 definition of pulmonary hypertension.

Parameters of cardiopulmonary exercise testing significantly discriminate between healthy subjects and patients with pulmonary hypertension (PH), also according to the new 2022 definition of pulmonary hypertension (mean pulmonary arterial pressure mPAP > 20 mmHg). The cut-offs indicating on PH were peakVO ≤ 16.7 mL/min/kg (Youden-Index YI = 0.

Synthesis and structural characterization of new macrocyclic inhibitors of the Zika virus NS2B-NS3 protease.

Three new series of macrocyclic active site-directed inhibitors of the Zika virus (ZIKV) NS2B-NS3 protease were synthesized. First, attempts were made to replace the basic P3 lysine residue of our previously described inhibitors with uncharged and more hydrophobic residues. This provided numerous compounds with inhibition constants between 30 and 50 nM.

What doesn't fit is made to fit: Pim-1 kinase adapts to the configuration of stilbene-based inhibitors.

Recently, we have developed novel Pim-1 kinase inhibitors starting from a dihydrobenzofuran core structure using a computational approach. Here, we report the design and synthesis of stilbene-based Pim-1 kinase inhibitors obtained by formal elimination of the dihydrofuran ring. These inhibitors of the first design cycle, which were obtained as inseparable cis/trans mixtures, showed affinities in the low single-digit micromolar range.

Severe autoimmune hemolytic anemia following immunotherapy with checkpoint inhibitors in two patients with metastatic melanoma: a case report.

Introduction: Over the past decade, immune checkpoint inhibitors such as antibodies against cytotoxicity T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have become an important armamentarium against a broad spectrum of malignancies. However, these specific inhibitors can cause adverse autoimmune reactions by impairing self-tolerance. Hematologic side effects of immune checkpoint inhibitors, including autoimmune hemolytic anemia (AIHA), are rare but can be life-threatening.

Rapid protection against viral infections by chemokine-accelerated post-exposure vaccination.

Introduction: Prophylactic vaccines generate strong and durable immunity to avoid future infections, whereas post-exposure vaccinations are intended to establish rapid protection against already ongoing infections. Antiviral cytotoxic CD8 T cells (CTL) are activated by dendritic cells (DCs), which themselves must be activated by adjuvants to express costimulatory molecules and so-called signal 0-chemokines that attract naive CTL to the DCs.

Hypothesis: Here we asked whether a vaccination protocol that combines two adjuvants, a toll-like receptor ligand (TLR) and a natural killer T cell activator, to induce two signal 0 chemokines, synergistically accelerates CTL activation.

Crystallographic Fragment Screening on the Type III Secretion System Chaperone IpgC.

The pathogenicity factor IpgC belongs to the class II of type III secretion system chaperones, whose members are characterized by a tetratricopeptide repeat (TPR) domain consisting of three and a half TPR motifs. Since IpgC is essential for virulence, we determined a high-resolution crystal structure of this chaperone to facilitate its use as a target for the structure-based design of anti-shigellosis compounds. The crystal structure revealed two possible homodimer assemblies, which strongly differ from the homodimer architectures so far known for IpgC and orthologues thereof.

Early combination therapy of COVID-19 in high-risk patients.

Purpose: Prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed in immunocompromised hosts. Early monotherapy with direct-acting antivirals or monoclonal antibodies, as recommended by the international guidelines, does not prevent this with certainty. Dual therapies may therefore have a synergistic effect.

[Fatal course of pulmonary embolism after successful pulmonary endarterectomy: a rare case].

We report a case of a 43-year-old woman who suffered from recurrent pulmonary embolism leading to chronic thromboembolic pulmonary hypertension. Pulmonary endarterectomy was performed with good result. However, two years later, after a SARS-CoV2 infection and despite oral anticoagulation therapy, the patient presented with clinical symptoms of pulmonary embolism, which was confirmed by computed tomography as an extensive pulmonary embolism.

Spoilt for choice: different immunosuppressive potential of anaplastic lymphoma kinase inhibitors for non small cell lung cancer.

Introduction: Several anaplastic lymphoma kinase (ALK)-inhibitors (ALKi) have been approved for the treatment of ALK-translocated advanced or metastatic Non Small Cell Lung Cancer (NSCLC), amongst crizotinib and alectinib. This forces physicians to choose the most suitable compound for each individual patient on the basis of the tumor´s genetic profile, but also in regard to toxicities and potential co-treatments. Moreover, targeted therapies might be combined with or followed by immunotherapy, which underlines the importance to gain detailed knowledge about potential immunomodulatory effects of these inhibitors.

Optimized Conformal Total Body Irradiation with VMAT Using a Linear-Accelerator-Based Radiosurgery Treatment System in Comparison to the Golden Standard Helical TomoTherapy.

Modern irradiation techniques for optimized conformal TBI can be realized by Helical Tomotherapy (HT) or Volumetric Modulated Arc Therapy (VMAT), depending on the availability of suitable specialized equipment. In this dosimetric planning study, we compared both modalities and addressed the question of whether VMAT with small field sizes is also suitable as a backup in case of HT equipment malfunctions. For this purpose, we retrospectively used planning computed tomography (CT) data from 10 patients treated with HT with a total dose of 8 Gy (n = 5) or 12 Gy (n = 5) for treatment planning for VMAT with a small field size (36 × 22 cm).

Biomarker-based risk prediction for the onset of neuroinflammation in X-linked adrenoleukodystrophy.

Background: X-linked adrenoleukodystrophy (X-ALD) is highly variable, ranging from slowly progressive adrenomyeloneuropathy to severe brain demyelination and inflammation (cerebral ALD, CALD) affecting males with childhood peak onset. Risk models integrating blood-based biomarkers to indicate CALD onset, enabling timely interventions, are lacking. Therefore, we evaluated the prognostic value of blood biomarkers in addition to current neuroimaging predictors for early detection of CALD.

The C-terminus of Sudan ebolavirus VP40 contains a functionally important CXC motif, a target for redox modifications.

The Ebola virus matrix protein VP40 mediates viral budding and negatively regulates viral RNA synthesis. The mechanisms by which these two functions are exerted and regulated are unknown. Using a high-resolution crystal structure of Sudan ebolavirus (SUDV) VP40, we show here that two cysteines in the flexible C-terminal arm of VP40 form a stabilizing disulfide bridge.