Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors.

Bivalent molecules consisting of groups connected through bridging linkers often exhibit strong target binding and unique biological effects. However, developing bivalent inhibitors with the desired activity is challenging due to the dual motif architecture of these molecules and the variability that can be introduced through differing linker structures and geometries. We report a set of alternatively linked bivalent EGFR inhibitors that simultaneously occupy the ATP substrate and allosteric pockets.

Pitfalls and Considerations in Determining the Potency and Mutant Selectivity of Covalent Epidermal Growth Factor Receptor Inhibitors.

Enzyme inhibitors that form covalent bonds with their targets are being increasingly pursued in drug development. Assessing their biochemical activity relies on time-dependent assays, which are distinct and more complex compared with methods commonly employed for reversible-binding inhibitors. To provide general guidance to the covalent inhibitor development community, we explored methods and reported kinetic values and experimental factors in determining the biochemical activity of various covalent epidermal growth factor receptor (EGFR) inhibitors.

Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors.

Bivalent molecules consisting of groups connected through bridging linkers often exhibit strong target binding and unique biological effects. However, developing bivalent inhibitors with the desired activity is challenging due to the dual motif architecture of these molecules and the variability that can be introduced through differing linker structures and geometries. We report a set of alternatively linked bivalent EGFR inhibitors that simultaneously occupy the ATP substrate and allosteric pockets.

[Registry Research Funding of the German Society of Plastic, Reconstructive and Aesthetic Surgery (DGPRÄC) and Research Funding Report 2021/2022].

Background: Research is an integral part of academic medicine. In plastic surgery, it sets the course for innovations in the specialty. The purpose of this study is to present the research performance of plastic surgeons in Germany for the period 2021/2022 and to compare it with previous periods.

Low dose pediatric chest computed tomography on a photon counting detector system - initial clinical experience.

Background: With the clinical release of a photon counting detector-based computed tomography (CT) system, the potential benefits of this new technology need to be evaluated clinically. Literature concerning this new generation of detector is sparse, especially in the field of pediatric radiology. Therefore, this study outlines our initial experience with ultra-low dose chest CT imaging on the new photon counting CT system.

Prognostic Factors for Effectiveness Outcomes After Transarterial Radioembolization in Metastatic Colorectal Cancer: Results From the Multicentre Observational Study CIRT.

Background: Transarterial radioembolisation (TARE) with Yttrium-90 resin microspheres is a treatment option for patients with metastatic colorectal cancer in the liver (mCRC). A better understanding of the prognostic factors and treatment application can improve survival outcomes.

Methods: We analysed the safety and effectiveness of 237 mCRC patients included in the prospective observational study CIRSE Registry for SIR-Spheres Therapy (CIRT) for independent prognostic factors for overall survival (OS), progression-free survival (PFS) and hepatic progression-free survival (hPFS) using the Cox proportional-hazard model.

Translational immunoPET imaging using a radiolabeled GD2-specific antibody in neuroblastoma.

Antibodies targeting surface expressed disialoganglioside GD2 are increasingly used in neuroblastoma immunotherapy and might also have potential for use in radioimmunotherapy. As such targeted treatments might benefit from a dedicated theranostic approach, we studied the influence of radiolabeling on the binding characteristics of ch14.18 antibodies produced by Chinese hamster ovary (CHO) cells and evaluated the benefit of GD2-ImmunoPET as a potential tool for therapy planning.

Detailed functional results after bladder-preserving surgery and high-dose-rate brachytherapy in pediatric bladder/prostate rhabdomyosarcoma.

Purpose: In pediatric bladder/prostate-rhabdomyosarcoma, the rate of bladder preservation after neoadjuvant chemotherapy is high, with an excellent oncological outcome. Information about functional urological long-term outcomes is rare.

Methods: Data of all patients who had undergone bladder-preserving surgery with or without brachytherapy at our institution between 2009 and 2020 were analyzed retrospectively.

Prospective validation of a new imaging scorecard to assess leptomeningeal metastasis: A joint EORTC BTG and RANO effort.

Background: Validation of the 2016 RANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. Accordingly, this joint EORTC Brain Tumor Group and RANO effort sought to prospectively validate a revised MRI scorecard for response assessment in leptomeningeal metastasis.

Methods: Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform.

Proteinuric chronic kidney disease is associated with altered red blood cell lifespan, deformability and metabolism.

Anemia is a common complication of chronic kidney disease, affecting the quality of life of patients. Among various factors, such as iron and erythropoietin deficiency, reduced red blood cell (RBC) lifespan has been implicated in the pathogenesis of anemia. However, mechanistic data on in vivo RBC dysfunction in kidney disease are lacking.

[Registry Research Funding of the German Society of Plastic, Reconstructive and Aesthetic Surgeons (DGPRÄC) and Research Funding Report 2019/2020].

Background:  Since 2015/16 the DGPRÄC collects, evaluates and publishes the research activities of academic sections, departments and clinics for plastic surgery at university hospitals in Germany, in order to raise the awareness of plastic surgical research performance.

Materials And Methods:  The directors of plastic surgical academic institutions were contacted via the DGPRÄC and asked to report any requested/approved and rejected research applications to public, non-public and industrial funding organizations. Data was collected in our previously established online database: https://docs.

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

Interactome maps are valuable resources to elucidate protein function and disease mechanisms. Here, we report on an interactome map that focuses on neurodegenerative disease (ND), connects ∼5,000 human proteins via ∼30,000 candidate interactions and is generated by systematic yeast two-hybrid interaction screening of ∼500 ND-related proteins and integration of literature interactions. This network reveals interconnectivity across diseases and links many known ND-causing proteins, such as α-synuclein, TDP-43, and ATXN1, to a host of proteins previously unrelated to NDs.

[Economic factors in microsurgery - Report of the consensus workshop of the German-Speaking Society for Microsurgery of Peripheral Nerves and Vessels - (DAM)].

In addition to outcome assessments, cost effectiveness of surgical treatments becomes increasingly important. Both, insurance companies and hospital administrations aim for short and efficient procedures to reduce costs.Microsurgical procedures are often surpassing traditional treatment options in terms of function and aesthetics.

Probing the Effects of Strong Electromagnetic Fields with Charge-Dependent Directed Flow in Pb-Pb Collisions at the LHC.

The first measurement at the LHC of charge-dependent directed flow (v_{1}) relative to the spectator plane is presented for Pb-Pb collisions at sqrt[s_{NN}]=5.02  TeV. Results are reported for charged hadrons and D^{0} mesons for the transverse momentum intervals p_{T}>0.

Evidence of Spin-Orbital Angular Momentum Interactions in Relativistic Heavy-Ion Collisions.

The first evidence of spin alignment of vector mesons (K^{*0} and ϕ) in heavy-ion collisions at the Large Hadron Collider (LHC) is reported. The spin density matrix element ρ_{00} is measured at midrapidity (|y|<0.5) in Pb-Pb collisions at a center-of-mass energy (sqrt[s_{NN}]) of 2.

E-vapor aerosols do not compromise bone integrity relative to cigarette smoke after 6-month inhalation in an ApoE mouse model.

Cigarette smoke (CS) exposure is one of the leading risk factors for human health. Nicotine-containing inhalable products, such as e-cigarettes, can effectively support tobacco harm reduction approaches. However, there are limited comparative data on the effects of the aerosols generated from electronic vapor products (e-vapor) and CS on bone.

The Role of Reconstructive Surgery and Brachytherapy in Pediatric Bladder/Prostate Rhabdomyosarcoma.

Purpose: The surgical approach to localized bladder/prostate rhabdomyosarcoma in children may change due to a new radiotherapeutic modality. We assessed the impact of brachytherapy following surgery for local tumor control, and report surgical techniques and outcomes.

Materials And Methods: We retrospectively analyzed the records of all children who underwent surgery for bladder/prostate rhabdomyosarcoma, including tumor relapse, at our institution from 2009 onward.

Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: a DeCOG* study in 380 patients.

Background: Nivolumab combined with ipilimumab have shown activity in melanoma brain metastasis (MBM). However, in most of the clinical trials investigating immunotherapy in this subgroup, patients with symptomatic MBM and/or prior local brain radiotherapy were excluded. We studied the efficacy of nivolumab plus ipilimumab alone or in combination with local therapies regardless of treatment line in patients with asymptomatic and symptomatic MBM.

Scattering Studies with Low-Energy Kaon-Proton Femtoscopy in Proton-Proton Collisions at the LHC.

The study of the strength and behavior of the antikaon-nucleon (K[over ¯]N) interaction constitutes one of the key focuses of the strangeness sector in low-energy quantum chromodynamics (QCD). In this Letter a unique high-precision measurement of the strong interaction between kaons and protons, close and above the kinematic threshold, is presented. The femtoscopic measurements of the correlation function at low pair-frame relative momentum of (K^{+}p⊕K^{-}p[over ¯]) and (K^{-}p⊕K^{+}p[over ¯]) pairs measured in pp collisions at sqrt[s]=5, 7, and 13 TeV are reported.

Differing Pulmonary Structural Abnormalities Detected on Pulmonary MR Imaging in Cystic Fibrosis Patients with Varying Pancreatic Function.

Purpose:  In cystic fibrosis (CF) the phenotypic expression of complaints varies widely. Genotypes with sufficient pancreatic function (PS) exhibit milder lung disease compared to CF patients with insufficient pancreatic function (PI). The purpose of this study was to evaluate structural lung disease (SLD) in CF patients with differing pancreatic status but similar results on pulmonary function testing using a pulmonary magnetic resonance imaging score (MR-CF score).

Correction to: Allogeneic hematopoietic stem cell transplantation in two brothers with DNA ligase IV deficiency: a case report and review of the literature.

After publication of the original article (1), it was brought to our attention that references 24 and 31 are inappropriately cited in the article.