MASTER-NAADP: a membrane permeable precursor of the Ca mobilizing second messenger NAADP.

Upon stimulation of membrane receptors, nicotinic acid adenine dinucleotide phosphate (NAADP) is formed as second messenger within seconds and evokes Ca signaling in many different cell types. Here, to directly stimulate NAADP signaling, MASTER-NAADP, a Membrane permeAble, STabilized, bio-rEversibly pRotected precursor of NAADP is synthesized and release of its active NAADP mimetic, benzoic acid C-nucleoside, 2'-phospho-3'F-adenosine-diphosphate, by esterase digestion is confirmed. In the presence of NAADP receptor HN1L/JPT2 (hematological and neurological expressed 1-like protein, HN1L, also known as Jupiter microtubule-associated homolog 2, JPT2), this active NAADP mimetic releases Ca and increases the open probability of type 1 ryanodine receptor.

10th European Calcium Society symposium: The Ca2+-signaling toolkit in cell function, health and disease.

The 10th European Calcium Society symposium, organized in Leuven, Belgium on November 15-17, 2023, focused on the role of Ca2+ signaling in cell function, health and disease. The symposium featured six scientific sessions, 16 invited speakers - of whom two were postdoctoral researchers - and 14 short talks. The talks covered various aspects of intracellular Ca2+ signaling and its implications in pathology.

Increasing the power and spectral efficiencies of an OFDM-based VLC system through multi-objective optimization.

The nonlinearity induced by light-emitting diodes in visible light communication (VLC) systems presents a challenge to the parametrization of orthogonal frequency division multiplexing (OFDM). The goal of the multi-objective optimization problem presented in this study is to maximize the transmitted power (superimposed LED bias-current and signal amplification) for both conventional and constant envelope (CE) OFDM while also maximizing spectral efficiency. The bit error rate (BER) metric is used to evaluate the optimization using the non-dominated sorting genetic algorithm II.

Impact of COVID-19 Related Restrictions on Infections in Children with Cancer or after Hematopoietic SCT.

Background: Infections are a major concern for immunocompromised children. We investigated whether non-pharmaceutical interventions (NPIs) implemented in the general population during the coronavirus disease 2019 (COVID-19) pandemic in Germany had an impact on frequency, type and severity of infections in these patients.

Patients And Methods: We analyzed all admissions to the clinic of pediatric hematology, oncology and stem cell transplantation (SCT) with (suspected) infection or fever of unknown origin (FUO) from 2018 to 2021.

The Effect of Physiatry Involvement for Patients With Acute Traumatic Spinal Cord Injury at a Level 1 Trauma Center.

Objective: To explore the impact of physiatry on acute traumatic spinal cord injury (ATSCI) outcomes using a propensity score matching (PSM) analysis.

Methods: We retrospectively reviewed all patients with ATSCI at a level 1 trauma center from 2018 to 2019. In a 1:1 fashion, we matched patients who were evaluated by physiatry to those who were not.

Pharmacokinetics of Ribavirin in the Treatment of Lassa Fever: An Observational Clinical Study at the Irrua Specialist Teaching Hospital, Edo State, Nigeria.

Background: Lassa fever is endemic in large parts of West Africa. The recommended antiviral treatment is ribavirin. Two treatment regimens are currently endorsed in Nigeria: the "McCormick regimen" based on a study published in 1986 and the "Irrua regimen" constituting a simplified schedule developed at the Irrua Specialist Teaching Hospital, Nigeria.

Examining the accuracy of the AM-PAC "6-clicks" at predicting discharge disposition in traumatic brain injury.

Objective: To assess the accuracy of the AM-PAC "6-Clicks" in predicting discharge dispositions among severely injured patients with an acute traumatic brain injury (TBI).

Methods: We performed a retrospective review of patients with a TBI who presented to our trauma center from 2016 through 2018 and received a "6-Clicks" assessment. Outcomes were hospital length of stay (LOS) and discharge disposition: home, inpatient rehabilitation facility (IRF), subacute location (SL), or death/hospice.

Chronic pharmacological antagonism of the GM-CSF receptor in mice does not replicate the pulmonary alveolar proteinosis phenotype but does alter lung surfactant turnover.

Granulocyte macrophage colony stimulating factor (GM-CSF) is a key participant in, and a clinical target for, the treatment of inflammatory diseases including rheumatoid arthritis (RA). Therapeutic inhibition of GM-CSF signalling using monoclonal antibodies to the α-subunit of the GM-CSF receptor (GMCSFRα) has shown clear benefit in patients with RA, giant cell arteritis (GCAs) and some efficacy in severe SARS-CoV-2 infection. However, GM-CSF autoantibodies are associated with the development of pulmonary alveolar proteinosis (PAP), a rare lung disease characterised by alveolar macrophage (AM) dysfunction and the accumulation of surfactant lipids.

Phase I Study of MEDI3726: A Prostate-Specific Membrane Antigen-Targeted Antibody-Drug Conjugate, in Patients with mCRPC after Failure of Abiraterone or Enzalutamide.

Purpose: MEDI3726 is an antibody-drug conjugate targeting the prostate-specific membrane antigen and carrying a pyrrolobenzodiazepine warhead. This phase I study evaluated MEDI3726 monotherapy in patients with metastatic castration-resistant prostate cancer after disease progression on abiraterone and/or enzalutamide and taxane-based chemotherapy.

Patients And Methods: MEDI3726 was administered at 0.

HER2-targeted antibody-drug conjugate induces host immunity against cancer stem cells.

We previously tested HER2-targeted antibody-drug conjugates (ADCs) in immunocompromised (SCID) mice, precluding evaluation of host immunity, impact on cancer stem cells (CSCs), and potential benefit when combined with PD-L1 blockade. In this study, we tested HER2-targeted ADC in two immunocompetent mouse tumor models. HER2-targeted ADC specifically inhibited the growth of HER2-expressing tumors, prolonged animal survival, and reduced HER2 and PD-L1 cells.

Adrenal venous sampling in primary hyperaldosteronism: correlation of hormone indices and collimated C-arm CT findings.

Purpose: To evaluate the feasibility and effect of an approach to adrenal venous sampling (AVS) analysis by combining established selective cortisol and aldosterone indices with the acquisition of a collimated C-arm CT(CACT).

Methods: Overall, 107 consecutive patients (45f,62 m; 54 ± 10 years) undergoing 111 AVS procedures without hormonal stimulation from 7/13 to 2/20 in a single institution were retrospectively analysed. Hormone levels were measured in sequential samples of the suspected adrenal veins and right iliac vein, and selectivity indices (SI) computed.

Implicit Theory of Mind under realistic social circumstances measured with mobile eye-tracking.

Recently, there has been a debate whether implicit Theory of Mind can be reliably measured using anticipatory looking tasks. Previous anticipatory looking paradigms used video stimuli to measure implicit Theory of Mind; however, numerous replications of these paradigms were unsuccessful. This lack of replications may be due to video stimuli not being sufficiently engaging.

Patient Selection Strategies to Maximize Therapeutic Index of Antibody-Drug Conjugates: Prior Approaches and Future Directions.

Antibody-drug conjugates (ADC) are targeted agents that have shown promise in treating cancer. A central challenge in development of ADCs is the relatively narrow therapeutic index observed in clinical studies. Patient selection strategies based on expression of the target in tumors have the potential to maximize benefit and provide the best chance of clinical success; however, implementation of biomarker-driven trials can be difficult both practically and scientifically.

Biosynthesis and characterization of a recombinant eukaryotic allophycocyanin using prokaryotic accessory enzymes.

Phycobiliproteins (PBPs) are colored fluorescent proteins present in cyanobacteria, red alga, and cryptophyta. These proteins have many potential uses in biotechnology going from food colorants to medical applications. Allophycocyanin, the simplest PBP, is a heterodimer of αβ subunits that oligomerizes as a trimer (αβ) .

Design and characterization of homogenous antibody-drug conjugates with a drug-to-antibody ratio of one prepared using an engineered antibody and a dual-maleimide pyrrolobenzodiazepine dimer.

Most strategies used to prepare homogeneous site-specific antibody-drug conjugates (ADCs) result in ADCs with a drug-to-antibody ratio (DAR) of two. Here, we report a disulfide re-bridging strategy to prepare homogeneous ADCs with DAR of one using a dual-maleimide pyrrolobenzodiazepine (PBD) dimer (SG3710) and an engineered antibody (Flexmab), which has only one intrachain disulfide bridge at the hinge. We demonstrate that SG3710 efficiently re-bridge a Flexmab targeting human epidermal growth factor receptor 2 (HER2), and the resulting ADC was highly resistant to payload loss in serum and exhibited potent anti-tumor activity in a HER2-positive gastric carcinoma xenograft model.

Humanised effector-null FcγRIIA antibody inhibits immune complex-mediated proinflammatory responses.

Objective: Immune complexes (ICs) play a critical role in the pathology of autoimmune diseases. The aim of this study was to generate and characterise a first-in-class anti-FcγRIIA antibody (Ab) VIB9600 (previously known as MEDI9600) that blocks IgG immune complex-mediated cellular activation for clinical development.

Methods: VIB9600 was humanised and optimised from the IV.

Preclinical evaluation of a GFRA1 targeted antibody-drug conjugate in breast cancer.

Despite recent advances in treatment, breast cancer remains the second-most common cause of cancer death among American women. A greater understanding of the molecular characteristics of breast tumors could ultimately lead to improved tumor-targeted treatment options, particularly for subsets of breast cancer patients with unmet needs. Using an unbiased genomics approach to uncover membrane-localized tumor-associated antigens (TAAs), we have identified glial cell line derived neurotrophic factor (GDNF) family receptor α 1 (GFRA1) as a breast cancer TAA.

Fractionated Dosing Improves Preclinical Therapeutic Index of Pyrrolobenzodiazepine-Containing Antibody Drug Conjugates.

To use preclinical models to identify a dosing schedule that improves tolerability of highly potent pyrrolobenzodiazepine dimers (PBDs) antibody drug conjugates (ADCs) without compromising antitumor activity. A series of dose-fractionation studies were conducted to investigate the pharmacokinetic drivers of safety and efficacy of PBD ADCs in animal models. The exposure-activity relationship was investigated in mouse xenograft models of human prostate cancer, breast cancer, and gastric cancer by comparing antitumor activity after single and fractionated dosing with tumor-targeting ADCs conjugated to SG3249, a potent PBD dimer.

Preclinical Evaluation of MEDI0641, a Pyrrolobenzodiazepine-Conjugated Antibody-Drug Conjugate Targeting 5T4.

Antibody-drug conjugates (ADC) are used to selectively deliver cytotoxic agents to tumors and have the potential for increased clinical benefit to cancer patients. 5T4 is an oncofetal antigen overexpressed on the cell surface in many carcinomas on both bulk tumor cells as well as cancer stem cells (CSC), has very limited normal tissue expression, and can internalize when bound by an antibody. An anti-5T4 antibody was identified and optimized for efficient binding and internalization in a target-specific manner, and engineered cysteines were incorporated into the molecule for site-specific conjugation.

An ABC Transporter Is Involved in the Silicon-Induced Formation of Casparian Bands in the Exodermis of Rice.

Silicon (Si) promotes the formation of Casparian bands (CB) in rice and reduces radial oxygen loss (ROL). Further transcriptomic approaches revealed several candidate genes involved in the Si-induced formation of CB such as ATP binding cassette (ABC) transporter, Class III peroxidases, ligases and transferases. Investigation of these genes by means of overexpression (OE) and knockout (KO) mutants revealed the contribution of the ABC transporter () to CB formation in the exodermis, which was also reflected in the expression of other in the Si-promoted formation of CB genes related to the phenylpropanoid pathway, such as phenylalanine-ammonia-lyase, diacylglycerol O-acyltransferase and 4-coumarate-CoA ligase.

[Piritramide : A critical review].

Background: In many European countries and particularly in Germany, piritramide is the first choice opioid analgesic for the management of postoperative and posttraumatic pain.

Objective: The aim of this study was to review the pharmacological properties of piritramide and to evaluate whether these result in any clinical advantages with respect to effectiveness, safety and side effect profile compared to other strong opioids.

Material And Methods: A systematic literature search was conducted in PubMed and Google Scholar and 27 articles published between 1961 and 2015 were retrieved and included in this review.

Interpreting and Integrating Clinical and Anatomic Pathology Results.

The continuing education course on integrating clinical and anatomical pathology data was designed to communicate the importance of using a weight of evidence approach to interpret safety findings in toxicology studies. This approach is necessary, as neither clinical nor anatomic pathology data can be relied upon in isolation to fully understand the relationship between study findings and the test article. Basic principles for correlating anatomic pathology and clinical pathology findings and for integrating these with other study end points were reviewed.

Expression profiles of the Gα subunits during Xenopus tropicalis embryonic development.

Heterotrimeric G protein signaling plays major roles during different cellular events. However, there is a limited understanding of the molecular mechanisms underlying G protein control during embryogenesis. G proteins are highly conserved and can be grouped into four subfamilies according to sequence homology and function.