Discovery of BAY-405: An Azaindole-Based MAP4K1 Inhibitor for the Enhancement of T-Cell Immunity against Cancer.

Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) is a serine/threonine kinase that acts as an immune checkpoint downstream of T-cell receptor stimulation. MAP4K1 activity is enhanced by prostaglandin E2 (PGE2) and transforming growth factor beta (TGFβ), immune modulators commonly present in the tumor microenvironment. Therefore, its pharmacological inhibition is an attractive immuno-oncology concept for inducing therapeutic T-cell responses in cancer patients.

On Normothermic Regional Perfusion.

This letter responds to the article "Neither Ethical nor Prudent: Why Not to Choose Normothermic Regional Perfusion," by Adam Omelianchuk et al., in the July-August 2024 issue of the Hastings Center Report.

Targeting the aryl hydrocarbon receptor (AhR) with BAY 2416964: a selective small molecule inhibitor for cancer immunotherapy.

Background: The metabolism of tryptophan to kynurenines (KYN) by indoleamine-2,3-dioxygenase or tryptophan-2,3-dioxygenase is a key pathway of constitutive and adaptive tumor immune resistance. The immunosuppressive effects of KYN in the tumor microenvironment are predominantly mediated by the aryl hydrocarbon receptor (AhR), a cytosolic transcription factor that broadly suppresses immune cell function. Inhibition of AhR thus offers an antitumor therapy opportunity via restoration of immune system functions.

How to obtain informed consent for psychotherapy: a reply to criticism.

In 'Psychotherapy, Placebos and Informed Consent', I argued that the minimal standard for informed consent in psychotherapy requires that 'patients understand that there is currently no consensus about the mechanisms of change in psychotherapy, and that the therapy on offer…is based on disputed theoretical foundations', and that the dissemination of this information is compatible with the delivery of many theory-specific forms of psychotherapy (including cognitive behavioural therapy (CBT)). I also argued that the minimal requirements for informed consent do not include information about the role of therapeutic common factors in healing (eg, expectancy effects and therapist effects); practitioners may discuss the common factors with patients, but they are not part of the 'core set' of information necessary to obtain informed consent.In a recent reply, Charlotte Blease criticises these two arguments by claiming they are not supported by empirical findings about the therapeutic common factors.

Psychotherapy, placebos, and informed consent.

Several authors have recently argued that psychotherapy, as it is commonly practiced, is deceptive and undermines patients' ability to give informed consent to treatment. This 'deception' claim is based on the findings that some, and possibly most, of the ameliorative effects in psychotherapeutic interventions are mediated by therapeutic common factors shared by successful treatments (eg, expectancy effects and therapist effects), rather than because of theory-specific techniques. These findings have led to claims that psychotherapy is, at least partly, likely a placebo, and that practitioners of psychotherapy have a duty to 'go open' to patients about the role of common factors in therapy (even if this risks negatively affecting the efficacy of treatment); to not 'go open' is supposed to unjustly restrict patients' autonomy.

Preclinical Antitumor Efficacy of BAY 1129980-a Novel Auristatin-Based Anti-C4.4A (LYPD3) Antibody-Drug Conjugate for the Treatment of Non-Small Cell Lung Cancer.

C4.4A (LYPD3) has been identified as a cancer- and metastasis-associated internalizing cell surface protein that is expressed in non-small cell lung cancer (NSCLC), with particularly high prevalence in the squamous cell carcinoma (SCC) subtype. With the exception of skin keratinocytes and esophageal endothelial cells, C4.

Molecular profiles and clinical outcome of stage UICC II colon cancer patients.

Purpose: Published multigene classifiers suggesting outcome prediction for patients with stage UICC II colon cancer have not been translated into a clinical application so far. Therefore, we aimed at validating own and published gene expression signatures employing methods which enable their reconstruction in routine diagnostic specimens.

Methods: Immunohistochemistry was applied to 68 stage UICC II colon cancers to determine the protein expression of previously published prognostic classifier genes (CDH17, LAT, CA2, EMR3, and TNFRSF11A).

Inhibition of the IL-2-inducible tyrosine kinase (Itk) activity: a new concept for the therapy of inflammatory skin diseases.

T-cell-mediated processes play an essential role in the pathogenesis of several inflammatory skin diseases such as atopic dermatitis, allergic contact dermatitis and psoriasis. The aim of this study was to investigate the role of the IL-2-inducible tyrosine kinase (Itk), an enzyme acting downstream of the T-cell receptor (TCR), in T-cell-dependent skin inflammation using three approaches. Itk knockout mice display significantly reduced inflammatory symptoms in mouse models of acute and subacute contact hypersensitivity (CHS) reactions.

Exon array analysis using re-defined probe sets results in reliable identification of alternatively spliced genes in non-small cell lung cancer.

Background: Treatment of non-small cell lung cancer with novel targeted therapies is a major unmet clinical need. Alternative splicing is a mechanism which generates diverse protein products and is of functional relevance in cancer.

Results: In this study, a genome-wide analysis of the alteration of splicing patterns between lung cancer and normal lung tissue was performed.

Dynamics of the transcriptome in the primate ovulatory follicle.

Experiments were designed to evaluate changes in the transcriptome (mRNA levels) in the ovulatory, luteinizing follicle of rhesus monkeys, using a controlled ovulation model that permits analysis of the naturally selected, dominant follicle at specific intervals (0, 12, 24 and 36 h) after exposure to an ovulatory (exogenous hCG) stimulus during the menstrual cycle. Total RNA was prepared from individual follicles (n= 4-8/timepoint), with an aliquot used for microarray analysis (Affymetrix Rhesus Macaque Genome Array) and the remainder applied to quantitative real-time PCR (q-PCR) assays. The microarray data from individual samples distinctly clustered according to timepoints, and ovulated follicles displayed markedly different expression patterns from unruptured follicles at 36 h.

Transcriptional profiling of the hormone-responsive stages of spermatogenesis reveals cell-, stage-, and hormone-specific events.

Spermatogenesis occurs within the highly complex seminiferous epithelium. This cyclic process is accompanied by dynamic stage-specific transcriptional changes and is driven by androgens and FSH by mechanisms that are unclear. Here we report the impact of acute androgen and FSH suppression on the transcriptional dynamics of the seminiferous epithelium.

DNA binding by estrogen receptor-alpha is essential for the transcriptional response to estrogen in the liver and the uterus.

The majority of the biological effects of estrogens in the reproductive tract are mediated by estrogen receptor (ER)alpha, which regulates transcription by several mechanisms. Because the tissue-specific effects of some ERalpha ligands may be caused by tissue-specific transcriptional mechanisms of ERalpha, we aimed to identify the contribution of DNA recognition to these mechanisms in two clinically important target organs, namely uterus and liver. We used a genetic mouse model that dissects DNA binding-dependent vs.

Interleukin-13 exerts autocrine growth-promoting effects on human pancreatic cancer, and its expression correlates with a propensity for lymph node metastases.

Background And Aims: Interleukin-13 (IL-13) is an anti-inflammatory cytokine produced in cells of hematopoetic origin. It is not known whether pancreatic cancer cells produce IL-13 or whether IL-13 can modulate pancreatic cancer cell growth and influence the frequency of lymph node metastases.

Materials And Methods: Cell growth and signaling were analyzed by cell counting, colorimetric proliferation assays, fluorescent-activated cell sorting, and in vitro kinase activity assays.

Strongyloides stercoralis: a rare cause of obstructive duodenal stenosis.

Background: Strongyloidiasis is a rare helminthic infection in Europe, and it may cause duodenal obstruction.

Methods: We report a patient who was admitted to our Medical Department with nausea and repeated vomiting since 10 years until food intake became impossible. Subsequent investigations revealed a duodenal obstruction at the upper third of the duodenum, as well as enterocolitis of the terminal ileum with eosinophils dispersed throughout the mucosa.

Pancreatic cancer--low survival rates.

Introduction: Cancers of the pancreas are identified in 11 800 to 13 500 patients each year in Germany. Epidemiological studies prove smoking and chronic alcohol consumption as causes of about 30% of pancreatic cancers.

Methods: Selective literature review.

Endotoxemia and endotoxin tolerance in patients with ARDS.

Background: The significance of endotoxemia in man is controversial, induces cytokine release and stimulates the immune system. Exaggerated cytokine release of mononuclear cells was observed in acute lung injury/acute respiratory distress syndrome (ALI/ARDS). However, repetitive administration of endotoxin can cause tolerance.

The tobacco carcinogen NNK is stereoselectively reduced by human pancreatic microsomes and cytosols.

Background/aims: Cigarette smoking increases the risk of cancer of the pancreas. The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is the only known environmental compound that induces pancreatic cancer in laboratory animals. Concentrations of NNK are significantly higher in the pancreatic juice of smokers than in that of nonsmokers.

[Rare cause of recurring necrotising pancreatitis].

Background: Necrotising pancreatitis may develop as a consequence of pancreatic duct obstruction by stones, tumors or in the presence of a pancreas divisum. Alcohol and nicotine are regarded as risk factors for the disease becoming chronic.

Patient And Course Of The Disease: A 63-year-old female patient with suspected cystadenocarcinoma of the pancreas tail, which was resolved as a pancreatic pseudocyst, was treated for recurrent pancreatitis for 2 years.

Experimental constraints on the spin and parity of the Lambdac(2880)+.

We report the results of several studies of the Lambda(c)(+)pi(+)pi(-)X final state in continuum e(+)e(-) annihilation data collected by the Belle detector. An analysis of angular distributions in Lambda(c)(2880)(+)-->Sigma(c)(2455)(0,++)pi(+,-) decays strongly favors a Lambda(c)(2880)(+) spin assignment of 5/2 over 3/2 or 1/2. We find evidence for Lambda(c)(2880)(+)-->Sigma(c)(2520)(0,++)pi(+,-) decay and measure the ratio of Lambda(c)(2880)(+) partial widths Gamma(Sigma(c)(2520)pi)/Gamma(Sigma(c)(2455)pi)=0.

Observation of the decay B(0)-->J/psieta.

We report the first observation of B(0)-->J/psieta decay. These results are obtained from a data sample that contains 449 x10(6) BB[over] pairs accumulated at the Upsilon(4S) resonance with the Belle detector at the KEKB asymmetric-energy e(+)e(-) collider. We observe a signal with a significance of 8.

MAPkinase gene expression, as determined by microarray analysis, distinguishes uncomplicated from complicated reconstitution after major surgical trauma.

Microarray expression analysis was performed in patients with major surgical trauma to identify signaling pathways which may be indicative for complicated versus uneventful reconstitution post trauma. In addition to a generalized upregulation of nonspecific stress response genes in all patients, a remarkable number of differences in gene expression patterns were found in individual patients. Some of the differing genes were associated with uncomplicated convalescence such as upregulation of both the ERK5 pathway (MAPK7 [mitogen-activated protein kinase-7]) and transcription factors which stimulate hematopoiesis and tissue reconstitution (MEF2, BMP-2, TNFRSF11A [RANK], and RUNX-1).

Observation of a charmoniumlike state produced in association with a J/psi in e+e- annihilation at sqrt[s] approximately equal to 10.6 GeV.

We report the first observation of a charmoniumlike state recoiling from the J/psi in the inclusive process e+e- -->J/psi+anything at a mass of (3.943+/-0.006+/-0.

Measurement of inclusive Ds, D0, and J/psi rates and determination of the Bs(*)Bs(*) production fraction in bb Events at the Upsilon(5S) resonance.

The inclusive production of D(s), D(0), and J/psi mesons is studied using a 1.86 fb(-1) data sample collected on the Upsilon(5S) resonance with the Belle detector at the KEKB asymmetric-energy e(+)e(-) collider. The number of bb events in this Upsilon(5S) data sample is determined.

Observation of time-dependent CP violation in B0 --> eta'K0 decays and improved measurements of CP asymmetries in B0 --> phiK0, KS0KS0KS0 and B0 --> J/psiK0 decays.

We present improved measurements of CP-violation parameters in B(0) --> phiK(0), eta(')K(0), KS(0)KS(0)KS(0) decays based on a sample of 535 x 10(6) BB pairs collected at the Upsilon(4S) resonance with the Belle detector at the KEKB energy-asymmetric e(+)e(-) collider. We obtain sin2phi1(eff)=+0.64+/-0.