Identification and in vitro characterization of UDP-GlcNAc-RNA cap-modifying and decapping enzymes.

In recent years, several noncanonical RNA caps derived from cofactors and metabolites have been identified. Purine-containing RNA caps have been extensively studied, with multiple decapping enzymes identified and efficient capture and sequencing protocols developed for nicotinamide adenine dinucleotide (NAD)-RNA, which allowed for a stepwise elucidation of capping functions. Despite being identified as an abundant noncanonical RNA-cap, UDP-sugar-capped RNA remains poorly understood, which is partly due to its complex in vitro preparation.

[Standardized and quality-assured predictive PD-L1 testing in the upper gastrointestinal tract. German version].

As a result of the high approval dynamics and the growing number of immuno-oncological therapy concepts, the complexity of therapy decisions and control in the area of carcinomas of the esophagus, gastroesophageal junction and stomach is constantly increasing. Since the treatment indication for PD‑1 inhibitors that are currently approved in the European Union is often linked to the expression of PD-L1 (programmed cell death-ligand 1), the evaluation of tissue-based predictive markers by the pathologist is of crucial importance for treatment stratification. Even though the immunohistochemical analysis of the PD-L1 expression status is one of the best studied, therapy-relevant biomarkers for an immuno-oncological treatment, due to the high heterogeneity of carcinomas of the upper gastrointestinal tract, there are challenges in daily clinical diagnostic work with regard to implementation, standardization and interpretation of testing.

Future Perspectives for the Identification and Sequencing of Nicotinamide Adenine Dinucleotide-Capped RNAs.

Ribonucleic acid (RNA) is composed primarily of four canonical building blocks. In addition, more than 170 modifications contribute to its stability and function. Metabolites like nicotinamide adenine dinucleotide (NAD) were found to function as 5'-cap structures of RNA, just like 7-methylguanosine (mG).

German, Austrian, and Swiss guidelines for systemic treatment of gastric cancer.

The updated edition of the German, Austrian and Swiss Guidelines for Systemic Treatment of Gastric Cancer was completed in August 2023, incorporating new evidence that emerged after publication of the previous edition. It consists of a text-based "Diagnosis" part and a "Therapy" part including recommendations and treatment algorithms. The treatment part includes a comprehensive description regarding perioperative and palliative systemic therapy for gastric cancer and summarizes recommended standard of care for surgery and endoscopic resection.

Pathogenic RAB34 variants impair primary cilium assembly and cause a novel oral-facial-digital syndrome.

Oral-facial-digital syndromes (OFDS) are a group of clinically and genetically heterogeneous disorders characterized by defects in the development of the face and oral cavity along with digit anomalies. Pathogenic variants in over 20 genes encoding ciliary proteins have been found to cause OFDS through deleterious structural or functional impacts on primary cilia. We identified by exome sequencing bi-allelic missense variants in a novel disease-causing ciliary gene RAB34 in four individuals from three unrelated families.

Metabolism-Guided Selective Androgen Receptor Antagonists: Design, Synthesis, and Biological Evaluation for Activity against Enzalutamide-Resistant Prostate Cancer.

A major challenge for new drug discovery in the area of androgen receptor (AR) antagonists lies in predicting the druggable properties that will enable small molecules to retain their potency and stability during further studies and . Indole (compound ) is a first-in-class AR antagonist with very high potency (IC = 0.085 μM) but is metabolically unstable.

A meta-analysis with systematic review: Efficacy and safety of immune checkpoint inhibitors in patients with advanced gastric cancer.

Background: While the efficacy of immune checkpoint inhibitors (ICIs) is increasingly recognized in advanced gastric cancer (aGC), overall survival (OS) has not been consistently improved across the different randomized controlled trials (RCTs). This meta-analysis aimed to quantify the efficacy and safety of ICI and explore potential predictive tumor tissue biomarkers in aGC.

Methods: A random-effect pairwise meta-analysis was used to evaluate the primary outcome of OS.

Integrative Analysis of Intrahepatic Cholangiocarcinoma Subtypes for Improved Patient Stratification: Clinical, Pathological, and Radiological Considerations.

Intrahepatic cholangiocarcinomas (iCCAs) may be subdivided into large and small duct types that differ in etiology, molecular alterations, therapy, and prognosis. Therefore, the optimal iCCA subtyping is crucial for the best possible patient outcome. In our study, we analyzed 148 small and 84 large duct iCCAs regarding their clinical, radiological, histological, and immunohistochemical features.

A prospective study of patients with low back pain attending a Canadian emergency department: Why they came and what happened?

Low back pain is a common presentation to emergency departments, but the reasons why people choose to attend the emergency department have not been explored. We aimed to fill this gap with this study to understand why persons with low back pain choose to attend the emergency department. Between July 4, 2017 and October 1, 2018, consecutive patients with a complaint of low back pain presenting to the University of Alberta Hospital emergency department were screened.

Exploration and Biological Evaluation of Basic Heteromonocyclic Propanamide Derivatives as SARDs for the Treatment of Enzalutamide-Resistant Prostate Cancer.

A series of propanamide derivatives were designed, synthesized, and pharmacologically characterized as selective androgen receptor degraders (SARDs) and pan-antagonists that exert a broad-scope androgen receptor (AR) antagonism. Incorporating different basic heteromonocyclic B-ring structural elements in the common A-ring-linkage-B-ring nonsteroidal antiandrogen general pharmacophore contributed to a novel scaffold of small molecules with SARD and pan-antagonist activities even compared to our recently published AF-1 binding SARDs such as UT-69 (), UT-155 (), and UT-34 (). Compound exhibited inhibitory and degradation effects in vitro in a wide array of wtAR, point mutant, and truncation mutant-driven prostate cancers (PCs).

An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer.

Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy.

Synthesis of 5'-Thiamine-Capped RNA.

RNA 5'-modifications are known to extend the functional spectrum of ribonucleotides. In recent years, numerous non-canonical 5'-modifications, including adenosine-containing cofactors from the group of B vitamins, have been confirmed in all kingdoms of life. The structural component of thiamine adenosine triphosphate (thiamine-ATP), a vitamin B1 derivative found to accumulate in and other organisms in response to metabolic stress conditions, suggests an analogous function as a 5'-modification of RNA.

Nutrient Composition of Different Hazelnut Cultivars Grown in Germany.

Hazelnuts are rarely cultivated in Germany, although they are a valuable source for macro- and micronutrients and can thus contribute to a healthy diet. Near the present, 15 varieties were cultivated in Thuringia, Germany, as a pilot study for further research. The aim of our study was to evaluate the micro- and macronutrient composition of representative, randomly mixed samples of the 15 different hazelnut cultivars.

Pilot Study on Malnutrition and DNA Damage in Patients with Newly Diagnosed Gastrointestinal Tumors: Is DNA Damage Reversible by Early Individualized Nutritional Support?

Background And Aims: Nutritional support (NS) in patients with malignancies and malnutrition improves outcome and treatment tolerance. The underlying mechanisms are not completely understood. We aimed to investigate for the first time the influence of an early individualized NS in newly diagnosed patients with gastrointestinal/hepato-pancreatic malignancies and malnutrition on DNA damage, oxidative stress and subclinical inflammation.

Pyrazol-1-yl-propanamides as SARD and Pan-Antagonists for the Treatment of Enzalutamide-Resistant Prostate Cancer.

We report herein the design, synthesis, and pharmacological characterization of a library of novel aryl pyrazol-1-yl-propanamides as selective androgen receptor degraders (SARDs) and pan-antagonists that exert broad-scope AR antagonism. Pharmacological evaluation demonstrated that introducing a pyrazole moiety as the B-ring structural element in the common A-ring-linkage-B-ring nonsteroidal antiandrogens' general pharmacophore allowed the development of a new scaffold of small molecules with unique SARD and pan-antagonist activities even compared to our recently published AF-1 binding SARDs such as UT-155 () and UT-34 (). Novel B-ring pyrazoles exhibited potent AR antagonist activities, including promising distribution, metabolism, and pharmacokinetic properties, and broad-spectrum AR antagonist properties, including potent antitumor activity.

The association between motor capacity and mobility performance: frailty as a moderator.

Background: In older adults, the linkage between laboratory-assessed 'motor capacity' and 'mobility performance' during daily routine is controversial. Understanding factors moderating this relationship could help developing more valid assessment as well as intervention approaches. We investigated whether the association between capacity and performance becomes evident with transition into frailty, that is, whether frailty status moderates their association.

The association between cognition and dual-tasking among older adults: the effect of motor function type and cognition task difficulty.

Background: Dual-task actions challenge cognitive processing. The usefulness of objective methods based on dual-task actions to identify the cognitive status of older adults has been previously demonstrated. However, the properties of select motor and cognitive tasks are still debatable.

The 4th St. Gallen EORTC Gastrointestinal Cancer Conference: Controversial issues in the multimodal primary treatment of gastric, junctional and oesophageal adenocarcinoma.

Multimodal primary treatment of localised adenocarcinoma of the stomach, the oesophagus and the oesophagogastric junction (AEG) was reviewed by a multidisciplinary expert panel in a moderated consensus session. Here, we report the key points of the discussion and the resulting recommendations. The exact definition of the tumour location and extent by white light endoscopy in conjunction with computed tomography scans is the backbone for any treatment decision.

Trauma Surgeon and Palliative Care Physician Attitudes Regarding Goals-of-Care Delineation for Injured Geriatric Patients.

Background: The value of defining goals of care (GoC) for geriatric patients is well known to the palliative care community but is a newer concept for many trauma surgeons. Palliative care specialists and trauma surgeons were surveyed to elicit the specialties' attitudes regarding (1) importance of GoC conversations for injured seniors; (2) confidence in their own specialty's ability to conduct these conversations; and (3) confidence in the ability of the other specialty to do so.

Methods: A 13-item survey was developed by the steering committee of a multicenter, palliative care-focused consortium and beta-tested by trauma surgeons and palliative care specialists unaffiliated with the consortium.

Upper-extremity function prospectively predicts adverse discharge and all-cause COPD readmissions: a pilot study.

Background: Frailty can inform management approaches for individuals with COPD. However, inpatient measures of frailty are seldom employed because they are time-consuming or inapplicable for bed-bound patients. We investigated the feasibility and potential of an innovative sensor-based upper-extremity function (UEF) test for frailty assessment in predicting adverse outcomes.

New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity.

In our effort to find small-molecule treatments of advanced prostate cancers (PCs), a novel series of indolyl and indolinyl propanamides (series II and III) were discovered as selective androgen receptor degraders (SARDs). Initial studies of androgen receptor (AR) antagonist (1) and agonist (2) propanamides yielded a tertiary aniline (3) with novel SARD activity but poor metabolic stability. Cyclization to II and III produced submicromolar AR antagonism and protein degradation selective to AR and AR splice variant (AR SV).

Burn Surgeon and Palliative Care Physician Attitudes Regarding Goals of Care Delineation for Burned Geriatric Patients.

Palliative care specialists (PCS) and burn surgeons (BS) were surveyed regarding: 1) importance of goals of care (GoC) conversations for burned seniors; 2) confidence in their own specialty's ability to conduct these conversations; and 3) confidence in the ability of the other specialty to do so. A 13-item survey was developed by the steering committee of a multicenter consortium dedicated to palliative care in the injured geriatric patient and beta-tested by BS and PCS unaffiliated with the consortium. The finalized instrument was electronically circulated to active physician members of the American Burn Association and American Academy for Hospice and Palliative Medicine.

Cytokeratin-18 fragments predict treatment response and overall survival in gastric cancer in a randomized controlled trial.

Background: Gastric cancer is common malignancy and exhibits a poor prognosis. At the time of diagnosis, the majority of patients present with metastatic disease which precludes curative treatment. Non-invasive biomarkers which discriminate early from advanced stages or predict the response to treatment are urgently required.