Developmental and epileptic encephalopathy 56 due to YWHAG variants: 12 new cases and review of the literature.

Background And Objectives: Developmental and epileptic encephalopathy 56 (DEE-56) is caused by pathogenic variants in YWHAG and is characterized by early-onset epilepsy and neurodevelopmental delay. This study reports on a cohort of DEE-56 individuals, correlating antiseizure medication usage and comorbidities, to aid in understanding disease evolution.

Methods: We analyzed data from thirty-nine individuals aged 3-40 years with YWHAG variants, including 12 previously unreported individuals (2 of these with recurrent distal 7q11.

Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes.

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. AMPARs form by homo- or heteromeric assembly of subunits encoded by the GRIA1-GRIA4 genes, of which only GRIA3 is X-chromosomal. Increasing numbers of GRIA3 missense variants are reported in patients with neurodevelopmental disorders (NDD), but only a few have been examined functionally.

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.

Back in Person: Frontiers in Medicinal Chemistry 2023.

The Frontiers in Medicinal Chemistry (FiMC) is the largest international Medicinal Chemistry conference in the German speaking area and took place from April 3 to 5 2023 in Vienna (Austria). Fortunately, after being cancelled in 2020 and two years (2021-2022) of entirely virtual meetings, due to the COVID-19 pandemic, the FiMC could be held in a face-to-face format again. Organized by the Division of Medicinal Chemistry of the German Chemical Society (GDCh), the Division of Pharmaceutical and Medicinal Chemistry of the German Pharmaceutical Society (DPhG), together with the Division of Medicinal Chemistry of the Austrian Chemical Society (GÖCH), the Austrian Pharmaceutical Society (ÖPhG), and a local organization committee from the University of Vienna headed by Thierry Langer, the meeting brought together 260 participants from 21 countries.

Long-term follow-up of 64 children with classical infantile-onset Pompe disease since 2004: A French real-life observational study.

Background: Classical infantile-onset Pompe disease (IOPD) is the most severe form of Pompe disease. Enzyme replacement therapy (ERT) has significantly increased survival but only a few studies have reported long-term outcomes.

Methods: We retrospectively analyzed the outcomes of classical IOPD patients diagnosed in France between 2004 and 2020.

Frontiers in Medicinal Chemistry 2022 Goes Virtual.

The Frontiers in Medicinal Chemistry (FiMC) meeting, which represents the largest international medicinal chemistry conference in Germany, took place from March 14 to 16 2022 in a fully virtual format. Organized by the Division of Medicinal Chemistry of the German Chemical Society (GDCh) together with the Division of Pharmaceutical & Medicinal Chemistry of the German Pharmaceutical Society (DPhG) and a "local" organization committee from the University of Freiburg headed by Manfred Jung, the meeting brought together 271 participants from around 20 countries. The program included 33 lectures by leading scientists from industry and academia as well as early career investigators.

MECP2 Dysautonomia Phenotypes in Boys.

Background: Recognizing and identifying dysautonomia would facilitate the diagnosis and management of MECP2 mutations in boys. We aimed to explore the prevalence of dysautonomia symptoms in boys with MECP2 mutations.

Method: We conducted a national, retrospective study (2000-2020) of medical records from boys who were aged less than 18 years when diagnosed with a pathogenic, or likely pathogenic, variant in the MECP2 gene.

Early Seizure Recurrence in Children Admitted for Nonfebrile Seizures in the Emergency Department: A Prospective Study.

Objective: This study was aimed to determine the rate, timing, and risk factors of acute recurrence of seizures in the children admitted for nonfebrile seizure in the emergency department (ED).

Methods: This multicenter prospective study was conducted in the ED of three hospitals. All consecutive visits of children aged 28 days to 15 years who attended the ED for a nonfebrile seizure for 1 year were included in the study and prospectively followed.

Molecular and clinical descriptions of patients with GABA receptor gene variants (GABRA1, GABRB2, GABRB3, GABRG2): A cohort study, review of literature, and genotype-phenotype correlation.

Objective: γ-Aminobutyric acid (GABA) -receptor subunit variants have recently been associated with neurodevelopmental disorders and/or epilepsy. The phenotype linked with each gene is becoming better known. Because of the common molecular structure and physiological role of these phenotypes, it seemed interesting to describe a putative phenotype associated with GABA -receptor-related disorders as a whole and seek possible genotype-phenotype correlations.

West Syndrome Is an Exceptional Presentation of Pyridoxine- and Pyridoxal Phosphate-Dependent Epilepsy: Data From a French Cohort and Review of the Literature.

To characterize the electro-clinical presentation of patients with pyridoxine-dependent epilepsy (PDE) and pyridoxal phosphate (PLP)-dependent epilepsy in order to determine whether some of them could be diagnosed as West syndrome, i. e., West syndrome that starts after the age of 2 months without other types of seizures (focal seizures for instance) before the onset of epileptic spasms.

The potent AMPK inhibitor BAY-3827 shows strong efficacy in androgen-dependent prostate cancer models.

Purpose: 5' adenosine monophosphate-activated kinase (AMPK) is an essential regulator of cellular energy homeostasis and has been associated with different pathologies, including cancer. Precisely defining the biological role of AMPK necessitates the availability of a potent and selective inhibitor.

Methods: High-throughput screening and chemical optimization were performed to identify a novel AMPK inhibitor.

Real-life use of videos in pediatric epilepsy consultations.

Paroxysmal events are usually not directly observed by physicians. The diagnosis remains challenging and relies mostly on the description of witnesses. The effectiveness of videos for seizure diagnosis has been validated by several studies, but their place in clinical practice is not yet clear.

Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models.

The ATR kinase plays a key role in the DNA damage response by activating essential signaling pathways of DNA damage repair, especially in response to replication stress. Because DNA damage and replication stress are major sources of genomic instability, selective ATR inhibition has been recognized as a promising new approach in cancer therapy. We now report the identification and preclinical evaluation of the novel, clinical ATR inhibitor BAY 1895344.

Palliative Care in SMA Type 1: A Prospective Multicenter French Study Based on Parents' Reports.

Spinal muscular atrophy type 1 (SMA-1) is a severe neurodegenerative disorder, which in the absence of curative treatment, leads to death before 1 year of age in most cases. Caring for these short-lived and severely impaired infants requires palliative management. New drugs (nusinersen) have recently been developed that may modify SMA-1 natural history and thus raise ethical concerns about the appropriate level of care for patients.

Discovery of BAY-985, a Highly Selective TBK1/IKKε Inhibitor.

The serine/threonine kinase TBK1 (TANK-binding kinase 1) and its homologue IKKε are noncanonical members of the inhibitor of the nuclear factor κB (IκB) kinase family. These kinases play important roles in multiple cellular pathways and, in particular, in inflammation. Herein, we describe our investigations on a family of benzimidazoles and the identification of the potent and highly selective TBK1/IKKε inhibitor BAY-985.

The Novel ATR Inhibitor BAY 1895344 Is Efficacious as Monotherapy and Combined with DNA Damage-Inducing or Repair-Compromising Therapies in Preclinical Cancer Models.

The DNA damage response (DDR) secures the integrity of the genome of eukaryotic cells. DDR deficiencies can promote tumorigenesis but concurrently may increase dependence on alternative repair pathways. The ataxia telangiectasia and Rad3-related (ATR) kinase plays a central role in the DDR by activating essential signaling pathways of DNA damage repair.

Clinical study of 19 patients with SCN8A-related epilepsy: Two modes of onset regarding EEG and seizures.

Objective: To describe the mode of onset of SCN8A-related severe epilepsy in order to facilitate early recognition, and eventually early treatment with sodium channel blockers.

Methods: We reviewed the phenotype of patients carrying a mutation in the SCN8A gene, among a multicentric cohort of 638 patients prospectively followed by several pediatric neurologists. We focused on the way clinicians made the diagnosis of epileptic encephalopathy, the very first symptoms, electroencephalography (EEG) findings, and seizure types.

Discovery and SAR of Novel 2,3-Dihydroimidazo[1,2-c]quinazoline PI3K Inhibitors: Identification of Copanlisib (BAY 80-6946).

The phosphoinositide 3-kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens.

Anti-tumor necrosis factor alpha therapy (adalimumab) in Rasmussen's encephalitis: An open pilot study.

Objective: Rasmussen's encephalitis (RE) is a severe chronic inflammatory brain disease affecting one cerebral hemisphere and leading to drug-resistant epilepsy, progressive neurologic deficit, and unilateral brain atrophy. Hemispherotomy remains the gold standard treatment but causes permanent functional impairment. No standardized medical treatment protocol currently exists for patients prior to indication of hemispherotomy, although some immunotherapies have shown partial efficacy with functional preservation but poor antiseizure effect.

Multimodal Outcome at 7 Years of Age after Neonatal Arterial Ischemic Stroke.

Objectives: To evaluate the epileptic, academic, and developmental status at age 7 years in a large population of term-born children who sustained neonatal arterial ischemic stroke (NAIS), and to assess the co-occurrence of these outcomes.

Study Design: A cohort study including 100 term newborns with NAIS was designed. Two infants died during the neonatal period, 13 families were lost to follow-up, and 5 families declined to participate in this evaluation.

[Stage IB2, IIA and IIB cervical carcinoma without lymph node extension treated with neoadjuvant chemoradiotherapy].

Purpose: To evaluate the results of preoperative chemoradiation for resectable bulky cervical carcinoma without lymph node involvement after surgical lymph node staging.

Patients And Methods: Between 2000 and 2010, 45 patients with cervical carcinoma stage IB2 (11 patients), IIA2 (3 patients) and IIB with proximal parametrial invasion (31 patients) were treated with pelvic radiation therapy at a dose of 40.5Gy and concurrent platin (44 patients) or mitomycin (one patient).

Synthetic approaches towards alkaloids bearing α-tertiary amines.

Alkaloids account for some of the most beautiful and biologically active natural products. Although they are usually classified along biosynthetic criteria, they can also be categorized according to certain structural motifs. Amongst these, the α-tertiary amine (ATA), i.

Growing teratoma syndrome of the ovary presenting with liver metastasis: report of a case.

Growing teratoma syndrome (GTS) is a rare condition among patients with non-seminomatous germ cell tumors who present with enlarging metastatic masses during appropriate systemic chemotherapy in the context of normalized serum markers. This is an infrequent event in the progression of testicular tumors, and is even less common in the case of ovarian germ cell tumors. The pathogenesis of GTS is not completely understood and diagnosis can only be made with certainty after complete pathologic examination.

Physicians' Attitudes Towards the Advice of a Guideline-Based Decision Support System: A Case Study With OncoDoc2 in the Management of Breast Cancer Patients.

When wrongly used, guideline-based clinical decision support systems (CDSSs) may generate inappropriate propositions that do not match the recommendations provided by clinical practice guidelines (CPGs). The user may decide to comply with or react to the CDSS, and her decision may finally comply or not with CPGs. OncoDoc2 is a guideline-based CDSS for breast cancer management.