Evasion of apoptosis and treatment resistance in squamous cell carcinoma of the head and neck.

Combinations of surgery, radiotherapy and chemotherapy can eradicate tumors in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN), but a significant proportion of tumors progress, recur, or do not respond to therapy due to treatment resistance. The prognosis for these patients is poor, thus new approaches are needed to improve outcomes. Key resistance mechanisms to chemoradiotherapy (CRT) in patients with LA SCCHN are alterations to the pathways that mediate apoptosis, a form of programmed cell death.

Model-Informed Selection of the Recommended Phase III Dose of the Inhibitor of Apoptosis Protein Inhibitor, Xevinapant, in Combination with Cisplatin and Concurrent Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck.

Xevinapant, an oral inhibitor of apoptosis protein (IAP) inhibitor, demonstrated efficacy in combination with chemoradiotherapy in a randomized phase II study (NCT02022098) in patients with locally advanced squamous cell carcinoma of the head and neck at 200 mg/day on days 1-14 of a 3-week cycle. To confirm 200 mg/day as the recommended phase III dose (RP3D), we integrated preclinical, clinical, pharmacokinetic/pharmacodynamic (PK/PD), and exposure-response modeling results. Population PK/PD modeling of IAP inhibition in peripheral blood mononuclear cells in 21 patients suggested the pharmacologically active dose range was 100-200 mg/day, with a trend for more robust inhibition at the end of the dosing interval at 200 mg/day based on an indirect response model.

Growth patterns in children and adolescents with cerebral palsy from Argentina and Germany.

To analyze growth patterns of children with CP between countries; to examine differences in growth; and to assess the fit of growth charts. Cross-sectional study in children with CP from 2 to 19 years old, 399 from Argentina and 400 from Germany. Growth measures were converted into z-scores and compared to WHO reference and US CP growth charts.

First-in-human phase Ib trial of M9241 (NHS-IL12) plus avelumab in patients with advanced solid tumors, including dose expansion in patients with advanced urothelial carcinoma.

Background: In preclinical studies, combining M9241 (a novel immunocytokine containing interleukin (IL)-12 heterodimers) with avelumab (anti-programmed death ligand 1 antibody) resulted in additive or synergistic antitumor effects. We report dose-escalation and dose-expansion results from the phase Ib JAVELIN IL-12 trial investigating M9241 plus avelumab.

Methods: In the dose-escalation part of JAVELIN IL-12 (NCT02994953), eligible patients had locally advanced or metastatic solid tumors; in the dose-expansion part, eligible patients had locally advanced or metastatic urothelial carcinoma (UC) that had progressed with first-line therapy.

Avelumab in Combination With Cetuximab and Chemotherapy as First-Line Treatment for Patients With Advanced Squamous NSCLC.

Introduction: We present the results of a phase 2a trial of first-line avelumab (anti-programmed death-ligand 1 antibody) plus cetuximab (anti-EGFR antibody) in patients with advanced squamous NSCLC.

Methods: Patients with recurrent or metastatic squamous NSCLC received avelumab 800 mg (d 1 and 8), cetuximab 250 mg/m (d 1) and 500 mg/m (d 8), cisplatin 75 mg/m (d 1), and gemcitabine 1250 mg/m (d 1 and 8) for four 3-week cycles, followed by avelumab 800 mg and cetuximab 500 mg/m every 2 weeks. The primary end point was the best overall response; the secondary end points were progression-free survival, duration of response, overall survival, and safety.

Inhibiting the inhibitors: Development of the IAP inhibitor xevinapant for the treatment of locally advanced squamous cell carcinoma of the head and neck.

Standard of care for patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) is surgery followed by chemoradiotherapy (CRT) or definitive CRT. However, approximately 50 % of patients with LA SCCHN develop disease recurrence or metastasis within 2 years of completing treatment, and the outcome for these patients is poor. Despite this, the current treatment landscape for LA SCCHN has remained relatively unchanged for more than 2 decades, and novel treatment options are urgently required.

Neurodevelopmental disorder with dystonia due to SOX6 mutations.

Background: Mutations in SOX6 have recently been recognized as a new molecular cause of neurodevelopmental disorders characterized by intellectual disability, behavioral changes, and nonspecific facial and digital skeletal abnormalities. To date, <25 cases have been reported in the literature.

Methods And Findings: Here we report a new case of SOX6-associated neurodegeneration and expand the phenotype to include ceratoconus.

Growth in infants, children and adolescents with unilateral and bilateral cerebral palsy.

To compare growth patterns during infancy, childhood and adolescence in children with unilateral and bilateral cerebral palsy (CP) phenotype and to assess the association with gross motor impairment, dysphagia and gestational age. We retrospectively studied 389 children with CP from a single center population in Munich, Germany. 1536 measurements of height and weight were tabulated and z-scored from 6 to 180 months of age.

Self-Rated Executive Function and Health-Related Quality of Life in Young Adults With Persistent Post-Concussion Symptoms: A Cross-Sectional Study.

Objective: To assess self-reported executive dysfunction in young adult patients with persistent post-concussion symptoms (PCS) 2-6 months post-injury, and the association with self-reported Health-Related Quality of Life (HRQoL).

Method: This cross-sectional study carried out in a hospital setting was a secondary analysis of data from a separate randomized trial testing the effect of a novel intervention, "Get going After concussIoN " (GAIN), for persistent PCS. Patients (18-30 years) were recruited from a clinical cohort of patients with a hospital diagnosis of concussion or referred by primary care physicians.

Novel Ultrabright and Air-Stable Photocathodes Discovered from Machine Learning and Density Functional Theory Driven Screening.

The high brightness, low emittance electron beams achieved in modern X-ray free-electron lasers (XFELs) have enabled powerful X-ray imaging tools, allowing molecular systems to be imaged at picosecond time scales and sub-nanometer length scales. One of the most promising directions for increasing the brightness of XFELs is through the development of novel photocathode materials. Whereas past efforts aimed at discovering photocathode materials have typically employed trial-and-error-based iterative approaches, this work represents the first data-driven screening for high brightness photocathode materials.

Quantitative Motion Measurements Based on Markerless 3D Full-Body Tracking in Children with SMA Highly Correlate with Standardized Motor Assessments.

Background: Spinal Muscular Atrophy (SMA) is the most common neurodegenerative disease in childhood. New therapeutic interventions have been developed to interrupt rapid motor deterioration. The current standard of clinical evaluation for severely weak infants is the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), originally developed for SMA type 1.

Avelumab and cetuximab as a therapeutic combination: An overview of scientific rationale and current clinical trials in cancer.

Treatment outcomes have improved with the advent of immune checkpoint inhibitors and small molecule inhibitors. However, many patients do not respond with single agents. Consequently, ongoing research is focused on the use of combination therapies to increase clinical efficacy by potential synergistic effects.

Surface conditioning of additively manufactured titanium implants and its influence on materials properties and in vitro biocompatibility.

Customized osteosynthesis materials of titanium alloy can be generated by additive manufacturing replacing the complex adaptation to the patient individual anatomy, especially to the lower jaw bone which shows a highly individual surface area. After printing further conditioning is necessary to adjust surface roughness. The aim of the present study was to analyse the effect of different grinding and polishing procedures on sample surface and composition and in vitro biocompatibility.

Ultracold Electrons via Near-Threshold Photoemission from Single-Crystal Cu(100).

Achieving a low mean transverse energy or temperature of electrons emitted from the photocathode-based electron sources is critical to the development of next-generation and compact x-ray free electron lasers and ultrafast electron diffraction, spectroscopy, and microscopy experiments. In this Letter, we demonstrate a record low mean transverse energy of 5 meV from the cryo-cooled (100) surface of copper using near-threshold photoemission. Further, we also show that the electron energy spread obtained from such a surface is less than 11.

Childhood Arterial Ischaemic Stroke: Clinical Presentation, Risk Factors and Management.

Childhood arterial ischaemic stroke (AIS) is a rare, but potentially life-threatening event which requires early diagnosis and adequate treatment. The reported significant time delay to childhood AIS diagnosis may be associated with low awareness, the more nonspecific clinical presentation as well as difficult clinical differentiation to more common "stroke mimics" and a less established "acute care structure" with delayed access to proper neuroimaging. Compared with adult stroke care, experiences with acute reperfusion therapies like thrombolysis and mechanical thrombectomy are promising but limited and not based on clinical trials.

Exposure and cognitive-behavioural therapy for chronic back pain: An RCT on treatment processes.

Background: To improve treatment outcomes, it is essential to understand the processes involved in therapeutic change. The aim of this study was to investigate the processes involved in treatment of individuals with chronic lower back pain (CLBP) and high fear-avoidance. Graded in vivo exposure (Exposure), a specific treatment, and cognitive-behavioural therapy (CBT), a general treatment, were compared.

Successful mechanical thrombectomy in a three-year-old boy with cardioembolic occlusion of both the basilar artery and the left middle cerebral artery.

Background: Paediatric stroke is a potentially life-threatening emergency and requires immediate treatment to improve clinical outcome. In contrast to adult treatment recommendations, little is known about safety and efficacy of thrombolysis and mechanical thrombectomy in children.

Case Description And Conclusion: We report on a three-year-old boy with a cardioembolic intracranial two-vessel occlusion and successful therapy with thrombolysis and mechanical thrombectomy.

Altered brain energetics induces mitochondrial fission arrest in Alzheimer's Disease.

Altered brain metabolism is associated with progression of Alzheimer's Disease (AD). Mitochondria respond to bioenergetic changes by continuous fission and fusion. To account for three dimensional architecture of the brain tissue and organelles, we applied 3-dimensional electron microscopy (3D EM) reconstruction to visualize mitochondrial structure in the brain tissue from patients and mouse models of AD.

Index of contrast sensitivity (ICS) in pseudophakic eyes with different intraocular lens designs.

Purpose: To evaluate the index of contrast sensitivity (ICS) in eyes after cataract surgery with various intraocular lens designs and to compare with the area under log contrast sensitivity curve (AULCSF).

Methods: The study comprised 395 eyes of 198 patients in the age of 73.1 ± 7.

Patient-specific determinants of responsiveness to robot-enhanced treadmill therapy in children and adolescents with cerebral palsy.

Aim: The aim of the study was to evaluate patient-specific determinants of responsiveness to robot-enhanced repetitive treadmill therapy (ROBERT) in patients with early-developed movement disorders.

Method: Patients were treated over 12 sessions during a 3-week period. Gross Motor Function Measure-66 (GMFM-66) scores 1 day before ROBERT were compared with scores recorded 1 day after ROBERT.

Self-reported neck pain is associated with migraine but not with tension-type headache in adolescents.

Aim: The aim of the present analysis is to confirm or refute the association of neck pain to migraine or tension-type headache and to assess whether this association is independent of other risk factors for headache.

Methods: Secondary school students were invited to complete a questionnaire on headache and lifestyle factors in a cross-sectional study. Neck pain was assessed via (a) a screening question concerning neck pain and (b) denoting affected areas in schematic drawings of the human body.

Reduced GM1 ganglioside in CFTR-deficient human airway cells results in decreased β1-integrin signaling and delayed wound repair.

Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function reduces chloride secretion and increases sodium uptake, but it is not clear why CFTR mutation also results in progressive lung inflammation and infection. We previously demonstrated that CFTR-silenced airway cells migrate more slowly during wound repair than CFTR-expressing controls. In addition, CFTR-deficient cells and mouse models have been reported to have altered sphingolipid levels.

Intrinsic electron beam emittance from metal photocathodes: the effect of the electron effective mass.

A theoretical development of prior analyses, together with our solenoid scan measurements on eight planar metal photocathodes (Ag, Be, Cr, Cu, Mo, Sn, Ta, and W) and previous data on Mg [X. J. Wang, M.

Early infantile sensory-motor neuropathy with late onset respiratory distress.

Children with spinal muscular atrophy with respiratory distress (SMARD1) usually present within their first year of life, with respiratory failure due to diaphragmatic paralysis and progressive distal limb weakness. We present a child with a confirmed compound heterozygous IGHMBP2 mutation c.[676G>T];[2083A>T] in whom severe sensory-motor neuropathy preceded diaphragmatic paralysis by almost 3years.