Identification of the Clinical Candidate (), a Highly Potent and Brain Penetrant BRAF Inhibitor for the Treatment of Cancer.

Mutant BRAF is one of the most common oncogenic drivers in metastatic melanoma. While first generation BRAF inhibitors are capable of controlling tumors systemically, they are unable to adequately treat tumors that have metastasized to the brain due to insufficient penetration across the blood-brain barrier (BBB). Through a combination of structure-based drug design (SBDD) and the optimization of physiochemical properties to enhance BBB penetration, we herein report the discovery of the brain-penetrant BRAF inhibitor () In mice studies, proved to be highly brain-penetrant and was able to drive regressions of A375 BRAF tumors implanted both subcutaneously and intracranially.

SPACEWALK: A Remote Participation Study of ALK Resistance Leveraging Plasma Cell-Free DNA Genotyping.

Introduction: Remote consent and enrollment offer a unique opportunity to provide rare cancer populations with access to clinical research. The genomic analysis of plasma cell-free DNA (cfDNA) permits remote characterization of the cancer genome. We hypothesized we could leverage these approaches to remotely study drug resistance in patients with metastatic -positive NSCLC.

Property-Guided Synthesis of Aza-Tricyclic Indolines: Development of Gold Catalysis En Route.

Antibiotic resistance is a worldwide public health threat that needs to be addressed by improved antibiotic stewardship and continuing development of new chemical entities to treat resistant bacterial infections. Compounds that work alongside known antibiotics as combination therapies offer an efficient and sustainable approach to counteract antibiotic resistance in bacteria. Guided by property-based analysis, a series of aza-tricyclic indolines (ATIs) were synthesized to optimize their physiochemical properties as novel combination therapies with β-lactams to treat methicillin-resistant (MRSA) infections.

Telehealth for patients with Parkinson's disease: delivering efficient and sustainable long-term care.

Objectives: We set out to demonstrate the benefits of providing long-term care via telehealth for patients with Parkinson's disease living in continuous care facilities.

Methods: A cohort of 16 patients with Parkinson's disease residing at one of 2 locations of a multi-facility continuous care retirement organization were seen virtually in follow-up over a 3-year period by Telehealth Services at a large, academic, tertiary care hospital in southeastern Pennsylvania. The data collected during that period, studied retrospectively, included demographic information, number of telehealth visits, and UPDRS scores obtained at each visit.

Spectrum and potential pathogenesis of reversible posterior leukoencephalopathy syndrome.

Background: Controversy still exists over the etiology and pathophysiology of reversible posterior leukoencephalopathy syndrome (RPLS). This large single-center case series aims to describe the clinical and imaging features of RPLS in an attempt to deduce the etiology of the disorder and the mechanisms of brain injury.

Methods: A retrospective chart and imaging review was conducted on 59 cases of RPLS in 55 patients.

Diagnosis and neuroimaging of acute stroke producing distal arm monoparesis.

Strokes which result in the isolated, pure motor weakness of an upper extremity are unusual and under-recognized cerebrovascular syndromes. Few reports in the literature describe the syndrome adequately or provide substantive clinical or anatomical correlation. Moreover, it may be misdiagnosed as a disorder of the peripheral nervous system because of the lack of pyramidal tract signs or the involvement of speech, the face, or lower limbs.

The influence of stress conditions on the wear of UHMWPE for total joint replacements.

In vitro studies of the effect of contact stress on the wear of ultra high molecular weight polyethylene (UHMWPE) in orthopaedic applications have produced contradictory results which predict both increased and decreased wear with increasing contact stress. In vivo studies of functioning hip prostheses have reported that 22 mm femoral heads generate lower linear and volumetric wear rates than 32 mm femoral heads. The effect of decreasing the head size will increase the contact stress but decrease the sliding distance per motion cycle.

A novel method for the prediction of functional biological activity of polyethylene wear debris.

The comparative performance of artificial hip joints has been extensively investigated in vitro through measurements of wear volumes. In vivo a major cause of long-term failure is wear-debris-induced osteolysis. These adverse biological reactions are not simply dependent on wear volume, but are also controlled by the size and volumetric concentration of the debris.

Comparative wear and wear debris under three different counterface conditions of crosslinked and non-crosslinked ultra high molecular weight polyethylene.

The wear debris generated from ultra high molecular weight polyethylene (UHMWPE) have been recognised as one of the major causes of failure in total hip replacements (THR). It is essential to reduce the wear debris generated from UHMWPE acetabular cups in order to minimise this problem. Debris in the submicron size range is believed to have greater osteolytic potential.

Hemiplegic migraine during pregnancy: unusual magnetic resonance appearance with SPECT scan correlation.

Objective: This article discusses the pathophysiology and implications for treatment of hemiplegic migraine within a case study presentation.

Background: We evaluated a 31-year-old white woman for hemiplegia in her 36th week of pregnancy. She initially presented with severe headache, dysarthria, lethargy, and left-sided numbness and weakness.

A hip joint simulator study using new and physiologically scratched femoral heads with ultra-high molecular weight polyethylene acetabular cups.

This study validates a hip joint simulator configuration as compared with other machines and clinical wear rates using smooth metal and ceramic femoral heads and ultra-high molecular weight polyethylene (UHMWPE) acetabular cups. Secondly the wear rate of UHMWPE cups is measured in the simulator with deliberately scratched cobalt-chrome heads to represent the type of mild and severe scratch damage found on retrieved heads. Finally, the scratching processes are described and the resulting scratches compared with those found in retrieved cobalt-chrome heads.

A hip joint simulator study using simplified loading and motion cycles generating physiological wear paths and rates.

In some designs of hip joint simulator the cost of building a highly complex machine has been offset with the requirement for a large number of test stations. The application of the wear results generated by these machines depends on their ability to reproduce physiological wear rates and processes. In this study a hip joint simulator has been shown to reproduce physiological wear using only one load vector and two degrees of motion with simplified input cycles.

A study of the wear resistance of three types of clinically applied UHMWPE for total replacement hip prostheses.

Ultra high molecular weight polyethylene (UHMWPE) is routinely used as one half of a bearing couple in clinical orthopaedic applications. This material is generally one of two grades, compression moulded GUR 1120, with a molecular weight of 4.4x 10(6) g mol(-1), or ram extruded GUR 4150HP with a molecular weight of 7.

A comparison of the wear and debris generation of GUR 1120 (compression moulded) and GUR 4150HP (ram extruded) ultra high molecular weight polyethylene.

The wear debris generated from UHMWPE (ultra high molecular weight polyethylene) has been recognised as one of the major causes of failure in THR (total hip replacement). GUR 1120 (compression moulded) and GUR 4150HP (ram extruded) which are currently the most frequently used materials in THR were studied in pin-on-plate wear test. The wear particles generated from this test were observed by scanning electron micrograph and analysed by image analysis.

Outcome of severe brain injury: a multimodality neurophysiologic study.

We screened all head-injured trauma patients admitted to Lehigh Valley Hospital during a 2-year period. From 725 screened patients, 69 patients in a coma on the second day after trauma were entered into this study. During the first week, these patients underwent electroencephalography (EEG), evoked potentials, ocular pneumoplethysmography, and transcranial Doppler (TCD) sonography.

Internal carotid artery redundancy is significantly associated with dissection.

Background And Purpose: Redundant internal carotid arteries have been considered a risk factor in tonsillectomy, adenoidectomy, and surgical treatment of peritonsillar abscess and also a potentially treatable cause of stroke. However, an association between internal carotid artery redundancy and spontaneous dissection has not yet been clearly demonstrated.

Methods: We reviewed, for spontaneous carotid artery dissection, records of all patients admitted to our institution during the period from 1986 through 1992 with the diagnosis of stroke or transient ischemic attack.

Development of a novel EEG rating scale for head injury using dichotomous variables.

We developed a new EEG rating scale for electrographic assessment of head injured patients. Phenomena present in posttraumatic EEG were scored as dichotomous variables (present or absent). These phenomena included background activity (alpha, beta, theta, delta), sleep spindles, focal abnormalities, reactivity and variability, epileptiform activity, and specific comatose patterns.

Alzheimer's disease in Down's syndrome with SPECT.

Alzheimer's disease often occurs in patients with Down's syndrome. SPECT scanning with I-123 IMP and Tc-99m HMPAO identifies decreased cerebral perfusion and metabolism in these patients at lower cost. In this case, SPECT scanning revealed changes in Alzheimer's disease in a Down's syndrome patient.

A private practice model for teaching and research activities.

The majority of neurologists in the United States are in fee for service patient management, dividing their time between hospital and office based practice. Many have had subspecialty training or have had research experience. It is our belief that research should be a component of a neurologist's practice.

Episodic low-amplitude events: an under-recognized phenomenon in clinical electroencephalography.

In a series of 20 EEGs from 15 patients, well-defined brief attenuations occurred interspersed among the background activity. These episodic low-amplitude events (ELAEs) typically lasted 0.5-4 s.

Patterns of osseous injuries and psychosocial factors affecting victims of child abuse.

The aim of this paper is to document experience in the management of cases of child abuse with suspected osseous injury, at the Adelaide Children's Hospital, during the period January 1974-December 1986. The study is a retrospective review of the casenotes, radiographs and radiologists' report of 108 consecutive cases with suspected osseous injuries. Information regarding the osseous injuries sustained and the pyschosocial environment surrounding the circumstances of the patients admitted was recorded.

Post traumatic extracranial vertebral artery dissection with locked-in syndrome: a case with MRI documentation and unusually favourable outcome.

A patient with a right vertebral artery dissection occurring after minor head trauma progressed to a massive pontine infarction. An unusually favourable outcome and MRI imaging are discussed.