Genomic and transcriptomic landscape of HER2-low breast cancer.

Background: Novel agents have expanded the traditional HER2 definitions to include HER2-Low (HER2L) Breast Cancer (BC). We sought to evaluate the distinct molecular characteristics of HER2L BC to understand potential clinical/biologic factors driving resistance and clinical outcomes.

Methods: Retrospective analysis was performed on 13,613 BC samples, tested at Caris Life Sciences via NextGen DNA/RNA Sequencing.

Molecular profiling METex14+ non-small cell lung cancer (NSCLC): Impact of histology.

Objectives: MET exon 14 skipping alterations (METex14+) represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) with distinct biological and genomic features. We characterized this heterogeneity in a large cohort, integrating genomic and transcriptomic profiling with clinical outcomes, to elucidate the histologic and molecular traits and survival patterns of METex14+ NSCLC.

Materials And Methods: NSCLC tissue samples (n = 28,739) underwent DNA-based next-generation sequencing (592 genes, NextSeq) or whole-exome sequencing (NovaSeq), RNA-sequencing including whole transcriptome sequencing (WTS, NovaSeq), and PD-L1 IHC (Dako 22C3) at Caris Life Sciences.

Molecular Landscape and Clinical Implication of CCNE1-amplified Esophagogastric Cancer.

Unlabelled: Cyclin E overexpression as a result of CCNE1 amplification is a critical driver of genomic instability in gastric cancer, but its clinical implication is largely unknown. Thus, we integrated genomic, transcriptomic, and immune profiling analysis of 7,083 esophagogastric tumors and investigated the impact of CCNE1 amplification on molecular features and treatment outcomes. We identified CCNE1 amplification in 6.

Multiomic Characterization Reveals a Distinct Molecular Landscape in Young-Onset Pancreatic Cancer.

Purpose: Using a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between patients with young-onset pancreatic cancer (YOPC; younger than 50 years) and patients with average-onset pancreatic cancer (AOPC; 70 years and older).

Methods: We analyzed matched whole-transcriptome and DNA sequencing data from 2,430 patient samples (YOPC, n = 292; AOPC, n = 2,138) from the Caris Life Sciences database (Phoenix, AZ). Immune deconvolution was performed using the quanTIseq pipeline.

Opposing Roles of Mutations in Human Prostate and Endometrial Cancers.

Purpose: Recurrent gene mutations in speckle-type POZ protein (), the substrate-binding component of E3 ubiquitin ligase, are associated with tumor progression in prostate and endometrial cancers. Here, we characterized mutations in these cancers and explored their association with molecular and immune signatures and patient outcomes.

Methods: There were 7,398 prostate cancer and 19,188 endometrial cancer samples analyzed for clinical and molecular profiles at Caris Life Sciences.

Comparative Genomic Analysis of Pancreatic Acinar Cell Carcinoma (PACC) and Pancreatic Ductal Adenocarcinoma (PDAC) Unveils New Actionable Genomic Aberrations in PACC.

Purpose: Pure pancreatic acinar cell carcinomas (PACC) are rare malignancies with no established treatment. PACC demonstrates significant genetic intertumoral heterogeneity with multiple pathways involved, suggesting using targeted cancer therapeutics to treat this disease. We aggregated one of the largest datasets of pure PACC to examine the genomic variability and explore patient-specific therapeutic targets.

Multi-omic characterization reveals a distinct molecular landscape in young-onset pancreatic cancer.

Purpose: Using a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between young-onset pancreatic cancer (YOPC; <50-yrs.) and average-onset pancreatic cancer (AOPC; ≥70-yrs.) patients.

Characterization of Exon 14 Skipping Alterations (in NSCLC) and Identification of Potential Therapeutic Targets Using Whole Transcriptome Sequencing.

Introduction: Genomic alterations in the juxtamembrane exon 14 splice sites in NSCLC lead to increased MET stability and oncogenesis. We present the largest cohort study of Exon 14 (ex14) using whole transcriptome sequencing.

Methods: A total of 21,582 NSCLC tumor samples underwent complete genomic profiling with next-generation sequencing of DNA (592 Gene Panel, NextSeq, whole exome sequencing, NovaSeq) and RNA (NovaSeq, whole transcriptome sequencing).

TRPV4 Antagonism Prevents Mechanically Induced Myotonia.

Objective: Myotonia is caused by involuntary firing of skeletal muscle action potentials and causes debilitating stiffness. Current treatments are insufficiently efficacious and associated with side effects. Myotonia can be triggered by voluntary movement (electrically induced myotonia) or percussion (mechanically induced myotonia).

Sustained activation of GABAA receptors in the suprachiasmatic nucleus mediates light-induced phase delays of the circadian clock: a novel function of ionotropic receptors.

The suprachiasmatic nucleus (SCN) contains a circadian clock that generates endogenous rhythmicity and entrains that rhythmicity with the day-night cycle. The neurochemical events that transduce photic input within the SCN and mediate entrainment by resetting the molecular clock have yet to be defined. Because GABA is contained in nearly all SCN neurons we tested the hypothesis that GABA serves as this signal in studies employing Syrian hamsters (Mesocricetus auratus).

Association of impaired fasting glucose, diabetes and their management with the presentation and outcome of peripheral artery disease: a cohort study.

Background: Pre-diabetes and untreated diabetes are common in patients with peripheral artery disease however their impact on outcome has not been evaluated. We examined the association of impaired fasting glucose, diabetes and their treatment with the presentation, mortality and requirement for intervention in peripheral artery disease patients.

Methods: We prospectively recruited 1637 patients with peripheral artery disease, measured fasting glucose, recorded medications for diabetes and categorised them by diabetes status.

Mechanisms of contrast-induced nephropathy reduction for saline (NaCl) and sodium bicarbonate (NaHCO3).

Nephropathy following contrast media (CM) exposure is reduced by administration before, during, and after the contrast procedure of either isotonic sodium chloride solution (Saline) or isotonic sodium bicarbonate solution (IsoBicarb). The reasons for this reduction are not well established for either sodium salt; probable mechanisms are discussed in this paper. For Saline, the mechanism for the decrease in CIN is likely related primarily to the increased tubular flow rates produced by volume expansion and therefore a decreased concentration of the filtered CM during transit through the kidney tubules.

Association of chronic kidney disease categories defined with different formulae with major adverse events in patients with peripheral vascular disease.

Objective: The aim of this study was to compare the ability of eGFR calculated by modification of diet in renal disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Lund-Malmö formulae in predicting major adverse events in peripheral vascular disease (PVD) patients.

Methods: We prospectively recruited 2137 patients, measured serum creatinine to calculate eGFR using three different formulae and grouped patients into eGFR categories ≥90, 60-89, 45-59, 30-44, 15-29 and <15 ml/min/1.73 m(2).

Finite-time statistics of scalar diffusion in Lagrangian coherent structures.

We study the variability of passive scalar diffusion via the statistics of stochastic particle dispersion in a chaotic flow. We find that at intermediate times when the statistics of individual trajectories start to exhibit scaling-law behaviors, scalar variance over the entire domain exhibits multimodal structure. We demarcate the domain based on Lagrangian coherent structures and find that the conditional statistics exhibit strong unimodal behavior, indicating coherence of effective diffusion among each Lagrangian partition of the flow.

Bilateral fractures of the scapula: Possible archeological examples of beatings from Europe, Africa and America.

Traumatic injuries to the scapula have received little attention in the paleopathological literature. They are rarely encountered in medical emergencies today due to the overlying muscles that protect the bone; they comprise just 1% of all fractures. This collaborative project brings together five cases of bilateral fractures of the scapulae in four ancient populations from three different time periods and three continents (France, Sudan and USA).

Identification of group affinity from cross-sectional contours of the human midfacial skeleton using digital morphometrics and 3D laser scanning technology.

Identifying group affinity from human crania is a long-standing problem in forensic and physical anthropology. Many craniofacial differences used in forensic skeletal identification are difficult to quantify, although certain measurements of the midfacial skeleton have shown high predictive value for group classifications. This study presents a new method for analyzing midfacial shape variation between different geographic groups.

Variation in the measurement of cranial volume and surface area using 3D laser scanning technology.

Three-dimensional (3D) laser scanner models of human crania can be used for forensic facial reconstruction, and for obtaining craniometric data useful for estimating age, sex, and population affinity of unidentified human remains. However, the use of computer-generated measurements in a casework setting requires the measurement precision to be known. Here, we assess the repeatability and precision of cranial volume and surface area measurements using 3D laser scanner models created by different operators using different protocols for collecting and processing data.

Trophy-taking and dismemberment as warfare strategies in prehistoric central California.

We document evidence for trophy-taking and dismemberment with a new bioarchaeological database featuring 13,453 individuals from prehistoric central California sites. Our study reveals 76 individuals with perimortem removal of body parts consistent with trophy-taking or dismemberment; nine of these individuals display multiple types of trophy-taking and dismemberment for a total of 87 cases. Cases span almost 5,000 years, from the Early Period (3000-500 BC) to the Late Period (AD 900-1700).

Technical note: prediction of sex based on five skull traits using decision analysis (CHAID).

Osteologists commonly assess the sex of skeletal remains found in forensic and archaeological contexts based on ordinal scores of subjectively assessed sexually dimorphic traits. Using known-sex samples, logistic regression (LR) discriminant functions have been recently developed, which allow sex probabilities to be determined. A limitation of LR is that it emphasizes main effects and not interactions.

The causes of porotic hyperostosis and cribra orbitalia: a reappraisal of the iron-deficiency-anemia hypothesis.

Porosities in the outer table of the cranial vault (porotic hyperostosis) and orbital roof (cribra orbitalia) are among the most frequent pathological lesions seen in ancient human skeletal collections. Since the 1950s, chronic iron-deficiency anemia has been widely accepted as the probable cause of both conditions. Based on this proposed etiology, bioarchaeologists use the prevalence of these conditions to infer living conditions conducive to dietary iron deficiency, iron malabsorption, and iron loss from both diarrheal disease and intestinal parasites in earlier human populations.

Sexing skulls using discriminant function analysis of visually assessed traits.

The accuracy of sex determinations based on visual assessments of the mental eminence, orbital margin, glabellar area, nuchal area, and mastoid process was tested on a series of 304 skulls of known age and sex from people of European American, African American, and English ancestry as well as on an ancient Native American sample of 156 individuals whose sex could be reliably determined based on pelvic morphology. Ordinal scores of these sexually dimorphic traits were used to compute sex determination discriminant functions. Linear, kth-nearest-neighbor, logistic, and quadratic discriminant analysis models were evaluated based on their capacity to minimize both misclassifications and sex biases in classification errors.

Brief communication: Comparison of methods for estimating chronological age at linear enamel formation on anterior dentition.

Linear enamel hypoplasia (LEH) is an enamel defect that records the effects of physiological stress on tooth formation. Estimating the age at which LEH defects form is integral to the reconstruction of population health in bioarcheological studies. Two principal methods for aging LEH defects have been introduced in the literature.

Vascular engineering for bypass surgery.

Since the introduction of synthetic vascular grafts in the 1960s, only two-stage endothelial cell seeding has demonstrated any significant improvement over conventional vascular grafts, and its benefits have yet to be demonstrated on a large scale. Tissue engineering is a rapidly expanding field with great potential, but efforts to construct tissue-engineered arterial grafts have, to date, yielded little clinical success. This review explores the latest approaches to the construction of a superior vascular graft, along with its potential for use in the clinic in the future.

3-D magnetic resonance angiography versus conventional angiography in peripheral arterial disease: pilot study.

Background: Angiography is usually performed as the preoperative road map for those requiring revascularization for lower extremity peripheral arterial disease (PAD). The alternative investigations are ultrasound, 3-D magnetic resonance angiography (3-D MRA) and computed tomography angiography. This pilot study aimed to assess whether 3-D MRA could replace the gold standard angiography in preoperative planning.