Irreversible HER2 inhibitors overcome resistance to the RSL3 ferroptosis inducer in non-HER2 amplified luminal breast cancer.

Ferroptosis, a form of programed cell death, can be promoted by inhibitors of the xCT transporter (erastin) or GPX4 (RSL3). We found that GPX4, but not the xCT transporter, is selectively elevated in luminal breast cancer. Consistent with this observation, the majority of luminal breast cancer cell lines are exquisitely sensitive to RSL3 with limited sensitivity to erastin. In RSL3-resistant, but not sensitive, luminal breast cancer cell lines, RSL3 induces HER2 pathway activation. Irreversible HER2 inhibitors including neratinib reversed RSL3 resistance in constitutively RSL3-resistant cell lines. Combination treatment with RSL3 and neratinib increases ferroptosis through mitochondrial iron-dependent reactive oxygen species production and lipid peroxidation. RSL3 also activated replication stress and concomitant S phase and G2/M blockade leading to sensitivity to targeting the DNA damage checkpoint. Together, our data support the exploration of RSL3 combined with irreversible HER2 inhibitors in clinical trials.

Identifying the essential knowledge and skills for Neonatal-Perinatal Medicine: a systematic analysis of practice.

The knowledge and skills expected for board certification in Neonatal-Perinatal Medicine (NPM) should reflect the clinical practice of neonatology. First, a 14-member panel of practicing neonatologists, convened by the American Board of Pediatrics (ABP), drafted a practice analysis document which identified the practice domains, tasks, knowledge, and skills deemed essential for clinical practice. NPM fellowship program directors provided feedback via online survey resulting in revisions to the document. During the second phase of the project, the panel organized testable knowledge areas into content domains and subdomains to update the existing ABP NPM content outline. All ABP board-certified neonatologists were asked to review via online survey, and results were used to guide final revisions to the content outline. The NPM practice analysis document and the updated NPM content outline should serve as helpful resources for educators, trainees, and practicing neonatologists.

Perceptions and Likelihood of Medical Students to Pursue a Career in Neurosurgery: Findings from the Philippines.

BACKGROUND: The number of neurosurgeons in the Philippines is less than ideal for its population, so there is a need to recruit and train more. This study aimed to determine medical students' perception of neurosurgery and their likelihood of pursuing a career in this specialty. METHODS: A cross-sectional survey was conducted of medical students in the Philippines to assess their perceptions and likelihood of pursuing a career in neurosurgery. Data obtained were analyzed using descriptive statistics and a χ2 test with a significance level of 0.05. RESULTS: A total of 627 medical students completed the survey, with a response rate of 72.4%. The mean age was 23.8 years, and almost half (49.1%) were women. They had mostly negative perceptions of neurosurgery, and only 18.7% were likely to pursue a career in this specialty. Reasons included poor work-life balance, poor understanding of neuroscience and neurosurgery, and the self-perceived lack of manual dexterity. The most common sources of their perceptions included lectures, movies, and neurosurgery residents and consultants whom they met in hospital. Previous exposure to neurosurgery lectures or rotations, going back to their hometown to work, and having a physician parent were associated with a higher likelihood of pursuing neurosurgery. CONCLUSIONS: Our study showed that medical students' perceptions of neurosurgery were generally negative and that only 18.7% were likely to pursue it as a career. Major changes would have to be made to improve students' perceptions to attract more students to the field and increase the neurosurgical workforce.

Precision oncology for breast cancer through clinical trials.

Precision treatment for breast cancers has made several notable advances in recent decades, but challenges of tumor heterogeneity, drug resistance, and aggressive recurrence and metastases remain. To meet and overcome these challenges, we must refine our understanding of breast subtypes and treatment biomarkers according to the knowledge afforded across the spectrum of 'omics assays. A critical aspect of harnessing this knowledge into actionable biomarkers for treatment decision relies on our ability to integrate knowledge across data types and leverage our insight in evidence-based clinical trials. We review recent advances in cutting-edge clinical trials for precision treatment of breast cancer, including chemotherapies, targeted therapies, immunotherapies, and combination therapies. We comment on promising future areas of development for this exciting point in precision breast cancer research.

Woven Endobridge device for treatment of dissection-related PICA aneurysm.

Ruptured vertebrobasilar dissecting aneurysms require urgent, often challenging treatment as they have with a high re-hemorrhage rate within the first 24 hours. The patient is a 57-year-old woman who presented with severe-sudden onset headache. Further work up showed a ruptured dissecting aneurysm of the caudal loop of the posterior inferior cerebellar artery (PICA) with associated narrowing distally, in the ascending limb. The aneurysm was immediately occluded with a Woven Endobridge (WEB) device (MicroVention, Tustin, CA, USA) while flow diversion treatment of the diseased ascending limb was postponed. Follow-up angiography three months later showed complete occlusion of the aneurysm, as well as healing of the diseased distal vessel, obviating the need for further intervention. WEB embolization of a ruptured dissecting posterior circulation aneurysm provided an excellent outcome for this patient.

Lowland and highland Varieties of Dioscorea esculenta tubers stimulate growth of Lactobacillus sp. over enterotoxigenic E. coli in vitro

@#<p style="text-align: justify;"><strong>Objectives:</strong> Probiotic supplementation often only leads to transient improvement in the gut microbiome. Potential prebiotics, such as the oligosaccharide-rich varieties of Dioscorea esculenta tubers, can potentially bridge the gap between supplementation and persistent colonization. Thus, this study aimed to assess the ability of D. esculenta tubers to promote the growth of probiotic Lactobacillus sp. in vitro selectively.</p><p style="text-align: justify;"><strong>Methods:</strong> The prebiotic activity of the selected varieties of Dioscorea esculenta tubers was evaluated via compe titive growth assay, wherein the ratios of probiotic Lactobacillus sp. over enterotoxigenic Escherichia coli (ETEC) or "prebiotic ratios" were compared following treatment.</p><p style="text-align: justify;"><strong>Results:</strong> Negative control (0.9% NaCl solution) produced a ratio of 0.88, Lowland and Highland varieties produced ratios of 1.26 and 1.29, respectively, and positive control (inulin) produced 1.54. The two varieties had comparable ratios to one another (p > 0.05), and significantly higher ratios than the negative control (p < 0.05). Both varieties have significant prebiotic activity. Compared to inulin, the two varieties' prebiotic activity was 84% as effective.</p><p style="text-align: justify;"><strong>Conclusion:</strong> Overall, the tubers promoted the growth of Lactobacillus sp. over ETEC. The crude tuber samples, given their availability and affordability, can be easily integrated into the local diet to contribute to the improvement of the general population's health.</p>

Functional genomic analysis identifies drug targetable pathways in invasive and metastatic cutaneous squamous cell carcinoma.

Although cutaneous squamous cell carcinoma (cSCC) is treatable in the majority of cases, deadly invasive and metastatic cases do occur. To date there are neither reliable predictive biomarkers of disease progression nor FDA-approved targeted therapies as standard of care. To address these issues, we screened patient-derived primary cultured cells from invasive/metastatic cSCC with 107 small-molecule inhibitors. In-house bioinformatics tools were used to cross-analyze drug responses and DNA mutations in tumors detected by whole-exome sequencing (WES). Aberrations in molecular pathways with evidence of potential drug targets were identified, including the Eph-ephrin and neutrophil degranulation signaling pathways. Using a screening panel of siRNAs, we identified EPHA6 and EPHA7 as targets within the Eph-ephrin pathway responsible for mitigating decreased cell viability. These studies form a plausible foundation for detecting biomarkers of high-risk progressive disease applicable in dermatopathology and for patient-specific therapeutic options for invasive/metastatic cSCC.

Efficacy of galcanezumab in patients with episodic migraine and a history of preventive treatment failure: results from two global randomized clinical trials.

BACKGROUND AND PURPOSE: The efficacy of galcanezumab, a monoclonal antibody for migraine prevention, has been demonstrated in two pivotal trials in patients with episodic migraine. METHODS: EVOLVE-1 and EVOLVE-2 were identical phase 3, randomized, double-blind, placebo-controlled studies in patients with episodic migraine. Mean migraine headache days per month at baseline was 9. Patients were randomized 2:1:1 to monthly injections of placebo, galcanezumab 120 mg/240 mg during the 6-month double-blind treatment period. Key efficacy outcomes were assessed in subgroups amongst patients for whom, previously, for efficacy and/or safety/tolerability reasons (i) one or more (≥1) preventives failed, (ii) two or more (≥2) preventives failed and (iii) preventives were never used, or used but not failed (no prior failure). RESULTS: In an integrated analysis of EVOLVE studies, galcanezumab 120 mg/240 mg versus placebo led to larger overall mean (SE) reductions in monthly migraine headache days across 6 months in patients with prior preventive failures (P < 0.001): ≥1 failure: 120 mg: -4.0 (0.4); 240 mg: -4.2 (0.5); placebo: -1.3 (0.4); ≥2 failures: 120 mg: -3.1 (0.7); 240 mg: -3.8 (0.8); placebo: -0.5 (0.6). Similar results were observed amongst patients with no prior failure, but the placebo response was larger: 120 mg: -4.7 (0.2); 240 mg: -4.5 (0.2); placebo: -3.0 (0.2) (P < 0.001 versus placebo). Significant improvements were observed with galcanezumab versus placebo for ≥50% and ≥75% reduction in monthly migraine headache days. CONCLUSION: In patients with episodic migraine treated with galcanezumab, those with ≥1 or ≥2 prior preventive failures had significantly larger improvements, versus placebo, in efficacy outcomes. Similar results were observed in patients with no prior failure, with a larger placebo response.

Positive response to galcanezumab following treatment failure to onabotulinumtoxinA in patients with migraine: post hoc analyses of three randomized double-blind studies.

BACKGROUND AND PURPOSE: Humanized monoclonal antibody galcanezumab, which binds to calcitonin-gene-related peptide, has shown efficacy for episodic and chronic migraine prevention. These analyses evaluated galcanezumab response for migraine headache prevention in patients who previously failed onabotulinumtoxinA ('nonresponse' or 'inadequate response' or safety reasons). METHODS: Post hoc analyses included data from three double-blind, placebo-controlled, phase 3 episodic or chronic migraine studies; 2886 patients randomly received 120 or 240 mg galcanezumab or placebo. During double-blind periods the study drug was administered subcutaneously once a month for 6 months in EVOLVE-1 and -2 and for 3 months in REGAIN. The 120 mg groups received a 240 mg loading dose at month 1. Pooled analyses included 129 patients who failed onabotulinumtoxinA. Using mixed effect model repeat measurements, the least squares mean change from baseline in the number of migraine headache days (MHDs) was calculated for the first 3 months of treatment. RESULTS: For pooled analyses, significant decreases from baseline in the number of MHDs were observed for 120 mg (-3.91) and 240 mg (-5.27) galcanezumab overall versus placebo (-0.88) across 3-month time points for patients who failed onabotulinumtoxinA. Corresponding data for patients with chronic migraine showed significant decreases: 120 mg (-3.18) and 240 mg (-4.26) galcanezumab versus placebo (0.16). Significant reductions in the number of MHDs per month with acute medication use included 120 mg galcanezumab (-4.35) and 240 mg galcanezumab (-4.55) versus placebo (-0.83). Estimates of ≥50% response during months 1-3 were 9.4% for placebo, 41.3% for 120 mg galcanezumab and 47.5% for 240 mg galcanezumab. CONCLUSION: Galcanezumab is an option for prevention of migraine in patients who have previously failed onabotulinumtoxinA preventive therapy.

Blood Pressure after Endovascular Therapy for Ischemic Stroke (BEST): A Multicenter Prospective Cohort Study.

Background and Purpose- To identify the specific post-endovascular stroke therapy (EVT) peak systolic blood pressure (SBP) threshold that best discriminates good from bad functional outcomes (a priori hypothesized to be 160 mm Hg), we conducted a prospective, multicenter, cohort study with a prespecified analysis plan. Methods- Consecutive adult patients treated with EVT for an anterior ischemic stroke were enrolled from November 2017 to July 2018 at 12 comprehensive stroke centers accross the United States. All SBP values within 24 hours post-EVT were recorded. Using Youden index, the threshold of peak SBP that best discriminated primary outcome of dichotomized 90-day modified Rankin Scale score (0-2 versus 3-6) was identified. Association of this SBP threshold with the outcomes was quantified using multiple logistic regression. Results- Among 485 enrolled patients (median age, 69 [interquartile range, 57-79] years; 51% females), a peak SBP of 158 mm Hg was associated with the largest difference in the dichotomous modified Rankin Scale score (absolute risk reduction of 19%). Having a peak SBP >158 mm Hg resulted in an increased likelihood of modified Rankin Scale score 3 to 6 (odds ratio, 2.24 [1.52-3.29], P<0.01; adjusted odds ratio, 1.29 [0.81-2.06], P=0.28, after adjustment for prespecified variables). Conclusions- A peak post-EVT SBP of 158 mm Hg was prospectively identified to best discriminate good from bad functional outcome. Those with a peak SBP >158 had an increased likelihood of having a bad outcome in unadjusted, but not in adjusted analysis. The observed effect size was similar to prior studies. This finding should undergo further testing in a future randomized trial of goal-targeted post-EVT antihypertensive treatment.

Illuminating biological pathways for drug targeting in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) remains a morbid disease with poor prognosis and treatment that typically leaves patients with permanent damage to critical functions such as eating and talking. Currently only three targeted therapies are FDA approved for use in HNSCC, two of which are recently approved immunotherapies. In this work, we identify biological pathways involved with this disease that could potentially be targeted by current FDA approved cancer drugs and thereby expand the pool of potential therapies for use in HNSCC treatment. We analyzed 508 HNSCC patients with sequencing information from the Genomic Data Commons (GDC) database and assessed which biological pathways were significantly enriched for somatic mutations or copy number alterations. We then further classified pathways as either "light" or "dark" to the current reach of FDA-approved cancer drugs using the Cancer Targetome, a compendium of drug-target information. Light pathways are statistically enriched with somatic mutations (or copy number alterations) and contain one or more targets of current FDA-approved cancer drugs, while dark pathways are enriched with somatic mutations (or copy number alterations) but not currently targeted by FDA-approved cancer drugs. Our analyses indicated that approximately 35-38% of disease-specific pathways are in scope for repurposing of current cancer drugs. We further assess light and dark pathways for subgroups of patient tumor samples according to HPV status. The framework of light and dark pathways for HNSCC-enriched biological pathways allows us to better prioritize targeted therapies for further research in HNSCC based on the HNSCC genetic landscape and FDA-approved cancer drug information. We also highlight the importance in the identification of sub-pathways where targeting and cross targeting of other pathways may be most beneficial to predict positive or negative synergy with potential clinical significance. This framework is ideal for precision drug panel development, as well as identification of highly aberrant, untargeted candidates for future drug development.

Visualization of drug target interactions in the contexts of pathways and networks with ReactomeFIViz.

The precision medicine paradigm is centered on therapies targeted to particular molecular entities that will elicit an anticipated and controlled therapeutic response. However, genetic alterations in the drug targets themselves or in genes whose products interact with the targets can affect how well a drug actually works for an individual patient. To better understand the effects of targeted therapies in patients, we need software tools capable of simultaneously visualizing patient-specific variations and drug targets in their biological context. This context can be provided using pathways, which are process-oriented representations of biological reactions, or biological networks, which represent pathway-spanning interactions among genes, proteins, and other biological entities. To address this need, we have recently enhanced the Reactome Cytoscape app, ReactomeFIViz, to assist researchers in visualizing and modeling drug and target interactions. ReactomeFIViz integrates drug-target interaction information with high quality manually curated pathways and a genome-wide human functional interaction network. Both the pathways and the functional interaction network are provided by Reactome, the most comprehensive open source biological pathway knowledgebase. We describe several examples demonstrating the application of these new features to the visualization of drugs in the contexts of pathways and networks. Complementing previous features in ReactomeFIViz, these new features enable researchers to ask focused questions about targeted therapies, such as drug sensitivity for patients with different mutation profiles, using a pathway or network perspective.

Coarse corn particles cause a negative effect on eggshell quality of semi-heavy laying hens.

One of the possible ways to optimize the productive performance of poultry is through the physical processing of ingredients, which can improve the use of nutrients in these animals. In this context, this study was to evaluate the effects of different corn particle sizes in diets on the productive performance and egg quality of semi-heavy laying hens. Sixty naked neck laying hens were used from 24 weeks of age and distributed in a completely randomized design. Experimental diets in different treatments contained corn grain ground into sieves with a diameter of 2, 4, or 8 mm to provide corn particles with a geometric mean diameter (GMD) of 605 (fine), 1,030 (medium), and 2,280 µm (coarse), respectively. The feed and leftovers were weighed daily throughout the experimental period to determine the feed intake and feed conversion. Different corn particle sizes did not affect any aspect of the productive performance of hens, except for feed intake. Hens fed fine and medium corn particles exhibited higher values for egg yolk color, eggshell weight, and eggshell thickness. It is suggested that semi-heavy laying hens should be fed mash diets containing corn particles with GMD from 605 to 1,030 µm, because coarse corn particles cause a negative effect on eggshell quality.

Sublaminar fixation for traumatic lumbar fracture subluxation with lateral listhesis in a 2-year-old patient.

Pediatric spinal trauma can present a surgeon with difficult management decisions given the rarity of these cases, pediatric anatomy, and a growing spine. The need to stabilize a traumatically unstable pediatric spine can be an operative challenge given the lack of instrumentation available. The authors present a surgical technique and an illustrative case that may offer a novel, less disruptive method of stabilization. A 2-year-old girl presented after an assault with an L1-2 fracture subluxation with lateral listhesis and fractured jumped facets exhibited on CT scans. CT also showed intact growth plates at the vertebral body, pedicles, and posterior elements. MRI showed severe ligamentous injury, conus medullaris compression, and an epidural hematoma. Neurologically, the patient moved both lower extremities asymmetrically. Given the severity of the deformity and neurological examination and disruption of the stabilizing structures, the authors made the decision to surgically decompress the L-1 and L-2 segments with bilateral laminotomies, evacuate the epidural hematoma, and reduce the deformity with sublaminar stabilization using braided polyester cables bilaterally, thus preserving the growth plates. They also performed a posterolateral onlay fusion at L-1 and L-2 using autograft and allograft placed due to the facet disruption. At the 42-month follow-up, imaging showed fusion of L-1 and L-2 with good alignment, and the hardware was subsequently explanted. The patient was neurologically symmetric in strength, ambulating, and had preserved alignment. Her bones and spinal canal continued to grow in relation to the other levels.

Intracranial Myeloid Sarcoma Metastasis Mimicking Acute Subdural Hematoma.

Myeloid sarcoma, a rare consequence of myeloproliferative disorders, is rarely seen in the central nervous system, most commonly in the pediatric population. Although there are a handful of case reports detailing initial presentation of CNS myeloid sarcoma in the adult population, we have been unable to find any reports of CNS myeloid sarcoma presenting as a large mass lesion in a herniating patient. Here, we present the case of a patient transferred to our facility for a very large subdural hematoma. Based on imaging characteristics, it was felt to be a spontaneous hematoma secondary to coagulopathy. No coagulopathy was found. Interestingly, he did have a history of acute myeloid leukemia (AML) diagnosed 2 months previously, and intraoperatively he was found to have a confluent white mass invading both the subdural and subarachnoid spaces. There was minimal associated hemorrhage and final pathology showed myeloid sarcoma. This is the first report we are aware of in which CNS myeloid sarcoma presented as a subdural metastasis and also the first report in which we are aware of this etiology causing a herniation syndrome secondary to mass effect.

Evidence-Based Precision Oncology with the Cancer Targetome.

A core tenet of precision oncology is the rational choice of drugs to interact with patient-specific biological targets of interest, but it is currently difficult for researchers to obtain consistent and well-supported target information for pharmaceutical drugs. We review current drug-target interaction resources and critically assess how supporting evidence is handled. We introduce the concept of a unified Cancer Targetome to aggregate drug-target interactions in an evidence-based framework. We discuss current unmet needs and the implications for evidence-based clinical omics. The focus of this review is precision oncology but the discussion is highly relevant to targeted therapies in any area.