The role of ERBB3 inhibitors as cancers therapeutics

Cancer is the most fatal disease after cardiovascular disease with over 8.2 million deaths worldwide each year. Ever since the serendipitous discovery of mustard gas as an anti-cancer therapeutic in the 1940s, serious efforts have been put into discovering more chemotherapies. Chemotherapies can be categorized into different groups such as alkylating agents (cisplatin, cyclophosphamide), antimetabolites (5-fluorouracil, Ara-C) and mitotic inhibitors (taxanes, vinca alkoids) among others. While chemotherapies have proven to kill cancer cells by targeting cell division processes, over time, tumor cells can adapt and become resistant to these drugs. With a growing understanding of cell signaling networks, targeted therapies are being developed to overcome the issue of chemotherapy resistance. Targeted therapies are highly specific molecules that bind to a specific cellular protein or molecule and block signaling networks associated with biological processes. One of the most frequently dysregulated receptor systems in cancers is the receptor tyrosine kinase family with ErbB being one of the most studied receptors families. ErbB or HER receptors consists of four structurally related receptor tyrosine kinases namely, EGFR/ErbB1, HER2/ErbB2, HER3/ErbB3 and HER4/ErbB4. The ErbB family of receptors plays a major role in morphogenesis of the human body as well as various cellular responses such as cell growth, differentiation and proliferation. Overexpression and dysregulation of these receptors, particularly EGFR and HER2, have been linked to a number of cancers such as breast cancer, gastric cancer, ovarian cancer and non-small cell lung cancer, to name a few. One of the most successful therapies against ErbB related cancers have been targeted therapies. Targeted therapies for ErbB related cancers are of two kinds: (i) Small molecule tyrosine kinase inhibitors (such as erlotinib and gefitinib against EGFR) and, (ii) Monoclonal antibodies (such as trastuzumab against HER2 and cetuximab against EGFR). These drugs function either by inhibiting the kinase activity of the receptor and preventing phosophorylation of tyrosine residues, or binding to some other site on the extracellular domain of the receptor and preventing ligand binding and heterodimerization of ErbB monomers. These drugs have proven to have limited efficacy as monotherapy, but are more effective in combination with standard chemotherapies. However, tumor cells can adapt their signaling networks developing resistance to targeted therapies over the course of treatment and lead to cancer progression. While overexpression and dysfunction of EGFR and HER2 are implicated in most ErbB driven cancers, recent studies have found HER3 playing a pivotal role in inducing resistance to EGFR and HER2 targeted therapies in various cancers and has been found to be the most sensitive node in driving the PI3K pathway leading to tumorigenesis. Thus, there is an urgent need to develop drugs targeted against HER3 and bring them into the clinic. Since HER3 lacks kinase activity, only monoclonal antibodies can be developed against it. Currently, there are a number of molecules in clinical development that target HER3. For example, patritumab and MM-121 are humanized monoclonal antibodies that target the extracellular domain of HER3 receptor and leads to inhibition of HER3-PI3K signaling followed by rapid internalization of the receptor. MM-111 and MM-141, two different bispecific monoclonal antibodies that bind to HER2, HER3 and IGFR-1, HER3, respectively, are currently in clinical development. HER3 inhibitors provide hope to effectively overcome HER3 induced tumor resistance and successfully treat several ErbB driven cancers. However, further development of HER3 inhibitors is necessary by taking strategic approaches. One of these approaches it the utilization of systems biology, a branch of biology that involves computational and mathematical modeling of complex biological systems with the aim of discovering emergent properties of biological systems. Systems biology enables researchers to get a deeper understanding of biological networks such as that of ErbB and make predictive models and test outcomes. This approach was used by Merrimack Pharmaceuticals to develop novel monoclonal antibodies against HER3. Computational outcomes were successfully validated by in vitro and in vivo experiments. Thus, this suggests that systems biology might be the future of designing and developing HER3 inhibitors that would successfully overcome HER3 resistance and cancer progression

RARE-30. PEDIATRIC GLIOBLASTOMA IN THE POST-TEMOZOLOMIDE ERA: OUTCOMES AND CHARACTERISTICS

Abstract INTRODUCTION Glioblastoma (GBM) is the most common brain tumor, however, is a rare occurrence in children and is poorly characterized. We evaluated the characteristics and outcomes of pediatric GBM (pGBM). METHODS Retrospective analysis of pediatric (age< 18) patients diagnosed with GBM undergoing first glioblastoma resection at our brain tumor center (2005- 2016). RESULTS From 1457 GBM patients, we identified twenty-four (1.65%) pGBMs (Median Age=9 years, Females=45.8%). Median overall survival (OS) was 32.1 months, while the median progression-free survival was 11.5 months. The commonest symptoms at presentation were headaches (54.2%,n=13) and motor symptoms (50%,n=12). Mean tumor diameter was 4.5 cm and 25% of the cohort underwent gross total resection (GTR) of their tumor. Univariate analysis revealed median OS significantly associated with tumor extent of resection (GTR=56.4 months; STR/Biopsy=13.7 months, p=0.001), age at surgery (>10 years=43.9 months, < 10 years= 17.2 months, p=0.01), tumor size (> 4cm= 9.1 months, < 4cm=56.9 months, p=0.01),motor symptoms at presentation (present=14.9 months, absent=41.04 months, p=0.02) and infratentorial tumors (infratentorial=17.4 vs supratentorial=53.4 months, p=0.02). Multivariate analysis revealed GTR (HR 0.2[95% CI 0.07–0.72]; p=0.03), Age >10 years (HR 0.6[95% CI 0.02–0.64]; p=0.002), tumor >4 cm (HR 2.89[95% CI 1.88–4.11]; p=0.001) and EGFR amplification (HR 3.48[95% CI 0.82–17.4]; p=0.005) to be independent predictors of OS. Comparing patients under and over 10 years, we found that older patients had smaller tumors at presentation (4.9 vs 3.6 cms, p=0.03), greater rates of preoperative temozolomide (n=1,7.7% vs n=6, 54.5%) and bevacizumab (n=1,7.7% vs n=4, 36.4%) treatment, and lower rates of EGFR amplification (66.7% vs 11.1%) that could explain survival disparities between groups. CONCLUSION Motor symptoms, larger tumors at presentation and tumor EGFR amplification may be indictive of poorer outcomes in pGBM. However, maximal tumor resection, aggressive chemoradiation and tumor presentation at age >10 years may confer better prognosis in these patients

Postoperative intracranial migration of a C2 odontoid screw: A case report and literature review.

Background: Intracranial migration of odontoid screws is a rare but serious complication of anterior odontoid screw fixation not often reported in literature by neurosurgeons. Here, we describe the second case in literature of intracranial migration of an odontoid screw. Case Description: A 64-year-old neurologically intact patient with a type II odontoid fracture secondary to trauma underwent anterior odontoid screw fixation without any intraoperative complications. He tolerated the procedure well, and postoperative imaging demonstrated near anatomic correction of the fracture with satisfactory placement of the lag screw. Unfortunately, the patient was subsequently lost to follow up and he presented 7 months later for a routine outpatient computed tomography (CT) of the cervical spine, which demonstrated upward migration of the screw into the intracranial cavity abutting the medulla, with CT angiography of the neck also confirming the screw lying between the two vertebral arteries. Magnetic resonance imaging of the cervical spine also demonstrated the odontoid screw lying within close proximity to the ventral cervicomedullary junction, marginating the left vertebral artery. Subsequently, the patient was managed with removal of the odontoid screw and posterior cervical arthrodesis and instrumented fusion. Conclusion: Our case demonstrates the rare but serious complication of intracranial odontoid screw migration, which we bring to the attention of the neurosurgical community. The recognition of risk factors for this complication and optimized management of this rare occurrence is important for surgeons to recognize

Hypothermia in Stroke Therapy: Systemic versus Local Application

Presently, there are no effective, widely applicable therapies for ischemic stroke. There is strong clinical evidence for the neuroprotective benefits of hypothermia, and surface-cooling methods have been utilized for decades in the treatment of cerebral ischemia during cardiac arrest, but complications with hypothermia induction have hindered its clinical acceptance in ischemic stroke therapy. Recently, the microcatheter-based local endovascular infusion (LEVI) of cold saline directly to the infarct site has been proposed as a solution to the drawbacks of surface cooling. The safety and efficacy of LEVI in rat models have been established, and implementation in larger animals has been similarly encouraging. A recent pilot study even established the safety of LEVI in humans. This review seeks to outline the major research on LEVI, discusses the mechanisms that mediate its superior neuroprotection over surface and systemic cooling, and identifies areas that warrant further investigation. While LEVI features improvements on surface cooling, its core mechanisms of neuroprotection are still largely shared with therapeutic hypothermia in general. As such, the mechanisms of hypothermia-based neuroprotection are discussed as well

Reducing Superfluous Opioid Prescribing Practices After Brain Surgery: It Is Time to Talk About Drugs

BACKGROUND: Opioids are prescribed routinely after cranial surgery despite a paucity of evidence regarding the optimal quantity needed. Overprescribing may adversely contribute to opioid abuse, chronic use, and diversion. OBJECTIVE: To evaluate the effectiveness of a system-wide campaign to reduce opioid prescribing excess while maintaining adequate analgesia. METHODS: A retrospective cohort study of patients undergoing a craniotomy for tumor resection with home disposition before and after a 2-mo educational intervention was completed. The educational initiative was composed of directed didactic seminars targeting senior staff, residents, and advanced practice providers. Opioid prescribing patterns were then assessed for patients discharged before and after the intervention period. RESULTS: A total of 203 patients were discharged home following a craniotomy for tumor resection during the study period: 98 who underwent surgery prior to the educational interventions compared to 105 patients treated post-intervention. Following a 2-mo educational period, the quantity of opioids prescribed decreased by 52% (median morphine milligram equivalent per day [interquartile range], 32.1 [16.1, 64.3] vs 15.4 [0, 32.9], P \u3c .001). Refill requests also decreased by 56% (17% vs 8%, P = .027) despite both groups having similar baseline characteristics. There was no increase in pain scores at outpatient follow-up (1.23 vs 0.85, P = .105). CONCLUSION: A dramatic reduction in opioids prescribed was achieved without affecting refill requests, patient satisfaction, or perceived analgesia. The use of targeted didactic education to safely improve opioid prescribing following intracranial surgery uniquely highlights the ability of simple, evidence-based interventions to impact clinical decision making, lessen potential patient harm, and address national public health concerns

Paneth cell dysfunction in radiation injury and radio-mitigation by human α-defensin 5

IntroductionThe mechanism underlying radiation-induced gut microbiota dysbiosis is undefined. This study examined the effect of radiation on the intestinal Paneth cell α-defensin expression and its impact on microbiota composition and mucosal tissue injury and evaluated the radio-mitigative effect of human α-defensin 5 (HD5).MethodsAdult mice were subjected to total body irradiation, and Paneth cell α-defensin expression was evaluated by measuring α-defensin mRNA by RT-PCR and α-defensin peptide levels by mass spectrometry. Vascular-to-luminal flux of FITC-inulin was measured to evaluate intestinal mucosal permeability and endotoxemia by measuring plasma lipopolysaccharide. HD5 was administered in a liquid diet 24 hours before or after irradiation. Gut microbiota was analyzed by 16S rRNA sequencing. Intestinal epithelial junctions were analyzed by immunofluorescence confocal microscopy and mucosal inflammatory response by cytokine expression. Systemic inflammation was evaluated by measuring plasma cytokine levels.ResultsIonizing radiation reduced the Paneth cell α-defensin expression and depleted α-defensin peptides in the intestinal lumen. α-Defensin down-regulation was associated with the time-dependent alteration of gut microbiota composition, increased gut permeability, and endotoxemia. Administration of human α-defensin 5 (HD5) in the diet 24 hours before irradiation (prophylactic) significantly blocked radiation-induced gut microbiota dysbiosis, disruption of intestinal epithelial tight junction and adherens junction, mucosal barrier dysfunction, and mucosal inflammatory response. HD5, administered 24 hours after irradiation (treatment), reversed radiation-induced microbiota dysbiosis, tight junction and adherens junction disruption, and barrier dysfunction. Furthermore, HD5 treatment also prevents and reverses radiation-induced endotoxemia and systemic inflammation.ConclusionThese data demonstrate that radiation induces Paneth cell dysfunction in the intestine, and HD5 feeding prevents and mitigates radiation-induced intestinal mucosal injury, endotoxemia, and systemic inflammation

Cross-cutting principles for planetary health education

Since the 2015 launch of the Rockefeller Foundation Lancet Commission on planetary health,1 an enormous groundswell of interest in planetary health education has emerged across many disciplines, institutions, and geographical regions. Advancing these global efforts in planetary health education will equip the next generation of scholars to address crucial questions in this emerging field and support the development of a community of practice. To provide a foundation for the growing interest and efforts in this field, the Planetary Health Alliance has facilitated the first attempt to create a set of principles for planetary health education that intersect education at all levels, across all scales, and in all regions of the world—ie, a set of cross-cutting principles

MUSiC : a model-unspecific search for new physics in proton-proton collisions at root s=13TeV

Results of the Model Unspecific Search in CMS (MUSiC), using proton-proton collision data recorded at the LHC at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1), are presented. The MUSiC analysis searches for anomalies that could be signatures of physics beyond the standard model. The analysis is based on the comparison of observed data with the standard model prediction, as determined from simulation, in several hundred final states and multiple kinematic distributions. Events containing at least one electron or muon are classified based on their final state topology, and an automated search algorithm surveys the observed data for deviations from the prediction. The sensitivity of the search is validated using multiple methods. No significant deviations from the predictions have been observed. For a wide range of final state topologies, agreement is found between the data and the standard model simulation. This analysis complements dedicated search analyses by significantly expanding the range of final states covered using a model independent approach with the largest data set to date to probe phase space regions beyond the reach of previous general searches.Peer reviewe

Search for new particles in events with energetic jets and large missing transverse momentum in proton-proton collisions at root s=13 TeV

A search is presented for new particles produced at the LHC in proton-proton collisions at root s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data sample corresponding to an integrated luminosity of 101 fb(-1), collected in 2017-2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with an earlier search based on a data sample of 36 fb(-1), collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control samples in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.Peer reviewe