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Exploitation of extrinsic apoptosis signaling via TRAILR2 activation represents a promising therapeutic concept in cancer treatment. The limited clinical success of previous TRAILR2 agonistic agents, to date, has been ascribed to either poor efficacy or hepatotoxicity. TR2/CDH3 BAB is a human bispecific antibody that relies on binding both CDH3 and TRAILR2 on cell surfaces to achieve TRAILR2 hyperclustering and efficient apoptosis induction by TRAILR2 signaling selectively in CDH3-expressing tumor cells. We demonstrate target-dependent TR2/CDH3 BAB anti-tumor activity in CRISPR/Cas9-engineered TRAILR2 or CDH3 knock-out cells. By utilizing the cell line screening platform PRISM, we found selective TR2/CDH3 BAB efficacy in various cancer types, such as pancreatic, gastric, colorectal, and triple negative breast cancer. The efficacy of TR2/CDH3 BAB correlated with caspase activation in cancer cell lines and in xenograft tumor tissues. In pancreatic ductal adenocarcinoma (PDAC), where patient benefit from current cytotoxic therapy options is unsatisfactory, a close to uniform cell surface expression of CDH3 and TRAILR2 was observed, which will qualify the majority of PDAC patients for TR2/CDH3 BAB-based treatment. TR2/CDH3 BAB demonstrated anti-tumor activity in a panel of PDAC patient-derived xenograft models, including tumor regressions. By combining TR2/CDH3 BAB with chemotherapeutic agents, deeper and more sustained anti-tumor responses were observed when compared to monotherapy. Together with the potential to deliver a favorable safety profile, these data support clinical testing of TR2/CDH3 BAB in patients with PDAC.

In neuroscience, the acquisition of neural signals from the brain cortex is crucial to analyze brain processes, detect neurological disorders, and offer therapeutic brain-computer interfaces. The design of neural interfaces conformable to the brain tissue is one of today's major challenges since the insufficient biocompatibility of those systems provokes a fibrotic encapsulation response, leading to an inaccurate signal recording and tissue damage precluding long-term/permanent implants. The design and production of a novel soft neural biointerface made of polyacrylamide hydrogels loaded with plasmonic silver nanocubes are reported herein. Hydrogels are surrounded by a silicon-based template as a supporting element for guaranteeing an intimate neural-hydrogel contact while making possible stable recordings from specific sites in the brain cortex. The nanostructured hydrogels show superior electroconductivity while mimicking the mechanical characteristics of the brain tissue. Furthermore, in vitro biological tests performed by culturing neural progenitor cells demonstrate the biocompatibility of hydrogels along with neuronal differentiation. In vivo chronic neuroinflammation tests on a mouse model show no adverse immune response toward the nanostructured hydrogel-based neural interface. Additionally, electrocorticography acquisitions indicate that the proposed platform permits long-term efficient recordings of neural signals, revealing the suitability of the system as a chronic neural biointerface.

Objective: The repercussions of ischemia-reperfusion and inflammatory response to surgical injury may compromise the return of physiologic processes in video-laparoscopic surgeries. Dexmedetomidine, as an adjuvant drug in general anesthesia, alters the neuroinflammatory reaction, provides better clinical outcomes in the perioperative period, and may reduce the excessive use of chronic medication in patients with a history of addiction. This study evaluated the immunomodulatory potential of dexmedetomidine on perioperative organ function in video-laparoscopic cholecystectomy patients., Methods: There were two groups: Sevoflurane and Dexmedetomidine A (26 patients) vs. Sevoflurane and Saline 0.9% B (26 patients). Three blood samples were collected three times: 1) before surgery, 2) 4-6h after surgery, and 3) 24h postoperatively. Inflammatory and endocrine mediators were protocolized for analysis. Finally, hemodynamic outcomes, quality upon awakening, pain, postoperative nausea and vomiting, and opioid use were compared between groups., Results: We have demonstrated a reduction of Interleukin 6 six hours after surgery in group A: 34.10 (IQR 13.88-56.15) vs. 65.79 (IQR 23.13-104.97; p = 0.0425) in group B. Systolic blood pressure, diastolic blood pressure, and mean arterial pressure was attenuated in group A in their measurement intervals ( p < 0.0001). There was a lower incidence of pain and opioid consumption in the first postoperative hour favoring this group ( p < 0.0001). We noticed better quality upon awakening after the intervention when comparing the values of peripheral oxygen saturation and respiratory rate., Conclusions: Dexmedetomidine provided anti-inflammatory benefits and contributed to postoperative analgesia without the depressive side effects on the respiratory and cardiovascular systems commonly observed with opioids., Trial Registration: Immunomodulatory Effect of Dexmedetomidine as an Adjuvant Drug in Laparoscopic Cholecystectomies, NCT05489900, Registered 5 August 2022-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05489900?term=NCT05489900&draw=2&rank=1.

Background: Pancreaticoduodenectomy is a highly invasive procedure associated with high morbidity. Several preoperative variables are associated with postoperative complications. The role of perioperative factors is uncertain. The use of perioperative epidural analgesia is potentially associated with fewer postoperative surgical complications. We hypothesize that perioperative epidural analgesia might be associated with fewer surgical complications., Methods: We reviewed data from 288 cases performed at our institution between 2012 and 2019, classifying patients into 2 groups: perioperative use of epidural analgesia and non-perioperative use of epidural analgesia. The decision to use epidural as an adjunct to general anesthesia was based on the judgment of the attending anesthesiologist. Uni- and multivariate analyses were then performed to determine factors associated with postoperative surgical complications, ie, postoperative pancreatic fistula, delayed gastric emptying, among others, after adjusting for confounders., Results: Baseline and intraoperative factors were similar between the groups, except for sex and postoperative surgical complications. In the univariate analyses, factors associated with fewer postoperative surgical complications were the diameter of the pancreatic duct ≥ 6 mm, hard pancreatic gland parenchyma texture, younger age (< 65 years), and perioperative use of epidural analgesia. In the multivariate analyses, perioperative use of epidural analgesia was significantly associated with fewer postoperative surgical complications (odds ratio = 0.31; 95% confidence interval: 0.13-0.75; P = .009), even after adjusting for significant covariates., Conclusion: Perioperative use of epidural analgesia might be associated with fewer postoperative surgical complications after pancreaticoduodenectomy even after adjusting for pancreatic gland parenchyma texture, pancreatic duct size, and age., (© 2022 The Authors.)

Purpose: Ceritinib is an orally bioavailable, small-molecule inhibitor of anaplastic lympoma kinase (ALK), insulin-like growth factor 1 receptor (IGFR1), and focal adhesion kinase (FAK), which are highly expressed in glioblastoma and many brain metastases. Preclinical and clinical studies indicate that ceritinib has antitumor activity in central nervous system (CNS) malignancies. This phase 0 trial measured the tumor pharmacokinetics (PK) and pharmacodynamics (PD) of ceritinib in patients with brain metastasis or recurrent glioblastoma., Patients and Methods: Preoperative patients with brain tumors demonstrating high expression of pSTAT5b/pFAK/pIGFR1 were administered ceritinib for 10 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at predefined timepoints following the final dose. Total and unbound drug concentrations were determined using LC-MS/MS. In treated tumor and matched archival tissues, tumor PD was quantified through IHC analysis of pALK, pSTAT5b, pFAK, pIGFR1, and pIRS1., Results: Ten patients (3 brain metastasis, 7 glioblastoma) were enrolled and no dose-limiting toxicities were observed. Ceritinib was highly bound to human plasma protein [median fraction unbound (Fu), 1.4%] and to brain tumor tissue (median Fu, 0.051% and 0.045% in gadolinium-enhancing and -nonenhancing regions respectively). Median unbound concentrations in enhancing and nonenhancing tumor were 0.048 and 0.006 μmol/L, respectively. Median unbound tumor-to-plasma ratios were 2.86 and 0.33 in enhancing and nonenhancing tumor, respectively. No changes in PD biomarkers were observed in the treated tumor samples as compared to matched archival tumor tissue., Conclusions: Ceritinib is highly bound to plasma proteins and tumor tissues. Unbound drug concentrations achieved in brain metastases and patients with recurrent glioblastoma were insufficient for target modulation., (©2021 The Authors; Published by the American Association for Cancer Research.)

This paper presents a SAR converter based mixed-signal multiplier for the feature extraction of neural signals using quadratic operators. After a thorough analysis of design principles and circuit-level aspects, the proposed architecture is explored for the implementation of two quadratic operators often used for the characterization of neural activity, the moving average energy (MAE) operator and the nonlinear energy operator (NEO). Programmable chips for both operators have been implemented in a HV-180 nm CMOS process. Experimental results confirm their suitability for energy computation and action potential detection and the accomplished area×power performance is compared to prior art. The MAE and NEO prototypes, at a sampling rate of 30kS/s, consume 116 nW and 178 nW, respectively, and digitize both the input neural signal and the operator outcome, with no need for digital multipliers.

Glioblastoma (GBM) is one of the deadliest forms of cancer. Despite many treatment options, prognosis of GBM remains dismal with a 5-year survival rate of 4.7%. Even then, tumors often recur after treatment. Tumor recurrence is hypothesized to be driven by glioma stem cell (GSC) populations which are highly tumorigenic, invasive, and resistant to several forms of therapy. GSCs are often concentrated around the tumor vasculature, referred to as the vascular niche, which are known to provide microenvironmental cues to maintain GSC stemness, promote invasion, and resistance to therapies. In this work, we developed a 3D organotypic microfluidic platform, integrated with hydrogel-based biomaterials, to mimic the GSC vascular niche and study the influence of endothelial cells (ECs) on patient-derived GSC behavior and identify signaling cues that mediate their invasion and phenotype. The established microvascular network enhanced GSC migration within a 3D hydrogel, promoted invasive morphology as well as maintained GSC proliferation rates and phenotype (Nestin, SOX2, CD44). Notably, we compared migration behavior to in vivo mice model and found similar invasive morphology suggesting that our microfluidic system could represent a physiologically relevant in vivo microenvironment. Moreover, we confirmed that CXCL12-CXCR4 signaling is involved in promoting GSC invasion in a 3D vascular microenvironment by utilizing a CXCR4 antagonist (AMD3100), while also demonstrating the effectiveness of the microfluidic as a drug screening assay. Our model presents a potential ex vivo platform for studying the interplay of GSCs with its surrounding microenvironment as well as development of future therapeutic strategies tailored toward disrupting key molecular pathways involved in GSC regulatory mechanisms., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The visual acuity loss enables the brain to access new pathways in the quest to overcome the visual limitation and this is wellknown as neuroplasticity which have mechanisms to cortical reorganization. In this review, we related the evidences about the neuroplasticity as well as cortical anatomical differences and functional repercussions in visual impairments. We performed a systematic review of PUBMED database, without date or status publication restrictions. The findings demonstrate that the visual impairment produce a compensatory sensorial effect, in which non-visual areas are related to both cross (visual congenital) and multimodal (late blind) neuroplasticity., Competing Interests: Conflict of interest: the authors declare no potential conflict of interest.

Neuromuscular diseases are multifactorial pathologies characterized by extensive muscle fiber damage that leads to the activation of satellite cells and to the exhaustion of their pool, with consequent impairment of neurobiological aspects, such as cognition and motor control. To review the knowledge and obtain a broad view of the cognitive impairment on Neuromuscular Diseases. Cognitive impairment in neuromuscular disease was explored; a literature search up to October 2017 was conducted, including experimental studies, case reports and reviews written in English. Keywords included Cognitive Impairment, Neuromuscular Diseases, Motor Neuron Diseases, Dystrophinopathies and Mitochondrial Disorders. Several cognitive evaluation scales, neuroimaging scans, genetic analysis and laboratory applications in neuromuscular diseases, especially when it comes to the Motor Neuron Diseases, Dystrophinopathies and Mitochondrial Disorders. In addition, organisms model using rats in the genetic analysis and laboratory applications to verify the cognitive and neuromuscular impacts. Several studies indicate that congenital molecular alterations in neuromuscular diseases promote cognitive dysfunctions. Understanding these mechanisms may in the future guide the proper management of the patient, evaluation, establishment of prognosis, choice of treatment and development of innovative interventions such as gene therapy., Competing Interests: Conflict of interest: the authors declare no potential conflict of interest.

The aim of this paper is to study the prevalence of Zika Virus (ZIKV) and the index of its neurological complications. This is a quantitative, cross-sectional epidemiological study. Data were collected through the compulsory notification of suspected ZIKV and its neurological alterations cases. 113 suspected ZIKV cases were reported, most of them in the summer, with a higher prevalence of females and in the fourth decade of life. Among the neurological changes, 15 Guillain-Barré Syndrome cases were reported, with one registered death. As neurological manifestations, most of them started 30 days after a ZIKV infection. No case has been confirmed laboratory. It is necessary to combat the vector, mainly in the summer, to reduce ZIKV infection and its neurological complications, besides instruction to the health professionals about these complications and serological tests requests for an accurate diagnosis., Competing Interests: Conflict of interest: the authors declare no conflict of interest.

Progenitors of cortical glutamatergic neurons (Glu progenitors) are usually thought to switch fate before birth to produce astrocytes. We used fate-mapping approaches to show that a large fraction of Glu progenitors persist in the postnatal forebrain after closure of the cortical neurogenesis period. Postnatal Glu progenitors do not accumulate during embryonal development but are produced by embryonal radial glial cells that persist after birth in the dorsal subventricular zone and continue to give rise to cortical neurons, although with low efficiency. Single-cell RNA sequencing reveals a dysregulation of transcriptional programs, which parallels changes in m 6 A methylation and correlates with the gradual decline in cortical neurogenesis observed in vivo. Rescuing experiments show that postnatal progenitors are partially permissive to genetic and pharmacological manipulations. Our study provides an in-depth characterization of postnatal Glu progenitors and identifies potential therapeutic targets for promoting brain repair., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Cervical spondylotic myelopathy is a well-known cause of disability among older people. A significant amount of these patients is asymptomatic. Once the symptoms start, the worsening may follow a progressive manner. We should suspect of spondylotic myelopathy in any individual over 55 years presenting progressive changes in gait or losing fine motor control of the upper limbs. Despite its frequent prevalence, this condition is still neglected and many times confused with other supratentorial lesions regarding diagnostic. Here we address some of most important aspects of this disease, calling attention to pathophysiology, the natural history, presentation, differential diagnosis, clinical assessment, and treatment., Competing Interests: the authors declare no potential conflict of interest.

In glioblastoma, invasion and proliferation are presumed to be mutually exclusive events; however, the molecular mechanisms that mediate this switch at the cellular level remain elusive. Previously, we have shown that phospho-OLIG2, a central-nervous-system-specific transcription factor, is essential for tumor growth and proliferation. Here, we show that the modulation of OLIG2 phosphorylation can trigger a switch between proliferation and invasion. Glioma cells with unphosphorylated OLIG2(S10, S13, S14) are highly migratory and invasive, both in vitro and in vivo. Mechanistically, unphosphorylated OLIG2 induces TGF-β2 expression and promotes invasive mesenchymal properties in glioma cells. Inhibition of the TGF-β2 pathway blocks this OLIG2-dependent invasion. Furthermore, ectopic expression of phosphomimetic Olig2 is sufficient to block TGF-β2-mediated invasion and reduce expression of invasion genes (ZEB1 and CD44). Our results not only provide a mechanistic insight into how cells switch from proliferation to invasion but also offer therapeutic opportunities for inhibiting dissemination of gliomas., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)