HDAC Inhibitors Enhance Efficacy of the Oncolytic Adenoviruses Ad∆∆ and Ad-3∆-A20T in Pancreatic and Triple-Negative Breast Cancer Models.

The prognosis for triple-negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC) is dismal. TNBC and PDAC are highly aggressive cancers with few treatment options and a potential for rapid resistance to standard-of-care chemotherapeutics. Oncolytic adenoviruses (OAds) represent a promising tumour-selective strategy that can overcome treatment resistance and eliminate cancer cells by lysis and host immune activation. We demonstrate that histone deacetylase inhibitors (HDACi) potently enhanced the cancer-cell killing of our OAds, Ad∆∆ and Ad-3∆-A20T in TNBC and PDAC preclinical models. In the TNBC cell lines MDA-MB-436, SUM159 and CAL51, cell killing, viral uptake and replication were increased when treated with sublethal doses of the Class-I-selective HDACis Scriptaid, Romidepsin and MS-275. The pan-HDACi, TSA efficiently improved OAd efficacy, both in vitro and in SUM159 xenograft models in vivo. Cell killing and Ad∆∆ replication was also significantly increased in five PDAC cell lines when pre-treated with TSA. Efficacy was dependent on treatment time and dose, and on the specific genetic alterations in each cell line. Expression of the cancer specific αvß6-integrin supported higher viral uptake of the integrin-retargeted Ad-3∆-A20T in combination with Scriptaid. In conclusion, we demonstrate that inhibition of specific HDACs is a potential means to enhance OAd activity, supporting clinical translation.

Salvage surgery for recurrent squamous cell carcinoma of the head and neck: Systematic review and meta-analysis.

The present study aims to estimate a pooled hazard ratio (HR) comparing overall survival (OS) for salvage surgery compared to nonsurgical management of recurrent head and neck squamous cell carcinoma (HNSCC). PubMed/MEDLINE and Embase-Ovid were searched on March 5, 2020, for English-language articles reporting survival for salvage surgery and nonsurgical management of recurrent HNSCC. Meta-analysis of HR estimates using random effects model was performed. Fifteen studies reported survival for salvage surgery and nonsurgical management of recurrence. Five-year OS ranged from 26% to 67% for the salvage surgery groups, compared to 0% to 32% for the nonsurgical management groups. Six studies reported HRs comparing salvage surgery to nonsurgical management; the pooled HR was 0.25 (95% CI [0.16, 0.38]; p < 0.0001). Selection for salvage surgery was associated with one quarter of the mortality rate associated with nonsurgical management in light of confounding factors including subsite and treatment intent.

Three-dimensional (3D) Printed Vestibular Schwannoma for Facial Nerve Tractography Validation.

OBJECTIVES: Predicting the course of cranial nerve (CN) VII in the cerebellopontine angle (CPA) on preoperative imaging for vestibular schwannoma (VS) may help guide surgical resection and reduce complications. Diffusion MRI based tractography has been used to identify cranial nerve trajectory, but intraoperative validation of this novel approach is challenging. Currently, validation is based on operative report descriptions of the course of cranial nerves, but yields a simplified picture of the three-dimensional (3D) course of CN VII. In this study, we investigate the accuracy of tractography with detailed patient-specific 3D-printed VS tumors. DESIGN: Retrospective case review. SETTING: Tertiary referral center. PARTICIPANTS: Twenty adult VS surgical candidates. MAIN OUTCOME MEASURES: We compared tractography with intraoperative 3D course of CN VII. The surgeons were blinded to tractography and drew the intraoperative course of the CN VII on a patient specific 3D-printed tumor model for detailed comparison with tractography. RESULTS: Of 20 patients, one was excluded due to subtotal removal and inability to assess CN VII course. In the remaining 19 patients, 84% (16/19) tractography was successful. In 94% of tumors with tractography (15/16), the intraoperative description of CN VII course matched the tractography finding. The maximum distance, however, between tractography and intraoperative course of CN VII was 3.7 mm ±â€Š4.2 mm. CONCLUSION: This study presents a novel approach to CN VII tractography validation in VS. Although descriptions of CN VII intraoperatively match tractography, caution is warranted as quantitative measures suggest a clinically significant distance between tractography and CN VII course.

Network machine learning maps phytochemically rich "Hyperfoods" to fight COVID-19.

In this paper, we introduce a network machine learning method to identify potential bioactive anti-COVID-19 molecules in foods based on their capacity to target the SARS-CoV-2-host gene-gene (protein-protein) interactome. Our analyses were performed using a supercomputing DreamLab App platform, harnessing the idle computational power of thousands of smartphones. Machine learning models were initially calibrated by demonstrating that the proposed method can predict anti-COVID-19 candidates among experimental and clinically approved drugs (5658 in total) targeting COVID-19 interactomics with the balanced classification accuracy of 80-85% in 5-fold cross-validated settings. This identified the most promising drug candidates that can be potentially "repurposed" against COVID-19 including common drugs used to combat cardiovascular and metabolic disorders, such as simvastatin, atorvastatin and metformin. A database of 7694 bioactive food-based molecules was run through the calibrated machine learning algorithm, which identified 52 biologically active molecules, from varied chemical classes, including flavonoids, terpenoids, coumarins and indoles predicted to target SARS-CoV-2-host interactome networks. This in turn was used to construct a "food map" with the theoretical anti-COVID-19 potential of each ingredient estimated based on the diversity and relative levels of candidate compounds with antiviral properties. We expect this in silico predicted food map to play an important role in future clinical studies of precision nutrition interventions against COVID-19 and other viral diseases.

Human Cochlear Nucleus on 7 Tesla Diffusion Tensor Imaging: Insights Into Micro-anatomy and Function for Auditory Brainstem Implant Surgery.

OBJECTIVE: The cochlear nucleus (CN) is the target of the auditory brainstem implant (ABI). Most ABI candidates have Neurofibromatosis Type 2 (NF2) and distorted brainstem anatomy from bilateral vestibular schwannomas. The CN is difficult to characterize as routine structural MRI does not resolve detailed anatomy. We hypothesize that diffusion tensor imaging (DTI) enables both in vivo localization and quantitative measurements of CN morphology. STUDY DESIGN: We analyzed 7 Tesla (T) DTI images of 100 subjects (200 CN) and relevant anatomic structures using an MRI brainstem atlas with submillimetric (50 µm) resolution. SETTING: Tertiary referral center. PATIENTS: Young healthy normal hearing adults. INTERVENTION: Diagnostic. MAIN OUTCOME MEASURES: Diffusion scalar measures such as fractional anisotropy (FA), mean diffusivity (MD), mode of anisotropy (Mode), principal eigenvectors of the CN, and the adjacent inferior cerebellar peduncle (ICP). RESULTS: The CN had a lamellar structure and ventral-dorsal fiber orientation and could be localized lateral to the inferior cerebellar peduncle (ICP). This fiber orientation was orthogonal to tracts of the adjacent ICP where the fibers run mainly caudal-rostrally. The CN had lower FA compared to the medial aspect of the ICP (0.44 ±â€Š0.09 vs. 0.64 ±â€Š0.08, p < 0.001). CONCLUSIONS: 7T DTI enables characterization of human CN morphology and neuronal substructure. An ABI array insertion vector directed more caudally would better correspond to the main fiber axis of CN. State-of-the-art DTI has implications for ABI preoperative planning and future image guidance-assisted placement of the electrode array.

Concepts in Neural Stimulation: Electrical and Optical Modulation of the Auditory Pathways.

Understanding the mechanisms of neural stimulation is necessary to improve the management of sensory disorders. Neurons can be artificially stimulated using electrical current, or with newer stimulation modalities, including optogenetics. Electrical stimulation forms the basis for all neuroprosthetic devices that are used clinically. Off-target stimulation and poor implant performance remain concerns for patients with electrically based neuroprosthetic devices. Optogenetic techniques may improve cranial nerve stimulation strategies used by various neuroprostheses and result in better patient outcomes. This article reviews the fundamentals of neural stimulation and provides an overview of recent major advancements in light-based neuromodulation."

Microstructured thin-film electrode technology enables proof of concept of scalable, soft auditory brainstem implants.

Auditory brainstem implants (ABIs) provide sound awareness to deaf individuals who are not candidates for the cochlear implant. The ABI electrode array rests on the surface of the cochlear nucleus (CN) in the brainstem and delivers multichannel electrical stimulation. The complex anatomy and physiology of the CN, together with poor spatial selectivity of electrical stimulation and inherent stiffness of contemporary multichannel arrays, leads to only modest auditory outcomes among ABI users. Here, we hypothesized that a soft ABI could enhance biomechanical compatibility with the curved CN surface. We developed implantable ABIs that are compatible with surgical handling, conform to the curvature of the CN after placement, and deliver efficient electrical stimulation. The soft ABI array design relies on precise microstructuring of plastic-metal-plastic multilayers to enable mechanical compliance, patterning, and electrical function. We fabricated soft ABIs to the scale of mouse and human CN and validated them in vitro. Experiments in mice demonstrated that these implants reliably evoked auditory neural activity over 1 month in vivo. Evaluation in human cadaveric models confirmed compatibility after insertion using an endoscopic-assisted craniotomy surgery, ease of array positioning, and robustness and reliability of the soft electrodes. This neurotechnology offers an opportunity to treat deafness in patients who are not candidates for the cochlear implant, and the design and manufacturing principles are broadly applicable to implantable soft bioelectronics throughout the central and peripheral nervous system.

Superior Canal Dehiscence Surgery Outcomes Following Failed Round Window Surgery.

OBJECTIVE: Round window (RW) occlusion or reinforcement is a less-invasive option compared with direct repair approaches to improve symptoms of superior canal dehiscence (SCD) syndrome. However, RW surgery is associated with variable outcomes. Middle fossa craniotomy or transmastoid repair is an option for SCD patients who fail RW surgery, but it is unknown whether sequential repair following RW plugging improves SCD symptoms or increases complications. The objective of this study is to evaluate outcomes of SCD repair via middle fossa craniotomy following failed RW surgery. STUDY DESIGN: Retrospective review. SETTING: Academic tertiary care center. PATIENTS: Adult patients with SCD syndrome who underwent failed RW surgery followed by sequential middle fossa craniotomy and plugging of the arcuate eminence defect. Patients with SCD associated with the superior petrosal sinus were excluded. INTERVENTION: None. MAIN OUTCOME MEASURE: Prospectively collected pre- and postoperative symptom questionnaires, threshold audiograms, and cervical vestibular evoked myogenic potentials (cVEMP). RESULTS: Seven SCD patients (out of a total of 194 surgical cases at our institution) underwent sequential middle-fossa SCD repair following failed RW surgery. Resolution of symptoms and reversal of diagnostic indicators were observed in the majority of subjects following sequential repair. Two of seven patients underwent a third procedure with plugging of the superior semicircular canal by a transmastoid approach due to the presence of residual symptoms. CONCLUSION: Middle fossa craniotomy and SCD occlusion is a safe and reasonable option for patients who fail RW surgery. Our cohort did not show increased risks of auditory or vestibular dysfunction.

Clinical and laboratory profile of children with Cystic Fibrosis: Experience of a tertiary care center in Pakistan.

OBJECTIVE: To determine the clinical presentation, diagnostic investigations and laboratory workup done in admitted children with cystic fibrosis at Aga Khan University Hospital Karachi, Pakistan. METHODS: This is athree years retrospective study from January 2013 to December 2015 conducted at The Aga Khan University Hospital Karachi Pakistan, enrolling admitted patient from birth to 15 years of either gender, diagnosed with CF on the basis of clinical features and positive sweat chloride test. Different clinical presentations were noted including initial presentations. Sweat chloride values more than 60mmol/L were labeled as positive and consistent with diagnosis of CF. Available Delta F-508 mutation analyses were noted. Relevant laboratory and radiological investigations including sputum culture and HR-CT chest findings were documented. Results were analyzed using SPSS version 20. RESULTS: Total 43 children were selected according to the inclusion criteria. Chronic cough (69.76%) was the most common initial clinical presentation. Mean age at onset of symptoms was 14.41± 26.18 months and mean age at diagnosis was 47.20 ± 45.80 months Respiratory features were most common in our cohort including chronic productive cough (90.71%), recurrent bronchopneumonia (72.09%) and asthma like presentation (44.19%) with wheezing and cough. 86% patients presented with failure to thrive. Gastroenterological features including steatorrhea were seen in 55.81% patients and 44.19% patients had abdominal distension. Mean sweat chloride value in our population was 82.70± 22.74. Gene analysis for Delta F-508 was identified in 12 (27.90%) patients. Bronchiectatic pulmonary changes on HRCT were seen in 18 patients (41.86%). Pseudomonas grew in 12 patients (27.90%) in sputum cultures at the time of diagnosis. CONCLUSION: Respiratory presentations predominate in CF children followed by gastrointestinal features. Nearly half of our patient had bronchiectatic changes on CT scan chest and more than quarter had pseudomonas colonization in the airways at the time of diagnosis. Delta F-508 mutation was found to be uncommon in our study population. There is significant delay in diagnosing patients with CF.