Anesthesia for Suboccipital Craniotomy in a Patient with Lymphangioleiomyomatosis: A Case Report

Lymphangioleiomyomatosis (LAM) is a rare pulmonary condition often presenting with spontaneous pneumothorax. Imaging or biopsy confirm the diagnosis. Published case reports describe the anesthetic management of patients with LAM undergoing brief procedures. No reports describe the anesthetic management for lengthy neurosurgical procedures. We describe anesthetic management for craniotomy in a patient with LAM. Clinical Features. A woman presented with 2 spontaneous left pneumothoraces. She received a diagnosis of LAM by imaging. She did well after pleurodesis. Hearing loss and tinnitus led to brain imaging demonstrating a large left cerebello-pontine angle mass. She presented for elective craniotomy to remove the mass while preserving cranial nerve function. Our technique for general endotracheal anesthesia aimed to reduce the likelihood of another pneumothorax while providing good surgical conditions and permitting neuromonitoring. Conclusion:. We demonstrate the successful anesthetic management of a patient with LAM undergoing a lengthy suboccipital craniotomy for a posterior fossa mass

Sensors for Wireless Body Monitoring Applications

Body monitoring systems have recently drawn great attention to modern electronic consumers due to their various health−care and security applications. However, most of the existing monitoring systems need wire connections that prevent free body movements. Complementary metal−oxide−semiconductor (CMOS) technology based wireless sensor systems need integration of different components that make the device volume and production cost high. In adition, their dependency on on−sensor power source limits the continuous monitoring capability. In the thesis, to demonstrate the feasibility of low cost and simple body monitoring systems, we propose a near−infrared (NIR) photodetector (PD) and a humidity sensor (HS) using low−temperature thin−film processes suitable for large−area electronics application. For NIR detection, a novel lateral metal−semiconductor−metal (MSM) PD architecture is proposed using low−temperature nanocrystalline silicon (nc−Si) as a NIR absorption layer and organic polyimide (PI) as a blocking layer. Experimental results show that addition of PI layer reduces the dark current (ID) up to 103−105 times compared with the PDs without PI layer. Fabricated devices exhibit a low ID of ~10−10 A, a response time of <1.5 ms, and an external quantum efficiency (EQE) of 35−15% for the 740−850 nm wavelengths of light under 100−150 V biasing conditions. Unlike the standard p−i−n PD, our high−performance lateral PD does not require doped p+ and n+ layers. Thus, the reported device is compatible with industry standard amorphous silicon (a−Si) thin−film transistor (TFT) fabrication process, which makes it promising for large−area full hand biometric imagers suitable for various non−invasive body monitoring applications. For humidity detection, a 30 mm diameter passive LC (p−LC) HS is formed by joining an octagonal planer inductor and a moisture sensitive interdigital zinc oxide (ZnO) capacitor in series. A PCB reader coil is also designed, which is able to sense the HS from <25 mm distance. The HS reads 30−90% of relative humidity (RH) by interrogating change of the resonance frequency (fR) of the reader−sensor system. The reading resolution is ±2.38%RH and the sensitivity is 53.33−93.33 kHz/1%RH for the above 45% RH measurements. Experimental results show that the proposed HS is operational in a range of 0−75 oC as long as recalibration is performed for a temperature drift of above ±3 oC, which makes it suitable for various promising applications operated at different temperatures. Above all, the presented results are promising for the continuous body monitoring applications to observe the humidity wirelessly without any power source on the sensor

Flip-Flop HSV-BAC: bacterial artificial chromosome based system for rapid generation of recombinant herpes simplex virus vectors using two independent site-specific recombinases

BACKGROUND: Oncolytic herpes simplex virus (HSV) vectors that specifically replicate in and kill tumor cells sparing normal cells are a promising cancer therapy. Traditionally, recombinant HSV vectors have been generated through homologous recombination between the HSV genome and a recombination plasmid, which usually requires laborious screening or selection and can take several months. Recent advances in bacterial artificial chromosome (BAC) technology have enabled cloning of the whole HSV genome as a BAC plasmid and subsequent manipulation in E. coli. Thus, we sought a method to generate recombinant oncolytic HSV vectors more easily and quickly using BAC technology. RESULTS: We have developed an HSV-BAC system, termed the Flip-Flop HSV-BAC system, for the rapid generation of oncolytic HSV vectors. This system has the following features: (i) two site-specific recombinases, Cre and FLPe, are used sequentially to integrate desired sequences and to excise the BAC sequences, respectively; and (ii) the size of the HSV-BAC-insert genome exceeds the packaging limit of HSV so only correctly recombined virus grows efficiently. We applied this to the construction of an HSV-BAC plasmid that can be used for the generation of transcriptionally-targeted HSV vectors. BAC sequences were recombined into the UL39 gene of HSV ICP4-deletion mutant d120 to generate M24-BAC virus, from which HSV-BAC plasmid pM24-BAC was isolated. An ICP4 expression cassette driven by an exogenous promoter was re-introduced to pM24-BAC by Cre-mediated recombination and nearly pure preparations of recombinant virus were obtained typically in two weeks. Insertion of the ICP4 coding sequence alone did not restore viral replication and was only minimally better than an ICP4-null construct, whereas insertion of a CMVIE promoter-ICP4 transgene (bM24-CMV) efficiently drove viral replication. The levels of bM24-CMV replication in tumor cells varied considerably compared to hrR3 (UL39 mutant). CONCLUSION: Our Flip-Flop HSV-BAC system enables rapid generation of HSV vectors carrying transgene inserts. By introducing a tumor-specific-promoter-driven ICP4 cassette into pM24-BAC using this system, one should be able to generate transcriptionally-targeted oncolytic HSV vectors. We believe this system will greatly facilitate the screening of a plethora of clinically useful tumor-specific promoters in the context of oncolytic HSV vectors

Combination of vinblastine and oncolytic herpes simplex virus vector expressing IL-12 therapy increases antitumor and antiangiogenic effects in prostate cancer models

Oncolytic herpes simplex virus-1 (oHSV)–based vectors selectively replicate in tumor cells causing direct killing, ie., oncolysis, while sparing normal cells. oHSV’sare promising anticancer agents, but their efficacy, when used as single agents, leaves room for improvement. We hypothesized that combining the direct oncolytic and antiangiogenic activities of the IL-12 secreting NV1042 oHSV with microtubule disrupting agents (MDA’s) would be an effective means to enhance antitumor efficacy. Vinblastine (VB) was identified among several MDA’s screened that displayed consistent and potent cytotoxic killing of both prostate cancer and endothelial cell lines. In matrigel tube forming assays, VB was found to be highly effective at inhibiting tube formation of HUVEC cells. The combination of VB with NV1023 (the parental virus lacking IL-12) or NV1042 showed additive or synergistic activity against prostate cancer cell lines and was not due to increased oHSV replication by VB. In athymic mice bearing CWR22 prostate tumors, VB in combination with NV1042 was superior to the combination of VB plus NV1023 in reducing tumor burden, appeared to be nontoxic and resulted in a statistically significant diminution in the number of CD31+ cells as compared to other treatment groups. In human organotypic cultures using surgical samples from radical prostatectomies, both NV1023 and NV1042 were localized specifically to the epithelial cells of prostatic glands but not to the surrounding stroma. These data highlight the therapeutic advantage of combining the dual-acting anti-tumor and anti-angiogenic activities of oHSV’s and MDA’s

Modification of Extracellular Matrix Enhances Oncolytic Adenovirus Immunotherapy in Glioblastoma

Purpose: Extracellular matrix (ECM) component hyaluronan (HA) facilitates malignant phenotypes of glioblastoma (GBM), however, whether HA impacts response to GBM immunotherapies is not known. Herein, we investigated whether degradation of HA enhances oncolytic virus immunotherapy for GBM. Experimental design: Presence of HA was examined in patient and murine GBM. Hyaluronidase-expressing oncolytic adenovirus, ICOVIR17, and its parental virus, ICOVIR15, without transgene, were tested to determine if they increased animal survival and modulated the immune tumor microenvironment (TME) in orthotopic GBM. HA regulation of NF-κB signaling was examined in virus-infected murine macrophages. We combined ICOVIR17 with PD-1 checkpoint blockade and assessed efficacy and determined mechanistic contributions of tumor-infiltrating myeloid and T cells. Results: Treatment of murine orthotopic GBM with ICOVIR17 increased tumor-infiltrating CD8+ T cells and macrophages, and upregulated PD-L1 on GBM cells and macrophages, leading to prolonged animal survival, compared with control virus ICOVIR15. High molecular weight HA inhibits adenovirus-induced NF-κB signaling in macrophages in vitro, linking HA degradation to macrophage activation. Combining ICOVIR17 with anti-PD-1 antibody further extended the survival of GBM-bearing mice, achieving long-term remission in some animals. Mechanistically, CD4+ T cells, CD8+ T cells, and macrophages all contributed to the combination therapy that induced tumor-associated proinflammatory macrophages and tumor-specific T-cell cytotoxicity locally and systemically. Conclusions: Our studies are the first to show that immune modulatory ICOVIR17 has a dual role of mediating degradation of HA within GBM ECM and subsequently modifying the immune landscape of the TME, and offers a mechanistic combination immunotherapy with PD-L1/PD-1 blockade that remodels innate and adaptive immune cells

The role of PIP5K1α/pAKT and targeted inhibition of growth of subtypes of breast cancer using PIP5K1α inhibitor

Despite recent improvement in adjuvant therapies, triple-negative, and ER+ subtypes of breast cancer (BC) with metastatic potentials remain the leading cause of BC-related deaths. We investigated the role of phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), a key upstream factor of PI3K/AKT, and the therapeutic effect of PIP5Kα inhibitor on subtypes of BC. The clinical importance of PIP5K1α and its association with survivals were analyzed using three BC cohorts from Nottingham (n = 913), KM plotter (n = 112) and TCGA (n = 817). Targeted overexpression or knockdown of PIP5K1α were introduced into BC cell lines. The effects of PIP5K1α and its inhibitor on growth and invasion of BC were confirmed by using in vitro assays including proliferation, migration, apoptosis and luciferase reporter assays and in vivo xenograft mouse models. All statistical tests were two-sided. PIP5K1α was associated with poor patient outcome in triple-negative BC (for PIP5K1α protein, p = 0.011 and for mRNA expression, p = 0.028, log-rank test). 29% of triple-negative BC had PIP5K1A gene amplification. Elevated level of PIP5K1α increased expression of pSer-473 AKT (p < 0.001) and invasiveness of triple-negative MDA-MB-231 cells (p < 0.001). Conversely, inhibition of PIP5K1α using its inhibitor ISA-2011B, or via knockdown suppressed growth and invasiveness of MDA-MB-231 xenografts (mean vehicle-treated controls = 2160 mm3, and mean ISA-2011B-treated = 600 mm3, p < 0.001). ISA-2011B-treatment reduced expression of pSer-473 AKT (p < 0.001) and its downstream effectors including cyclin D1, VEGF and its receptors, VEGFR1 and VEGFR2 (p < 0.001) in xenograft tumors. In ER+ cancer cells, PIP5K1α acted on pSer-473 AKT, and was in complexes with VEGFR2, serving as co-factor of ER-alpha to regulate activities of target genes including cyclin D1 and CDK1. Our study suggests that our developed PIP5K1α inhibitor has a great potential on refining targeted therapeutics for treatment of triple-negative and ER+ BC with abnormal PI3K/AKT pathways

Indocyanine Green Angiographic Findings of Obscure Choroidal Abnormalities in Neurofibromatosis

We report two cases of choroidal neurofibromatosis, detected with the aid of indocyanine green angiography (ICGA) in patients with neurofibromatosis (NF)-1, otherwise having obscure findings based on ophthalmoscopy and fluoresceine angiography (FA). In case 1, the ophthalmoscopic exam showed diffuse bright or yellowish patched areas with irregular and blunt borders at the posterior pole. The FA showed multiple hyperfluorescent areas at the posterior pole in the early phase, which then showed more hyperfluorescence without leakage or extent in the late phase. The ICGA showed diffuse hypofluorescent areas in both the early and late phases, and the deep choroidal vessels were also visible. In case 2, the fundus showed no abnormal findings, and the FA showed weakly hypofluorescent areas with indefinite borders in both eyes. With the ICGA, these areas were more hypofluorescent and had clear borders. Choroidal involvement in NF-1 seems to occur more than expected. In selected cases, ICGA is a useful tool to be utilized when an ocular examination is conducted in a patient that has no definite findings based on the ophthalmoscope, B-scan, or FA tests

Machine Learning and Meta-Analysis Approach to Identify Patient Comorbidities and Symptoms that Increased Risk of Mortality in COVID-19

Background: Providing appropriate care for people suffering from COVID-19, the disease caused by the pandemic SARS-CoV-2 virus is a significant global challenge. Many individuals who become infected have pre-existing conditions that may interact with COVID-19 to increase symptom severity and mortality risk. COVID-19 patient comorbidities are likely to be informative about individual risk of severe illness and mortality. Accurately determining how comorbidities are associated with severe symptoms and mortality would thus greatly assist in COVID-19 care planning and provision. Methods: To assess the interaction of patient comorbidities with COVID-19 severity and mortality we performed a meta-analysis of the published global literature, and machine learning predictive analysis using an aggregated COVID-19 global dataset. Results: Our meta-analysis identified chronic obstructive pulmonary disease (COPD), cerebrovascular disease (CEVD), cardiovascular disease (CVD), type 2 diabetes, malignancy, and hypertension as most significantly associated with COVID-19 severity in the current published literature. Machine learning classification using novel aggregated cohort data similarly found COPD, CVD, CKD, type 2 diabetes, malignancy and hypertension, as well as asthma, as the most significant features for classifying those deceased versus those who survived COVID-19. While age and gender were the most significant predictor of mortality, in terms of symptom-comorbidity combinations, it was observed that Pneumonia-Hypertension, Pneumonia-Diabetes and Acute Respiratory Distress Syndrome (ARDS)-Hypertension showed the most significant effects on COVID-19 mortality. Conclusions: These results highlight patient cohorts most at risk of COVID-19 related severe morbidity and mortality which have implications for prioritization of hospital resources