UW Neurological Surgery Recent PubMed Publications

CBASS Immunity Uses CARF-Related Effectors to Sense 3'-5'- and 2'-5'-Linked Cyclic Oligonucleotide Signals and Protect Bacteria from Phage Infection.

Cell. 2020 07 09;182(1):38-49.e17

Authors: Lowey B, Whiteley AT, Keszei AFA, Morehouse BR, Mathews IT, Antine SP, Cabrera VJ, Kashin D, Niemann P, Jain M, Schwede F, Mekalanos JJ, Shao S, Lee ASY, Kranzusch PJ

Abstract
cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzymes are immune sensors that synthesize nucleotide second messengers and initiate antiviral responses in bacterial and animal cells. Here, we discover Enterobacter cloacae CD-NTase-associated protein 4 (Cap4) as a founding member of a diverse family of >2,000 bacterial receptors that respond to CD-NTase signals. Structures of Cap4 reveal a promiscuous DNA endonuclease domain activated through ligand-induced oligomerization. Oligonucleotide recognition occurs through an appended SAVED domain that is an unexpected fusion of two CRISPR-associated Rossman fold (CARF) subunits co-opted from type III CRISPR immunity. Like a lock and key, SAVED effectors exquisitely discriminate 2'-5'- and 3'-5'-linked bacterial cyclic oligonucleotide signals and enable specific recognition of at least 180 potential nucleotide second messenger species. Our results reveal SAVED CARF family proteins as major nucleotide second messenger receptors in CBASS and CRISPR immune defense and extend the importance of linkage specificity beyond mammalian cGAS-STING signaling.

PMID: 32544385 [PubMed - indexed for MEDLINE]

The stress-inducible molecular chaperone GRP78 as potential therapeutic target for coronavirus infection.

J Infect. 2020 09;81(3):452-482

Authors: Ha DP, Van Krieken R, Carlos AJ, Lee AS

PMID: 32535155 [PubMed - indexed for MEDLINE]

A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways.

Nat Commun. 2020 06 12;11(1):2977

Authors: Pattwell SS, Arora S, Cimino PJ, Ozawa T, Szulzewsky F, Hoellerbauer P, Bonifert T, Hoffstrom BG, Boiani NE, Bolouri H, Correnti CE, Oldrini B, Silber JR, Squatrito M, Paddison PJ, Holland EC

Abstract
Independent scientific achievements have led to the discovery of aberrant splicing patterns in oncogenesis, while more recent advances have uncovered novel gene fusions involving neurotrophic tyrosine receptor kinases (NTRKs) in gliomas. The exploration of NTRK splice variants in normal and neoplastic brain provides an intersection of these two rapidly evolving fields. Tropomyosin receptor kinase B (TrkB), encoded NTRK2, is known for critical roles in neuronal survival, differentiation, molecular properties associated with memory, and exhibits intricate splicing patterns and post-translational modifications. Here, we show a role for a truncated NTRK2 splice variant, TrkB.T1, in human glioma. TrkB.T1 enhances PDGF-driven gliomas in vivo, augments PDGF-induced Akt and STAT3 signaling in vitro, while next generation sequencing broadly implicates TrkB.T1 in the PI3K signaling cascades in a ligand-independent fashion. These TrkB.T1 findings highlight the importance of expanding upon whole gene and gene fusion analyses to include splice variants in basic and translational neuro-oncology research.

PMID: 32532995 [PubMed - indexed for MEDLINE]

Variation in hospital charges in patients with external ventricular drains: comparison between the intensive care and surgical floor settings.

J Neurosurg Pediatr. 2019 04 19;24(1):29-34

Authors: Chu JK, Feroze AH, Collins K, McGrath LB, Young CC, Williams JR, Browd SR

Abstract
OBJECTIVE: Placement of an external ventricular drain (EVD) is a common and potentially life-saving neurosurgical procedure, but the economic aspect of EVD management and the relationship to medical expenditure remain poorly studied. Similarly, interinstitutional practice patterns vary significantly. Whereas some institutions require that patients with EVDs be monitored strictly within the intensive care unit (ICU), other institutions opt primarily for management of EVDs on the surgical floor. Therefore, an ICU burden for patients with EVDs may increase a patient's costs of hospitalization. The objective of the current study was to examine the expense differences between the ICU and the general neurosurgical floor for EVD care.
METHODS: The authors performed a retrospective analysis of data from 2 hospitals within a single, large academic institution-the University of Washington Medical Center (UWMC) and Seattle Children's Hospital (SCH). Hospital charges were evaluated according to patients' location at the time of EVD management: SCH ICU, SCH floor, or UWMC ICU. Daily hospital charges from day of EVD insertion to day of removal were included and screened for days that would best represent baseline expenses for EVD care. Independent-samples Kruskal-Wallis analysis was performed to compare daily charges for the 3 settings.
RESULTS: Data from a total of 261 hospital days for 23 patients were included in the analysis. Ten patients were cared for in the UWMC ICU and 13 in the SCH ICU and/or on the SCH neurosurgical floor. The median values for total daily hospital charges were $19,824.68 (interquartile range [IQR] $12,889.73-$38,494.81) for SCH ICU care, $8,620.88 (IQR $6,416.76-$11,851.36) for SCH floor care, and $10,002.13 (IQR $8,465.16-$12,123.03) for UWMC ICU care. At SCH, it was significantly more expensive to provide EVD care in the ICU than on the floor (p < 0.001), and the daily hospital charges for the UWMC ICU were significantly greater than for the SCH floor (p = 0.023). No adverse clinical event related to the presence of an EVD was identified in any of the settings.
CONCLUSIONS: ICU admission solely for EVD care is costly. If safe EVD care can be provided outside of the ICU, it would represent a potential area for significant cost savings. Identifying appropriate patients for EVD care on the floor is multifactorial and requires vigilance in balancing the expenses associated with ICU utilization and optimal patient care.

PMID: 31003227 [PubMed - indexed for MEDLINE]

Correlation between epicardial adipose tissue and body mass index in New Zealand ethnic populations.

N Z Med J. 2020 06 12;133(1516):22-32

Authors: Moharram MA, Aitken-Buck HM, Reijers R, Hout IV, Williams MJ, Jones PP, Whalley GA, Lamberts RR, Coffey S

Abstract
AIM: We aimed to investigate the correlation between epicardial adipose tissue (EAT) and body mass index (BMI) in different ethnic groups in New Zealand.
METHODS: The study included 205 individuals undergoing open heart surgery. Māori and Pacific groups were combined to increase statistical power. EAT was measured using 2D echocardiography.
RESULTS: There were 164 New Zealand Europeans (NZE) and 41 Māori/Pacific participants. The mean (SD) age of the study group was 67.9 (10.1) years, 69.1 (9.5) for NZE and 63.5 (11.4) for Māori/Pacific. BMI was 29.6 (5.5) kg/m2 for NZE and 31.8 (6.2) for Māori/Pacific. EAT thickness was 6.2 (2.2) mm and 6.0 (1.8) mm for NZE and Māori/Pacific, respectively. Using univariate linear regression, BMI showed moderate correlation with EAT in NZE (R2=0.26, p<0.001); however, there was no significant correlation between BMI and EAT in Māori/Pacific patients (R2=0.05, p=0.17). Using multivariate analysis, BMI remained a significant predictor of EAT thickness in NZE (R2 =0.27, p<0.001).
CONCLUSIONS: BMI was associated with EAT thickness in NZE patients, but not in Māori/Pacific patients. The same level of BMI can carry different connotations of risk in different ethnic groups, with BMI likely being an inconsistent measure of obesity in in Māori/Pacific patients.

PMID: 32525859 [PubMed - indexed for MEDLINE]

AOSpine Consensus Paper on Nomenclature for Working-Channel Endoscopic Spinal Procedures.

Global Spine J. 2020 Apr;10(2 Suppl):111S-121S

Authors: Hofstetter CP, Ahn Y, Choi G, Gibson JNA, Ruetten S, Zhou Y, Li ZZ, Siepe CJ, Wagner R, Lee JH, Sairyo K, Choi KC, Chen CM, Telfeian AE, Zhang X, Banhot A, Lokhande PV, Prada N, Shen J, Cortinas FC, Brooks NP, Van Daele P, Kotheeranurak V, Hasan S, Keorochana G, Assous M, Härtl R, Kim JS

Abstract
Study Design: International consensus paper on a unified nomenclature for full-endoscopic spine surgery.
Objectives: Minimally invasive endoscopic spinal procedures have undergone rapid development during the past decade. Evolution of working-channel endoscopes and surgical instruments as well as innovation in surgical techniques have expanded the types of spinal pathology that can be addressed. However, there is in the literature a heterogeneous nomenclature defining approach corridors and procedures, and this lack of common language has hampered communication between endoscopic spine surgeons, patients, hospitals, and insurance providers.
Methods: The current report summarizes the nomenclature reported for working-channel endoscopic procedures that address cervical, thoracic, and lumbar spinal pathology.
Results: We propose a uniform system that defines the working-channel endoscope (full-endoscopic), approach corridor (anterior, posterior, interlaminar, transforaminal), spinal segment (cervical, thoracic, lumbar), and procedure performed (eg, discectomy, foraminotomy). We suggest the following nomenclature for the most common full-endoscopic procedures: posterior endoscopic cervical foraminotomy (PECF), transforaminal endoscopic thoracic discectomy (TETD), transforaminal endoscopic lumbar discectomy (TELD), transforaminal lumbar foraminotomy (TELF), interlaminar endoscopic lumbar discectomy (IELD), interlaminar endoscopic lateral recess decompression (IE-LRD), and lumbar endoscopic unilateral laminotomy for bilateral decompression (LE-ULBD).
Conclusions: We believe that it is critical to delineate a consensus nomenclature to facilitate uniformity of working-channel endoscopic procedures within academic scholarship. This will hopefully facilitate development, standardization of procedures, teaching, and widespread acceptance of full-endoscopic spinal procedures.

PMID: 32528794 [PubMed]

Development of a Curriculum for Minimally Invasive Spine Surgery (MISS).

Global Spine J. 2020 Apr;10(2 Suppl):122S-125S

Authors: Schmidt FA, Wong T, Kirnaz S, Taboada N, Assaker R, Hofstetter C, Kim JS, Parajón A, Taylor P, Assous M, Härtl R

Abstract
The purpose of this review is to describe how a curriculum for minimally invasive spine surgery (MISS) was developed and implemented. The authors discuss the curriculum roadmap, its target audience, and the educational process for teaching general skills and specific procedures in MISS. Initiated by AOSpine, a panel of experts within spinal surgery from multiple centers formed the minimally invasive spine surgery task force. Together, task force members redefined the standards and milestones of the MISS education and training. Therefore, we conclude that the MISS task force created a structured curriculum which will have a positive influence on daily practice for surgeons and patients worldwide.

PMID: 32528795 [PubMed]

Pay-it-forward gonorrhoea and chlamydia testing among men who have sex with men in China: a randomised controlled trial.

Lancet Infect Dis. 2020 08;20(8):976-982

Authors: Yang F, Zhang TP, Tang W, Ong JJ, Alexander M, Forastiere L, Kumar N, Li KT, Zou F, Yang L, Mi G, Wang Y, Huang W, Lee A, Zhu W, Luo D, Vickerman P, Wu D, Yang B, Christakis NA, Tucker JD

Abstract
BACKGROUND: WHO recommends that men who have sex with men (MSM) receive gonorrhoea and chlamydia testing, but many evidence-based preventive services are unaffordable. The pay-it-forward strategy offers an individual a gift (eg, a test for sexually transmitted diseases) and then asks whether they would like to give a gift (eg, a future test) to another person. This study examined the effectiveness of a pay-it-forward programme to increase gonorrhoea and chlamydia testing among MSM in China.
METHODS: We did a randomised controlled superiority trial at three HIV testing sites run by MSM community-based organisations in Guangzhou and Beijing, China. We included MSM aged 16 years or older who were seeking HIV testing and met indications for gonorrhoea and chlamydia testing. Restricted randomisation was done using computer-generated permuted blocks. 30 groups were randomised into three arms (1:1:1): a pay-it-forward arm in which men were offered free gonorrhoea and chlamydia testing and then asked whether they would like to donate for testing of prospective participants, a pay-what-you-want arm in which men were offered free testing and given the option to pay any desired amount for the test, and a standard-of-care arm in which testing was offered at ¥150 (US$22). There was no masking to arm assignment. The primary outcome was gonorrhoea and chlamydia test uptake ascertained by administrative records. We used generalised estimating equations to estimate intervention effects with one-sided 95% CIs and a prespecified superiority margin of 20%. The trial is registered with ClinicalTrials.gov, NCT03741725.
FINDINGS: Between Dec 8, 2018, and Jan 19, 2019, 301 men were recruited and included in the analysis. 101 were randomly assigned to the pay-it-forward group, 100 to the pay-what-you-want group, and 100 to the standard-of-care group. Test uptake for gonorrhoea and chlamydia was 56% (57 of 101 participants) in the pay-it-forward arm, 46% (46 of 100 participants) in the pay-what-you-want arm, and 18% (18 of 100 participants) in the standard-of-care arm. The estimated difference in test uptake between the pay-it-forward and standard-of-care group was 38·4% (95% CI lower bound 28·4%). Among men in the pay-it-forward arm, 54 of 57 (95%) chose to donate to support testing for others.
INTERPRETATION: The pay-it-forward strategy can increase gonorrhoea and chlamydia testing uptake among Chinese MSM and could be a useful tool for scaling up preventive services that carry a mandatory fee.
FUNDING: US National Institute of Health; Special Programme for Research and Training in Tropical Diseases, sponsored by UNICEF, UNDP, World Bank, and WHO; the National Key Research and Development Program of China; Doris Duke Charitable Foundation; and Social Entrepreneurship to Spur Health.

PMID: 32530426 [PubMed - indexed for MEDLINE]

Adverse Childhood Experiences in Trainees and Physicians With Professionalism Lapses: Implications for Medical Education and Remediation.

Acad Med. 2020 Jun 09;:

Authors: Williams BW, Welindt D, Hafferty FW, Stumps A, Flanders P, Williams MV

Abstract
PURPOSE: Unprofessional behavior, which can include failure to engage, dishonest and/or disrespectful behavior, and poor self-awareness, can be demonstrated by medical trainees and practicing physicians. In the authors' experience, these types of behaviors are associated with exposure to adverse childhood experiences (ACEs). Given this overlap, the authors studied the percentage of ACEs among trainees and physicians referred for fitness-for-duty evaluations and patterns between the types of ACEs experienced and the reason for referral.
METHOD: A final sample of 123 cases of U.S. trainees and physicians who had been referred to a Midwestern center for assessment and remediation of professionalism issues from 2013 to 2018 was created. Included professionalism lapses fell within 3 categories: boundary violation, disruptive behavior, or potential substance use disorder concerns. All participants completed a psychosocial developmental interview, which includes questions about ACE exposure. Overall rate of reported ACEs and types of ACEs reported were explored.
RESULTS: Eighty-six (70%) participants reported at least 1 ACE, while 27 (22%) reported 4 or more. Compared to national data, these results show significantly higher occurrence rates of 1 or more ACEs and a lower occurrence rate of 0 ACEs. ACEs that predicted reasons for referral were physical or sexual abuse, feeling unwanted or unloved, witnessing abuse of their mother or stepmother, or caretaker substance use.
CONCLUSIONS: In this sample, ACE exposure was associated with professionalism issues. Remediating individuals with professionalism issues and exposure to ACEs can be complicated by heightened responses to stressful stimuli, difficulties with collaboration and trust, and decreased self-efficacy. Adoption of a trauma-informed medical education approach may help those that have been impacted by trauma rebuild a sense of control and empowerment. The findings of this study may be useful predictors in identifying those at risk of problematic behavior and recidivism prior to a sentinel event.

PMID: 32520753 [PubMed - as supplied by publisher]

Risks for cold frequency vary by sex: role of asthma, age, TLR7 and leukocyte subsets.

Eur Respir J. 2020 Jun 08;:

Authors: Murray LM, Yerkovich ST, Ferreira MA, Upham JW

Abstract
Viral respiratory infections are usually benign but can trigger asthma exacerbations. The factors associated with upper respiratory tract infection (cold) frequency are not fully understood, nor is it clear whether such factors differ between women and men.To determine which immunological and clinical variables associate with the frequency of self-reported respiratory infections (colds), 150 asthma cases and 151 controls were recruited. Associations between antiviral immune response variables - TLR7/8 gene expression, plasmacytoid dendritic cell (pDC) numbers and interferon-alpha, TNF and IL-12 production - and asthma were then examined that might explain cold frequency.People with asthma cases reported more colds per year (median 3 versus 2, p<0.001) and had lower baseline TLR7 gene expression (odds ratio (OR)=0.12, p=0.02) than controls. Associations between many variables and cold frequency differed between women and men. In women, high blood neutrophil counts (beta=0.096, p=0.002), and younger age (beta= -0.017, p<0.001), but not exposure to children, were independently associated with more frequent colds. In men, low TLR7 expression (beta= -0.96, p=0.041) and high CLEC4C gene expression (a marker of pDC; beta=0.88, p=0.008) were independently associated with more frequent colds. Poor asthma symptom control was independently associated with reduced TLR8 gene expression (beta= -1.4, p=0.036) and high BMI (beta=0.041, p=0.004).Asthma, age and markers of inflammation and antiviral immunity in peripheral blood are associated with frequent colds. Interestingly, the variables associated with cold frequency differed between women and men.

PMID: 32513781 [PubMed - as supplied by publisher]

Screening for Drug Use in Primary Care: Practical Implications of the New USPSTF Recommendation.

JAMA Intern Med. 2020 08 01;180(8):1050-1051

Authors: Bradley KA, Lapham GT, Lee AK

PMID: 32515790 [PubMed - indexed for MEDLINE]

Editorial overviews: Editorial matters - point of clarification.

Curr Opin Pharmacol. 2020 02;50:107-108

Authors: Williams M

PMID: 32506004 [PubMed - indexed for MEDLINE]

Antiepileptic Drugs and Bone Health: Current Concepts.

Psychopharmacol Bull. 2020 May 19;50(2):36-44

Authors: Siniscalchi A, Murphy S, Cione E, Piro L, Sarro G, Gallelli L

Abstract
Chronic use of antiepileptic drugs (AEDs) can induce the development of adverse effects on bone metabolism. In epileptic patients treated with AED, the monitoring of biochemical markers of bone turnover, such as the measurement of serum 25 (OH) vitamin D, bone mineral density, before the beginning of the treatment and during the follow-up is not routinely required. In the future, monitoring of biochemical markers in epileptic patients treated with AED may help us for adequate prevention therapy.

PMID: 32508365 [PubMed - in process]

Utilizing Organoid and Air-Liquid Interface Models as a Screening Method in the Development of New Host Defense Peptides.

Front Cell Infect Microbiol. 2020;10:228

Authors: Choi KG, Wu BC, Lee AH, Baquir B, Hancock REW

Abstract
Host defense peptides (HDPs), also known as antimicrobial peptides, are naturally occurring polypeptides (~12-50 residues) composed of cationic and hydrophobic amino acids that adopt an amphipathic conformation upon folding usually after contact with membranes. HDPs have a variety of biological activities including immunomodulatory, anti-inflammatory, anti-bacterial, and anti-biofilm functions. Although HDPs have the potential to address the global threat of antibiotic resistance and to treat immune and inflammatory disorders, they have yet to achieve this promise. Indeed, there are several challenges associated with bringing peptide-based drug candidates from the lab bench to clinical practice, including identifying appropriate indications, stability, toxicity, and cost. These challenges can be addressed in part by the development of innate defense regulator (IDR) peptides and peptidomimetics, which are synthetic derivatives of HDPs with similar or better efficacy, increased stability, and reduced toxicity and cost of the original HDP. However, one of the largest gaps between basic research and clinical application is the validity and translatability of conventional model systems, such as cell lines and animal models, for screening HDPs and their derivatives as potential drug therapies. Indeed, such translation has often relied on animal models, which have only limited validity. Here we discuss the recent development of human organoids for disease modeling and drug screening, assisted by the use of omics analyses. Organoids, developed from primary cells, cell lines, or human pluripotent stem cells, are three-dimensional, self-organizing structures that closely resemble their corresponding in vivo organs with regards to immune responses, tissue organization, and physiological properties; thus, organoids represent a reliable method for studying efficacy, formulation, toxicity and to some extent drug stability and pharmacodynamics. The use of patient-derived organoids enables the study of patient-specific efficacy, toxicogenomics and drug response predictions. We outline how organoids and omics data analysis can be leveraged to aid in the clinical translation of IDR peptides.

PMID: 32509598 [PubMed - in process]

Pseudoaneurysm of the Superficial Temporal Artery After Intracranial Pressure Monitoring Device Placement: Case Report of a Rare Complication.

Oper Neurosurg (Hagerstown). 2020 Jun 05;:

Authors: Pan J, Barros G, Greil ME, Meyer RM, Ene CI, Chesnut RM

Abstract
BACKGROUND AND IMPORTANCE: Pseudoaneurysms involving the superficial temporal artery (STA), either iatrogenic or caused by direct trauma, are rare. The STA is prone to injury due to its long course throughout the scalp. Injuries can cause cosmetic defects and/or skin breakdown leading to further complications.
CLINICAL PRESENTATION: We report a case of delayed iatrogenic pseudoaneurysm of the STA after placement of an intracranial pressure monitor in the setting of acute traumatic brain injury. The patient had a delayed development of a pulsatile mass over his right frontal region, with computed tomography angiography concerning for a pseudoaneurysm of the STA. This was managed with surgical resection with complete resolution of symptoms at follow-up.
CONCLUSION: We review the literature regarding the etiology, pathogenesis, and management of these lesions. While iatrogenic injuries to the STA have been previously reported, this is a curious case related to placement of an intracranial pressure monitor. We recommend direct surgical resection of the pseudoaneurysm for cosmetic effect and prevention of further wound breakdown.

PMID: 32503046 [PubMed - as supplied by publisher]

Small Bowel Gastrointestinal Stromal Tumor as a Gateway for Streptococcus anginosus Causing Multiple Liver Abscesses.

World J Oncol. 2020 Jun;11(3):116-121

Authors: Conte GA, Harmon JS, Masia RA, Marchesani D, Sun X, Pichardo EM, Parrilla FB, Levitt MJ, Chinnici AA

Abstract
Gastrointestinal stromal tumors (GISTs) are the most common type of mesenchymal neoplasm of the gastrointestinal tract but consist of only 1% of all primary gastrointestinal neoplasms. Differentiated from other spindle cell tumors, GISTs are uniquely positive for CD117 expression which allows for molecular targeting therapy with imatinib mesylate (Gleevec). Clinical presentations are variable, ranging from asymptomatic to vague symptoms of abdominal pain, early satiety, abdominal distention or gastrointestinal bleeding. Very rarely, patients can present with tumor-bowel fistula and intra-abdominal abscesses. In this article, we discuss a rare presentation of a middle-aged male with multiple liver abscesses found to have a primary small bowel GIST. This patient received prompt intravenous antibiotics; however, hepatic abscesses can be easily misinterpreted as cystic hepatic metastases which can delay appropriate therapy. Streptococcus anginosus was found to be responsible for the formation of the liver abscesses visualized on computed tomography (CT) scan. Similar to Streptococcus bovis, knowledge in the literature is arising about the association between S. anginosus and gastrointestinal malignancies. This case highlights the importance of identifying concomitant primary GISTs with intra-hepatic abscesses, as these lesions can be easily misconstrued as liver metastases and consequently mismanaged. We herein emphasize that hepatic abscesses are a potential sequela of GISTs and should thus prompt further investigation for potential malignancies, if warranted, so that there is no delay in treatment of these gastrointestinal tumors.

PMID: 32494319 [PubMed]

Targeting therapeutic vulnerabilities with PARP inhibition and radiation in IDH-mutant gliomas and cholangiocarcinomas.

Sci Adv. 2020 Apr;6(17):eaaz3221

Authors: Wang Y, Wild AT, Turcan S, Wu WH, Sigel C, Klimstra DS, Ma X, Gong Y, Holland EC, Huse JT, Chan TA

Abstract
Mutations in isocitrate dehydrogenase (IDH) genes occur in multiple cancer types, lead to global changes in the epigenome, and drive tumorigenesis. Yet, effective strategies targeting solid tumors harboring IDH mutations remain elusive. Here, we demonstrate that IDH-mutant gliomas and cholangiocarcinomas display elevated DNA damage. Using multiple in vitro and preclinical animal models of glioma and cholangiocarcinoma, we developed treatment strategies that use a synthetic lethality approach targeting the reduced DNA damage repair conferred by mutant IDH using poly(adenosine 5'-diphosphate) ribose polymerase inhibitors (PARPis). The therapeutic effects are markedly enhanced by cotreatment with concurrent, localized radiation therapy. PARPi-buttressed multimodality therapies may represent a readily applicable approach that is selective for IDH-mutant tumor cells and has potential to improve outcomes in multiple cancers.

PMID: 32494639 [PubMed - in process]

Antiviral activity of PLK1-targeting siRNA delivered by lipid nanoparticles in HBV-infected hepatocytes.

Antivir Ther. 2020 Jun 04;:

Authors: Foca A, Dhillon A, Lahlali T, Lucifora J, Salvetti A, Rivoire M, Lee A, Durantel D

Abstract
BACKGROUND: A link between HBV and PLK1 was clearly evidenced in HBV-driven carcinogenesis, and we have also recently shown that PLK1 is a proviral factor in the early phases of HBV infection. Moreover, we have shown that BI-2536, a small molecule PLK1 inhibitor, was very efficient at inhibiting HBV DNA neosynthesis, notably by affecting nucleocapsid assembly as a result of the modulation of HBc phosphorylation. Yet, as small molecule kinase inhibitors often feature poor selectivity, a more specific and safer strategy to target PLK1 would be needed for a potential development against chronic HBV infections.
METHODS: Here, we analysed using both freshly isolated primary human hepatocytes and differentiated HepaRG, the anti-HBV properties of an LNP-encapsulated PLK1-targeting siRNA. Standard assays were used to monitor the effect of LNP siPLK1, or controls (LNP siHBV and LNP siNon-Targeting), on HBV replication and cell viability.
RESULTS: A dose as low as 100ng/mL of LNP-siPLK1 resulted in a >75% decrease in secreted HBV DNA (viral particles), which was comparable to that obtained with LNP siHBV or 10 µM of Tenofovir (TFV), without affecting cell viability. Interestingly, and in contrast to that obtained with TFV, a strong inhibition of viral RNA and HBe/HBsAg secretions was also observed under LNP siPLK1 treatment. This correlated with a significant intracellular decrease of vRNA accumulation, which was independent of any change in cccDNA levels, thus suggesting a transcriptional or post-transcriptional modulation. Such an effect was not obtained with a biochemical approach of PLK1 inhibition, suggesting an enzymatic-independent role of PLK1.
CONCLUSIONS: This study emphasizes that a specific PLK1 inhibition could help achieving an improved HBsAg loss in CHB patients, likely in combination with other HBsAg-targeting strategies.

PMID: 32496211 [PubMed - as supplied by publisher]

The Dancing Cord: Inherent Spinal Cord Motion and Its Effect on Cord Dose in Spine Stereotactic Body Radiation Therapy.

Neurosurgery. 2020 Jun 04;:

Authors: Oztek MA, Mayr NA, Mossa-Basha M, Nyflot M, Sponseller PA, Wu W, Hofstetter CP, Saigal R, Bowen SR, Hippe DS, Yuh WTC, Stewart RD, Lo SS

Abstract
BACKGROUND: Spinal cord dose limits are critically important for the safe practice of spine stereotactic body radiotherapy (SBRT). However, the effect of inherent spinal cord motion on cord dose in SBRT is unknown.
OBJECTIVE: To assess the effects of cord motion on spinal cord dose in SBRT.
METHODS: Dynamic balanced fast field echo (BFFE) magnetic resonance imaging (MRI) was obtained in 21 spine metastasis patients treated with SBRT. Planning computed tomography (CT), conventional static T2-weighted MRI, BFFE MRI, and dose planning data were coregistered. Spinal cord from the dynamic BFFE images (corddyn) was compared with the T2-weighted MRI (cordstat) to analyze motion of corddyn beyond the cordstat (Dice coefficient, Jaccard index), and beyond cordstat with added planning organ at risk volume (PRV) margins. Cord dose was compared between cordstat, and corddyn (Wilcoxon signed-rank test).
RESULTS: Dice coefficient (0.70-0.95, median 0.87) and Jaccard index (0.54-0.90, median 0.77) demonstrated motion of corddyn beyond cordstat. In 62% of the patients (13/21), the dose to corddyn exceeded that of cordstat by 0.6% to 13.8% (median 4.3%). The corddyn spatially excursed outside the 1-mm PRV margin of cordstat in 9 patients (43%); among these dose to corddyn exceeded dose to cordstat >+ 1-mm PRV margin in 78% of the patients (7/9). Corddyn did not excurse outside the 1.5-mm or 2-mm PRV cord cordstat margin.
CONCLUSION: Spinal cord motion may contribute to increases in radiation dose to the cord from SBRT for spine metastasis. A PRV margin of at least 1.5 to 2 mm surrounding the cord should be strongly considered to account for inherent spinal cord motion.

PMID: 32497210 [PubMed - as supplied by publisher]

Reducing Sitting Time in Obese Older Adults: The I-STAND Randomized Controlled Trial.

J Aging Phys Act. 2020 Jun 04;:1-11

Authors: Rosenberg DE, Anderson ML, Renz A, Matson TE, Lee AK, Greenwood-Hickman MA, Arterburn DE, Gardiner PA, Kerr J, McClure JB

Abstract
BACKGROUND: The authors tested the efficacy of the "I-STAND" intervention for reducing sitting time, a novel and potentially health-promoting approach, in older adults with obesity.
METHODS: The authors recruited 60 people (mean age = 68 ± 4.9 years, 68% female, 86% White; mean body mass index = 35.4). The participants were randomized to receive the I-STAND sitting reduction intervention (n = 29) or healthy living control group (n = 31) for 12 weeks. At baseline and at 12 weeks, the participants wore activPAL devices to assess sitting time (primary outcome). Secondary outcomes included fasting glucose, blood pressure, and weight. Linear regression models assessed between-group differences in the outcomes.
RESULTS: The I-STAND participants significantly reduced their sitting time compared with the controls (-58 min per day; 95% confidence interval [-100.3, -15.6]; p = .007). There were no statistically significant changes in the secondary outcomes.
CONCLUSION: I-STAND was efficacious in reducing sitting time, but not in changing health outcomes in older adults with obesity.

PMID: 32498040 [PubMed - as supplied by publisher]