Publications by authors named "Jonathan Harris"

198 Publications

The impact of age on outcome in phase III NRG Oncology/RTOG trials of radiotherapy (XRT) +/- systemic therapy in locally advanced head and neck cancer.

J Geriatr Oncol 2021 Apr 1. Epub 2021 Apr 1.

Stanford University, United States of America.

Purpose: To examine the role age plays in the treatment and prognosis of locally advanced head and neck cancer (LAHNC) treated definitively with radiation alone or combined modality therapy.

Methods: A retrospective analysis was performed of three NRG/RTOG trials examining either radiation alone or combined radiation and systemic therapy for LAHNC. The effect of age (≥70 yrs.) on cause-specific survival (CSS), overall survival (OS), and toxicity was evaluated.

Results: A total of 2688 patients were analyzed, of whom 309 patients (11.5%) were ≥ 70. For all studies combined, the hazard ratio (HR) for CSS for patients age ≥ 70 vs. those <70 was 1.33 (95%CI: 1.14-1.55, p < 0.001). For OS, the HR for patients age ≥ 70 vs. those <70 for all studies combined was 1.55 (95% CI 1.35-1.77, p < 0.001). After adjustment for all covariates, age ≥ 70 was associated with worse OS regardless of adjustment for smoking and p16 status. The survival difference was more pronounced in those receiving combined radiation and systemic therapy. Hematologic and renal toxicities were increased in combined modality trials in patients ≥70 years old.

Conclusions: Patients age ≥ 70 with LAHNC were underrepresented in these clinical trials. Their CSS and OS proved inferior to patients <70 years old.
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http://dx.doi.org/10.1016/j.jgo.2021.03.011DOI Listing
April 2021

Risk groups of laryngeal cancer treated with chemoradiation according to nomogram scores - A pooled analysis of RTOG 0129 and 0522.

Oral Oncol 2021 Feb 25;116:105241. Epub 2021 Feb 25.

Department of Radiation Oncology, Case Western Reserve University, Cleveland, OH, United States.

Objectives: To develop nomograms predicting overall survival (OS), freedom from locoregional recurrence (FFLR), and freedom from distant metastasis (FFDM) for patients receiving chemoradiation for laryngeal squamous cell carcinoma (LSCC).

Material And Methods: Clinical and treatment data for patients with LSCC enrolled on NRG Oncology/RTOG 0129 and 0522 were extracted from the RTOG database. The dataset was partitioned into 70% training and 30% independent validation datasets. Significant predictors of OS, FFLR, and FFDM were obtained using univariate analysis on the training dataset. Nomograms were built using multivariate analysis with four a priori variables (age, gender, T-stage, and N-stage) and significant predictors from the univariate analyses. These nomograms were internally and externally validated using c-statistics (c) on the training and validation datasets, respectively.

Results: The OS nomogram included age, gender, T stage, N stage, and number of cisplatin cycles. The FFLR nomogram included age, gender, T-stage, N-stage, and time-equivalent biologically effective dose. The FFDM nomogram included age, gender, N-stage, and number of cisplatin cycles. Internal validation of the OS nomogram, FFLR nomogram, and FFDM nomogram yielded c = 0.66, c = 0.66 and c = 0.73, respectively. External validation of these nomograms yielded c = 0.59, c = 0.70, and c = 0.73, respectively. Using nomogram score cutoffs, three risk groups were separated for each outcome.

Conclusions: We have developed and validated easy-to-use nomograms for LSCC outcomes using prospective cooperative group trial data.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105241DOI Listing
February 2021

Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group.

Radiother Oncol 2021 03 27;156:281-293. Epub 2021 Jan 27.

Cleveland Clinic Foundation, OH, USA; Institut Saint Catherine, France.

Background And Purpose: The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results.

Materials And Methods: Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint.

Results: For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 [0.74; 0.95], p = 0.005).

Conclusion: The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.
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http://dx.doi.org/10.1016/j.radonc.2021.01.013DOI Listing
March 2021

Comprehensive In Silico Evaluation of Accessory Rod Position, Rod Material and Diameter, Use of Cross-connectors, and Anterior Column Support in a Pedicle Subtraction Osteotomy Model: Part II: Effects on Lumbosacral Rod and Screw Strain.

Spine (Phila Pa 1976) 2021 Jan;46(1):E12-E22

Musculoskeletal Education and Research Center, A Division of Globus Medical, Inc., Audubon, PA.

Study Design: In silico finite element study.

Objective: The aim of this study was to evaluate effects of six construct factors on rod and screw strain at the lumbosacral junction in an in silico pedicle subtraction osteotomy (PSO) model: traditional inline and alternative Ames-Deviren-Gupta (ADG) multi-rod techniques, number of accessory rods (three-rod vs. four-rod), rod material (cobalt-chrome [CoCr] or stainless steel [SS] vs. titanium [Ti]), rod diameter (5.5 vs. 6.35 mm), and use of cross-connectors (CC), or anterior column support (ACS).

Summary Of Background Data: Implant failure and pseudoarthrosis at the lumbosacral junction following PSO are frequently reported. Clinicians may modulate reconstructs with multiple rods, rod position, rod material, and diameter, and with CC or ACS to reduce mechanical demand. An evaluation of these features' effects on rod and screw strains is lacking.

Methods: A finite element model (T12-S1) with intervertebral discs and ligaments was created and validated with cadaveric motion data. Lumbosacral rod and screw strain data were collected for 96 constructs across all six construct factors and normalized to the Ti 2-Rod control.

Results: The inline technique resulted in 12.5% to 51.3% more rod strain and decreased screw strain (88.3% to 95%) compared to ADG at the lumbosacral junction. An asymmetrical strain distribution was observed in the three-rod inline technique in comparison to four-rod, which was more evenly distributed. Regardless of construct features, rod strain was significantly decreased by rod material (CoCr > SS > Ti), and increasing rod diameter from 5.5 mm to 6.35 mm reduced strain by 9.9% to 22.1%. ACS resulted in significant reduction of rod (37.8%-59.8%) and screw strains (23.2%-65.8%).

Conclusion: Increasing rod diameter, using CoCr rods, and ACS were the most effective methods in reducing rod strain at the lumbosacral junction. The inline technique decreased screw strain and increased rod strain compared to ADG.

Level Of Evidence: N/A.
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http://dx.doi.org/10.1097/BRS.0000000000003720DOI Listing
January 2021

Comprehensive Evaluation of Accessory Rod Position, Rod Material and Diameter, Use of Cross-connectors, and Anterior Column Support in a Pedicle Subtraction Osteotomy Model: Part I: Effects on Apical Rod Strain: An In Vitro and In Silico Biomechanical Study.

Spine (Phila Pa 1976) 2021 Jan;46(1):E1-E11

Musculoskeletal Education and Research Center, A Division of Globus Medical, Inc., Audubon, PA.

Study Design: In silico finite element study.

Objective: The aim of this study was to evaluate the effect of six construct factors on apical rod strain in an in silico pedicle subtraction osteotomy (PSO) model: traditional inline and alternative Ames-Deviren-Gupta (ADG) multi-rod techniques, number of accessory rods (three- vs. four-rod), rod material (cobalt-chrome [CoCr] or stainless steel [SS] vs. titanium [Ti]), rod diameter (5.5 vs. 6.35 mm), and use of cross-connectors (CC), or anterior column support (ACS).

Summary Of Background Data: Rod fracture following lumbar PSO is frequently reported. Clinicians may modulate reconstructs with multiple rods, rod position, rod material and diameter, and with CC or ACS to reduce mechanical demand or rod contouring. A comprehensive evaluation of these features on rod strain is lacking.

Methods: A finite element model (T12-S1) with intervertebral discs and ligaments was created and validated with cadaveric motion data. Apical rod strain of primary and accessory rods was collected for 96 constructs across all six construct factors, and normalized to the Ti two-rod control.

Results: Regardless of construct features, CoCr and SS material reduced strain across all rods by 49.1% and 38.1%, respectively; increasing rod diameter from 5.5 mm to 6.35 mm rods reduced strain by 32.0%. Use of CC or lumbosacral ACS minimally affected apical rod strain (<2% difference from constructs without CC or ACS). Compared to the ADG technique, traditional inline reconstruction reduced primary rod strain by 32.2%; however, ADG primary rod required 14.2° less rod contouring. The inline technique produced asymmetrical loading between left and right rods, only when three rods were used.

Conclusion: The number of rods and position of accessory rods affected strain distribution on posterior fixation. Increasing rod diameter and using CoCr rods was most effective in reducing rod strain. Neither CC nor lumbosacral ACS affected apical rod strain.

Level Of Evidence: N/A.
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http://dx.doi.org/10.1097/BRS.0000000000003723DOI Listing
January 2021

Bridge Plate Design Effects on Yield and Fatigue in Distal Radius Fracture Model.

J Wrist Surg 2020 Dec 6;9(6):475-480. Epub 2020 Jul 6.

Musculoskeletal Education and Research Center (MERC), A Division of Globus Medical Inc., Audubon, Pennsylvania.

 Bridge plating for distal radius fractures is indicated for complex fractures with comminution, extensive articular involvement, and/or cases requiring immediate weight bearing. Bridge plate fixation of distal radius fractures is a well-documented treatment method; however, failures have been reported with repetitive loading through the bridged distal radius fracture. Plate design is implicated as a cause of plate fracture in select clinical studies but few mechanical tests comparing bridge plate designs have been reported. This study sought to determine the impact of plate design on bridge plates intended to allow for immediate weight-bearing.  Axial static (  = 3) and dynamic testing (  = 3) was performed on three distraction plates designs: bridge plate 1 (BP1) with central holes, bridge plate 2 (BP2) without central holes, and locking compression plate (BP3). Plates were loaded in axial compression with a simulated 10-mm fracture gap.  Significant static load differences were noted between all groups. Static load to failure for BP1, BP3, and BP2 were 240 ± 5 N, 398 ± 9 N, and 420 ± 3 N, respectively (  < 0.05). BP1 was the only plate series that failed during dynamic testing; all other plates achieved 100,000 cycles. Failure mode was a fracture occurring through the central screw hole of BP1. Finite element analysis demonstrated the effects of central screw holes on stress, strain, and plastic deformation under loading.  Unused screw holes are the mechanical weak points; plates designed without these central screw holes are expected to survive greater load values. The threshold for clinical importance will need to be determined by future studies.
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http://dx.doi.org/10.1055/s-0040-1713419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708032PMC
December 2020

KLK4 Induces Anti-Tumor Effects in Human Xenograft Mouse Models of Orthotopic and Metastatic Prostate Cancer.

Cancers (Basel) 2020 Nov 24;12(12). Epub 2020 Nov 24.

Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, QLD 4102, Australia.

Recent reports have suggested the role of kallikrein-related peptidase 4 (KLK4) to be that of remodeling the tumor microenvironment in many cancers, including prostate cancer. Notably, these studies have suggested a pro-tumorigenic role for KLK4, especially in prostate cancer. However, these have been primarily in vitro studies, with limited in vivo studies performed to date. Herein, we employed an orthotopic inoculation xenograft model to mimic the growth of primary tumors, and an intracardiac injection to induce metastatic dissemination to determine the in vivo tumorigenic effects of KLK4 overexpressed in PC3 prostate cancer cells. Notably, we found that these KLK4-expressing cells gave rise to smaller localized tumors and decreased metastases than the parent PC-3 cells. To our knowledge, this is the first report of an anti-tumorigenic effect of KLK4, particularly in prostate cancer. These findings also provide a cautionary tale of the need for in vivo analyses to substantiate in vitro experimental data.
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http://dx.doi.org/10.3390/cancers12123501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761350PMC
November 2020

Processing and Sectioning Undecalcified Murine Bone Specimens.

Methods Mol Biol 2021 ;2230:231-257

Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.

Preparation of mineralized tissue specimens for bone-specific staining encompasses a critical sequence of histological techniques that provides visualization of tissue and cellular morphology. Bone specimens are fixed in 10% neutral buffered formalin (NBF), dehydrated in graded ethanol (EtOH) solutions (and optionally cleared in xylene), infiltrated and embedded in polymethyl methacrylate (methyl methacrylate or MMA), classically sliced into 4-10 micrometer (μm) sections, and stained with bone-specific histological stains such as von Kossa (with either nuclear fast red solution counterstain or MacNeal's tetrachrome counterstain), modified Goldner's trichrome, Alizarin Red S, Safranin O, and tartrate-resistant acid phosphatase (TRAP) stain. Here, we describe the tissue processing of mineralized mouse bones from dissection to staining for histological analysis by light microscopy.
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http://dx.doi.org/10.1007/978-1-0716-1028-2_14DOI Listing
March 2021

Guidelines for cortical screw versus pedicle screw selection from a fatigued decompressive lumbar laminectomy model show similar stability and less bone mineral density dependency.

Clin Biomech (Bristol, Avon) 2020 12 10;80:105195. Epub 2020 Oct 10.

Musculoskeletal Education and Research Center (MERC), A Division of Globus Medical, Inc., 2560 General Armistead Avenue, Audubon, PA 19403, USA. Electronic address:

Background: Traditional pedicle screws are the gold standard for lumbar spine fixation; however, cortical screws along the midline cortical bone trajectory may be advantageous when lumbar decompression is required. While biomechanic investigation of both techniques exists, cortical screw performance in a multi-level lumbar laminectomy and fusion model is unknown. Furthermore, longer-term viability of cortical screws following cyclic fatigue has not been investigated.

Methods: Fourteen human specimens (L1-S1) were divided into cortical and pedicle screw treatment groups. Motion was captured for the following conditions: intact, bilateral posterior fixation (L3-L5), fixation with laminectomy at L3-L5, fixation with laminectomy and transforaminal lumbar interbody fusion at L3-L5 both prior to, and following, simulated in vivo fatigue. Following fatigue, screw pullout force was collected and "effective shear stress" [pullout force/screw surface area] (N/mm) was calculated; comparisons and correlations were performed.

Findings: In flexion-extension and lateral bending, all operative constructs significantly reduced motion compared to intact (P < 0.05), regardless of pedicle or cortical screws; only posterior fixation with and without laminectomy significantly reduced motion in axial rotation (P < 0.05). Pedicle screws significantly increased average pullout strength (944.2 N vs. 690.2 N, P < 0.05), but not the "effective shear stress" (1.01 N/mm vs. 1.1 N/mm, P > 0.05).

Interpretation: In a posterior laminectomy and fusion model, cortical screws provided equivalent stability to pedicle screw fixation, yet had significantly lower screw pullout force. No differences in "effective shear stress" warrant further investigation of the effect of screw length/diameter in the aforementioned screw trajectories.
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http://dx.doi.org/10.1016/j.clinbiomech.2020.105195DOI Listing
December 2020

Predictive classifier for intensive treatment of head and neck cancer.

Cancer 2020 Dec 5;126(24):5263-5273. Epub 2020 Oct 5.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California.

Background: This study was designed to test the hypothesis that the effectiveness of intensive treatment for locoregionally advanced head and neck cancer (LAHNC) depends on the proportion of patients' overall event risk attributable to cancer.

Methods: This study analyzed 22,339 patients with LAHNC treated in 81 randomized trials testing altered fractionation (AFX; Meta-Analysis of Radiotherapy in Squamous Cell Carcinomas of Head and Neck [MARCH] data set) or chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC] data set). Generalized competing event regression was applied to the control arms in MARCH, and patients were stratified by tertile according to the ω score, which quantified the relative hazard for cancer versus competing events. The classifier was externally validated on the MACH-NC data set. The study tested for interactions between the ω score and treatment effects on overall survival (OS).

Results: Factors associated with a higher ω score were a younger age, a better performance status, an oral cavity site, higher T and N categories, and a p16-negative/unknown status. The effect of AFX on OS was greater in patients with high ω scores (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.85-0.99) and medium ω scores (HR, 0.91; 95% CI, 0.84-0.98) versus low ω scores (HR, 0.97; 95% CI, 0.90-1.05; P for interaction = .086). The effect of chemotherapy on OS was significantly greater in patients with high ω scores (HR, 0.81; 95% CI, 0.75-0.88) and medium ω scores (HR, 0.86; 95% CI, 0.78-0.93) versus low ω scores (HR, 0.96; 95% CI, 0.86-1.08; P for interaction = .011).

Conclusions: LAHNC patients with a higher risk of cancer progression relative to competing mortality, as reflected by a higher ω score, selectively benefit from more intensive treatment.
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http://dx.doi.org/10.1002/cncr.33212DOI Listing
December 2020

Assessment of Surgical Procedural Time, Pedicle Screw Accuracy, and Clinician Radiation Exposure of a Novel Robotic Navigation System Compared With Conventional Open and Percutaneous Freehand Techniques: A Cadaveric Investigation.

Global Spine J 2020 Oct 24;10(7):814-825. Epub 2019 Sep 24.

Musculoskeletal Education and Research Center, A Division of 110044Globus Medical, Inc, Audubon, PA, USA.

Study Design: Cadaveric study.

Objective: To evaluate accuracy, radiation exposure, and surgical time of a new robotic-assisted navigation (RAN) platform compared with freehand techniques in conventional open and percutaneous procedures.

Methods: Ten board-certified surgeons inserted 16 pedicle screws at T10-L5 (n = 40 per technique) in 10 human cadaveric torsos. Pedicle screws were inserted with (1) conventional MIS technique (L2-L5, patient left pedicles), (2) MIS RAN (L2-L5, patient right pedicles), (3) conventional open technique (T10-L1, patient left pedicles), and (4) open RAN (T10-L1, patient right pedicles). Output included (1) operative time, (2) number of fluoroscopic images, and (3) screw accuracy.

Results: In the MIS group, compared with the freehand technique, RAN allowed for use of larger screws (diameter: 6.6 ± 0.6 mm vs 6.3 ± 0.5 mm; length: 50.3 ± 4.1 mm vs 46.9 ± 3.5 mm), decreased the number of breaches >2 mm (0 vs 7), fewer fluoroscopic images (0 ± 0 vs 108.3 ± 30.9), and surgical procedure time per screw (3.6 ± 0.4 minutes vs 7.6 ± 2.0 minutes) (all < .05). Similarly, in the open group, RAN allowed for use of longer screws (46.1 ± 4.1 mm vs 44.0 ± 3.8 mm), decreased the number of breaches >2 mm (0 vs 13), fewer fluoroscopic images (0 ± 0 vs 24.1 ± 25.8) (all < .05), but increased total surgical procedure time (41.4 ± 8.8 minutes vs 24.7 ± 7.0 minutes, = .000) while maintaining screw insertion time (3.31.4 minutes vs 3.1 ± 1.0 minutes, = .650).

Conclusion: RAN significantly improved accuracy and decreased radiation exposure in comparison to freehand techniques in both conventional open and percutaneous surgical procedures in cadavers. RAN significantly increased setup time compared with both conventional procedures.
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http://dx.doi.org/10.1177/2192568219879083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485081PMC
October 2020

WHO led the digital transformation of your company? A reflection of IT related challenges during the pandemic.

Int J Inf Manage 2020 Dec 6;55:102166. Epub 2020 Jun 6.

ICT Industry, United Kingdom.

In this paper we reflect on a number of IT related challenges during the COVID19 pandemic, primarily from a CIO and IT professionals perspective. We consider three time periods, namely the period before the pandemic, the response to the pandemic and the period after it. For each period we discuss the key challenges that practitioners faced and outline important areas to consider for the future. Hopefully, the lessons learnt and the experiences gained will positively inform future academic research and practice.
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http://dx.doi.org/10.1016/j.ijinfomgt.2020.102166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275158PMC
December 2020

Hierarchical TiO Nanoflower Photocatalysts with Remarkable Activity for Aqueous Methylene Blue Photo-Oxidation.

ACS Omega 2020 Aug 22;5(30):18919-18934. Epub 2020 Jul 22.

School of Chemical Sciences, The University of Auckland, Auckland 1010, New Zealand.

This study systematically evaluates the performance of a series of TiO nanoflower (TNF) photocatalysts for aqueous methylene blue photo-oxidation under UV irradiation. TNF nanoflowers were synthesized from Ti(IV) butoxide by a hydrothermal method and then calcined at different temperatures ( = 400-800 °C) for specific periods of time ( = 1-5 h). By varying the calcination conditions, TNF-T-t photocatalysts with diverse physicochemical properties and anatase/rutile ratios were obtained. Many of the TNF-T-1 photocatalysts demonstrated remarkable activity for aqueous methylene blue photo-oxidation at pH 6 under UV excitation (365 nm), with activities following the order TNF-700-1 > TNF-600-1 > TNF-500-1 > TNF-400-1 ∼ P25 TiO ≫ TNF-800-1. The activity of the TNF-700-1 photocatalyst (99% anatase, 1% rutile) was 2.3 times that of P25 TiO at pH 6 and 14.4 times that of P25 TiO at pH 4. Prolonged calcination of the TNFs at 700 °C proved detrimental to dye degradation performance due to excessive rutile formation, which reduced the photocatalyst surface area and suppressed OH generation. The outstanding activities of TNF-700-1 and TNF-600-1 are attributed to their hierarchical nanoflower morphology which benefitted UV absorption, a near-ideal anatase crystallite size for efficient charge separation, and their unusually low isoelectric point (IEP = 4.3-4.5).
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http://dx.doi.org/10.1021/acsomega.0c02142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408212PMC
August 2020

Impact of Self-Assembled Monolayer Design and Electrochemical Factors on Impedance-Based Biosensing.

Sensors (Basel) 2020 Apr 16;20(8). Epub 2020 Apr 16.

711th Human Performance Wing, Air Force Research Laboratory, Wright-Patterson AFB, OH 45433, USA.

Real-time sensing of proteins, especially in wearable devices, remains a substantial challenge due to the need to convert a binding event into a measurable signal that is compatible with the chosen analytical instrumentation. Impedance spectroscopy enables real-time detection via either measuring electrostatic interactions or electron transfer reactions while simultaneously being amenable to miniaturization for integration into wearable form-factors. To create a more robust methodology for optimizing impedance-based sensors, additional fundamental studies exploring components influencing the design and implementation of these sensors are needed. This investigation addresses a sub-set of these issues by combining optical and electrochemical characterization to validate impedance-based sensor performance as a function of (1) biorecognition element density, (2) self-assembled monolayer chain length, (3) self-assembled monolayer charge density, (4) the electrochemical sensing mechanism and (5) the redox reporter selection. Using a pre-existing lysozyme aptamer and lysozyme analyte combination, we demonstrate a number of design criteria to advance the state-of-the-art in protein sensing. For this model system we demonstrated the following: First, denser self-assembled monolayers yielded substantially improved sensing results. Second, self-assembled monolayer composition, including both thickness and charge density, changed the observed peak position and peak current. Third, single frequency measurements, while less informative, can be optimized to replace multi-frequency measurements and in some cases (such as that with zwitterionic self-assembled monolayers) are preferred. Finally, various redox reporters traditionally not used in impedance sensing should be further explored. Collectively, these results can help limit bottlenecks associated with device development, enabling realization of next-generation impedance-based biosensing with customize sensor design for the specific application.
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http://dx.doi.org/10.3390/s20082246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218866PMC
April 2020

Lumbar Percutaneous Pedicle Screw Breach Rates: A Comparison of Robotic Navigation Platform Versus Conventional Techniques.

Clin Spine Surg 2020 05;33(4):E162-E167

Musculoskeletal Education and Research Center, A Division of Globus Medical Inc., Audubon, PA.

Study Design: Cadaveric study.

Summary Of Background Data: Pedicle screw fixation is an established means of stabilizing the thoracic and lumbar spine. However, there are associated complications including pedicle breach which can result in neurological injury, durotomy, vascular injury, and suboptimal fixation.

Objective: The aim of this study is to determine whether use of a navigated robotic platform results in fewer pedicle breaches and the underlying reasons for any difference in pedicle breach rates.

Materials And Methods: Ten board-certified neuro- and orthopedic spine surgeons inserted 80 percutaneous lumbar screws in 10 unembalmed human cadavers. Forty screws were inserted using conventional fluoroscopic guidance and 40 were inserted using a navigated robotic platform. None of the participating surgeons had any prior experience with navigated robotic spine surgery. At the end of the study each screw was assessed with a computed tomography scan, plain radiographs and visual inspection to determine the presence or absence of pedicle breaches.

Results: Forty percent (40%) of screws inserted using conventional fluoroscopic guidance breached compared with 2.5% of screws inserted with robot assistance (P=0.00005). Lateral breaches accounted for 88.2% (15/17) of all breaches. Detailed analysis revealed that the starting point of screws that breached laterally were significantly more lateral than that of the contralateral accurate screw (P=0.016). Pedicle screw diameter, length, and angulation in the transverse plane did not differ significantly between accurate screws and those that breached (P>0.05).

Conclusions: The use of a navigated robotic platform in the present study resulted in significantly fewer pedicle breaches. This was achieved through correct starting point selection with subsequent safe pedicle screw insertion.
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http://dx.doi.org/10.1097/BSD.0000000000000963DOI Listing
May 2020

Mobilizing serum factors and immune cells through exercise to counteract age-related changes in cancer risk.

Exerc Immunol Rev 2020 ;26:80-99

School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.

An increasing body of evidence suggests that age-related immune changes and chronic inflammation contribute to cancer development. Recognizing that exercise has protective effects against cancer, promotes immune function, and beneficially modulates inflammation with ageing, this review outlines the current evidence indicating an emerging role for exercise immunology in preventing and treating cancer in older adults. A specific focus is on data suggesting that muscle- derived cytokines (myokines) mediate anti-cancer effects through promoting immunosurveillance against tumourigenesis or inhibiting cancer cell viability. Previous studies suggested that the exercise-induced release of myokines and other endocrine factors into the blood increases the capacity of blood serum to inhibit cancer cell growth in vitro. However, little is known about whether this effect is influenced by ageing. Prostate cancer is the second most common cancer in men. We therefore examined the effects of serum collected before and after exercise from healthy young and older men on the metabolic activity of androgen-responsive LNCaP and androgen-unresponsive PC3 prostate cancer cells. Exercise-conditioned serum collected from the young group did not alter cell metabolic activity, whereas post-exercise serum (compared with pre-exercise serum) from the older men inhibited the metabolic activity of LNCaP cancer cells. Serum levels of candidate cancer-inhibitory myokines oncostatin M and osteonectin increased in both age groups following exercise. Serum testosterone increased only in the younger men postexercise, potentially attenuating inhibitory effects of myokines on the LNCaP cell viability. The data from our study and the evidence in this review suggest that mobilizing serum factors and immune cells may be a key mechanism of how exercise counteracts cancer in the older population.
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March 2020

A role for caveola-forming proteins caveolin-1 and CAVIN1 in the pro-invasive response of glioblastoma to osmotic and hydrostatic pressure.

J Cell Mol Med 2020 03 17;24(6):3724-3738. Epub 2020 Feb 17.

School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia.

In solid tumours, elevated interstitial fluid pressure (osmotic and hydrostatic pressure) is a barrier to drug delivery and correlates with poor prognosis. Glioblastoma (GBM) further experience compressive force when growing within a space limited by the skull. Caveolae are proposed to play mechanosensing roles, and caveola-forming proteins are overexpressed in GBM. We asked whether caveolae mediate the GBM response to osmotic pressure. We evaluated in vitro the influence of spontaneous or experimental down-regulation of caveola-forming proteins (caveolin-1, CAVIN1) on the proteolytic profile and invasiveness of GBM cells in response to osmotic pressure. In response to osmotic pressure, GBM cell lines expressing caveola-forming proteins up-regulated plasminogen activator (uPA) and/or matrix metalloproteinases (MMPs), some EMT markers and increased their in vitro invasion potential. Down-regulation of caveola-forming proteins impaired this response and prevented hyperosmolarity-induced mRNA expression of the water channel aquaporin 1. CRISPR ablation of caveola-forming proteins further lowered expression of matrix proteases and EMT markers in response to hydrostatic pressure, as a model of mechanical force. GBM respond to pressure by increasing matrix-degrading enzyme production, mesenchymal phenotype and invasion. Caveola-forming proteins mediate, at least in part, the pro-invasive response of GBM to pressure. This may represent a novel target in GBM treatment.
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http://dx.doi.org/10.1111/jcmm.15076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7131935PMC
March 2020

A Versatile and Robust Serine Protease Inhibitor Scaffold from .

Mar Drugs 2019 Dec 12;17(12). Epub 2019 Dec 12.

Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4059, Australia.

Serine proteases play pivotal roles in normal physiology and a spectrum of patho-physiological processes. Accordingly, there is considerable interest in the discovery and design of potent serine protease inhibitors for therapeutic applications. This led to concerted efforts to discover versatile and robust molecular scaffolds for inhibitor design. This investigation is a bioprospecting study that aims to isolate and identify protease inhibitors from the cnidarian The study isolated two Kunitz-type protease inhibitors with very similar sequences but quite divergent inhibitory potencies when assayed against bovine trypsin, chymostrypsin, and a selection of human sequence-related peptidases. Homology modeling and molecular dynamics simulations of these inhibitors in complex with their targets were carried out and, collectively, these methodologies enabled the definition of a versatile scaffold for inhibitor design. Thermal denaturation studies showed that the inhibitors were remarkably robust. To gain a fine-grained map of the residues responsible for this stability, we conducted in silico alanine scanning and quantified individual residue contributions to the inhibitor's stability. Sequences of these inhibitors were then used to search for Kunitz homologs in an transcriptome library, resulting in the discovery of a further 14 related sequences. Consensus analysis of these variants identified a rich molecular diversity of Kunitz domains and expanded the palette of potential residue substitutions for rational inhibitor design using this domain.
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http://dx.doi.org/10.3390/md17120701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950308PMC
December 2019

Influence of the Conservation Reserve Program (CRP) and playa wetlands on pollinator communities in the Southern High Plains, USA.

J Environ Manage 2020 Feb 4;256:109910. Epub 2019 Dec 4.

Department of Integrative Biology, Oklahoma State University, 501 Life Sciences West, Stillwater, OK, 74078, USA. Electronic address:

Numerous studies have documented that invertebrate pollinator services are critical to the world economy. Factors including habitat loss and agricultural practices, however, threaten pollinator populations. Many counties in the Southern High Plains were identified as at risk for a shortage of pollination service from wild bees. This region also has one of the highest concentrations of Conservation Reserve Program (CRP) contracts in the US. The CRP is the largest, voluntary, private lands conservation program in the US and was targeted as a program to improve pollinator habitat. Our objective was to determine how the predominant land uses in the SHP (native grassland, CRP, and cropland) affect pollinator abundance and species richness, and more specifically if the CRP can provide quality habitat for pollinators. We also examined how the keystone habitat, playa wetlands, embedded within these land uses contribute to pollinator habitat (land type: uplands vs. wetland). We used blue vane traps placed in playa basins and adjacent uplands to determine Hymenoptera abundance and richness from April to October in 2013 and 2014. The CRP had lower abundance than cropland and native grassland, and generally less richness. Uplands and playa wetlands had little difference in Hymenoptera abundance and richness. Patch size negatively influenced abundance but had a positive influence on richness. The interaction of vegetation height and percent bare ground positively influenced abundance in cropland and native grasslands, and positively influenced richness in all land uses. In the CRP, vegetation height negatively influenced Hymenoptera abundance and percent bare ground had a positive influence. The years sampled in this study were during a severe extended drought; therefore, these results may be reflective of poor floral resources. The CRP has potential to create valuable habitat for pollinators if land managers incorporate a diversity of native grasses and native forbs into plantings to enhance pollinator foraging and nesting habitat.
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http://dx.doi.org/10.1016/j.jenvman.2019.109910DOI Listing
February 2020

Plexiform Neurofibroma of the Uterus: A Case Report.

Int J Gynecol Pathol 2021 Jan;40(1):94-96

The female genital tract system is rarely affected by neurofibromatosis type 1 (NF1). Plexiform neurofibromas are congenital lesions that occur in patients with NF1. The vulva is the most frequent genital location but vaginal, cervical, uterine, and ovarian neurofibromas have rarely been reported. We describe a case of plexiform neurofibromas involving the uterine cervix in a patient with known NF1 that presented with chronic pelvic pain and heavy menstrual bleeding.
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http://dx.doi.org/10.1097/PGP.0000000000000647DOI Listing
January 2021

Stabilizing effect of the rib cage on adjacent segment motion following thoracolumbar posterior fixation of the human thoracic cadaveric spine: A biomechanical study.

Clin Biomech (Bristol, Avon) 2019 Dec 19;70:217-222. Epub 2019 Oct 19.

Musculoskeletal Education and Research Center, Globus Medical, Inc., 2560 General Armistead Avenue, Audubon, PA 19403, USA. Electronic address:

Background: Although the rib cage provides substantial stability to the thoracic spine, few biomechanical studies have incorporated it into their testing model, and no studies have determined the influence of the rib cage on adjacent segment motion of long fusion constructs. The present biomechanical study aimed to determine the mechanical contribution of the intact rib cage during the testing of instrumented specimens.

Methods: A cyclic loading (CL) protocol with instrumentation (T4-L2 pedicle screw-rod fixation) was conducted on five thoracic spines (C7-L2) with intact rib cages. Range of motion (±5 Nm pure moment) in flexion-extension, lateral bending, and axial rotation was captured for intact ribs, partial ribs, and no ribs conditions. Comparisons at the supra-adjacent (T2-T3), adjacent (T3-T4), first instrumented (T4-T5), and second instrumented (T5-T6) levels were made between conditions (P ≤ 0.05).

Findings: A trend of increased motion at the adjacent level was seen for partial ribs and no ribs in all 3 bending modes. This trend was also observed at the supra-adjacent level for both conditions. No significant changes in motion compared to the intact ribs condition were seen at the first and second instrumented levels (P > 0.05).

Interpretation: The segment adjacent to long fusion constructs, which may appear more grossly unstable when tested in the disarticulated spine, is reinforced by the rib cage. In order to avoid overestimating adjacent level motion, when testing the effectiveness of surgical techniques of the thoracic spine, inclusion of the rib cage may be warranted to better reflect clinical circumstances.
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http://dx.doi.org/10.1016/j.clinbiomech.2019.10.008DOI Listing
December 2019

Biomechanical evaluation comparing zero-profile devices versus fixed profile systems in a cervical hybrid decompression model: a biomechanical in vitro study.

Spine J 2020 04 18;20(4):657-664. Epub 2019 Oct 18.

Musculoskeletal Education and Research Center, Globus Medical, Inc., Audubon, PA, USA.

Background Context: The use of zero-profile devices and the need for posterior fixation in conjunction with a cervical hybrid decompression model have yet to be investigated.

Purpose: To compare the biomechanics of zero-profile and fixed profile cervical hybrid constructs composed of anterior cervical discectomy and fusion (ACDF) and anterior cervical corpectomy and fusion (ACCF). Fixed profile devices included anterior plating, whereas zero-profile devices included integrated screws.

Study Design: In vitro cadaveric biomechanical study.

Methods: Twelve fresh-frozen cadaveric spines (C2-C7) were divided into two groups of equal bone mineral density, fixed profile versus zero profile (n=6). Groups were instrumented from C3-C6 with either (1) an expandable ACCF device and a static ACDF spacer with an anterior plate (Hybrid-AP) or (2) a zero-profile ACCF spacer with adjacent zero-profile ACDF spacer (Hybrid-Z). Motion was captured for the (1) intact condition, (2) a hybrid model with lateral mass screws (LMS), (3) a hybrid model without LMS, and (4) a hybrid model without LMS following simulated repetitive loading (fatigue).

Results: Hybrid-AP with LMS reduced motion in flexion-extension (FE), lateral bending (LB), and axial rotation (AR) by 77%, 88%, and 82%, respectively, compared with intact. Likewise, Hybrid-Z with LMS exhibited the greatest reduction in motion relative to intact in FE, LB, and AR by 90%, 95%, and 66%, respectively. Following simulated in vivo fatiguing, an increase in motion was observed for both groups in all planes, particularly during Hybrid-Z postfatigue condition where motion increased relative to intact by 29%. Overall, biomechanical equivalency was observed between Hybrid-AP and Hybrid-Z groups (p>.05). Three (50%) of the Hybrid-Z group specimens exhibited signs of implant migration from the inferior endplate during testing.

Conclusions: Fixed profile systems using an anterior plate for supplemental fixation is biomechanically more favorable to maintain stability and prevent dislodgement. Dislodgement of 50% of the Hybrid-Z group without LMS emphasizes the necessity for posterior fixation in a zero-profile cervical hybrid decompression model.
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http://dx.doi.org/10.1016/j.spinee.2019.10.004DOI Listing
April 2020

The molecular function of kallikrein-related peptidase 14 demonstrates a key modulatory role in advanced prostate cancer.

Mol Oncol 2020 01 28;14(1):105-128. Epub 2019 Nov 28.

Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Institute of Health & Biomedical Innovation, Queensland University of Technology, Woolloongabba, Australia.

Kallikrein-related peptidase 14 (KLK14) is one of the several secreted KLK serine proteases involved in prostate cancer (PCa) pathogenesis. While relatively understudied, recent reports have identified KLK14 as overexpressed during PCa development. However, the modulation of KLK14 expression during PCa progression and the molecular and biological functions of this protease in the prostate tumor microenvironment remain unknown. To determine the modulation of KLK14 expression during PCa progression, we analyzed the expression levels of KLK14 in patient samples using publicly available databases and immunohistochemistry. In order to delineate the molecular mechanisms involving KLK14 in PCa progression, we integrated proteomic, transcriptomic, and in vitro assays with the goal to identify substrates, related-signaling pathways, and functional roles of this protease. We showed that KLK14 expression is elevated in advanced PCa, and particularly in metastasis. Additionally, KLK14 levels were found to be decreased in PCa tissues from patients responsive to neoadjuvant therapy compared to untreated patients. Furthermore, we also identified that KLK14 expression reoccurred in patients who developed castrate-resistant PCa. The combination of proteomic and transcriptomic analysis as well as functional assays revealed several new KLK14 substrates (agrin, desmoglein 2, vitronectin, laminins) and KLK14-regulated genes (Interleukin 32, midkine, SRY-Box 9), particularly an involvement of the mitogen-activated protein kinase 1 and interleukin 1 receptor pathways, and an involvement of KLK14 in the regulation of cellular migration, supporting its involvement in aggressive features of PCa progression. In conclusion, our work showed that KLK14 expression is associated with the development of aggressive PCa suggesting that targeting this protease could offer a novel route to limit the progression of prostate tumors. Additional work is necessary to determine the benefits and implications of targeting/cotargeting KLK14 in PCa as well as to determine the potential use of KLK14 expression as a predictor of PCa aggressiveness or response to treatment.
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http://dx.doi.org/10.1002/1878-0261.12587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944120PMC
January 2020

Single-Level In Vitro Kinematic Comparison of Novel Inline Cervical Interbody Devices With Intervertebral Screw, Anchor, or Blade.

Global Spine J 2019 Oct 28;9(7):697-707. Epub 2019 Feb 28.

Musculoskeletal Education and Research Center, a Division of Globus Medical, Inc, Audubon, PA, USA.

Study Design: In vitro cadaveric biomechanical study.

Objective: To compare the biomechanics of integrated anchor and blade versus traditional screw fixation techniques for interbody fusion.

Methods: Fifteen cadaveric cervical spines were divided into 3 equal groups (n = 5). Each spine was tested: intact, after discectomy (simulating an injury model), interbody spacer alone (S), integrated interbody spacer (iSA), and integrated spacer with lateral mass screw and rod fixation (LMS+iS). Each treatment group included integrated spacers with either screw, anchor, or blade integrated spacers. Constructs were tested in flexion-extension (FE), lateral bending (LB), and axial rotation (AR) under pure moments (±1.5 N m).

Results: Across all 3 planes, the following range of motion trend was observed: Injured > Intact > S > iSA > LMS+iS. In FE and LB, integrated anchor and blade significantly decreased motion compared with intact and injured conditions, before and after supplemental posterior fixation ( < .05). Comparing tested devices revealed biomechanical equivalence between screw, anchor, and blade fixation methods in all loading modes ( > .05).

Conclusion: All integrated interbody devices reduced intact and injured motion; lateral mass screws and rods further stabilized the single motion segment. Comparing screw, anchor, or bladed integrated anterior cervical discectomy and fusion spacers revealed no significant differences.
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http://dx.doi.org/10.1177/2192568219833055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745635PMC
October 2019

The effects of spaceflight and fracture healing on distant skeletal sites.

Sci Rep 2019 08 6;9(1):11419. Epub 2019 Aug 6.

Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.

Spaceflight results in reduced mechanical loading of the skeleton, which leads to dramatic bone loss. Low bone mass is associated with increased fracture risk, and this combination may compromise future, long-term, spaceflight missions. Here, we examined the systemic effects of spaceflight and fracture surgery/healing on several non-injured bones within the axial and appendicular skeleton. Forty C57BL/6, male mice were randomized into the following groups: (1) Sham surgery mice housed on the earth (Ground + Sham); (2) Femoral segmental bone defect surgery mice housed on the earth (Ground + Surgery); (3) Sham surgery mice housed in spaceflight (Flight + Sham); and (4) Femoral segmental bone defect surgery mice housed in spaceflight (Flight + Surgery). Mice were 9 weeks old at the time of launch and were euthanized approximately 4 weeks after launch. Micro-computed tomography (μCT) was used to evaluate standard bone parameters in the tibia, humerus, sternebra, vertebrae, ribs, calvarium, mandible, and incisor. One intriguing finding was that both spaceflight and surgery resulted in virtually identical losses in tibial trabecular bone volume fraction, BV/TV (24-28% reduction). Another important finding was that surgery markedly changed tibial cortical bone geometry. Understanding how spaceflight, surgery, and their combination impact non-injured bones will improve treatment strategies for astronauts and terrestrial humans alike.
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http://dx.doi.org/10.1038/s41598-019-47695-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684622PMC
August 2019

Further evidence that calcinosis is associated with repetitive trauma in systemic sclerosis.

Semin Arthritis Rheum 2020 02 8;50(1):E4-E5. Epub 2019 Jul 8.

Centre for Musculoskeletal Research, The University of Manchester, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK; NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, UK.

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http://dx.doi.org/10.1016/j.semarthrit.2019.07.001DOI Listing
February 2020

Role of chemotherapy in 5000 patients with head and neck cancer treated by curative surgery: A subgroup analysis of the meta-analysis of chemotherapy in head and neck cancer.

Oral Oncol 2019 08 15;95:106-114. Epub 2019 Jun 15.

Meta-Analysis Unit, Service de Biostatistique et d'Epidémiologie, Gustave Roussy Cancer Campus, INSERM U1018, CESP, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.

Objective: To evaluate the effect of chemotherapy added to a surgical locoregional treatment (LRT) for patients with locally advanced head and neck squamous cell carcinoma (HNSCC).

Materials And Methods: We studied the sub-group of trials with surgical LRT included in the meta-analysis on chemotherapy in head and neck cancer (MACH-NC). Data from published and unpublished randomized trials comparing the addition of chemotherapy to LRT in HNSCC patients were sought using electronic database searching for the period 1965-2000, hand searching and by contacting experts in the field. Trials with less than 60 patients, or preoperative radiotherapy or where the type of LRT could not be individually determined were excluded. All individual patient data were checked for internal consistency, compared with published reports, and validated with trialists. Data were pooled using a fixed-effect model. Heterogeneity was assessed using Cochrane test and I statistic.

Results: Twenty-four trials were eligible (5000 patients). Chemotherapy improved overall survival (HR = 0.92 [95%CI: 0.85-0.99] p = 0.02). There was a significant interaction between treatment effect and timing of chemotherapy (p = 0.08 at pre-specified threshold of 0.10) with a greater effect for concomitant chemotherapy (HR = 0.79, 95%CI: 0.69-0.92). The benefit of chemotherapy was greater in women (HR = 0.63, 95%CI: 0.50-0.80) compared to men (HR = 0.96, 95%CI: 0.89-1.04; p for interaction = 0.001).

Conclusions: This analysis confirmed the benefit of concomitant chemotherapy added to surgical LRT. The role of induction therapy as yet to be determined as it did not improve OS. Women may benefit more than men from chemotherapy.
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http://dx.doi.org/10.1016/j.oraloncology.2019.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029787PMC
August 2019

KLK4 Inhibition by Cyclic and Acyclic Peptides: Structural and Dynamical Insights into Standard-Mechanism Protease Inhibitors.

Biochemistry 2019 05 13;58(21):2524-2533. Epub 2019 May 13.

Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute , Monash University , Clayton , Victoria 3800 , Australia.

Sunflower trypsin inhibitor (SFTI-1) is a 14 amino acid serine protease inhibitor. The dual antiparallel β-sheet arrangement of SFTI-1 is stabilized by an N-terminal-C-terminal backbone cyclization and a further disulfide bridge to form a final bicyclic structure. This constrained structure is further rigidified by an extensive network of internal hydrogen bonds. Thus, the structure of SFTI-1 in solution resembles the protease-bound structure, reducing the entropic penalty upon protease binding. When cleaved at the scissile bond, it is thought that the rigidifying features of SFTI-1 maintain its structure, allowing the scissile bond to be reformed. The lack of structural plasticity for SFTI-1 is proposed to favor initial protease binding and continued occupancy in the protease active site, resulting in an equilibrium between the cleaved and uncleaved inhibitor in the presence of a protease. We have determined, at 1.15 Å resolution, the X-ray crystal structures of complexes between human kallikrein-related peptidase 4 (KLK4) and SFTI-FCQR(Asn14) and between KLK4 and an acyclic form of the same inhibitor, SFTI-FCQR(Asn14)[1,14], with the latter displaying a cleaved scissile bond. Structural analysis and MD simulations together reveal the roles of the altered contact sequence, intramolecular hydrogen bonding network, and backbone cyclization in altering the state of SFTI's scissile bond ligation at the protease active site. Taken together, the data presented reveal insights into the role of dynamics in the standard-mechanism inhibition and suggest that modifications on the non-contact strand may be a useful, underexplored approach for generating further potent or selective SFTI-based inhibitors against members of the serine protease family.
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http://dx.doi.org/10.1021/acs.biochem.9b00191DOI Listing
May 2019

Biomechanical evaluation of traditional posterior versus anterior spondylolisthesis reduction in a cadaveric grade I slip model.

J Neurosurg Spine 2019 May 3:1-9. Epub 2019 May 3.

2Musculoskeletal Education and Research Center, A Division of Globus Medical, Inc., Audubon, Pennsylvania.

OBJECTIVEPosterior reduction with pedicle screws is often used for stabilization of unstable spondylolisthesis to directly reduce misalignment or protect against micromotion while fusion of the affected level occurs. Optimal treatment of spondylolisthesis combines consistent reduction with a reduced risk of construct failure. The authors compared the reduction achieved with a novel anterior integrated spacer with a built-in reduction mechanism (ISR) to the reduction achieved with pedicle screws alone, or in combination with an anterior lumbar interbody fusion (ALIF) spacer, in a cadaveric grade I spondylolisthesis model.METHODSGrade I slip was modeled in 6 cadaveric L5-S1 segments by creation of a partial nucleotomy and facetectomy and application of dynamic cyclic loading. Following the creation of spondylolisthesis, reduction was performed under increasing axial loads, simulating muscle trunk forces between 50 and 157.5 lbs, in the following order: bilateral pedicle screws (BPS), BPS with an anterior spacer (BPS+S), and ISR. Percent reduction and reduction failure load-the axial load at which successful reduction (≥ 50% correction) was not achieved-were recorded along with the failure mechanism. Corrections were evaluated using lateral fluoroscopic images.RESULTSThe average loads at which BPS and BPS+S failed were 92.5 ± 6.1 and 94.2 ± 13.9 lbs, respectively. The ISR construct failed at a statistically higher load of 140.0 ± 27.1 lbs. Reduction at the largest axial load (157.5 lbs) by the ISR device was tested in 67% (4 of 6) of the specimens, was successful in 33% (2 of 6), and achieved 68.3 ± 37.4% of the available reduction. For the BPS and BPS+S constructs, the largest axial load was 105.0 lbs, with average reductions of 21.3 ± 0.0% (1 of 6) and 32.4 ± 5.7% (3 of 6) respectively.CONCLUSIONSWhile both posterior and anterior reduction devices maintained reduction under gravimetric loading, the reduction capacity of the novel anterior ISR device was more effective at greater loads than traditional pedicle screw techniques. Full correction was achieved with pedicle screws, with or without ALIF, but under significantly lower axial loads. The anterior ISR may prove useful when higher reduction forces are required; however, additional clinical studies will be needed to evaluate the effectiveness of anterior devices with built-in reduction mechanisms.
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http://dx.doi.org/10.3171/2019.2.SPINE18726DOI Listing
May 2019

Imaging calcinosis in patients with systemic sclerosis by radiography, computerised tomography and magnetic resonance imaging.

Semin Arthritis Rheum 2019 10 9;49(2):279-282. Epub 2019 Mar 9.

Centre for Musculoskeletal Research, The University of Manchester, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK; NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, UK.

Introduction: Objective outcome measures are needed to facilitate clinical trials of much needed treatments for calcinosis in systemic sclerosis (SSc). Our primary aim was to compare radiography, computed tomography (CT) and magnetic resonance imaging (MRI) to measure calcinotic lesions. Secondary objectives included to examine reproducibility of radiography and MRI, and inter-rater reliability of MRI.

Materials And Methods: 15 patients with SSc and clinically apparent calcinosis were studied. On one hand, radiography, CT and MRI were performed. The number (all techniques), area (radiography) and volume (CT and MRI) of calcinotic areas were extracted by 'blinded' musculoskeletal radiologists.

Results: No significant difference (P = 0.289) in the mean (SD) number of lesions (per hand) was seen between radiography: 5.4 (4.6), CT: 6.3 (6.5) and MRI: 5.2 (3.9). Mean (SD) lesion volumes were systematically higher as measured by CT: 656.7 (1939.9) mm compared to MRI: 442 (1083.2) mm. Radiographic area was highly correlated (P = <0.0001) with volume for both CT and MRI (rho=0.91 and 0.87, respectively).

Discussion: It was possible to measure calcinotic lesions by radiography, CT and MRI, with CT volume being higher than MRI volume. Radiographic area was highly correlated with CT and MRI volume, suggesting that low cost radiographs may give comparable information to 3-dimensional imaging. Our findings provide further insight into the development of objective outcome measures to facilitate future calcinosis clinical trials.
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http://dx.doi.org/10.1016/j.semarthrit.2019.03.001DOI Listing
October 2019