Publications by authors named "Sriram Balasubramanian"

82 Publications

Development of a Finite Element Model of the Pediatric Thoracic and Lumbar Spine, Ribcage, and Pelvis With Orthotropic Region-Specific Vertebral Growth.

J Biomech Eng 2022 Oct;144(10)

Division of Orthopaedics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.

Finite element (FE) modeling of the spine has increasingly been applied in orthopedic precision-medicine approaches. Previously published FE models of the pediatric spine growth have made simplifications in the geometry of anatomical structures, material properties, and representation of vertebral growth. To address those limitations, a comprehensive FE model of a pediatric (10-year-old) osteo-ligamentous thoracic and lumbar spine (T1-L5 with intervertebral discs (IVDs) and ligaments), ribcage, and pelvis with age- and level-specific ligament properties and orthotropic region-specific vertebral growth was developed and validated. Range of motion (ROM) measures, namely, lateral bending, flexion-extension, and axial rotation, of the current 10 YO FE model were generally within reported ranges of scaled in vitro adult ROM data. Changes in T1-L5 spine height, as well as kyphosis (T2-T12) and lordosis (L1-L5), angles in the current FE model for two years of growth (from ages 10 to 12 years) were within ranges reported from corresponding pediatric clinical data. The use of such comprehensive pediatric FE models can provide clinically relevant insights into normative and pathological biomechanical responses of the spine, and also contribute to the development and optimization of clinical interventions for spine deformities.
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http://dx.doi.org/10.1115/1.4054410DOI Listing
October 2022

Effects of Prestretch on Neonatal Peripheral Nerve: An Study.

J Brachial Plex Peripher Nerve Inj 2022 Jan 8;17(1):e1-e9. Epub 2022 Apr 8.

Drexel University School of Biomedical Engineering, Science, and Health Systems, Philadelphia, Pennsylvania, United States.

 Characterizing the biomechanical failure responses of neonatal peripheral nerves is critical in understanding stretch-related peripheral nerve injury mechanisms in neonates.  This in vitro study investigated the effects of prestretch magnitude and duration on the biomechanical failure behavior of neonatal piglet brachial plexus (BP) and tibial nerves.  BP and tibial nerves from 32 neonatal piglets were harvested and prestretched to 0, 10, or 20% strain for 90 or 300 seconds. These prestretched samples were then subjected to tensile loading until failure. Failure stress and strain were calculated from the obtained load-displacement data.  Prestretch magnitude significantly affected failure stress but not the failure strain. BP nerves prestretched to 10 or 20% strain, exhibiting significantly lower failure stress than those prestretched to 0% strain for both prestretch durations (90 and 300 seconds). Likewise, tibial nerves prestretched to 10 or 20% strain for 300 seconds, exhibiting significantly lower failure stress than the 0% prestretch group. An effect of prestretch duration on failure stress was also observed in the BP nerves when subjected to 20% prestretch strain such that the failure stress was significantly lower for 300 seconds group than 90 seconds group. No significant differences in the failure strains were observed. When comparing BP and tibial nerve failure responses, significantly higher failure stress was reported in tibial nerve prestretched to 20% strain for 300 seconds than BP nerve.  These data suggest that neonatal peripheral nerves exhibit lower injury thresholds with increasing prestretch magnitude and duration while exhibiting regional differences.
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http://dx.doi.org/10.1055/s-0042-1743132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8993512PMC
January 2022

Surfactant-Assisted Synthesis of Praseodymium Orthovanadate Nanofiber-Supported NiFe-Layered Double Hydroxide Bifunctional Catalyst: The Electrochemical Detection and Degradation of Diphenylamine.

Inorg Chem 2022 Apr 4;61(15):5824-5835. Epub 2022 Apr 4.

Department of Chemistry, Stella Maris College, Affiliated to the University of Madras, Chennai600086, Tamil Nadu, India.

Physiological storage disorders are caused by ineffective post-harvest handling of horticultural crops, particularly fruits. To address these post-harvest concerns, diphenylamine (DPAH) is widely used as a preservative to prevent fruit degradation and surface scald during storage around the world. Humans are negatively affected by the use of high concentrations of DPAH because of the various health complications related to its exposure. As a result, accurate detection and quantification of DPAH residues in treated fruits are critical. Rare earth metal orthovanadates, which have excellent physical and chemical properties, are potential materials for electrochemical sensors in this area. Herein, we present a simple and direct ultrasonication technique for the surfactant-assisted synthesis of praseodymium orthovanadate (PrVO or PrV) loaded on nickel iron layered double hydroxide (NiFe-LDH) synthesized with deep eutectic solvent assistance, as well as its application as an effective catalyst in the detection and degradation of DPAH in fruits and water samples. The current work presents supreme electrochemical features of a [email protected] screen-printed carbon electrode (SPCE) where cetyltrimethylammonium bromide (CTAB) surfactant-driven fabrication of PrV directs the formation of highly qualified engineered structures and the deep eutectic solvent based green synthesis of NiFe-LDH creates hierarchical lamellar structures following the principles of green chemistry. PrV and NiFe-LDH combine to produce a synergistic effect that improves the number of active sites, charge transfer kinetics, and electronic conductivity. Differential pulse voltammetry analysis of [email protected]/SPCE reveals a dynamic working range (0.005-226.26 μM), increased sensitivity (133.13 μA μM cm), enhanced photocatalytic activity, and low detection limit (0.001 μM), which are considered significant when compared with the former reported electrodes in the literature for the determination of DPAḢ for its real-time applications.
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http://dx.doi.org/10.1021/acs.inorgchem.2c00052DOI Listing
April 2022

Identification of a genetic signature enriching for response to ibrutinib in relapsed/refractory follicular lymphoma in the DAWN phase 2 trial.

Cancer Med 2022 01 17;11(1):61-73. Epub 2021 Nov 17.

Division of Medical Oncology, Department of Medicine, The University of Washington, Seattle, Washington, USA.

Background: The single-arm DAWN trial (NCT01779791) of ibrutinib monotherapy in patients with relapsed/refractory follicular lymphoma (FL) showed an overall response rate (ORR) of 20.9% and a median response duration of 19.4 months. This biomarker analysis of the DAWN dataset sought to determine genetic classifiers for prediction of response to ibrutinib treatment.

Methods: Whole exome sequencing was performed on baseline tumor samples. Potential germline variants were excluded; a custom set of 1216 cancer-related genes was examined. Responder- versus nonresponder-associated variants were identified using Fisher's exact test. Classifiers with increasing numbers of genes were created using a greedy algorithm that repeatedly selected genes, adding the most nonresponders to the existing "predicted nonresponders" set and were evaluated with 10-fold cross-validation.

Results: Exome data were generated from 88 patient samples and 13,554 somatic mutation variants were inferred. Response data were available for 83 patients (17 responders, 66 nonresponders). Each sample showed 100 to >500 mutated genes, with greater variance across nonresponders. The overall variant pattern was consistent with previous FL studies; 75 genes had mutations in >10% of patients, including genes previously reported as associated with FL. Univariate analysis yielded responder-associated genes FANCA, HISTH1B, ANXA6, BTG1, and PARP10, highlighting the importance of functions outside of B-cell receptor signaling, including epigenetic processes, DNA damage repair, cell cycle/proliferation, and cell motility/invasiveness. While nonresponder-associated genes included well-known TP53 and CARD11, genetic classifiers developed using nonresponder-associated genes included ATP6AP1, EP400, ARID1A, SOCS1, and TBL1XR1, suggesting resistance to ibrutinib may be related to broad biological functions connected to epigenetic modification, telomere maintenance, and cancer-associated signaling pathways (mTOR, JAK/STAT, NF-κB).

Conclusion: The results from univariate and genetic classifier analyses provide insights into genes associated with response or resistance to ibrutinib in FL and identify a classifier developed using nonresponder-associated genes, which warrants further investigation.

Trial Registration: NCT01779791.
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http://dx.doi.org/10.1002/cam4.4422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704158PMC
January 2022

Effect of ibrutinib with R-CHOP chemotherapy in genetic subtypes of DLBCL.

Cancer Cell 2021 12 4;39(12):1643-1653.e3. Epub 2021 Nov 4.

Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Center for Cancer Genomics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

In diffuse large B cell lymphoma (DLBCL), tumors belonging to the ABC but not GCB gene expression subgroup rely upon chronic active B cell receptor signaling for viability, a dependency that is targetable by ibrutinib. A phase III trial ("Phoenix;" ClinicalTrials.gov: NCT01855750) showed a survival benefit of ibrutinib addition to R-CHOP chemotherapy in younger patients with non-GCB DLBCL, but the molecular basis for this benefit was unclear. Analysis of biopsies from Phoenix trial patients revealed three previously characterized genetic subtypes of DLBCL: MCD, BN2, and N1. The 3-year event-free survival of younger patients (age ≤60 years) treated with ibrutinib plus R-CHOP was 100% in the MCD and N1 subtypes while the survival of patients with these subtypes treated with R-CHOP alone was significantly inferior (42.9% and 50%, respectively). This work provides a mechanistic understanding of the benefit of ibrutinib addition to chemotherapy, supporting its use in younger patients with non-GCB DLBCL.
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http://dx.doi.org/10.1016/j.ccell.2021.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8722194PMC
December 2021

Combined ibrutinib and venetoclax treatment vs single agents in the TCL1 mouse model of chronic lymphocytic leukemia.

Blood Adv 2021 12;5(23):5410-5414

AbbVie Oncology Discovery, North Chicago, IL.

The covalent inhibitor of Bruton's tyrosine kinase ibrutinib and the specific Bcl-2 inhibitor venetoclax are both highly efficacious single-agent drugs in the treatment of chronic lymphocytic leukemia (CLL). Based on their complementary modes of action, ibrutinib and venetoclax are hypothesized to act in a synergistic fashion. Currently, it is unclear whether combined treatment is indeed superior to continuous single-agent treatment and what mechanisms underlie the resistance to combination treatment. In addition, the effects of such treatment on the skewed T-cell compartment characteristic of CLL are as yet unknown. In the murine Eµ-TCL1 adoptive transfer model resembling aggressive CLL, we found that combined treatment resulted in the deepest responses, with the longest duration related to a combination of decreased proliferation and increased induction of apoptosis. In addition, alterations in T-cell subsets were most prominent after combination treatment, with increased naive cells and reduced effector memory cells. Remarkably, effects of single agents but also combination treatment were eventually interrupted by relapse, and we found downregulation of BIM expression as a plausible cause of acquired drug resistance. Nevertheless, in this murine model, the combination of venetoclax and ibrutinib has increased efficacy over single agents, accompanied by a restoration of the T-cell compartment.
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http://dx.doi.org/10.1182/bloodadvances.2021004861DOI Listing
December 2021

Circulating tumor DNA for comprehensive noninvasive monitoring of lymphoma treated with ibrutinib plus nivolumab.

Blood Adv 2021 11;5(22):4674-4685

Laboratory of Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland.

To advance the use of circulating tumor DNA (ctDNA) applications, their broad clinical validity must be tested in different treatment settings, including targeted therapies. Using the prespecified longitudinal systematic collection of plasma samples in the phase 1/2a LYM1002 trial (registered on www.clinicaltrials.gov as NCT02329847), we tested the clinical validity of ctDNA for baseline mutation profiling, residual tumor load quantification, and acquisition of resistance mutations in patients with lymphoma treated with ibrutinib+nivolumab. Inclusion criterion for this ancillary biological study was the availability of blood collected at baseline and cycle 3, day 1. Overall, 172 ctDNA samples from 67 patients were analyzed by the LyV4.0 ctDNA Cancer Personalized Profiling Deep Sequencing Assay. Among baseline variants in ctDNA, only TP53 mutations (detected in 25.4% of patients) were associated with shorter progression-free survival; clones harboring baseline TP53 mutations did not disappear during treatment. Molecular response, defined as a >2-log reduction in ctDNA levels after 2 cycles of therapy (28 days), was achieved in 28.6% of patients with relapsed diffuse large B-cell lymphoma who had ≥1 baseline variant and was associated with best response and improved progression-free survival. Clonal evolution occurred frequently during treatment, and 10.3% new mutations were identified after 2 treatment cycles in nonresponders. PLCG2 was the topmost among genes that acquired new mutations. No patients acquired the C481S BTK mutation implicated in resistance to ibrutinib in CLL. Collectively, our results provide the proof of concept that ctDNA is useful for noninvasive monitoring of lymphoma treated with targeted agents in the clinical trial setting.
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http://dx.doi.org/10.1182/bloodadvances.2021004528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759132PMC
November 2021

In-vitro stress relaxation response of neonatal peripheral nerves.

J Biomech 2021 11 19;128:110702. Epub 2021 Aug 19.

Department of Biomedical Engineering, Widener University School of Engineering, One University Place, Chester, PA 19013, United States. Electronic address:

Characterizing the viscoelastic behavior of neonatal peripheral nerves is critical in understanding stretch-related peripheral nerve injuries (PNIs) in neonates. This study investigated the in-vitro viscoelastic stress relaxation response of neonatal piglet brachial plexus (BP) and tibial nerves at two different strain levels (10% and 20%) and stress relaxation testing durations (90- and 300-seconds). BP and tibial nerves from 20 neonatal piglets were harvested and pre-stretched to either 10% or 20% strain at a dynamic rate of 100 mm/min to simulate conditions, such as shoulder dystocia, that may lead to stretch-related PNIs in neonates. At constant strain, the reduction in stress was recorded for 90- or 300-seconds. The biomechanical data were then fit to a viscoelastic model to acquire the short- and long-term stress relaxation time-constants. Though no significant differences in the degree of stress relaxation were found between the two tested strain levels after 90 seconds in both nerve types, reduction in stress was moderately greater (p = 0.056) at 10% strain than at 20% for BP after 300 seconds. The reduction in stress was significantly higher in nerves subjected to a 300 second testing duration than 90 second for both strain levels and nerve types. When comparing BP and tibial nerve stress relaxation response, BP nerve relaxed significantly more than tibial at both strain levels after 90 seconds, but no significant differences were observed after 300 seconds. Our results confirm that neonatal peripheral nerve tissue is highly viscoelastic. These novel biomechanical data can be incorporated into finite element and computational models studying neonatal PNIs.
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http://dx.doi.org/10.1016/j.jbiomech.2021.110702DOI Listing
November 2021

Well-Designed Construction of Yttrium Orthovanadate Confined on Graphitic Carbon Nitride Sheets: Electrochemical Investigation of Dimetridazole.

Inorg Chem 2021 Sep 25;60(17):13150-13160. Epub 2021 Aug 25.

Department of Chemistry, Stella Maris College, Affiliated to the University of Madras, Chennai, 600 086 Tamil Nadu, India.

Antibiotics are the most important drugs for people and animals to fight bacterial illnesses. Overuse of antibiotics has had unintended consequences, such as antibiotic resistance and ecosystem eradication owing to toxic chemical discharge, which have a negative influence on the biome. Herein, we report the synthesis of a hollow ellipsoid-shaped yttrium vanadate/graphitic carbon nitride ([email protected]) nanocomposite by a hydrothermal approach followed by a sonochemical method for the effective detection of dimetridazole (DMZ). The synergic and coupling effect between both the phases offer non-linear cumulative ramifications which can positively enhance the individual properties of the materials under consideration. This positive hybrid effect increases the conductivity, shortens the ion-diffusion pathway, enhances the electron/ion transportation, and provides more active sites and electron-conducting channels. The accurate optimization of the experimental conditions proposes good electrocatalytic activity for the [email protected] catalyst, exhibiting a good response toward DMZ detection. It reveals an extensive linear concentration range (0.001-153.3 and 176.64-351.6 μM), a low detection limit (0.8 nM), higher sensitivity (4.98 μA μM cm), appreciable selectivity, increased operational stability (2200 s), and good cycle stability (60 cycles). The electrochemical performance of [email protected] indicates its practical application in real-time sample analysis of several families of nitroimidazole drugs.
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http://dx.doi.org/10.1021/acs.inorgchem.1c01548DOI Listing
September 2021

Toward the Development of Disposable Electrodes Based on Holmium Orthovanadate/-Boron Nitride: Impacts and Electrochemical Performances of Emerging Inorganic Contaminants.

Inorg Chem 2021 Aug 26;60(16):12425-12435. Epub 2021 Jul 26.

Department of Chemistry, Stella Maris College, Affiliated to the University of Madras, Chennai, Tamil Nadu 600086, India.

Rare-earth metal orthovanadates have great technological relevance in the family of rare-earth compounds owing to their excellent physical and chemical properties. A significant number of studies have been carried out on this class of compounds to exploit their electrochemical properties in virtue of variable oxidation states. But holmium vanadate (HoV) and its morphology selective synthesis have not been considered, which can have potential applications similar to the rest of the family. In this work, we propose the synthesis of superior architectures of HoV with a functionalized boron nitride (-BN) nanocomposite. The synergistic effect between HoV and -BN can have a positive effect on the physical characteristics of the nanocomposite, which can be explored for its electrochemical capacity. Here, HoV incorporated with -BN is explored for the electrochemical detection of Hg ions, which is known for its toxicity-induced environmental health hazards. The structural and compositional revelation reveals higher conductivity and faster electron transfer in the composite, which facilitates a wide working range (0.02-53.8 and 64.73-295.4 μM), low limit of detection (5 nM), higher sensitivity (66.6 μA μM cm), good selectivity over 10-fold higher concentration of other interfering compounds compared to Hg ion concentration, and good cycles stability (30 segments) toward Hg ion detection. This also envisages the morphology selective synthesis and utilization of other rare-earth metals, whose electrochemical capacities are unexplored.
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http://dx.doi.org/10.1021/acs.inorgchem.1c01678DOI Listing
August 2021

The association between early impairment in cerebral autoregulation and outcome in a pediatric swine model of cardiac arrest.

Resusc Plus 2020 Dec 5;4:100051. Epub 2020 Dec 5.

Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, USA.

Aims: Evaluate cerebral autoregulation (CAR) by intracranial pressure reactivity index (PRx) and cerebral blood flow reactivity index (CBFx) during the first four hours following return of spontaneous circulation (ROSC) in a porcine model of pediatric cardiac arrest. Determine whether impaired CAR is associated with neurologic outcome.

Methods: Four-week-old swine underwent seven minutes of asphyxia followed by ventricular fibrillation induction and hemodynamic-directed CPR. Those achieving ROSC had arterial blood pressure, intracranial pressure (ICP), and microvascular cerebral blood flow (CBF) monitored for 4 h. Animals were assigned an 8 -h post-ROSC swine cerebral performance category score (1 = normal; 2-4=abnormal neurologic function). In this secondary analytic study, we calculated PRx and CBFx using a continuous, moving correlation coefficient between mean arterial pressure (MAP) and ICP, and between MAP and CBF, respectively. Burden of impaired CAR was the area under the PRx or CBFx curve using a threshold of 0.3 and normalized as percentage of monitoring duration.

Results: Among 23 animals, median PRx was 0.14 [0.06,0.25] and CBFx was 0.36 [0.05,0.44]. Median burden of impaired CAR was 21% [18,27] with PRx and 30% [17,40] with CBFx. Neurologically abnormal animals (n = 10) did not differ from normal animals (n = 13) in post-ROSC MAP (63 vs. 61 mmHg, p = 0.74), ICP (15 vs. 14 mmHg, p = 0.78) or CBF (274 vs. 397 Perfusion Units, p = 0.12). CBFx burden was greater among abnormal than normal animals (45% vs. 24%, p = 0.001), but PRx burden was not (25% vs. 20%, p = 0.38).

Conclusion: CAR is impaired early after ROSC. A greater burden of CAR impairment measured by CBFx was associated with abnormal neurologic outcome.CHOP Institutional Animal Care and Use Committee protocol 19-001327.
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http://dx.doi.org/10.1016/j.resplu.2020.100051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244245PMC
December 2020

A Systematic Review of the Tensile Biomechanical Properties of the Neonatal Brachial Plexus.

J Biomech Eng 2021 11;143(11)

Department of Biomedical Engineering, Widener University, One University Place, Chester, PA 19013.

Brachial plexus (BP) birth injury has a reported incidence of 1 to 4 per 1000 live births. During complicated deliveries, neonatal, maternal, and other birth-related factors can cause over-stretching or avulsion of the neonatal brachial plexus leading to injury. Understanding biomechanical responses of the neonate brachial plexus when subjected to stretch can offer insight into the injury outcomes while guiding the development of preventative maneuvers that can help reduce the occurrence of neonatal brachial plexus injuries. This review article aims to offer a comprehensive overview of existing literature reporting biomechanical responses of the brachial plexus, in both adults and neonates, when subjected to stretch. Despite the discrepancies in the reported biomechanical properties of the brachial plexus, available studies confirm the loading rate and loading direction dependency of the brachial plexus tissue. Future studies, possibly in vivo, that utilize clinically relevant neonatal large animal models can provide translational failure values of the biomechanical parameters for the neonatal brachial plexus when subjected to stretch.
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http://dx.doi.org/10.1115/1.4051399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299814PMC
November 2021

An In Vitro Study to Investigate Biomechanical Responses of Peripheral Nerves in Hypoxic Neonatal Piglets.

J Biomech Eng 2021 11;143(11)

School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104.

Despite occurrence of neonatal hypoxia and peripheral nerve injuries in complicated birthing scenarios, the effect of hypoxia on the biomechanical responses of neonatal peripheral nerves is not studied. In this study, neonatal brachial plexus (BP) and tibial nerves, obtained from eight normal and eight hypoxic 3-5-day-old piglets, were tested in uniaxial tension until failure at a rate of 0.01 mm/s or 10 mm/s. Failure load, stress, and modulus of elasticity were reported to be significantly lower in hypoxic neonatal BP and tibial nerves than respective normal tissue at both 0.01 and 10 mm/s rates. Failure strain was significantly lower in the hypoxic neonatal BP nerves only at 10 mm/s rate when compared to normal BP nerve. This is the first available data that indicate weaker mechanical behavior of hypoxic neonatal peripheral nerves as compared to normal tissue and offer an understanding of the biomechanical responses of peripheral nerves of hypoxic neonatal piglets.
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http://dx.doi.org/10.1115/1.4051283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299807PMC
November 2021

Comparison of immunohistochemistry and gene expression profiling subtyping for diffuse large B-cell lymphoma in the phase III clinical trial of R-CHOP ± ibrutinib.

Br J Haematol 2021 07 3;194(1):83-91. Epub 2021 May 3.

National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

We assessed the concordance between immunohistochemistry (IHC) and gene expression profiling (GEP) for determining diffuse large B-cell lymphoma (DLBCL) cell of origin (COO) in the phase III PHOENIX trial of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) with or without ibrutinib. Among 910 of 1114 screened patients with non-germinal centre B cell-like (non-GCB) DLBCL by IHC, the concordance with GEP for non-GCB calls was 82·7%, with 691 (75·9%) identified as activated B cell-like (ABC), and 62 (6·8%) as unclassified. Among 746 of 837 enrolled patients with verified non-GCB DLBCL by IHC, the concordance with GEP was 82·8%, with 567 (76·0%) identified as ABC and 51 (6·8%) unclassified; survival outcomes were similar regardless of COO or treatment, whereas among patients with ABC DLBCL aged <60 years, the overall and event-free survival were substantially better with ibrutinib versus placebo plus R-CHOP [hazard ratio (HR) 0·365, 95% confidence interval (CI) 0·147-0·909, P = 0·0305; HR 0·561, 95% CI 0·326-0·967, P = 0·0348, respectively]. IHC and GEP showed high concordance and consistent survival outcomes among tested patients, indicating centralised IHC may be used to enrich populations for response to ibrutinib plus R-CHOP.
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http://dx.doi.org/10.1111/bjh.17450DOI Listing
July 2021

Quantifying lung and diaphragm morphology using radiographs in normative pediatric subjects, and predicting CT-derived lung volume.

Pediatr Pulmonol 2021 07 6;56(7):2177-2185. Epub 2021 May 6.

School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania, USA.

Objective: To quantify the effect of age on two-dimensional (2D) radiographic lung and diaphragm morphology and determine if 2D radiographic lung measurements can be used to estimate computer tomography (CT)-derived lung volume in normative pediatric subjects.

Materials And Methods: Digitally reconstructed radiographs (DRRs) were created using retrospective chest CT scans from 77 pediatric male and female subjects aged birth to 19 years. 2D lung and diaphragm measurements were made on the DRRs using custom MATLAB code, and Spearman correlations and exponential regression equations were used to relate 2D measurements with age. In addition, 3D lung volumes were segmented using CT scans, and power regression equations were fitted to predict each lung's CT-derived volume from 2D lung measurements. The coefficient of determination (R ) and standard error of the estimate (SEE) were used to assess the precision of the predictive equations with p < .05 indicating statistical significance.

Results: All 2D radiographic lung and diaphragm measurements showed statistically significant positive correlations with age (p < .01), including lung major axis (Spearman rho ≥  0.90). Precise estimations of CT-derived lung volumes can be made using 2D lung measurements (R  ≥ 0.95), including lung major axis (R  ≥ 0.97).

Interpretations: The reported pediatric age-specific reference data on 2D lung and diaphragm morphology and growth rates could be clinically used to identify lung and diaphragm pathologies during chest X-ray evaluations. The simple, precise, and clinically adaptable radiographic method for estimating CT-derived lung volumes may be used when pulmonary function tests are not readily available or difficult to perform.
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http://dx.doi.org/10.1002/ppul.25429DOI Listing
July 2021

Synergy of the LaVO/h-BN Nanocomposite: A Highly Active Electrocatalyst for the Rapid Analysis of Carbendazim.

Inorg Chem 2021 Apr 18;60(7):5271-5281. Epub 2021 Mar 18.

Department of Chemistry, Stella Maris College, Affiliated to the University of Madras, Chennai 600086, Tamil Nadu, India.

In the field of agriculture fungicides are vital, providing the most important ecosystem service for food production. The widespread use of these chemicals can significantly lead to various ecotoxicological threats with adverse effects, such as environmental changes, microbial resistance, and phytotoxicity. Electrochemical sensors offer enormous potential for the identification and monitoring of hazardous substances in accordance with their constructive characteristics, namely, precision, accuracy, sensitivity, and selectivity, over traditional analytical techniques. Here, we thus report the synthesis of the lanthanum vanadate/hexagonal boron nitride (LaV/h-BN) composite for the electrochemical determination of carbendazim (CZ), which is a widely used fungicide for disease management with critical risks associated with its overexposure. The combination of LaV and h-BN accelerates the formation of active sites, facilitating faster charge transfer and higher electronic conductivity. The synergistic effects greatly improve the preference of the modified electrode with increased sensitivity, a lower limit of detection, and wide linear responses toward CZ detection. The existence of variable oxidation states in the orthovanadate together with the unique properties of h-BN mark LaV/h-BN as an advanced material for specific applications in the family of rare-earth metal orthovanadate. Also, the deep eutectic solvent-assisted synthesis of the material creates an environmentally efficient system with reduced energy requisites to allow for applications in effective environmental monitoring.
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http://dx.doi.org/10.1021/acs.inorgchem.1c00253DOI Listing
April 2021

Part 2. Review and meta-analysis of studies on modulation of longitudinal bone growth and growth plate activity: A micro-scale perspective.

J Orthop Res 2021 05 29;39(5):919-928. Epub 2021 Jan 29.

School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania, USA.

Macro-scale changes in longitudinal bone growth resulting from mechanical loading were shown in Part 1 of this review to depend on load magnitude, anatomical location, and species. While no significant effect on longitudinal growth was observed by varying frequency and amplitude of cyclic loading, such variations, in addition to loading duration and species, were shown to affect the morphology, viability, and gene and protein expression within the growth plate. Intermittent compression regimens were shown to preserve or increase growth plate height while stimulating increased chondrocyte presence in the hypertrophic zone relative to persistent and static loading regimens. Gene and protein expressions related to matrix synthesis and degradation, as well as regulation of chondrocyte apoptosis were shown to exhibit magnitude-, frequency-, and duration-dependent responses to loading regimen. Chondrocyte viability was shown to be largely preserved within physiological bounds of magnitude, frequency, amplitude, and duration. Persistent static loading was shown to be associated with overall growth plate height in tension only, reducing it in compression, while affecting growth plate zone heights differently across species and encouraging mineralization relative to intermittent cyclic loading. Lateral loading of the growth plate, as well as microfluidic approaches are relatively understudied, and age, anatomical location, and species effects within these approaches are undefined. Understanding the micro-scale effects of varied loading regimes can assist in the development of growth modulation methods and device designs optimized for growth plate viability preservation or mineralization stimulation based on patient age and anatomical location.
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http://dx.doi.org/10.1002/jor.24992DOI Listing
May 2021

Biomarkers of response to ibrutinib plus nivolumab in relapsed diffuse large B-cell lymphoma, follicular lymphoma, or Richter's transformation.

Transl Oncol 2021 Jan 6;14(1):100977. Epub 2020 Dec 6.

Oncology Translational Research, Janssen Research & Development, Spring House, PA 19477, United States. Electronic address:

We analyzed potential biomarkers of response to ibrutinib plus nivolumab in biopsies from patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Richter's transformation (RT) from the LYM1002 phase I/IIa study, using programmed death ligand 1 (PD-L1) immunohistochemistry, whole exome sequencing (WES), and gene expression profiling (GEP). In DLBCL, PD-L1 elevation was more frequent in responders versus nonresponders (5/8 [62.5%] vs. 3/16 [18.8%]; p = 0.065; complete response 37.5% vs. 0%; p = 0.028). Overall response rates for patients with WES and GEP data, respectively, were: DLBCL (38.5% and 29.6%); FL (46.2% and 43.5%); RT (76.5% and 81.3%). In DLBCL, WES analyses demonstrated that mutations in RNF213 (40.0% vs. 6.2%; p = 0.055), KLHL14 (30.0% vs. 0%; p = 0.046), and LRP1B (30.0% vs. 6.2%; p = 0.264) were more frequent in responders. No responders had mutations in EBF1, ADAMTS20, AKAP9, TP53, MYD88, or TNFRSF14, while the frequency of these mutations in nonresponders ranged from 12.5% to 18.8%. In FL and RT, genes with different mutation frequencies in responders versus nonresponders were: BCL2 (75.0% vs. 28.6%; p = 0.047) and ROS1 (0% vs. 50.0%; p = 0.044), respectively. Per GEP, the most upregulated genes in responders were LEF1 and BTLA (overall), and CRTAM (germinal center B-cell-like DLBCL). Enriched pathways were related to immune activation in responders and resistance-associated proliferation/replication in nonresponders. This preliminary work may help to generate hypotheses regarding genetically defined subsets of DLBCL, FL, and RT patients most likely to benefit from ibrutinib plus nivolumab.
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http://dx.doi.org/10.1016/j.tranon.2020.100977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723809PMC
January 2021

Thoracic vertebral morphology in normal and scoliosis deformity in skeletally immature rabbits: A Longitudinal study.

JOR Spine 2020 Dec 17;3(4):e1118. Epub 2020 Sep 17.

School of Biomedical Engineering, Science and Health Systems Drexel University Philadelphia Pennsylvania USA.

Objective: To measure age-related changes in thoracic vertebral body heights (VBH) in skeletally immature normative and scoliotic rabbits to assess how VBH change during growth. To examine the potential link between the moment-arm of the rib tether and vertebral wedging as well as the sum of the curvature angles at the apical level (T7). To assess the correlation between the magnitude of initial spine curve and final spine curve in the scoliotic group.

Methods: Eight healthy, skeletally immature normative New Zealand rabbits and ten skeletally immature scoliotic rabbits which underwent unilateral rib tethering were included retrospectively. Each rabbit was scanned at two to four time points (at 7, 11, 14 and 28 weeks). Three dimensional bone models of thoracic vertebrae (T1-T12) were digitally segmented and reconstructed. VBH were calculated using surface landmark points from each thoracic vertebra. Apical level (T7) ± 2 levels in scoliotic rabbits were compared to their corresponding levels and time points in the normative group. The moment-arms between the centroids of 2D projections of T3-T9 vertebral bodies and the line which connects the centroids of the end levels were calculated.

Results: Bilateral left-right (L-R) symmetry and anterior-posterior (A-P) asymmetry were observed in normative VBH. Bilateral concave-convex (CC-CX) asymmetry and (A-P) asymmetry were observed in scoliotic VBH. No significant differences in growth rates were found between the normative and scoliotic groups. Vertebral wedging as well as curvature magnitude were positively correlated with the moment-arms.

Conclusion: Unilateral rib tether applies compressive forces on both concave and convex sides, whereas compressive forces are lower on the latter. Knowing the amount of vertebral wedging or curve magnitude would enable us to predict the applied force (moment-arms), which is important for planning a corrective surgery.
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http://dx.doi.org/10.1002/jsp2.1118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770206PMC
December 2020

Integration of samarium vanadate/carbon nanofiber through synergy: An electrochemical tool for sulfadiazine analysis.

J Hazard Mater 2021 04 24;408:124940. Epub 2020 Dec 24.

Department of Chemistry, Stella Maris College, Affiliated to the University of Madras, Chennai 600086, Tamil Nadu, India. Electronic address:

Antibiotic pollution causes worldwide concern due to its more apparent consequences, namely antibiotic resistance and destruction of the environment. Extensive use of antibiotics in human and veterinary drugs releases a significant amount of toxins into the sphere of living matter, causing adverse ecological impacts. This requires the design of new analytical protocols for the effective mitigation and monitoring of hazardous pharmaceutical products to reduce the environmental burden. Therefore, we present here the hydrothermal synthesis of samarium vanadate/carbon nanofiber (SmV/CNF) composite for the determination of sulfadiazine (SFZ). The synergistic effect arising from the combination of SmV and CNF accelerates charge transfer kinetics along with the creation of more surface-active sites that benefit effective detection. The structural and compositional disclosure indicates the high purity and superior attributes of the composite material that possesses the ability to improve catalytic performance. The proposed SmV/CNF sensor exhibits important static characteristics such as wide linear response ranges, low detection limit, high sensitivity and selectivity, and increased stability. To the best of our knowledge, this is the first report on the electrochemical performance of SmV/CNF, establishing its potential application in real-time analysis of environmentally hazardous contaminants.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124940DOI Listing
April 2021

Part 1. Review and meta-analysis of studies on modulation of longitudinal bone growth and growth plate activity: A macro-scale perspective.

J Orthop Res 2021 05 13;39(5):907-918. Epub 2021 Jan 13.

School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, Pennsylvania, USA.

Growth modulation is an emerging method for treatment of angular skeletal deformities such as adolescent idiopathic scoliosis (AIS). The Hueter-Volkmann law, by which growth is stimulated in tension and inhibited in compression, is widely understood, and applied in current growth-modulating interventions such as anterior vertebral body tethering (AVBT) for AIS. However, without quantification of the growth rate effects of tension or compression, the possibility of under- or over- correction exists. A definitive mechanical growth modulation relationship relating to treatment of such skeletal deformities is yet to exist, and the mechanisms by which growth rate is regulated and altered are not fully defined. Review of current literature demonstrates that longitudinal (i.e., lengthwise) growth rate in multiple animal models depend on load magnitude, anatomical location, and species. Additionally, alterations in growth plate morphology and viability vary by loading parameters such as magnitude, frequency, and whether the load was applied persistently or intermittently. The aggregate findings of the reviewed studies will assist in work towards increasingly precise and clinically successful growth modulation methods. Part 1 of this review focuses on the effects of mechanical loading, species, age, and anatomical location on the macro-scale alterations in longitudinal bone growth, as well as factors that affect growth plate material properties. Part 2 considers the effects on micro-scale alterations in growth plate morphology such as zone heights and proportions, chondrocyte viability, and related gene and protein expression.
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http://dx.doi.org/10.1002/jor.24976DOI Listing
May 2021

Activity of ibrutinib plus R-CHOP in diffuse large B-cell lymphoma: Response, pharmacodynamic, and biomarker analyses of a phase Ib study.

Cancer Treat Res Commun 2020 1;25:100235. Epub 2020 Nov 1.

Janssen Research & Development, 1400 McKean Road, Spring House, PA 19477, United States. Electronic address:

Introduction: This unplanned post-hoc analysis was based on data from the phase Ib DBL1002 study (NCT01569750) and evaluated the association between molecular biomarkers and clinical response to combined treatment with ibrutinib plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in diffuse large B-cell lymphoma (DLBCL) subtypes.

Methods: DLBCL subtyping was conducted using immunohistochemistry. Next-generation sequencing using immunoglobulin H primers assessed minimal residual disease (MRD). A quantitative assay evaluated Bruton's tyrosine kinase (BTK) occupancy by ibrutinib in peripheral blood mononuclear cells. Targeted DNA sequencing examined genetic variants by DLBCL subtype. Secreted protein expression was evaluated with a SomaLogic analyte panel.

Results: Among 21 patients with DLBCL (median age 53.5 years), 17 achieved a complete response (CR) and 4 a partial response (PR). Of the 11 subtyped patients, 9 had a CR (5/7 germinal center B-cell-like [GCB] and 4/4 non-GCB) and 2 had a PR (both GCB). Nine of 12 patients tested for MRD achieved early (cycle 2 day 1) MRD negativity; most had a CR. There was near-complete BTK occupancy at 4 h postdose. Mutation analysis (n = 19) revealed variants including CREBBP, KMT2D, LRP1B, BCL2, and TNFRSF14; only 1 CD79B and TP53 each; no CARD11 or MYD88.

Conclusions: In this study, first-line ibrutinib plus R-CHOP benefited patients with DLBCL, with good overall response rate and early MRD negativity. With a caveat of small sample size, our results showed that a favorable genetic profile and younger patient age may be important to beneficial clinical outcome with ibrutinib plus R-CHOP in DLBCL.
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http://dx.doi.org/10.1016/j.ctarc.2020.100235DOI Listing
November 2021

Cobalt molybdate nanorods decorated on boron-doped graphitic carbon nitride sheets for electrochemical sensing of furazolidone.

Mikrochim Acta 2020 11 12;187(12):654. Epub 2020 Nov 12.

Surfactant Research Chair, Chemistry Department, College of Science, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia.

A nanorod-like structured CoMoO embedded on boron doped-graphitic carbon nitride composite (CoMoO/BCN) has been developed by a simple sonochemical method for electrochemical detection of furazolidone (FUZ). Interestingly, the impedance of CoMoO/BCN fabricated screen-printed carbon electrode (SPCE) possesses a lower resistance charge transfer (R), which favors superior electrochemical detection of FUZ. Such CoMoO/BCN/SPCE exhibits an ultralow detection limit of 1.6 nM with a concentration range of 0.04-408.9 μM, and high sensitivity of 11.6 μA μM cm by DPV method. In addition, biological and water samples were used for demonstration of practical application of CoMoO/BCN/SPCE towards electrochemical detection of FUZ, and the result exhibits a satisfactory recovery.Graphical abstract.
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http://dx.doi.org/10.1007/s00604-020-04590-3DOI Listing
November 2020

Highly sensitive determination of cancer toxic mercury ions in biological and human sustenance samples based on green and robust synthesized stannic oxide nanoparticles decorated reduced graphene oxide sheets.

Anal Chim Acta 2020 Nov 17;1137:181-190. Epub 2020 Sep 17.

Surfactant Research Chair, Chemistry Department, College of Science, King Saud University, P.O. Box-2455, Riyadh, 11451, Saudi Arabia. Electronic address:

This work proposes the conventional sonochemical synthesis of nanoparticles of tin (IV) oxide on reduced graphene oxide ([email protected]) influencing the formation of a composite with enhanced properties. The combination of SnO nanoparticles with rGOS weakens the accumulation in layered structures of the latter system, which leads to better exposure of SnO active sites and thus increases the conductivity of [email protected] composite. This validates the improved electro-catalytic activity of the composite based on previous reports for its successful utilization in the electrochemical determination of toxic contaminants. The quantitative determination of mercury ions, through the use of the electrochemical sensor based on [email protected] manifests several advantages such as simple operator, promptness, cost effectiveness and time independency when compared to other traditional techniques. The fabricated sensor displays two wide linear responses in the range of 0.25-705.3 μM for mercury ions, with a rapid response time about 1 s, and with a high sensitivity of 10.18 μA μM cm under optimized conditions. The accumulation of traces of mercury in the bodies of fish in the marine eco system marks the significance of its detection in real samples. The satisfactory results of the proposed sensor establish the supreme efficacy of layered nanomaterials in conjunction with nanoparticles for the simple, rapid and efficient detection of pollutants in food and biological samples.
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http://dx.doi.org/10.1016/j.aca.2020.09.014DOI Listing
November 2020

Morphology and growth of the pediatric lumbar vertebrae.

Spine J 2021 04 3;21(4):682-697. Epub 2020 Nov 3.

School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut St, Bossone 718, Philadelphia, PA 19104, USA. Electronic address:

Background Context: The majority of existing literature describing pediatric lumbar vertebral morphology are limited to characterization of the vertebral bodies, pedicles, and spinal canal and no study has described the rates of growth for any lumbar vertebral structure. While it is known that growth of the lumbar vertebrae results in changes in vertebral shape, the dimension ratios used to quantify these shape changes do not represent the 3D morphology of the vertebral structures. Additionally, many of the previous evaluations of growth and shape are purely descriptive and do not investigate sexual dimorphism or variations across vertebral levels.

Purpose: This study aims to establish a database of pediatric lumbar vertebra dimension, growth, and shape data for subjects between and ages of 1 and 19 years.

Study Design: A retrospective study of computed tomography (CT) data.

Methods: Retrospective, abdominal, CT scans of 102 skeletally normal pediatric subjects (54 males, 48 females) between the ages of 1 and 19 years were digitally reconstructed and manually segmented. Thirty surface landmark points (LMPs), 30 vertebral measurements, the centroid size, centroid location, and the local orientation were collected for each lumbar vertebra along with the centroid size of the LMPs comprising each subject's full lumbar spine and their intervertebral disc (IVD) heights. Nonparametric statistics were used to compare dimension values across vertebral levels and between sexes. Linear models with age as the independent variable were used to characterize dimension growth for each sex and vertebral level. Age-dependent quadratic equations were fit to LMP distributions resulting from a generalized Procrustes analysis (GPA) of the vertebrae and fixed effects models were used to investigate differences in model coefficients across levels and between sexes.

Results: Intervertebral level dimension differences were observed across all vertebral structures in both sexes while pedicle widths and IVDs heights were the only measurements found to be sexually dimorphic. Dimension growth rates generally varied across vertebral levels and the growth rates of males were typically larger than those of females. Differences between male and female vertebral shapes were also found for all lumbar vertebral structures.

Conclusions: To the authors' knowledge, this is the first study to report growth rates for the majority of pediatric lumbar vertebral structures and the first to describe the 3D age-dependent shapes of the pediatric lumbar spine and vertebrae. In addition to providing a quantitative database, the dimension, growth, and shape data reported here would have applications in medical device design, surgical planning, surgical training, and biomechanical modeling.
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http://dx.doi.org/10.1016/j.spinee.2020.10.029DOI Listing
April 2021

A Systematic Review of the Electrodiagnostic Assessment of Neonatal Brachial Plexus.

Neurol Neurobiol (Tallinn) 2020 5;3(2). Epub 2020 Jun 5.

Widener University, School of Engineering, Chester, Pennsylvania, USA.

Despite improvements in obstetric care, neonatal brachial plexus palsy continues to significantly impact infants' lives worldwide, with an incidence of 1 to 4 per 1000 live births. While a majority of affected infants recover spontaneously by three months, 20-30% suffer permanent functional deficits that significantly impair their quality of life. Anatomical complexity of the brachial plexus results in varying degrees of injury and pathological changes at multiple levels within the plexus. Current clinical diagnosis relies on electrodiagnostic techniques such as nerve conduction (i.e., motor and sensory) and electromyography studies. These techniques not only aid clinicians to differentiate between axonal and demyelinating lesions, evident by changes in signal shape and conduction, but also provide prognostic information in cases of brachial plexus injuries. The presented study offers a comprehensive review of existing literature on electrodiagnostic techniques employed for assessing neonatal brachial plexus injuries.
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http://dx.doi.org/10.31487/j.nnb.2020.02.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546533PMC
June 2020

Deep eutectic solvent-based manganese molybdate nanosheets for sensitive and simultaneous detection of human lethal compounds: comparing the electrochemical performances of M-molybdate (M = Mg, Fe, and Mn) electrocatalysts.

Nanoscale 2020 Oct 23;12(38):19719-19731. Epub 2020 Sep 23.

Department of Chemistry, Stella Maris College, Affiliated to the University of Madras, Chennai-600 086, Tamil Nadu, India.

Potentially hazardous chemical contaminants endanger the environment and human well-being, challenging scientists and policy makers to develop holistic alternative approaches for remediation. The addition or accumulation of these chemicals can have a series of far-reaching consequences and have direct and indirect effects at multiple levels of ecological organization. Therefore, the development of a sensitive tool for the comprehensive evaluation of chemical concentrations is highly relevant. Herein, we thus report the simultaneous electrochemical detection of highly toxic hydroquinone (HQ), Hg, and nitrite (NO) compounds using nanostructured metal molybdate (M = Mg, Fe and Mn) catalysts. These functional nanomaterials are synthesized using a deep eutectic solvent (DES) modified hydrothermal method that provides sustainable aspects and energy efficient synthesis strategies. Choline chloride (ChCl)-urea DES used in this study exhibits an all-in-one behaviour by simultaneously acting as a template, reducing agent, and homogeneous means for stabilizing metal ions. This stimulates the fabrication of hierarchical structures of metal molybdates with high surface activities that cause their remarkable properties with minimal waste generation. The structural, morphological, catalytic, and electrochemical capacities of the as-synthesized MgMoO, Fe(MoO), and MnMoO materials are explored through various techniques and comparatively, MnMoO presents superior characterization features such as a reduced particle size, increased surface area and hierarchical architectures. Owing to the exceptional physicochemical attributes, the MnMoO modified glassy carbon electrode (GCE) demonstrates superior electrochemical activities towards the individual and simultaneous detection of HQ, Hg, and NO. Well-defined and separate peaks are observed for the simultaneous detection of HQ, Hg, and NO which is influenced by the binding energies of these pollutants. Furthermore, the modified electrode exhibits a high sensitivity of 23.8, 17.7 and 10.2 μA μM cm with a limit of detection (LOD) of 0.026, 0.05, and 0.01 μM for HQ, Hg, and NO respectively under ideal conditions. Also, the reproducibility and anti-interference ability reinforce the application potential of the MnMoO modified electrode for the simultaneous electrochemical detection of HQ, Hg, and NO in real samples with better recoveries, thus assessing the effect of these hazardous chemicals on humanity.
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http://dx.doi.org/10.1039/d0nr05533fDOI Listing
October 2020

Final 5-year findings from the phase 3 HELIOS study of ibrutinib plus bendamustine and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma.

Leuk Lymphoma 2020 12 6;61(13):3188-3197. Epub 2020 Aug 6.

Department I of Internal Medicine and German CLL Study Group, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.

We report final analysis outcomes from the phase 3 HELIOS study (NCT01611090). Patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma without deletion 17p ( = 578) were randomized 1:1 to 420 mg daily ibrutinib or placebo plus ≤6 cycles of bendamustine plus rituximab (BR), followed by ibrutinib or placebo alone. Median follow-up was 63.7 months. Median investigator-assessed progression-free survival was longer with ibrutinib plus BR (65.1 months) than placebo plus BR (14.3 months; hazard ratio [HR] 0.229 [95% confidence interval (CI) 0.183-0.286];  < .0001). Despite crossover of 63.3% of patients from the placebo plus BR arm to ibrutinib treatment upon disease progression, ibrutinib plus BR versus placebo plus BR demonstrated an overall survival benefit (HR 0.611 [95% CI 0.455-0.822];  = .0010; median not reached in either arm). Long-term follow-up data confirm the survival benefit of ibrutinib plus BR over BR alone. Safety profiles were consistent with those known for ibrutinib and BR.
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http://dx.doi.org/10.1080/10428194.2020.1795159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9094431PMC
December 2020

Using Virtual Reality in Biomedical Engineering Education.

J Biomech Eng 2020 11;142(11)

School of Biomedical Engineering, Sciences and Health Systems, Drexel University, Philadelphia, PA 19104.

This study explored virtual reality (VR) as an educational tool to offer immersive and experiential learning environments to biomedical engineering (BME) students. VR and traditional two-dimensional (2D) videos were created and used to teach required communication skills to BME students' while working with clinical partners in healthcare settings. The videos of interdisciplinary teams (engineering and nursing students) tackling medical device-related problems, similar to those commonly observed in healthcare settings, were shown to BME students. Student surveys indicated that, through VR videos, they felt more immersed in real-world clinical scenarios while learning about the clinical problems, each team-member's areas of expertise, their roles and responsibilities, and how an interdisciplinary team operated collectively to solve a problem in the presented settings. Students with a prior in-person immersion experience, in the presented settings, reported VR videos to serve as a possible alternative to in-person immersion and a useful tool for their preparedness for real-world clinical immersion. We concluded that VR holds promise as an educational tool to offer simulated clinical scenarios that are effective in training BME students for interprofessional collaborations.
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http://dx.doi.org/10.1115/1.4048005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580657PMC
November 2020

Coding and noncoding drivers of mantle cell lymphoma identified through exome and genome sequencing.

Blood 2020 07;136(5):572-584

Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.

Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established, and the features that contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes and 34 genomes alongside previously published exome cohorts. To confirm our findings, we resequenced the genes identified in the exome cohort in 191 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations. Our sequencing revealed novel recurrent noncoding mutations surrounding a single exon of the HNRNPH1gene. In RNA-seq data from 103 of these cases, MCL tumors with these mutations had a distinct imbalance of HNRNPH1 isoforms. This altered splicing of HNRNPH1 was associated with inferior outcomes in MCL and showed a significant increase in protein expression by immunohistochemistry. We describe a functional role for these recurrent noncoding mutations in disrupting an autoregulatory feedback mechanism, thereby deregulating HNRNPH1 protein expression. Taken together, these data strongly imply a role for aberrant regulation of messenger RNA processing in MCL pathobiology.
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http://dx.doi.org/10.1182/blood.2019002385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440974PMC
July 2020
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