Publications by authors named "Amit Roy"

153 Publications

Radiation-Induced Brachial Plexopathy in Patients With Breast Cancer Treated With Comprehensive Adjuvant Radiation Therapy.

Adv Radiat Oncol 2021 Jan-Feb;6(1):100602. Epub 2020 Oct 27.

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri.

Purpose: Our purpose was to describe the risk of radiation-induced brachial plexopathy (RIBP) in patients with breast cancer who received comprehensive adjuvant radiation therapy (RT).

Methods And Materials: Records for 498 patients who received comprehensive adjuvant RT (treatment of any residual breast tissue, the underlying chest wall, and regional nodes) between 2004 and 2012 were retrospectively reviewed. All patients were treated with conventional 3 to 5 field technique (CRT) until 2008, after which intensity modulated RT (IMRT) was introduced. RIBP events were determined by reviewing follow-up documentation from oncologic care providers. Patients with RIBP were matched (1:2) with a control group of patients who received CRT and a group of patients who received IMRT. Dosimetric analyses were performed in these patients to determine whether there were differences in ipsilateral brachial plexus dose distribution between RIBP and control groups.

Results: Median study follow-up was 88 months for the overall cohort and 92 months for the IMRT cohort. RIBP occurred in 4 CRT patients (1.6%) and 1 IMRT patient (0.4%) ( = .20). All patients with RIBP in the CRT cohort received a posterior axillary boost. Maximum dose to the brachial plexus in RIBP, CRT control, and IMRT control patients had median values of 56.0 Gy (range, 49.7-65.1), 54.8 Gy (47.4-60.5), and 54.8 Gy (54.2-57.3), respectively.

Conclusions: RIBP remains a rare complication of comprehensive adjuvant breast radiation and no clear dosimetric predictors for RIBP were identified in this study. The IMRT technique does not appear to adversely affect the development of this late toxicity.
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http://dx.doi.org/10.1016/j.adro.2020.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897772PMC
October 2020

Concurrent paclitaxel and radiation therapy for the treatment of cutaneous angiosarcoma.

Clin Transl Radiat Oncol 2021 Mar 28;27:114-120. Epub 2021 Jan 28.

Department of Radiation Oncology, Washington University School of Medicine, 4921 Parkview Place, St. Louis, MO 63110, United States.

Introduction: We compared clinical outcomes in patients with cutaneous angiosarcoma receiving concurrent paclitaxel-based chemoradiotherapy (CRT) vs. other modalities (Non-CRT).

Materials And Methods: Patients with non-metastatic cutaneous angiosarcoma diagnosed from 1998 to 2018 at two institutions were identified. In the CRT cohort, paclitaxel 80 mg/m weekly was given for up to 12 weeks and patients received radiotherapy (RT) during the final 6 weeks of chemotherapy. The RT dose was 50-50.4 Gy delivered in 1.8-2 Gy per fraction with an optional post-operative boost of 10-16 Gy. Kaplan-Meier and log-rank statistics were used to compare the outcomes between the two groups.  < 0.05 was considered statistically significant.

Results: Fifty-seven patients were included: 22 CRT and 35 Non-CRT. The CRT cohort had more patients > 60 years (100% vs. 60%, p < 0.001) and tumors >5 cm (68.2% vs 54.3%,  = 0.023). The median follow-up was 25.8 (1.5-155.2) months. There was no significant difference in 2-year local control (LC), distant control (DC), or progression-free survival (PFS) between the two groups. The 2-year overall survival (OS) was significantly higher for the CRT cohort (94.1% vs. 71.6%,  = 0.033). Amongst the subset of patients in the CRT cohort who received trimodality therapy, the 2-year LC, DC, PFS, and OS was 68.6%, 100%, 68.6%, and 100%, respectively.

Conclusion: The use of concurrent paclitaxel CRT demonstrates promising outcomes. Given these results, we are currently evaluating the safety and efficacy of this regimen in prospective, phase 2 trial (NCT03921008).
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http://dx.doi.org/10.1016/j.ctro.2021.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876514PMC
March 2021

The Novel Use of a Commercially Available Video-Conference Platform to Facilitate Multidisciplinary Target Volume Review and Delineation for Skull-Base Radiation Therapy During the Coronavirus Disease 2019 Pandemic.

Adv Radiat Oncol 2021 Mar-Apr;6(2):100598. Epub 2020 Oct 24.

Department of Radiation Oncology, Washington University School of Medicine, St Louis, Missouri.

Multidisciplinary involvement in radiation therapy (RT) treatment planning is currently underused. A radiation oncologist sought input for generating target contours from a neuro-radiologist (NR) and otolaryngologist (OL) for 3 patients requiring skull-base RT during the coronavirus disease 2019 pandemic. A Health Insurance Portability and Accountability Act compliant virtual meeting between the radiation oncologist, NR, and OL was arranged. Involvement of the OL and NR led to significant changes in the clinical target volume for all patients. Our experience highlights the feasibility of using commercially available video-conference platforms for multidisciplinary target volume delineation for complex RT cases. Further applications include interdisciplinary contour review for RT cases requiring special expertise and joint attending/resident physician contour review for resident education. The video-conference platform technology has demonstrated benefit during the coronavirus disease 2019 pandemic, and we believe it will remain an integral component of our field moving forward.
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http://dx.doi.org/10.1016/j.adro.2020.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833513PMC
October 2020

The HIV - 1 protease inhibitor Amprenavir targets Leishmania donovani topoisomerase I and induces oxidative stress-mediated programmed cell death.

Parasitol Int 2021 Jun 27;82:102287. Epub 2021 Jan 27.

Division of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, India.

The global prevalence of HIV is a major challenge for the control of visceral leishmaniasis. Although the effectiveness and usefulness of amprenavir (APV) are well studied in anti-retroviral regimens, very little is known on HIV/VL-co-infected patients. In the present study, we report for the first time the protective efficacy of APV against visceral leishmaniasis by inhibition of DNA Topoisomerase I (LdTOP1LS) and APV-induced downstream pathway in programmed cell death (PCD). During the early phase of activation, reactive oxygen species (ROS) is increased inside the cells, which causes subsequent elevation of lipid peroxidation. Endogenous ROS formation and lipid peroxidation cause eventual depolarization of mitochondrial membrane potential (ΔΨ). Furthermore, the release of cytochrome c and activation of CED3/CPP32 group of proteases lead to the formation of oxidative DNA lesions followed by DNA fragmentation. The promising in vitro and ex vivo results promoted to substantiate further by in vivo animal experiment, which showed a significant reduction of splenic and hepatic parasites burden compared to infected controls. Interestingly, APV selectively targets LdTOPILS and does not inhibit the catalytic activity of human topoisomerase I (hTopI). Moreover, based on the cytotoxicity test APV is not toxic for host macrophage cells, which is correlated with non-responsiveness of inhibition of catalytic activity of hTopI. Taken together, this study provides the opportunity for discovering and evaluating newer potential molecular therapeutic targets for drug designing. The present study might be exploited in future as important therapeutics, which will be useful for treatment of VL as well as HIV-VL co-infection.
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http://dx.doi.org/10.1016/j.parint.2021.102287DOI Listing
June 2021

Clinical Benefit-Risk Assessment of Nivolumab 240 mg Every 2 Weeks in Chinese Patients With Advanced and Metastatic Solid Tumors.

J Clin Pharmacol 2021 Jan 27. Epub 2021 Jan 27.

Bristol Myers Squibb, Lawrenceville, New Jersey, USA.

Nivolumab 240 mg every 2 weeks is approved in China by the National Medical Product Agency for squamous cell carcinoma of the head and neck and gastric cancer, based on population pharmacokinetic (PPK) analyses and benefit-risk assessment of safety/efficacy in solid tumors, including Chinese and global populations. The aim of this assessment was to investigate exposure and risk for adverse events (AEs) with flat dosing compared with weight-based dosing. Nivolumab 240-mg and 3-mg/kg every-2-week exposures in Chinese patients were simulated using PPK modeling, and AEs in Chinese and pooled global populations were compared by dosing regimen, exposure, and weight. The 10-mg/kg every-2-week regimen was included because it is known to be well tolerated. Predicted nivolumab exposure in Chinese patients receiving 240 mg every 2 weeks was ∼25% higher versus 3 mg/kg every 2 weeks, but ∼60% lower versus 10 mg/kg every 2 weeks. Grade 3/4 AE incidence in Chinese patients receiving nivolumab 3 mg/kg every 2 weeks was similar with 240-mg every-2-week dosing and with patients from global populations treated with 3 or 10 mg/kg every 2 weeks. There was no trend toward increased AE incidence with high versus low nivolumab exposure or in global patients of varying body weight receiving 3 or 10 mg/kg every 2 weeks. Objective response rates were similar in Chinese and global patients with squamous and nonsquamous NSCLC. Results showed that benefit-risk profiles with nivolumab 240 mg every 2 weeks were similar to those of the 3-mg/kg every-2-week regimen in Chinese patients and global populations, providing an alternative treatment option to Chinese patients.
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http://dx.doi.org/10.1002/jcph.1821DOI Listing
January 2021

Enhanced metabolism and target gene overexpression confer resistance against acetolactate synthase-inhibiting herbicides in Bromus sterilis.

Pest Manag Sci 2021 Apr 1;77(4):2122-2128. Epub 2021 Jan 1.

Department of Agroecology and Crop Production, Faculty of Agrobiology, Food and Natural Resources, Czech University of Life Sciences Prague, Prague, Czech Republic.

Background: Intensive application of acetolactate synthase (ALS)-inhibiting herbicides has resulted in herbicide-resistance in many weeds, including Bromus sterilis. The present study was conducted to identify the mechanisms conferring resistance to ALS-inhibiting herbicides in a Bromus sterilis biotype.

Results: Dose-response studies revealed the resistant biotype to be 288 times less sensitive to pyroxsulam than the susceptible biotype. Furthermore, experiment with a single-dose, proved this biotype was also cross-resistant to propoxycarbazone, iodosulfuron plus mesosulfuron and sulfosulfuron. Prior treatment with malathion, a known inhibitor of cytochrome P450s, reduced the level of resistance to pyroxsulam. No mutations were detected from the partial ALS gene sequencing. Flow cytometry and chromosome counting rejected ploidy level variation between the susceptible and resistant biotypes. Relative copy number variation ruled out gene amplification. Quantitative real-time polymerase chain reaction (PCR) detected a significant difference in ALS gene expression between the susceptible and resistant biotypes.

Conclusions: Target gene overexpression and enhanced metabolism by cytochrome P450s are likely mechanisms of resistance to pyroxsulam in Bromus sterilis. The current findings highlight the need to monitor additional brome populations for herbicide resistance in Europe and endorse the need for alternate herbicides in integrated weed management to delay the possible evolution of herbicide resistance in these species. © 2020 Society of Chemical Industry.
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http://dx.doi.org/10.1002/ps.6241DOI Listing
April 2021

Model-Based Selection and Recommendation for Subcutaneous Abatacept Dose in Patients With Polyarticular Juvenile Idiopathic Arthritis.

J Clin Pharmacol 2021 May 18;61(5):688-699. Epub 2021 Jan 18.

Bristol Myers Squibb, Princeton, New Jersey, USA.

The selective T-cell costimulation modulator abatacept is approved for treatment of adult rheumatoid arthritis (RA) and polyarticular juvenile idiopathic arthritis (pJIA; 6-17 years [intravenous] and 2-17 years [subcutaneous]). An extrapolation approach was taken to determine subcutaneous weight-tiered doses of abatacept to evaluate in patients with pJIA. Population pharmacokinetic (PPK) and exposure-response (E-R) analyses were conducted to determine whether the weight-tiered subcutaneous regimen provides near-maximal efficacy and is therapeutically comparable to the intravenous regimen in patients with pJIA aged 2-17 years. Combined study data from intravenous or subcutaneous abatacept were used to assess clinically relevant exposure outcomes. The PPK model was developed with data from 13 phase 2/3 studies in RA and pJIA; the E-R model for the American College of Rheumatology pediatric scores (JIA-ACR 30/50/70/100 responses) in month 4 was developed with data from 2 phase 3 pJIA studies. Predefined covariates were investigated in both analyses. PPK model-predicted exposures were steady-state peak, trough (C ), and time-averaged concentrations. Abatacept PK was characterized by a linear 2-compartment model (zero-order intravenous infusion, first-order subcutaneous absorption, first-order elimination); body weight was the only clinically relevant covariate. C was the best exposure predictor for the JIA-ACR response: log odds for response increased in proportion to log-transformed C ; JIA-ACR30 approached a plateau when C ≥ 10 μg/mL. The PPK and E-R analyses demonstrated that the weight-tiered subcutaneous and intravenous abatacept dosing regimens provide near-maximal efficacy and are clinically comparable across children with pJIA who are > 2 years old.
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http://dx.doi.org/10.1002/jcph.1797DOI Listing
May 2021

Interface-Driven Multifunctionality in Two-Dimensional TiO Nanosheet/Poly(Dimercaptothiadiazole-Triazine) Hybrid Resistive Random Access Memory Device.

ACS Appl Mater Interfaces 2020 Dec 7;12(50):56568-56578. Epub 2020 Dec 7.

Department of Physics, School of Applied Sciences, REVA University, Bengaluru 560064, India.

Interface-driven multifunctional facets are gearing up in the field of science and technology. Here, we present the interface-activated resistive switching (RS), negative differential resistance, diode behavior, and ultraviolet (UV) light sensing in nanosheet-based hybrid devices. A hybrid device i.e., titanium dioxide nanosheet (TiO-NS)/poly(dimercaptothiadiazole-triazine)[Poly(DMcT-CC)] is fabricated by spin coating Poly(DMcT-CC) polymer on hydrothermally as-grown TiO-NS. The pristine devices of both materials show either small or no magnitude of RS, but the hybrid device shows highly enhanced RS of nearly four orders due to the formation of a p-n junction at the NS/polymer interface. The resistive random access memory feature appears to be more prominent in the hybrid device i.e., high and low current states are found to be stable in repetitive cycles since the interface acts as a trapping center for the carriers. The UV sensing ability of the hybrid device has been demonstrated by a threefold increment in a current at 60 mV. The impedance spectroscopy has been employed to show that the multifunctional features are directly associated to the NS/polymer interface, which deduce that the manipulation of such interfaces can pave the way for developing the hybrid structures.
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http://dx.doi.org/10.1021/acsami.0c16451DOI Listing
December 2020

Unravelling the gut bacteriome of Ips (Coleoptera: Curculionidae: Scolytinae): identifying core bacterial assemblage and their ecological relevance.

Sci Rep 2020 10 29;10(1):18572. Epub 2020 Oct 29.

Excellent Team for Mitigation (ETM), Faculty of Forestry and Wood Sciences, Czech University of Life Sciences Prague, Kamýcká 129, Suchdol, 165 21, Prague 6, Czech Republic.

Bark beetles often serve as forest damaging agents, causing landscape-level mortality. Understanding the biology and ecology of beetles are important for both, gathering knowledge about important forest insects and forest protection. Knowledge about the bark beetle gut-associated bacteria is one of the crucial yet surprisingly neglected areas of research with European tree-killing bark beetles. Hence, in this study, we survey the gut bacteriome from five Ips and one non-Ips bark beetles from Scolytinae. Results reveal 69 core bacterial genera among five Ips beetles that may perform conserved functions within the bark beetle holobiont. The most abundant bacterial genera from different bark beetle gut include Erwinia, Sodalis, Serratia, Tyzzerella, Raoultella, Rahnella, Wolbachia, Spiroplasma, Vibrio, and Pseudoxanthomonas. Notable differences in gut-associated bacterial community richness and diversity among the beetle species are observed. Furthermore, the impact of sampling location on the overall bark beetle gut bacterial community assemblage is also documented, which warrants further investigations. Nevertheless, our data expanded the current knowledge about core gut bacterial communities in Ips bark beetles and their putative function such as cellulose degradation, nitrogen fixation, detoxification of defensive plant compounds, and inhibition of pathogens, which could serve as a basis for further metatranscriptomics and metaproteomics investigations.
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http://dx.doi.org/10.1038/s41598-020-75203-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596566PMC
October 2020

Core Mycobiome and Their Ecological Relevance in the Gut of Five Bark Beetles (Coleoptera: Curculionidae: Scolytinae).

Front Microbiol 2020 3;11:568853. Epub 2020 Sep 3.

Excellent Team for Mitigation, Faculty of Forestry and Wood Sciences, Czech University of Life Sciences, Prague, Czechia.

Bark beetles are destructive forest pests considering their remarkable contribution to forest depletion. Their association with fungi is useful against the challenges of survival on the noxious and nutritionally limited substrate, i.e., conifer tissues. Fungal symbionts help the beetles in nutrient acquisition and detoxification of toxic tree secondary metabolites. Although gut is the prime location for food digestion and detoxification, limited information is available on gut-mycobiome of bark beetles. The present study screened the gut-mycobiont from six bark beetles (five and one non-) from Scolytinae subfamily using high-throughput sequencing and explored their putative role in symbiosis with the host insect. Results revealed the predominance of four fungal classes- Sordariomycetes, Saccharomycetes, Eurothiomycetes, and Dothidomycetes in all bark beetles. Apart from these, Agaricomycetes, Leothiomycetes, Incertae sedis Basidiomycota, Tremellomycetes, Lecanoromycetes, and Microbotryomycetes were also documented in different beetles. Five bark beetles share a consortium of core fungal communities in their gut tissues consisting of 47 operational taxonomic units (OTUs) belonging to 19 fungal genera. The majority of these core fungal genera belong to the phylum Ascomycota. LEfSe analysis revealed a set of species-specific fungal biomarkers in bark beetles. The present study identified the gut mycobiont assemblage in bark beetles and their putative ecological relevance. An enriched understanding of bark beetle-fungal symbiosis is not only filling the existing knowledge gap in the field but may also unleash an unforeseen potential for future bark beetle management.
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http://dx.doi.org/10.3389/fmicb.2020.568853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496905PMC
September 2020

Oculomotor inhibition precedes temporally expected auditory targets.

Nat Commun 2020 07 14;11(1):3524. Epub 2020 Jul 14.

School of Psychological Sciences, Tel-Aviv University, Ramat Aviv, 6997801, Tel Aviv-Yafo, Israel.

Eye movements are inhibited prior to the onset of temporally-predictable visual targets. This oculomotor inhibition effect could be considered a marker for the formation of temporal expectations and the allocation of temporal attention in the visual domain. Here we show that eye movements are also inhibited before predictable auditory targets. In two experiments, we manipulate the period between a cue and an auditory target to be either predictable or unpredictable. The findings show that although there is no perceptual gain from avoiding gaze-shifts in this procedure, saccades and blinks are inhibited prior to predictable relative to unpredictable auditory targets. These findings show that oculomotor inhibition occurs prior to auditory targets. This link between auditory expectation and oculomotor behavior reveals a multimodal perception action coupling, which has a central role in temporal expectations.
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http://dx.doi.org/10.1038/s41467-020-17158-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360783PMC
July 2020

Model-Based Determination of Elotuzumab Pharmacokinetics in Japanese Patients With Multiple Myeloma Incorporating Time-Varying M Protein.

J Clin Pharmacol 2021 Jan 12;61(1):64-73. Epub 2020 Jul 12.

Bristol-Myers Squibb, Tokyo, Japan.

A population pharmacokinetic model was developed to evaluate the effects of Japanese ethnicity, prior line of therapy (0 or ≥1), time-varying M protein, and maintenance dosing regimens (10 mg/kg intravenously every 2 weeks or 20 mg/kg intravenously every 4 weeks beginning in cycle 19) on the pharmacokinetics of elotuzumab in patients with multiple myeloma treated with elotuzumab plus lenalidomide/dexamethasone. Elotuzumab pharmacokinetics were characterized by a 2-compartment model with parallel linear (nonspecific) and Michaelis-Menten elimination from the central compartment and target-mediated elimination from the peripheral compartment. Asian race on nonspecific clearance (CL) and central volume of distribution, prior line of therapy on CL, and maximum target-mediated elimination rate (V ) were statistically significant but not considered clinically relevant (magnitude < 20%). Time-varying M protein on V was statistically significant, and the magnitude was >20%; however, clinical implications in the setting of combination therapy were not expected. Model-predicted steady-state elotuzumab exposure in cycle 12 were similar in Japanese and non-Japanese patients and in Japanese patients with 0 and ≥1 prior lines of therapy. Elotuzumab 20 mg/kg intravenously every 4 weeks beginning in cycle 19 produced time-averaged concentrations similar to elotuzumab 10 mg/kg intravenously every 2 weeks, although maximum and minimum concentrations after elotuzumab 20 mg/kg intravenous every-4-week dosing were slightly higher and lower, respectively. In conclusion, the current analysis demonstrates that Japanese ethnicity, prior line of therapy, time-varying M protein, and change in elotuzumab dosing regimen in cycle 19 have no clinically meaningful impact on elotuzumab pharmacokinetics and exposure in Japanese patients with multiple myeloma.
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http://dx.doi.org/10.1002/jcph.1698DOI Listing
January 2021

Identification of Non-Small Cell Lung Cancer Sensitive to Systemic Cancer Therapies Using Radiomics.

Clin Cancer Res 2020 05 20;26(9):2151-2162. Epub 2020 Mar 20.

Department of Radiology, Columbia University Medical Center/New York Presbyterian Hospital, New York, New York.

Purpose: Using standard-of-care CT images obtained from patients with a diagnosis of non-small cell lung cancer (NSCLC), we defined radiomics signatures predicting the sensitivity of tumors to nivolumab, docetaxel, and gefitinib.

Experimental Design: Data were collected prospectively and analyzed retrospectively across multicenter clinical trials [nivolumab, = 92, CheckMate017 (NCT01642004), CheckMate063 (NCT01721759); docetaxel, = 50, CheckMate017; gefitinib, = 46, (NCT00588445)]. Patients were randomized to training or validation cohorts using either a 4:1 ratio (nivolumab: 72T:20V) or a 2:1 ratio (docetaxel: 32T:18V; gefitinib: 31T:15V) to ensure an adequate sample size in the validation set. Radiomics signatures were derived from quantitative analysis of early tumor changes from baseline to first on-treatment assessment. For each patient, 1,160 radiomics features were extracted from the largest measurable lung lesion. Tumors were classified as treatment sensitive or insensitive; reference standard was median progression-free survival (NCT01642004, NCT01721759) or surgery (NCT00588445). Machine learning was implemented to select up to four features to develop a radiomics signature in the training datasets and applied to each patient in the validation datasets to classify treatment sensitivity.

Results: The radiomics signatures predicted treatment sensitivity in the validation dataset of each study group with AUC (95 confidence interval): nivolumab, 0.77 (0.55-1.00); docetaxel, 0.67 (0.37-0.96); and gefitinib, 0.82 (0.53-0.97). Using serial radiographic measurements, the magnitude of exponential increase in signature features deciphering tumor volume, invasion of tumor boundaries, or tumor spatial heterogeneity was associated with shorter overall survival.

Conclusions: Radiomics signatures predicted tumor sensitivity to treatment in patients with NSCLC, offering an approach that could enhance clinical decision-making to continue systemic therapies and forecast overall survival.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2942DOI Listing
May 2020

Selenium Nanoparticle Protection of Fibroblast Stress: Activation of ATF4 and Bcl-xL Expression.

Int J Nanomedicine 2019 20;14:9995-10007. Epub 2019 Dec 20.

Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA.

Background: In recent years, selenium nanostructures have been researched due to their antibacterial properties, low toxicity to mammalian cells, and high biological efficacy. However, the clinical implementation of the use of selenium has received mixed results, and there is much work needed to improve the understanding of the biological mechanisms involved in the observed cellular responses.

Materials And Methods: In this work, an investigation into the mechanistic pathways of selenium nanoparticles (SeNPs) in biological systems was conducted by studying the changes in gene expression of ATF4, Bcl-xL, BAD2, HSP70, and SOD2 in non-cancerous human dermal fibroblasts (HDF) under oxidative stress, nutrient deprivation stress, and no treatment (control) conditions.

Results: This study revealed that SeNP incubation led to reduced internal reactive oxygen species (ROS) generation for all conditions tested, thus, providing a protective environment for HDF. At the stress conditions, the expression of ATF4 and Bcl-xL increased for cells treated with SeNP incubation, leading to attenuation of the cells under stress. These results also hint at reductive stress causing a detrimental impact to cell proliferation under routine cell passaging conditions.

Conclusion: In summary, this study highlights some possible mechanistic pathways implicated in the action of SeNPs that warrant further investigation (specifically, reducing stress conditions for HDF) and continues to support the promise of SeNPs in a wide range of medical applications.
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http://dx.doi.org/10.2147/IJN.S172236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930226PMC
April 2020

Development of a prognostic composite cytokine signature based on the correlation with nivolumab clearance: translational PK/PD analysis in patients with renal cell carcinoma.

J Immunother Cancer 2019 12 11;7(1):348. Epub 2019 Dec 11.

Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ, 08543, USA.

Background: Although several therapeutic options for patients with renal cell carcinoma (RCC) have been approved over recent years, including immune checkpoint inhibitors, considerable need remains for molecular biomarkers to assess disease prognosis. The higher pharmacokinetic (PK) clearance of checkpoint inhibitors, such as the anti-programmed death-1 (PD-1) therapies nivolumab and pembrolizumab, has been shown to be associated with poor overall survival (OS) across several tumor types. However, determination of PK clearance requires the collection and analysis of post-treatment serum samples, limiting its utility as a prognostic biomarker. This report outlines a translational PK-pharmacodynamic (PD) methodology used to derive a baseline composite cytokine signature correlated with nivolumab clearance using data from three clinical trials in which nivolumab or everolimus was administered.

Methods: Peripheral serum cytokine (PD) and nivolumab clearance (PK) data from patients with RCC were analyzed using a PK-PD machine-learning model. Nivolumab studies CheckMate 009 (NCT01358721) and CheckMate 025 (NCT01668784) (n = 480) were used for PK-PD analysis model development and cytokine feature selection (training dataset). Validation of the model and assessment of the prognostic value of the cytokine signature was performed using data from CheckMate 010 (NCT01354431) and the everolimus comparator arm of CheckMate 025 (test dataset; n = 453).

Results: The PK-PD analysis found a robust association between the eight top-ranking model-selected baseline inflammatory cytokines and nivolumab clearance (area under the receiver operating characteristic curve = 0.7). The predicted clearance (high vs low) based on the cytokine signature was significantly associated with long-term OS (p < 0.01) across all three studies (training and test datasets). Furthermore, cytokines selected from the model development trials also correlated with OS of the everolimus comparator arm (p < 0.01), suggesting the prognostic nature of the composite cytokine signature for RCC.

Conclusions: Here, we report a PK-PD translational approach to identify a molecular prognostic biomarker signature based on the correlation with nivolumab clearance in patients with RCC. This composite biomarker signature may provide improved prognostic accuracy of long-term clinical outcome compared with individual cytokine features and could be used to ensure the balance of patient randomization in RCC clinical trials.
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http://dx.doi.org/10.1186/s40425-019-0819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907258PMC
December 2019

Benefit-risk assessment of nivolumab 240 mg flat dose relative to 3 mg/kg Q2W regimen in Japanese patients with advanced cancers.

Cancer Sci 2020 Feb 21;111(2):528-535. Epub 2020 Jan 21.

Bristol-Myers Squibb K.K, Tokyo, Japan.

Nivolumab 3 mg/kg every 2 weeks (Q2W) has been approved in Japan for various cancers; however, use of a flat dose is expected to simplify dosing and administration. A quantitative clinical pharmacology approach was used to assess the benefit-risk profile of nivolumab 240 mg Q2W relative to the approved dose of nivolumab 3 mg/kg Q2W in Japanese patients. Three exposure-response safety analyses were performed for adverse events that led to discontinuation/death, were grade 3 or higher, and were immune-mediated and grade 2 or higher for Japanese patients diagnosed with one of multiple tumor types. Exposure-response analyses of efficacy were evaluated for overall survival and objective response rate. Exposures of nivolumab 240 mg Q2W were 37% higher than those of nivolumab 3 mg/kg Q2W in Japanese patients across the tumor types analyzed. Predicted safety profiles at the two doses differed by less than 2% across tumor types for adverse events leading to discontinuation/death, adverse events of grade 3 or higher, or immune-mediated adverse events of grade 2 or higher. In addition, the predicted 1-year and 2-year overall survival rates, the mean overall survival and the objective response rates were comparable between the doses regardless of the tumor type analyzed. Overall, these results demonstrated that the benefit-risk of nivolumab 240 mg Q2W was comparable to that of the previously approved 3 mg/kg Q2W dosing regimen, and was the basis for the approval of the 240 mg Q2W as an alternative dosing regimen for treatment in Japanese patients across multiple tumor types.
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http://dx.doi.org/10.1111/cas.14252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004547PMC
February 2020

A Machine-Learning Approach to Identify a Prognostic Cytokine Signature That Is Associated With Nivolumab Clearance in Patients With Advanced Melanoma.

Clin Pharmacol Ther 2020 04 19;107(4):978-987. Epub 2019 Dec 19.

Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Lawrenceville, New Jersey, USA.

Lower clearance of immune checkpoint inhibitors is a predictor of improved overall survival (OS) in patients with advanced cancer. We investigated a novel approach using machine learning to identify a baseline composite cytokine signature via clearance, which, in turn, could be associated with OS in advanced melanoma. Peripheral nivolumab clearance and cytokine data from patients treated with nivolumab in two phase III studies (n = 468 (pooled)) and another phase III study (n = 158) were used for machine-learning model development and validation, respectively. Random forest (Boruta) algorithm was used for feature selection and classification of nivolumab clearance. The 16 top-ranking baseline inflammatory cytokines reflecting immune-cell modulation were selected as a composite signature to predict nivolumab clearance (area under the curve (AUC) = 0.75; accuracy = 0.7). Predicted clearance (high vs. low) via the cytokine signature was significantly associated with OS across all three studies (P < 0.01), regardless of treatment (nivolumab vs. chemotherapy).
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http://dx.doi.org/10.1002/cpt.1724DOI Listing
April 2020

Population Pharmacokinetics of Nivolumab in Combination With Ipilimumab in Patients With Advanced Malignancies.

CPT Pharmacometrics Syst Pharmacol 2019 12 1;8(12):962-970. Epub 2019 Dec 1.

Bristol-Myers Squibb, Princeton, New Jersey, USA.

Nivolumab is a fully human monoclonal antibody that inhibits programmed cell death-1 activation. To assess covariate effects on nivolumab clearance (CL), a population pharmacokinetics model was developed using data from 6,468 patients with colorectal cancer, hepatocellular carcinoma, melanoma, non-small cell lung cancer, renal cell carcinoma, or small cell lung cancer who received nivolumab as monotherapy or in combination with ipilimumab or chemotherapy across 25 clinical studies. Nivolumab CL was similar across the tumor types examined; CL was higher for ipilimumab 1 mg/kg every 6 weeks (by 17%) and 3 mg/kg every 3 weeks (by 29%) vs. nivolumab monotherapy. Nivolumab CL over time was partially explained by time-varying covariates. A greater decrease in nivolumab time-varying CL was associated with increased albumin and body weight and a responder status. Our findings support the observed association between nivolumab CL and disease severity.
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http://dx.doi.org/10.1002/psp4.12476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930858PMC
December 2019

Population Pharmacokinetics of Ipilimumab in Combination With Nivolumab in Patients With Advanced Solid Tumors.

CPT Pharmacometrics Syst Pharmacol 2020 01 1;9(1):29-39. Epub 2019 Dec 1.

Bristol-Myers Squibb, Princeton, New Jersey, USA.

Ipilimumab is a fully human monoclonal antibody approved for the treatment of melanoma as monotherapy and for the treatment of melanoma, renal cell carcinoma, and colorectal cancer in combination with nivolumab. Ipilimumab time-varying clearance (CL) was assessed by a population pharmacokinetics (PPK) model developed using statistically significant covariates identified in a previous PPK analysis plus additional covariates. Data from 3,411 patients who received ipilimumab 0.3-10 mg/kg alone or in combination with nivolumab in 16 clinical trials were analyzed. Ipilimumab CL decreased over time; the change in CL was greater in patients treated with nivolumab combination than ipilimumab alone and in responders vs. nonresponders. Time-varying covariates including body weight, lactate dehydrogenase, albumin, and performance status were evaluated on change in ipilimumab CL. In addition, ipilimumab CL was similar across different tumor types, nivolumab dosing regimens, and lines of therapy. These data suggest an association of ipilimumab CL with disease severity.
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http://dx.doi.org/10.1002/psp4.12477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966186PMC
January 2020

Is PFNA-II a better implant for stable intertrochanteric fractures in elderly population ? A prospective randomized study.

J Clin Orthop Trauma 2019 Oct 7;10(Suppl 1):S71-S76. Epub 2019 Feb 7.

Department of Orthopedics, All India Institute of Medical Sciences, New Delhi, India.

Introduction: Intertrochanteric fracture is one of the most common and severe fractures occurring in the elderly population. We conducted a randomized prospective study to compare the functional and radiological outcome of Proximal Femoral Nail anti-rotation-Asia(PFNA-II) and Dynamic Hip screw (DHS) used in fixation of stable (AO type 31 A1-A2.1) intertrochanteric fractures in elderly.

Methods: 60 elderly patients with stable intertrochanteric fractures treated with DHS and PFNA-II between August 2014 to Dec 2016 were enrolled in the study. Intraoperative variables-surgical time, blood loss, fluoroscopy time and post-operative variables-union rate, change in neck shaft angle(NSA), functional outcome in terms of Modified Harris Hip Score(HHS) & SF-12, complication rate and mortality at one year were studied and compared between both the groups.

Results: The mean age of patients in our study was 70.96 years. We found patients treated with DHS required significantly longer surgical time and had more blood loss compared to PFNA-II group. However, there was no significant difference in both the groups in terms of intra-operative fluoroscopy time, change in neck shaft angle, union rate, complication rate and Modified Harris Hip Score & SF-12 at three months; six months and one year follow-up.

Conclusions: Both DHS and PFNA-II can be used effectively in the treatment of elderly patients with stable intertrochanteric fracture with comparable outcome. However, in high-risk elderly patients requiring shorter surgical time and less blood loss, PFNA-II can be used.
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http://dx.doi.org/10.1016/j.jcot.2019.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823828PMC
October 2019

Linking Tumor Growth Dynamics to Survival in Ipilimumab-Treated Patients With Advanced Melanoma Using Mixture Tumor Growth Dynamic Modeling.

CPT Pharmacometrics Syst Pharmacol 2019 11 13;8(11):825-834. Epub 2019 Aug 13.

Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Princeton, New Jersey, USA.

Early tumor assessments have been widely used to predict overall survival (OS), with potential application to dose selection and early go/no-go decisions. Most published tumor dynamic models assume a uniform pattern of tumor growth dynamics (TGDs). We developed a mixture TGD model to characterize different patterns of longitudinal tumor sizes. Data from 688 patients with advanced melanoma who received ipilimumab 3 or 10 mg/kg every 3 weeks in a phase III study (NCT01515189) were used in a TGD-OS analysis. The mixture model described TGD profiles using three subpopulations (no-growth, intermediate, and fast). The TGD model showed a positive exposure/dose-response (i.e., a higher proportion of patients in no/intermediate growth subpopulations and a lower tumor growth rate with ipilimumab 10 mg/kg relative to the 3 mg/kg dose). Finally, the mixture TGD model-based measures of tumor response provided better predictions of OS compared with the nonmixture model.
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http://dx.doi.org/10.1002/psp4.12454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875707PMC
November 2019

Structural insights of a cellobiose dehydrogenase enzyme from the basidiomycetes fungus Termitomyces clypeatus.

Comput Biol Chem 2019 Oct 30;82:65-73. Epub 2019 May 30.

Department of Biotechnology, Visva-Bharati University, Santiniketan, 731235, West Bengal, India. Electronic address:

Filamentous fungi secrete various oxidative enzymes to degrade the glycosidic bonds of polysaccharides. Cellobiose dehydrogenase (CDH) (E.C.1.1.99.18) is one of the important lignocellulose degrading enzymes produced by various filamentous fungi. It contains two stereo specific ligand binding domains, cytochrome and dehydrogenase - one for heme and the other for flavin adenine dinucleotide (FAD) respectively. The enzyme is of commercial importance for its use in amperometric biosensor, biofuel production, lactose determination in food, bioremediation etc. Termitomyces clypeatus, an edible fungus belonging to the basidiomycetes group, is a good producer of CDH. In this paper we have analyzed the structural properties of this enzyme from T. clypeatus and identified a distinct carbohydrate binding module (CBM) which is not present in most fungi belonging to the basidiomycetes group. In addition, the dehydrogenase domain of T. clypeatus CDH exhibited the absence of cellulose binding residues which is in contrast to the dehydrogenase domains of CDH of other basidiomycetes. Sequence analysis of cytochrome domain showed that the important residues of this domain were conserved like in other fungal CDHs. Phylogenetic tree, constructed using basidiomycetes and ascomycetes CDH sequences, has shown that very surprisingly the CDH from T. clypeatus, which is classified as a basidiomycetes fungus, is clustered with the ascomycetes group. A homology model of this protein has been constructed using the CDH enzyme of ascomycetes fungus Myricoccum thermophilum as a template since it has been found to be the best match sequence with T. clypeatus CDH. We also have modelled the protein with its substrate, cellobiose, which has helped us to identify the substrate interacting residues (L354, P606, T629, R631, Y649, N732, H733 and N781) localized within its dehydrogenase domain. Our computational investigation revealed for the first time the presence of all three domains - cytochrome, dehydrogenase and CBM - in the CDH of T. clypeatus, a basidiomycetes fungus. In addition to discovering the unique structural attributes of this enzyme from T. clypeatus, our study also discusses the possible phylogenetic status of this fungus.
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http://dx.doi.org/10.1016/j.compbiolchem.2019.05.013DOI Listing
October 2019

Evaluation of covariate effects on pharmacokinetics of monoclonal antibodies in oncology.

Br J Clin Pharmacol 2019 09 17;85(9):2045-2058. Epub 2019 Jul 17.

Bristol-Myers Squibb, Princeton, NJ, USA.

Aims: The development of monoclonal antibodies (mAbs) requires an understanding of the interindividual variability (IIV) in pharmacokinetics (PK) at the population level facilitated by population PK (PopPK) modelling. However, there is no clear rationale for selecting which covariates to screen during PopPK model development. Here, we compare the effect of covariates on PK parameters for mAbs in oncology and identify the most commonly used covariates affecting PK parameters.

Methods: All 25 mAbs approved for therapeutic use in oncology until December 2017 by the Food and Drug Administration and the European Medicines Agency were selected for study. Literature searches revealed 23 available PopPK models for these mAbs. To understand the magnitude and types of covariate effect on PK parameters, all covariates included in the final PopPK model for each mAb were summarized.

Results: The most commonly identified covariates were baseline body weight (BW; 17 mAbs), baseline serum albumin (8 mAbs), and sex (7 mAbs) on clearance; and BW (16 mAbs) and sex (12 mAbs) on central volume of distribution. A reduced PopPK model was developed for nivolumab and ipilimumab using these covariates, and the percentage of explained IIV from the reduced model (20.3% and 16.8%, respectively) was compared with that from the full model (24.5% and 27.9%, respectively).

Conclusions: This analysis provides a uniform platform for selecting covariates and suggests that the effect of BW, albumin and sex should be included during the development of PopPK models for mAbs in oncology. The reduced model was able to explain IIV to a similar extent as the full model.
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http://dx.doi.org/10.1111/bcp.13996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710515PMC
September 2019

Transcriptome Analysis of Gene Families Involved in Chemosensory Function in Spodoptera littoralis (Lepidoptera: Noctuidae).

BMC Genomics 2019 May 28;20(1):428. Epub 2019 May 28.

Department of Plant Protection Biology, Swedish University of Agricultural Sciences, Sundsvägen 14, 230 53, Alnarp, Sweden.

Background: Deciphering the molecular mechanisms mediating the chemical senses, taste, and smell has been of vital importance for understanding the nature of how insects interact with their chemical environment. Several gene families are implicated in the uptake, recognition, and termination of chemical signaling, including binding proteins, chemosensory receptors and degrading enzymes. The cotton leafworm, Spodoptera littoralis, is a phytophagous pest and current focal species for insect chemical ecology and neuroethology.

Results: We produced male and female Illumina-based transcriptomes from chemosensory and non-chemosensory tissues of S. littoralis, including the antennae, proboscis, brain and body carcass. We have annotated 306 gene transcripts from eight gene families with known chemosensory function, including 114 novel candidate genes. Odorant receptors responsive to floral compounds are expressed in the proboscis and may play a role in guiding proboscis probing behavior. In both males and females, expression of gene transcripts with known chemosensory function, including odorant receptors and pheromone-binding proteins, has been observed in brain tissue, suggesting internal, non-sensory function for these genes.

Conclusions: A well-curated set of annotated gene transcripts with putative chemosensory function is provided. This will serve as a resource for future chemosensory and transcriptomic studies in S. littoralis and closely related species. Collectively, our results expand current understanding of the expression patterns of genes with putative chemosensory function in insect sensory and non-sensory tissues. When coupled with functional data, such as the deorphanization of odorant receptors, the gene expression data can facilitate hypothesis generation, serving as a substrate for future studies.
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http://dx.doi.org/10.1186/s12864-019-5815-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540431PMC
May 2019

Model-Based Population Pharmacokinetic Analysis of Nivolumab in Chinese Patients With Previously Treated Advanced Solid Tumors, Including Non-Small Cell Lung Cancer.

J Clin Pharmacol 2019 10 22;59(10):1415-1424. Epub 2019 May 22.

Bristol-Myers Squibb, Princeton, NJ, USA.

Nivolumab is the first anti-programmed death-1 agent approved in China for treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). Here, we characterize the population pharmacokinetics (PPK) of nivolumab monotherapy in Chinese patients with previously treated advanced/recurrent solid tumors, including NSCLC and nasopharyngeal cancer (NPC), using data from 2 predominantly Chinese (CheckMate 077 and 078), and 5 global (MDX1106-01, CA209-003, and CheckMate 017, 057, and 063) studies. The PPK model was developed by reestimating parameters of a prior global population model with Chinese patient data. Model reestimates showed nivolumab pharmacokinetics (PK) to be linear and dose proportional. Race did not have a clinically meaningful effect on nivolumab clearance. Body weight, Asian race, sex, and performance status had significant effects on clearance. Baseline clearance was 9% lower in the Asian versus the global population but not considered clinically relevant. Change in time-varying clearance and predicted nivolumab exposures with 3 mg/kg every 2 weeks (Q2W) were similar in Chinese, non-Chinese Asian, and non-Asian patients. In Chinese patients, the predicted nivolumab exposure with a 240-mg Q2W regimen was ∼25% higher than with 3 mg/kg Q2W, but ∼62% lower than that of a previously evaluated, well-tolerated regimen of 10 mg/kg Q2W (global population). Differences in nivolumab baseline clearance and exposures between patients with NPC and NSCLC were not clinically meaningful (<20%). Overall, PPK analysis demonstrated that nivolumab was not sensitive to race when evaluated in Chinese and non-Asian patients and exhibited similar PK in NSCLC and NPC.
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http://dx.doi.org/10.1002/jcph.1432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767401PMC
October 2019

Nivolumab Clearance Is Stationary in Patients With Resected Melanoma on Adjuvant Therapy: Implications of Disease Status on Time-Varying Clearance.

Clin Pharmacol Ther 2019 11 10;106(5):1018-1027. Epub 2019 Jul 10.

Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Princeton, New Jersey, USA.

Nivolumab clearance (CL) in patients with advanced melanoma (MEL) decreases over the treatment duration, with change in CL associated with improved disease status, measured by reduced tumor burden. Here, we characterize the pharmacokinetics of nivolumab administered as adjuvant therapy for patients with MEL (AdjMEL) whose tumors were removed by surgical resection. A population pharmacokinetic model was developed using data from 1,773 patients with AdjMEL, MEL, non-small cell lung cancer, and other solid tumors who received nivolumab over a dose range of 0.1-20 mg/kg every 2 weeks. In patients with AdjMEL, the geometric mean nivolumab CL of 6.0 mL/hour was 40% lower at baseline and did not vary with time and 20% lower at steady state compared with patients with MEL. Lower nivolumab CL in patients with AdjMEL and absence of time dependence support the hypothesis that changes in nivolumab CL in the metastatic setting are associated with disease status after treatment.
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http://dx.doi.org/10.1002/cpt.1502DOI Listing
November 2019

A vivid cytokines interaction model on psoriasis with the effect of impulse biologic (TNF-α inhibitor) therapy.

J Theor Biol 2019 08 11;474:63-77. Epub 2019 Apr 11.

Centre for Mathematical Biology and Ecology, Department of Mathematics, Jadavpur University, Kolkata 700032, India. Electronic address:

Psoriasis is a chronic skin condition that produces plaques of condensed, scaling skin due to excessively rapid proliferation of keratinocytes. During the disease progression, keratinocyte proliferation is influenced by many immune cells and cytokines. This article deals with a five dimensional deterministic model, which has been derived using quasi-steady-state approximation for describing the dynamics of psoriasis in various cytokines environment. Equilibrium analysis of the system shows that either the system converges to a stable steady state or exhibits a periodic oscillation depending upon system parameters. Finally, introducing a one dimensional impulsive system, we have determined the perfect dose and perfect dosing interval for biologic (TNF-α inhibitor) therapy to control the hyper-proliferation of keratinocytes. We have studied the effect of TNF-α inhibitor by considering both perfect and imperfect dosing during the inductive phase. The maximum possible number of drug holidays and the minimal number of doses that must subsequently be taken while avoiding drug resistance have been calculated for imperfect dosing. Since, psoriasis is non-curable but treatable disease, so the aim is to investigate the minimum dose with highest efficacy and proper dosing interval of TNF-α inhibitor for a psoriatic patient. Through numerical simulations, we have given a detailed prediction about the maximum drug holidays, tolerable for a patient, without loss of previous drug effects. Our theoretical predictions and numerical outcomes may be useful in guiding the design of future clinical trials.
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http://dx.doi.org/10.1016/j.jtbi.2019.04.007DOI Listing
August 2019

Outcomes and toxicity following Yttrium-90 radioembolization for hepatic metastases from neuroendocrine tumors-a single-institution experience.

J Gastrointest Oncol 2019 Feb;10(1):118-127

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.

Background: The prognosis of patients with hepatic metastases from neuroendocrine tumors (NET) is generally good, and radioembolization with Yttrium-90 microspheres is a locoregional therapy that is used in efforts to improve hepatic disease control and survival. This study aims to describe the survival outcomes and toxicities associated with radioembolization for hepatic-predominant metastatic NET in a large single-institution cohort.

Methods: A total of 59 patients underwent radioembolization for metastatic NET with hepatic predominant disease at a single academic center. Patient outcomes were analyzed by Kaplan-Meier survival analysis and toxicities were detailed and described. Ten patients within the cohort underwent post-treatment dosimetric analysis using PET-MRI and normal liver dosimetry was correlated with hepatic fibrosis and toxicity.

Results: Median overall survival from time of radioembolization in the patient cohort was 31 months, and the 1- and 2-year overall survival was 80.4% and 65.6% respectively. Median hepatic progression-free survival and overall progression-free survival were 18 and 13 months, respectively. Three patients died of hepatic failure that was possibly therapy-related. Ten patients underwent evaluation of post-treatment dosimetry following radioembolization. In patients who did not develop hepatotoxicity or hepatic fibrosis, mean dose to normal liver was 25.4 Gy, while the mean liver dose in patients who experienced toxicity (hepatic fibrosis in n=2 and death from hepatic failure in n=1) was 59.1 Gy.

Conclusions: Overall survival following radioembolization for hepatic metastases from NET is excellent; however, deaths that are potentially treatment-related have been observed. Preliminary data regarding dose to normal liver is suggestive of a relation between dosimetry and toxicity, however further work is required to further elucidate the mechanism, correlation with dosimetry, as well as additional patient and tumor factors that may predispose these patients to toxicity.
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http://dx.doi.org/10.21037/jgo.2018.10.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351300PMC
February 2019

Population pharmacokinetics analysis of nivolumab in Asian and non-Asian patients with gastric and gastro-esophageal junction cancers.

Cancer Chemother Pharmacol 2019 04 21;83(4):705-715. Epub 2019 Jan 21.

Bristol-Myers Squibb, Princeton, NJ, USA.

Purpose: Nivolumab monotherapy provided clinically meaningful antitumor activity in Asian and non-Asian patients with chemotherapy-refractory gastric cancer (GC) or gastro-esophageal junction cancer (GEJC) in the ATTRACTION-2 and CheckMate 032 studies, respectively. This analysis assessed the population pharmacokinetics (PopPK) of nivolumab, the impact of covariates on pharmacokinetics (PK), and the PK of nivolumab flat dosing in GC/GEJC using samples from these studies.

Methods: PopPK analyses were conducted using data from 1302 patients with solid tumors, including 387 patients with GC/GEJC who had received nivolumab 3 mg/kg once every 2 weeks (Q2W). The impact of covariates on nivolumab PK was assessed in the full model. Nivolumab exposures following a flat dose of 240 mg Q2W in patients with GC/GEJC were simulated and compared with those of 3 mg/kg Q2W.

Results: Nivolumab PK was described using a 2-compartment, zero-order intravenous infusion and time-varying clearance (CL) model. Baseline CL in patients with GC/GEJC was ~ 33% greater than in patients with non-small cell lung cancer (NSCLC) in second line or subsequent lines of treatment (2L+). The effect of race was not clinically relevant (< 20% difference). Nivolumab exposures following 240 mg Q2W were similar to 3 mg/kg Q2W in non-Asian patients and 46% higher in Asian patients due to lower body weight.

Conclusions: Nivolumab CL was increased in GC/GEJC relative to NSCLC 2L+. Higher nivolumab exposures achieved with 240 mg Q2W in Asian patients are predicted to be below the acceptable safety margin, supporting the use of a flat dose in both patient populations.
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http://dx.doi.org/10.1007/s00280-019-03771-zDOI Listing
April 2019

Transient and sustained effects of stimulus properties on the generation of microsaccades.

J Vis 2019 01;19(1)

Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.

Saccades shift the gaze rapidly every few hundred milliseconds from one fixated location to the next, producing a flow of visual input into the visual system even in the absence of changes in the environment. During fixation, small saccades called microsaccades are produced 1-3 times per second, generating a flow of visual input. The characteristics of this visual flow are determined by the timings of the saccades and by the characteristics of the visual stimuli on which they are performed. Previous models of microsaccade generation have accounted for the effects of external stimulation on the production of microsaccades, but they have not considered the effects of the prolonged background stimulus on which microsaccades are performed. The effects of this stimulus on the process of microsaccade generation could be sustained, following its prolonged presentation, or transient, through the visual transients produced by the microsaccades themselves. In four experiments, we varied the properties of the constant displays and examined the resulting modulation of microsaccade properties: their sizes, their timings, and the correlations between properties of consecutive microsaccades. Findings show that displays of higher spatial frequency and contrast produce smaller microsaccades and longer minimal intervals between consecutive microsaccades; and smaller microsaccades are followed by smaller and delayed microsaccades. We explain these findings in light of previous models and suggest a conceptual model by which both sustained and transient effects of the stimulus have central roles in determining the generation of microsaccades.
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http://dx.doi.org/10.1167/19.1.6DOI Listing
January 2019