Publications by authors named "Ashish Saxena"

65 Publications

Lung Cancer Stage Shift as a Result of COVID-19 Lockdowns in New York City, a Brief Report.

Clin Lung Cancer 2021 Aug 29. Epub 2021 Aug 29.

Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY. Electronic address:

Introduction: The COVID-19 pandemic reached New York City in early March 2020 resulting in an 11-week lockdown period to mitigate further spread. It has been well documented that cancer care was drastically affected as a result. Given New York City's early involvement, we attempted to identify any stage shift that may have occurred in the diagnoses of non-small cell lung cancer (NSCLC) at our institution as a result of these lockdowns.

Patients And Methods: We conducted a retrospective review of a prospective database of lung cancer patients at our institution from July 1, 2019 until March 31, 2021. Patients were grouped by calendar year quarter in which they received care. Basic demographics and clinical staging were compared across quarters.

Results: Five hundred and fifty four patients were identified that underwent treatment during the time period of interest. During the lockdown period, there was a 50% reduction in the mean number of patients seen (15 ± 3 vs. 28 ± 7, P = .004). In the quarter following easing of restrictions, there was a significant trend towards earlier stage (cStage I/II) disease. In comparison to quarters preceding the pandemic lockdown, there was a significant increase in the proportion of patients with Stage IV disease in the quarters following phased reopening (P = .026).

Conclusion: After a transient but significant increase in Stage I/II disease with easing of restrictions there was a significant increase in patients with Stage IV disease. Extended longitudinal studies must be conducted to determine whether COVID-19 lockdowns will lead to further increases in the proportion of patients with advanced NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2021.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403338PMC
August 2021

Framework for quantitative three-dimensional choroidal vasculature analysis using optical coherence tomography.

Biomed Opt Express 2021 Aug 19;12(8):4982-4996. Epub 2021 Jul 19.

Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

Choroidal vasculature plays an important role in the pathogenesis of retinal diseases, such as myopic maculopathy, age-related macular degeneration, diabetic retinopathy, central serous chorioretinopathy, and ocular inflammatory diseases. Current optical coherence tomography (OCT) technology provides three-dimensional visualization of the choroidal angioarchitecture; however, quantitative measures remain challenging. Here, we propose and validate a framework to segment and quantify the choroidal vasculature from a prototype swept-source OCT (PLEX Elite 9000, Carl Zeiss Meditec, USA) using a 3×3 mm scan protocol centered on the macula. Enface images referenced from the retinal pigment epithelium were reconstructed from the volumetric data. The boundaries of the choroidal volume were automatically identified by tracking the choroidal vessel feature structure over the depth, and a selective sliding window was applied for segmenting the vessels adaptively from attenuation-corrected enface images. We achieved a segmentation accuracy of 96% ± 1% as compared with manual annotation, and a dice coefficient of 0.83 ± 0.04 for repeatability. Using this framework on both control (0.00 D to -2.00 D) and highly myopic (-8.00 D to -11.00 D) eyes, we report a decrease in choroidal vessel volume (p<0.001) in eyes with high myopia.
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http://dx.doi.org/10.1364/BOE.426093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407849PMC
August 2021

Mechanisms of Ischemic Stroke in Patients with Cancer: A Prospective Study.

Ann Neurol 2021 07 3;90(1):159-169. Epub 2021 Jun 3.

Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.

Objective: The objective of this study was to examine the pathophysiology of ischemic stroke with cancer.

Methods: We conducted a prospective cross-sectional study from 2016 to 2020 at 2 hospitals. We enrolled 3 groups of 50 adult participants each. The main group included patients with active solid tumor cancer and acute ischemic stroke. The control groups included patients with acute ischemic stroke only or active cancer only. The patients with stroke-only and patients with cancer-only were matched to the patients with cancer-plus-stroke by age, sex, and cancer type, if applicable. The outcomes were prespecified hematological biomarkers and transcranial Doppler microemboli detection. Hematological biomarkers included markers of coagulation (D-dimer and thrombin-antithrombin), platelet function (P-selectin), and endothelial integrity (thrombomodulin, soluble intercellular adhesion molecule-1 [sICAM-1], and soluble vascular cell adhesion molecule-1 [sVCAM-1]). Hematological biomarkers were compared between groups using the Kruskal-Wallis and Wilcoxon Rank-Sum tests. In multivariable linear regression models, we adjusted for race, number of stroke risk factors, smoking, stroke severity, and antithrombotic use. Transcranial Doppler microemboli presence was compared between groups using chi-square tests.

Results: Levels of all study biomarkers were different between groups. In univariate between-group comparisons, patients with cancer-plus-stroke had higher levels of D-dimer, sICAM-1, sVCAM-1, and thrombomodulin than both control groups; higher levels of thrombin-antithrombin than patients with cancer-only; and higher levels of P-selectin than patients with stroke-only. Findings were similar in multivariable analyses. Transcranial Doppler microemboli were detected in 32% of patients with cancer-plus-stroke, 16% of patients with stroke-only, and 6% of patients with cancer-only (p = 0.005).

Interpretation: Patients with cancer-related stroke have higher markers of coagulation, platelet, and endothelial dysfunction, and more circulating microemboli, than matched controls. ANN NEUROL 2021;90:159-169.
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http://dx.doi.org/10.1002/ana.26129DOI Listing
July 2021

Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial.

Lancet Oncol 2021 06 18;22(6):824-835. Epub 2021 May 18.

Department of Radiation Oncology, Weill Cornell Medicine-New York Presbyterian Hospital, New York, NY, USA.

Background: Previous phase 2 trials of neoadjuvant anti-PD-1 or anti-PD-L1 monotherapy in patients with early-stage non-small-cell lung cancer have reported major pathological response rates in the range of 15-45%. Evidence suggests that stereotactic body radiotherapy might be a potent immunomodulator in advanced non-small-cell lung cancer (NSCLC). In this trial, we aimed to evaluate the use of stereotactic body radiotherapy in patients with early-stage NSCLC as an immunomodulator to enhance the anti-tumour immune response associated with the anti-PD-L1 antibody durvalumab.

Methods: We did a single-centre, open-label, randomised, controlled, phase 2 trial, comparing neoadjuvant durvalumab alone with neoadjuvant durvalumab plus stereotactic radiotherapy in patients with early-stage NSCLC, at NewYork-Presbyterian and Weill Cornell Medical Center (New York, NY, USA). We enrolled patients with potentially resectable early-stage NSCLC (clinical stages I-IIIA as per the 7th edition of the American Joint Committee on Cancer) who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients were randomly assigned (1:1) to either neoadjuvant durvalumab monotherapy or neoadjuvant durvalumab plus stereotactic body radiotherapy (8 Gy × 3 fractions), using permuted blocks with varied sizes and no stratification for clinical or molecular variables. Patients, treating physicians, and all study personnel were unmasked to treatment assignment after all patients were randomly assigned. All patients received two cycles of durvalumab 3 weeks apart at a dose of 1·12 g by intravenous infusion over 60 min. Those in the durvalumab plus radiotherapy group also received three consecutive daily fractions of 8 Gy stereotactic body radiotherapy delivered to the primary tumour immediately before the first cycle of durvalumab. Patients without systemic disease progression proceeded to surgical resection. The primary endpoint was major pathological response in the primary tumour. All analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrial.gov, NCT02904954, and is ongoing but closed to accrual.

Findings: Between Jan 25, 2017, and Sept 15, 2020, 96 patients were screened and 60 were enrolled and randomly assigned to either the durvalumab monotherapy group (n=30) or the durvalumab plus radiotherapy group (n=30). 26 (87%) of 30 patients in each group had their tumours surgically resected. Major pathological response was observed in two (6·7% [95% CI 0·8-22·1]) of 30 patients in the durvalumab monotherapy group and 16 (53·3% [34·3-71·7]) of 30 patients in the durvalumab plus radiotherapy group. The difference in the major pathological response rates between both groups was significant (crude odds ratio 16·0 [95% CI 3·2-79·6]; p<0·0001). In the 16 patients in the dual therapy group with a major pathological response, eight (50%) had a complete pathological response. The second cycle of durvalumab was withheld in three (10%) of 30 patients in the dual therapy group due to immune-related adverse events (grade 3 hepatitis, grade 2 pancreatitis, and grade 3 fatigue and thrombocytopaenia). Grade 3-4 adverse events occurred in five (17%) of 30 patients in the durvalumab monotherapy group and six (20%) of 30 patients in the durvalumab plus radiotherapy group. The most frequent grade 3-4 events were hyponatraemia (three [10%] patients in the durvalumab monotherapy group) and hyperlipasaemia (three [10%] patients in the durvalumab plus radiotherapy group). Two patients in each group had serious adverse events (pulmonary embolism [n=1] and stroke [n=1] in the durvalumab monotherapy group, and pancreatitis [n=1] and fatigue [n=1] in the durvalumab plus radiotherapy group). No treatment-related deaths or deaths within 30 days of surgery were reported.

Interpretation: Neoadjuvant durvalumab combined with stereotactic body radiotherapy is well tolerated, safe, and associated with a high major pathological response rate. This neoadjuvant strategy should be validated in a larger trial.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S1470-2045(21)00149-2DOI Listing
June 2021

Impact of Use of Antibiotics on Response to Immune Checkpoint Inhibitors and Tumor Microenvironment.

Am J Clin Oncol 2021 06;44(6):247-253

Department of Medicine, Division of Hematology/Oncology.

Background: Antibiotic use can result in reduced efficacy of immune checkpoint blockade (ICB), presumably because of dysbiosis of the intestinal microbiome. We sought to determine the precise temporal relation between antibiotic therapy and its possible effects on ICB efficacy. We also investigated the histologic changes in the tumor microenvironment secondary to antibiotics use.

Methods And Objectives: This was a single institution retrospective study that evaluated the impact of antibiotics on outcomes of patients with advanced or metastatic malignancy who were treated with ICB. Use of antibiotics among patients treated with ICB was assessed during a 12-week period before and after initiation of ICB. The primary outcome was response to ICB. Histologic changes in the tumor microenvironment following antibiotics use were also examined.

Results: Between January 1, 2011 and December 31, 2018, 414 patients were identified who received ICB, and 207 patients (50%) received antibiotics within 12 weeks (before/after) of initiation of ICB. In univariate analysis, antibiotic use following initiation of ICB was associated with a significantly reduced response (odds ratio [OR]: 0.33, 95% confidence interval [CI]: 0.2-0.52, P<0.001). There was no significant negative impact on response to immunotherapy when antibiotics were used before ICB initiation (OR: 0.87, 95% CI: 0.55-1.34, P=0.52). The maximal negative impact of antibiotics occurred in the first 6 weeks after initiating ICB, and was independently associated with significantly reduced likelihood of response to immunotherapy in multivariable analysis (OR: 0.48, 95% CI: 0.29-0.8, P=0.01).

Conclusions: This study demonstrates that the use of antibiotics during ICB significantly negatively impacts the efficacy of immunotherapy. The maximal negative impact occurs if the antibiotics are used in the first 6 weeks after initiating ICB.
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http://dx.doi.org/10.1097/COC.0000000000000813DOI Listing
June 2021

A method to produce high contrast vein visualization in active dynamic thermography (ADT).

Comput Biol Med 2021 05 6;132:104309. Epub 2021 Mar 6.

Department of Mechanical Engineering, National Institute of Technology, Silchar, 788010, India.

In this study, a method that will aid in the visualization of vein topology on a target area on the body of a human subject is demonstrated. An external cooling means is configured to cool the left forearm of fourteen study participants, effecting an active thermal change or recovery in the target area upon removal of cooling. An infrared (IR) thermal camera was used to capture a series of transient thermal images. These images were then processed to extract Dynamic synthetic images (SI) throughout the active thermal change or recovery process. Dynamic SI was calculated using a quantitative parameter called tissue activity ratio (TAR), which is defined by the rate of rewarming to the rate of cooling at each pixel of interest. A fixed step size of rewarming temperature (0.5 °C) was used to progressively extract multiple synthetic images throughout the whole recovery process. Compared to a Static SI extraction method, where only a single SI results from the whole active dynamic thermography (ADT) sequence, this study demonstrates a live feed of high contrast vein visualizations by using the Dynamic SI method. Furthermore, the dependency of Dynamic SI contrast on the temperature of the external cooling stimulation was investigated. Three cooling stimulation temperatures (5 °C, 8 °C, and 11 °C) were tested, where no statistically significant difference in the resulting SI contrast was found. Lastly, a discussion is put forth on assisting venipuncture or cannulation-based clinical applications, through the incorporation of the proposed method with a projection system.
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http://dx.doi.org/10.1016/j.compbiomed.2021.104309DOI Listing
May 2021

Extracellular vesicles from human airway basal cells respond to cigarette smoke extract and affect vascular endothelial cells.

Sci Rep 2021 03 17;11(1):6104. Epub 2021 Mar 17.

Department of Cell Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

The human airway epithelium lining the bronchial tree contains basal cells that proliferate, differentiate, and communicate with other components of their microenvironment. One method that cells use for intercellular communication involves the secretion of exosomes and other extracellular vesicles (EVs). We isolated exosome-enriched EVs that were produced from an immortalized human airway basal cell line (BCi-NS1.1) and found that their secretion is increased by exposure to cigarette smoke extract, suggesting that this stress stimulates release of EVs which could affect signaling to other cells. We have previously shown that primary human airway basal cells secrete vascular endothelial growth factor A (VEGFA) which can activate MAPK signaling cascades in endothelial cells via VEGF receptor-2 (VEGFR2). Here, we show that exposure of endothelial cells to exosome-enriched airway basal cell EVs promotes the survival of these cells and that this effect also involves VEGFR2 activation and is, at least in part, mediated by VEGFA present in the EVs. These observations demonstrate that EVs are involved in the intercellular signaling between airway basal cells and the endothelium which we previously reported. The downstream signaling pathways involved may be distinct and specific to the EVs, however, as increased phosphorylation of Akt, STAT3, p44/42 MAPK, and p38 MAPK was not seen following exposure of endothelial cells to airway basal cell EVs.
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http://dx.doi.org/10.1038/s41598-021-85534-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969738PMC
March 2021

Radiation Therapy for Small-Cell Lung Cancer: ASCO Guideline Endorsement of an ASTRO Guideline.

J Clin Oncol 2021 03 27;39(8):931-939. Epub 2021 Jan 27.

University of Michigan School of Medicine, Ann Arbor, MI.

Purpose: The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on radiation therapy (RT) for small-cell lung cancer (SCLC). Because of the relevance of this topic to ASCO membership, ASCO reviewed the guideline, applying a set of procedures and policies used to critically examine guidelines developed by other organizations.

Methods: The ASTRO guideline on RT for SCLC was reviewed for developmental rigor by methodologists. Then, an ASCO Expert Panel reviewed the content and the recommendations.

Results: The ASCO Expert Panel determined that the recommendations from ASTRO guideline on RT for SCLC, published in June 2020, are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed ASTRO guideline on RT for SCLC with a few discussion points.

Recommendations: Recommendations addressed thoracic radiotherapy for limited-stage SCLC, role of stereotactic body radiotherapy in stage I or II node-negative SCLC, prophylactic cranial radiotherapy, and thoracic consolidation for extensive-stage SCLC.Additional information is available at www.asco.org/thoracic-cancer-guidelines.
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http://dx.doi.org/10.1200/JCO.20.03364DOI Listing
March 2021

Aldose reductase regulates doxorubicin-induced immune and inflammatory responses by activating mitochondrial biogenesis.

Eur J Pharmacol 2021 Mar 20;895:173884. Epub 2021 Jan 20.

Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, 77555, USA. Electronic address:

We have recently demonstrated that aldose reductase (AR) inhibitor; fidarestat prevents doxorubicin (Dox)-induced cardiotoxic side effects and inflammation in vitro and in vivo. However, the effect of fidarestat and its combination with Dox on immune cell activation and the immunomodulatory effects are not known. In this study, we examined the immunomodulatory effects of fidarestat in combination with Dox in vivo and in vitro. We observed that fidarestat decreased Dox-induced upregulation of CD11b in THP-1 monocytes. Fidarestat further attenuated Dox-induced upregulation of IL-6, IL-1β, and Nos2 in murine BMDM. Fidarestat also attenuated Dox-induced activation and infiltration of multiple subsets of inflammatory immune cells identified by expression of markers CD11b, CD11bF4/80, Ly6CCCR2, and Ly6CCD11b in the mouse spleen and liver. Furthermore, significant upregulation of markers of mitochondrial biogenesis PGC-1α, COX IV, TFAM, and phosphorylation of AMPKα1 (Ser485) was observed in THP-1 cells and livers of mice treated with Dox in combination with fidarestat. Our results suggest that fidarestat by up-regulating mitochondrial biogenesis exerts protection against Dox-induced immune and inflammatory responses in vitro and in vivo, providing further evidence for developing fidarestat as a combination agent with anthracycline drugs to prevent chemotherapy-induced inflammation and toxicity.
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http://dx.doi.org/10.1016/j.ejphar.2021.173884DOI Listing
March 2021

Development of the Oncolo-GIST ("Giving Information Strategically & Transparently") Intervention Manual for Oncologist Skills Training in Advanced Cancer Prognostic Information Communication.

J Pain Symptom Manage 2021 07 27;62(1):10-19.e4. Epub 2020 Nov 27.

Weill Cornell Medicine, New York, New York, USA.

Context: Patient prognostic understanding is improved by oncologists' discussions of life expectancy. Most patients deem it important to discuss prognosis with their oncologists, but a minority of cancer patients within months of death report that they had such a discussion with their oncologist.

Objectives: To query stakeholders about their perspectives on the clinical approach and utility of an Oncolo-GIST manualized communication intervention, designed to enhance oncologists' ability to convey the gist of prognostic information simply, clearly, and effectively in the setting of progressing solid tumors and limited life expectancy.

Methods: We obtained and analyzed feedback on the intervention from solid tumor oncology clinicians and bereaved family caregivers, soliciting opinions on the clinical approach taken in the videos, acceptability and likely impact of the instructions, and specific phrases recommended in the manual.

Results: Twenty stakeholders (9 clinicians, 11 caregivers) participated. All agreed that oncologists should broach prognosis with patients, balancing honesty and sensitivity. Participants also advocated for oncologists to involve interprofessional team members (e.g., nurses, social workers) when serious mental health concerns arose. After the research team's discussion of the stakeholder feedback, the manual was modified to include or exclude preferred language and approaches.

Conclusion: The Oncolo-GIST intervention was characterized as simple and potentially effective at conveying prognoses to advanced cancer patients. Future research should determine if this approach to medical communication, which distills the essence of prognostic messages clearly and simply, is associated with improvements in patients' prognostic understanding.
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http://dx.doi.org/10.1016/j.jpainsymman.2020.11.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155099PMC
July 2021

Relation Between Neck Skin Temperature Measurement and Carotid Artery Stenosis: In-Vitro Evaluation.

J Biomech Eng 2020 11;142(11)

School of Mechanical and Aerospace Engineering, Nanyang Technological University, Block N3, Nanyang Ave, Singapore 639798.

Carotid artery stenosis is a form of atherosclerosis, where thrombus formation restricts the passage of blood through the carotid artery leading to irreversible damage in the brain tissue. The presence of stenosis in the carotid artery results in abnormal temperature maps on the external skin surface, which can be captured and quantified using noncontact/noninvasive infrared (IR) thermal imaging/thermography. In this study, a thermally charged in vitro carotid artery flow loop, using 0% and 75% stenosis models, was designed to study the thermal effect on the external skin surface. The carotid artery flow was encapsulated with polydimethylsiloxane (PDMS) resembling neck tissue, of which the external surface temperature maps were studied using IR thermography. Using the mean temperature as a threshold value, the resultant thermal image was processed and normalized. Between the two stenosis models, disruption in the thermal features corresponding to the presence of stenosis was observed. The method described in this study paves the path to experimentally study the thermal effect of the presence of stenosis in the carotid artery.
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http://dx.doi.org/10.1115/1.4048423DOI Listing
November 2020

Intestinal estrogen receptor beta suppresses colon inflammation and tumorigenesis in both sexes.

Cancer Lett 2020 11 23;492:54-62. Epub 2020 Jul 23.

Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, 171 21, Solna, Sweden; Department of Biosciences and Nutrition, Karolinska Institutet, 141 83, Huddinge, Sweden. Electronic address:

Estrogen hormones protect against colorectal cancer (CRC) and a preventative role of estrogen receptor beta (ERβ) on CRC has been supported using full knockout animals. However, it is unclear through which cells or organ ERβ mediates this effect. To investigate the functional role of intestinal ERβ during colitis-associated CRC we used intestine-specific ERβ knockout mice treated with azoxymethane and dextran sodium sulfate, followed by ex vivo organoid culture to corroborate intrinsic effects. We explored genome-wide impact on TNFα signaling using human CRC cell lines and chromatin immunoprecipitation assay to mechanistically characterize the regulation of ERβ. Increased tumor formation in males and tumor size in females was noted upon intestine-specific ERβ knockout, accompanied by enhanced local expression of TNFα, deregulation of key NFκB targets, and increased colon ulceration. Unexpectedly, we noted especially strong effects in males. We corroborated that intestinal ERβ protects against TNFα-induced damage intrinsically, and characterized an underlying genome-wide signaling mechanism in CRC cell lines whereby ERβ binds to cis-regulatory chromatin areas of key NFκB regulators. Our results support a protective role of intestinal ERβ against colitis-associated CRC, proposing new therapeutic strategies.
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http://dx.doi.org/10.1016/j.canlet.2020.06.021DOI Listing
November 2020

Active dynamic thermography to detect the presence of stenosis in the carotid artery.

Comput Biol Med 2020 05 24;120:103718. Epub 2020 Mar 24.

Department of Cardiology, National Heart Center Singapore, 5 Hospital Dr, 169609, Singapore.

Unlike passive infrared (IR) thermal imaging/thermography, where no external stimulation is applied, active dynamic thermography (ADT) results in a high contrast thermal image. In ADT, transient thermal images of the skin surface are captured using an IR thermal camera while the skin surface is stimulated externally, followed by a recovery phase. Upon the application of external stimulation, the presence of stenosis in the carotid artery is expected to differ the recovery rate of the external neck skin surface from the case with no stenosis. In this prospective study, using an external cooling stimulation, the ADT procedure was performed on a total of 54 (N) samples (C: N = 19, 0% stenosis; D1: N = 17, 10%-29% stenosis; D2: N = 18, ≥30% stenosis using Duplex Ultrasound). Analyzing the ADT sequence with a parameter called tissue activity ratio (TAR), the samples were classified using a cut-off value: C versus (D1+D2) and (C + D1) versus D2. As the degree of stenosis increases, the value of the TAR parameter depreciates with a significant difference among the sample groups (C:0.97 ± 0.05, D1:0.80 ± 0.04, D2:0.75 ± 0.02; p < 0.05). Under the two classification scenarios, classification accuracies of 90% and 85%, respectively, were achieved. This study suggests the potential of screening CAS with the proposed ADT procedure.
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http://dx.doi.org/10.1016/j.compbiomed.2020.103718DOI Listing
May 2020

MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer.

Clin Cancer Res 2020 06 21;26(11):2535-2545. Epub 2020 Feb 21.

Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.

Purpose: Most -positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed.

Experimental Design: We performed FISH and/or next-generation sequencing on 207 posttreatment tissue ( = 101) or plasma ( = 106) specimens from patients with ALK-positive lung cancer to detect genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 patients with MET-driven resistance.

Results: amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation ALK inhibitor in the first-line setting were more likely to develop amplification than those who had received next-generation ALK inhibitors after crizotinib ( = 0.019). Two tumor specimens harbored an identical rearrangement, one of which had concurrent amplification. Expressing in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition resensitized a patient-derived cell line harboring both and amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired alterations achieved rapid responses to ALK/MET combination therapy.

Conclusions: Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired alterations may derive clinical benefit from therapies that target both ALK and MET.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269872PMC
June 2020

Skin temperature maps as a measure of carotid artery stenosis.

Comput Biol Med 2020 01 15;116:103548. Epub 2019 Nov 15.

School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore. Electronic address:

In this study, the effect of carotid artery stenosis on the neck skin temperature maps was investigated. With the presence of stenosis, alterations in the carotid artery hemodynamics bring about changes in the heat transfer to the surrounding tissue. This is expected to be captured in the resulting temperature map over the external neck skin surface; possibly it correlates to the presence of stenosis. A total of twenty carotid artery samples, from ten patients with both sides normal (0% stenosis), stenosis (>50%) on one side, and stenosis (>50%) on both sides, were studied. Duplex Ultrasound and infrared (IR) thermography examinations were performed. A computational study, on an ideal 3-dimensional (3D) carotid artery and jugular vein model encapsulated with a solid neck tissue phantom resembling the human neck, was carried out. Incorporating the patient-specific geometrical (depth of artery and stenosis) and flow (peak systolic and end diastolic inlet velocity) boundary conditions, conjugate bio-heat transfer was studied using a finite volume numerical scheme. Simulation results and in-vivo thermal maps show that the average temperature on the external neck skin surface is significantly higher for normal patients (32.82 ± 0.53 °C versus 32.00 ± 0.37 °C, p < 0.001). Furthermore, the thermal region of interests (TROIs) were extracted from the in-vivo thermal images, which both qualitatively and quantitatively distinguish the normal and diseased cases. This study suggests the potential of thermal feature-based screening of patients with carotid artery stenosis.
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http://dx.doi.org/10.1016/j.compbiomed.2019.103548DOI Listing
January 2020

Cancer-Related Ischemic Stroke Has a Distinct Blood mRNA Expression Profile.

Stroke 2019 11 12;50(11):3259-3264. Epub 2019 Sep 12.

Department of Neurology, University of California, Davis (H.H., G.C.J., F.R.S., B.P.A., B.S.).

Background and Purpose- Comorbid cancer is common in patients with acute ischemic stroke (AIS). As blood mRNA profiles can distinguish AIS mechanisms, we hypothesized that cancer-related AIS would have a distinctive gene expression profile. Methods- We evaluated 4 groups of 10 subjects prospectively enrolled at 3 centers from 2009 to 2018. This included the group of interest with active solid tumor cancer and AIS and 3 control groups with active cancer only, AIS only, or vascular risk factors only. Subjects in the AIS-only and cancer-only groups were matched to subjects in the cancer-stroke group by age, sex, and cancer type (if applicable). Subjects in the vascular risk factor group were matched to subjects in the cancer-stroke and stroke-only groups by age, sex, and vascular risk factors. Blood was drawn 72 to 120 hours after stroke. Total RNA was processed using 3' mRNA sequencing. ANOVA and Fisher least significant difference contrast methods were used to estimate differential gene expression between groups. Results- In the cancer-stroke group, 50% of strokes were cryptogenic. All groups had differentially expressed genes that could distinguish among them. Comparing the cancer-stroke group to the stroke-only group and after accounting for cancer-only genes, 438 genes were differentially expressed, including upregulation of multiple genes/pathways implicated in autophagy signaling, immunity/inflammation, and gene regulation, including IL (interleukin)-1, interferon, relaxin, mammalian target of rapamycin signaling, SQSTMI1 (sequestosome-1), and CREB1 (cAMP response element binding protein-1). Conclusions- This study provides evidence for a distinctive molecular signature in blood mRNA expression profiles of patients with cancer-related AIS. Future studies should evaluate whether blood mRNA can predict detection of occult cancer in patients with AIS. Clinical Trial Registration- URL: https://clinicaltrials.gov. Unique identifier: NCT02604667.
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http://dx.doi.org/10.1161/STROKEAHA.119.026143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817410PMC
November 2019

Infrared (IR) thermography as a potential screening modality for carotid artery stenosis.

Comput Biol Med 2019 10 28;113:103419. Epub 2019 Aug 28.

Department of Cardiology, National Heart Center Singapore, 5 Hospital Dr, 169609, Singapore.

In the present study, an infrared (IR) thermal camera was used to map the temperature of the target skin surface, and the resulting thermal image was evaluated for the presence of carotid artery stenosis (CAS). In the presence of stenosis in the carotid artery, abnormal temperature maps are expected to occur on the external skin surface, which could be captured and quantified using IR thermography. A Duplex Ultrasound (DUS) examination was used to establish the ground truth. In each patient, the background-subtracted thermal image, referred to as full thermal image, was used to extract novel parametric cold thermal feature images. From these images, statistical features, viz., correlation, energy, homogeneity, contrast, entropy, mean, standard deviation (SD), skewness, and kurtosis, were calculated and the two groups of patients (control and diseased: a total of 80 carotid artery samples) were classified. Both cut-off value- and support vector machine (SVM)-based binary classification models were tested. While the cut-off value classification model resulted in a moderate performance (70% accurate), SVM was found to have classified the patients with high accuracy (92% or higher). This preliminary study suggests the potential of IR thermography as a possible screening tool for CAS patients.
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http://dx.doi.org/10.1016/j.compbiomed.2019.103419DOI Listing
October 2019

Imaging modalities to diagnose carotid artery stenosis: progress and prospect.

Biomed Eng Online 2019 May 28;18(1):66. Epub 2019 May 28.

Department of Cardiology, National Heart Center Singapore, 5 Hospital Dr, Singapore, 169609, Singapore.

In the past few decades, imaging has been developed to a high level of sophistication. Improvements from one-dimension (1D) to 2D images, and from 2D images to 3D models, have revolutionized the field of imaging. This not only helps in diagnosing various critical and fatal diseases in the early stages but also contributes to making informed clinical decisions on the follow-up treatment profile. Carotid artery stenosis (CAS) may potentially cause debilitating stroke, and its accurate early detection is therefore important. In this paper, the technical development of various CAS diagnosis imaging modalities and its impact on the clinical efficacy is thoroughly reviewed. These imaging modalities include duplex ultrasound (DUS), computed tomography angiography (CTA) and magnetic resonance angiography (MRA). For each of the imaging modalities considered, imaging methodology (principle), critical imaging parameters, and the extent of imaging the vulnerable plaque are discussed. DUS is usually the initial recommended CAS diagnostic examination. However, for the therapeutic intervention, either MRA or CTA is recommended for confirmation, and for added information on intracranial cerebral circulation and aortic arch condition for procedural planning. Over the past few decades, the focus of CAS diagnosis has also shifted from pure stenosis quantification to plaque characterization. This has led to further advancement in the existing imaging tools and development of other potential imaging tools like Optical coherence tomography (OCT), photoacoustic tomography (PAT), and infrared (IR) thermography.
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http://dx.doi.org/10.1186/s12938-019-0685-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537161PMC
May 2019

Didymin by suppressing NF-κB activation prevents VEGF-induced angiogenesis in vitro and in vivo.

Vascul Pharmacol 2019 04 8;115:18-25. Epub 2019 Jan 8.

Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston TX-77555, USA. Electronic address:

Although didymin, a dietary flavonoid glycoside from citrus fruits, known to be a potent antioxidant with anti-cancer activities, its role in angiogenesis is not known. In this study, we examined the effect of didymin on VEGF-induced angiogenesis in vitro and in vivo models. Our results suggest that treatment of human umbilical vein endothelial cell (HUVECs) with didymin significantly prevented the VEGF-induced cell proliferation, migration, and invasion. Further, didymin significantly prevented the VEGF-induced endothelial tube formation in culture. Didymin also attenuated the VEGF-induced generation of ROS, activation of NF-κB and the expression of adhesion molecules such as VCAM-1, ICAM-1, and E-selectin in HUVECs. Further, didymin also prevented the VEGF-induced microvessel sprouting in ex vivo mouse aortic rings. Most importantly, didymin significantly prevented the invasion of endothelial cells and formation of blood capillary-like structures in Matrigel plug model of angiogenesis in mice. Thus, our results suggest a novel antiangiogenic efficacy of didymin in addition to its reported anti-cancer properties, which warrant further development of this agent for cancer therapy.
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http://dx.doi.org/10.1016/j.vph.2019.01.002DOI Listing
April 2019

The lung microenvironment: an important regulator of tumour growth and metastasis.

Nat Rev Cancer 2019 01;19(1):9-31

Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA.

Lung cancer is a major global health problem, as it is the leading cause of cancer-related deaths worldwide. Major advances in the identification of key mutational alterations have led to the development of molecularly targeted therapies, whose efficacy has been limited by emergence of resistance mechanisms. US Food and Drug Administration (FDA)-approved therapies targeting angiogenesis and more recently immune checkpoints have reinvigorated enthusiasm in elucidating the prognostic and pathophysiological roles of the tumour microenvironment in lung cancer. In this Review, we highlight recent advances and emerging concepts for how the tumour-reprogrammed lung microenvironment promotes both primary lung tumours and lung metastasis from extrapulmonary neoplasms by contributing to inflammation, angiogenesis, immune modulation and response to therapies. We also discuss the potential of understanding tumour microenvironmental processes to identify biomarkers of clinical utility and to develop novel targeted therapies against lung cancer.
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http://dx.doi.org/10.1038/s41568-018-0081-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749995PMC
January 2019

Colitis-induced colorectal cancer and intestinal epithelial estrogen receptor beta impact gut microbiota diversity.

Int J Cancer 2019 06 11;144(12):3086-3098. Epub 2019 Jan 11.

Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden.

Chronic inflammation of the colon (colitis) is a risk factor for colorectal cancer (CRC). Hormone-replacement therapy reduces CRC incidences, and the estrogen receptor beta (ERβ/ESR2) has been implicated in this protection. Gut microbiota is altered in both colitis and CRC and may influence the severity of both. Here we test the hypothesis that intestinal ERβ impacts the gut microbiota. Mice with and without intestine-specific deletion of ERβ (ERβKO ) were generated using the Cre-LoxP system. Colitis and CRC were induced with a single intraperitoneal injection of azoxymethane (AOM) followed by administration of three cycles of dextran sulfate sodium (DSS) in drinking water. The microbiota population were characterized by high-throughput 16S rRNA gene sequencing of DNA extracted from fecal samples (N = 39). Differences in the microbiota due to AOM/DSS and absence of ERβ were identified through bioinformatic analyses of the 16S-Seq data, and the distribution of bacterial species was corroborated using qPCR. We demonstrate that colitis-induced CRC reduced the gut microbiota diversity and that loss of ERβ enhanced this process. Further, the Bacteroidetes genus Prevotellaceae_UCG_001 was overrepresented in AOM/DSS mice compared to untreated controls (3.5-fold, p = 0.004), and this was enhanced in females and in ERβKO mice. Overall, AOM/DSS enriched for microbiota impacting immune system diseases and metabolic functions, and lack of ERβ in combination with AOM/DSS enriched for microbiota impacting carbohydrate metabolism and cell motility, while reducing those impacting the endocrine system. Our data support that intestinal ERβ contributes to a more favorable microbiome that could attenuate CRC development.
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http://dx.doi.org/10.1002/ijc.32037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519213PMC
June 2019

Extracellular vesicles in DLBCL provide abundant clues to aberrant transcriptional programming and genomic alterations.

Blood 2018 08 2;132(7):e13-e23. Epub 2018 Jul 2.

Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine/New York Presbyterian Hospital, New York, NY.

The biological role of extracellular vesicles (EVs) in diffuse large B-cell lymphoma (DLBCL) initiation and progression remains largely unknown. We characterized EVs secreted by 5 DLBCL cell lines, a primary DLBCL tumor, and a normal control B-cell sample, optimized their purification, and analyzed their content. We found that DLBCLs secreted large quantities of CD63, Alix, TSG101, and CD81 EVs, which can be extracted using an ultracentrifugation-based method and traced by their cell of origin surface markers. We also showed that tumor-derived EVs can be exchanged between lymphoma cells, normal tonsillar cells, and HK stromal cells. We then examined the content of EVs, focusing on isolation of high-quality total RNA. We sequenced the total RNA and analyzed the nature of RNA species, including coding and noncoding RNAs. We compared whole-cell and EV-derived RNA composition in benign and malignant B cells and discovered that transcripts from EVs were involved in many critical cellular functions. Finally, we performed mutational analysis and found that mutations detected in EVs exquisitely represented mutations in the cell of origin. These results enhance our understanding and enable future studies of the role that EVs may play in the pathogenesis of DLBCL, particularly with regards to the exchange of genomic information. Current findings open a new strategy for liquid biopsy approaches in disease monitoring.
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http://dx.doi.org/10.1182/blood-2017-12-821843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265635PMC
August 2018

Brigatinib in Patients With Alectinib-Refractory ALK-Positive NSCLC.

J Thorac Oncol 2018 10 20;13(10):1530-1538. Epub 2018 Jun 20.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Introduction: The second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib recently showed superior efficacy compared to the first-generation ALK inhibitor crizotinib in advanced ALK-rearranged NSCLC, establishing alectinib as the new standard first-line therapy. Brigatinib, another second-generation ALK inhibitor, has shown substantial activity in patients with crizotinib-refractory ALK-positive NSCLC; however, its activity in the alectinib-refractory setting is unknown.

Methods: A multicenter, retrospective study was performed at three institutions. Patients were eligible if they had advanced, alectinib-refractory ALK-positive NSCLC and were treated with brigatinib. Medical records were reviewed to determine clinical outcomes.

Results: Twenty-two patients were eligible for this study. Confirmed objective responses to brigatinib were observed in 3 of 18 patients (17%) with measurable disease. Nine patients (50%) had stable disease on brigatinib. The median progression-free survival was 4.4 months (95% confidence interval [CI]: 1.8-5.6 months) with a median duration of treatment of 5.7 months (95% CI: 1.8-6.2 months). Among 9 patients in this study who underwent post-alectinib/pre-brigatinib biopsies, 5 had an ALK I1171X or V1180L resistance mutation; of these, 1 had a confirmed partial response and 3 had stable disease on brigatinib. One patient had an ALK G1202R mutation in a post-alectinib/pre-brigatinib biopsy, and had progressive disease as the best overall response to brigatinib.

Conclusions: Brigatinib has limited clinical activity in alectinib-refractory ALK-positive NSCLC. Additional studies are needed to establish biomarkers of response to brigatinib and to identify effective therapeutic options for alectinib-resistant ALK-positive NSCLC patients.
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http://dx.doi.org/10.1016/j.jtho.2018.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341982PMC
October 2018

Molecular Testing for Stage IV Non-Small Cell Lung Cancer Patients With Targetable Mutations Following Disease Progression.

Authors:
Ashish Saxena

Arch Pathol Lab Med 2018 07 12;142(7):799-800. Epub 2018 Apr 12.

From the Department of Medicine, Division of Hematology & Medical Oncology, Thoracic Oncology Service, Weill Cornell Medicine, New York, New York. Dr Saxena has received honoraria and consulting fees from Genentech, Lily Oncology, Clovis Oncology, AstraZeneca, Takeda, ARIAD Pharmaceuticals, GfK, and Guardant Health.

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http://dx.doi.org/10.5858/arpa.2018-0111-EDDOI Listing
July 2018

Didymin prevents hyperglycemia-induced human umbilical endothelial cells dysfunction and death.

Biochem Pharmacol 2018 06 14;152:1-10. Epub 2018 Mar 14.

Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address:

Although didymin, a flavonoid-O-glycosides compound naturally found in the citrus fruits, has been reported to be a potent anticancer agent in the prevention of various cancers, its role in the prevention of cardiovascular complications is unclear. Most importantly, its effect in the prevention of endothelial dysfunction, a pathological process involved in the atherogenesis, is unknown. We have examined the efficacy of didymin in preventing the high glucose (HG; 25 mM)-induced human umbilical vein endothelial cells (HUVECs) dysfunction. Our results indicate that incubation of HUVECs with HG resulted in the loss of cell viability, and pre-incubation of didymin prevented it. Further, didymin prevented the HG-induced generation of reactive oxygen species (ROS) as well as lipid peroxidation product, malondialdehyde. Pretreatment of HUVECs with didymin also prevented the HG-induced decrease in eNOS and increase in iNOS expressions. Further, didymin prevented the HG-induced monocytes cell adhesion to endothelial cells, expressions of ICAM-1 and VCAM-1 and activation of NF-κB. Didymin also prevented the release of various inflammatory cytokines and chemokines in HG-treated HUVECs. In conclusion, our results demonstrate that didymin with its anti-oxidative and anti-inflammatory actions prevents hyperglycemia-induced endothelial dysfunction and death. Thus, it could be developed as a potential natural therapeutic agent for the prevention of cardiovascular complications in diabetes.
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http://dx.doi.org/10.1016/j.bcp.2018.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960604PMC
June 2018

Vialinin A, an Edible Mushroom-Derived p-Terphenyl Antioxidant, Prevents VEGF-Induced Neovascularization In Vitro and In Vivo.

Oxid Med Cell Longev 2018 6;2018:1052102. Epub 2018 Feb 6.

Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.

Increased side toxicities and development of drug resistance are the major concern for the cancer chemotherapy using synthetic drugs. Therefore, identification of novel natural antioxidants with potential therapeutic efficacies is important. In the present study, we have examined how the antioxidant and anti-inflammatory activities of vialinin A, a p-terphenyl compound derived from Chinese edible mushroom and , prevents human umbilical vascular endothelial cell (HUVEC) neovascularization in vitro and in vivo models. Pretreatment of HUVECs with vialinin A prevents vascular endothelial growth factor- (VEGF) induced HUVEC cell growth in a dose-dependent manner. Further, vialinin A also inhibits VEGF-induced migration as well as tube formation of HUVECs. Treatment of HUVECs prevents VEGF-induced generation of reactive oxygen species (ROS) and malondialdehyde (MDA) and also inhibits VEGF-induced NF-B nuclear translocation as well as DNA-binding activity. The VEGF-induced release of various angiogenic cytokines and chemokines in HUVECs was also significantly blunted by vialinin A. Most importantly, in a mouse model of Matrigel plug assay, vialinin A prevents the formation of new blood vessels and the expression of CD31 and vWF. Thus, our results indicate a novel role of vialinin A in the prevention of neovascularization and suggest that anticancer effects of vialinin A could be mediated through its potent antioxidant and antiangiogenic properties.
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http://dx.doi.org/10.1155/2018/1052102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818888PMC
September 2018

Aldose reductase inhibitor, fidarestat prevents doxorubicin-induced endothelial cell death and dysfunction.

Biochem Pharmacol 2018 04 16;150:181-190. Epub 2018 Feb 16.

Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address:

Despite doxorubicin (Dox) being one of the most widely used chemotherapy agents for breast, blood and lung cancers, its use in colon cancer is limited due to increased drug resistance and severe cardiotoxic side effects that increase mortality associated with its use at high doses. Therefore, better adjuvant therapies are warranted to improve the chemotherapeutic efficacy and to decrease cardiotoxicity. We have recently shown that aldose reductase inhibitor, fidarestat, increases the Dox-induced colon cancer cell death and reduces cardiomyopathy. However, the efficacy of fidarestat in the prevention of Dox-induced endothelial dysfunction, a pathological event critical to cardiovascular complications, is not known. Here, we have examined the effect of fidarestat on Dox-induced endothelial cell toxicity and dysfunction in vitro and in vivo. Incubation of human umbilical vein endothelial cells (HUVECs) with Dox significantly increased the endothelial cell death, and pre-treatment of fidarestat prevented it. Further, fidarestat prevented the Dox-induced oxidative stress, formation of reactive oxygen species (ROS) and activation of Caspase-3 in HUVECs. Fidarestat also prevented Dox-induced monocyte adhesion to HUVECs and expression of ICAM-1 and VCAM-1. Fidarestat pre-treatment to HUVECs restored the Dox-induced decrease in the Nitric Oxide (NO)-levels and eNOS expression. Treatment of HUVECs with Dox caused a significant increase in the activation of NF-κB and expression of various inflammatory cytokines and chemokines which were prevented by fidarestat pre-treatment. Most importantly, fidarestat prevented the Dox-induced mouse cardiac cell hypertrophy and expression of eNOS, iNOS, and 3-Nitrotyrosine in the aorta tissues. Further, fidarestat blunted the Dox-induced expression of various inflammatory cytokines and chemokines in vivo. Thus, our results suggest that by preventing Dox-induced endothelial cytotoxicity and dysfunction, AR inhibitors could avert cardiotoxicity associated with anthracycline chemotherapy.
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http://dx.doi.org/10.1016/j.bcp.2018.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866779PMC
April 2018

Aldose reductase inhibitor, fidarestat regulates mitochondrial biogenesis via Nrf2/HO-1/AMPK pathway in colon cancer cells.

Cancer Lett 2017 12 3;411:57-63. Epub 2017 Oct 3.

Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address:

Although we have shown earlier that aldose reductase (AR) inhibitors prevent colorectal cancer cell (CRC) growth in culture as well as in nude mice xenografts, the mechanism(s) is not well understood. In this study, we have investigated how AR inhibition prevents CRC growth by regulating the mitochondrial biogenesis via Nrf2/HO-1 pathway. Incubation of CRC cells such as SW-480, HT29, and HCT116 with AR inhibitor, fidarestat that non-covalently binds to the enzyme, increases the expression of Nrf2. Further, fidarestat augmented the EGF-induced expression of Nrf2 in CRC cells. Fidarestat also increased the Nrf2 -DNA binding activity as well as expression of HO-1 and NQO1 and activation of SOD and catalase in SW480 cells. Similarly, in nude mice xenograft tumor tissues, Nrf2 and HO-1 levels were significantly higher in fidarestat-treated mice compared to controls. Further, stimulation of CRC cells with EGF in the presence of fidarestat increased the mRNA levels of PGC-1α, Nrf1 and TFAM and protein levels of PGC-1α, TFAM and COX-IV and decreased the mitochondrial DNA damage as measured by 8-hydroxy-2'-deoxyguanosine levels. AR inhibitor also modulated the phosphorylations of AMPK and mTOR and expression of p53 in EGF-treated cells. Collectively, our results indicate that AR inhibitor prevents CRC growth by increasing mitochondrial biogenesis via increasing the expression of Nrf2/HO-1/AMPK/p53 and decreasing the mitochondrial DNA damage.
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http://dx.doi.org/10.1016/j.canlet.2017.09.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5693654PMC
December 2017

Atezolizumab-Induced New Onset Diabetes Mellitus With Ketoacidosis.

Am J Ther 2018 Sep/Oct;25(5):e565-e568

Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York City, NY.

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http://dx.doi.org/10.1097/MJT.0000000000000644DOI Listing
March 2019
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