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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.

Background Glucose absorption in patients on peritoneal dialysis (PD) may contribute to adverse metabolic effects. Previous studies on glucose absorption were done on patients on continuous ambulatory PD, with a long dwell time. However, the growing majority of contemporary patients on PD perform automated PD with a short dwell time. Moreover, membrane characteristics and dwell time determine small-solute transport across the peritoneal membrane. Methods In our pilot study, we used data from the peritoneal equilibration test (PET) to develop a model to estimate glucose absorption. In six randomly selected patients on PD, we calculated actual glucose absorption from directly measuring effluent glucose concentration. We then used the R programming language to create a nonlinear, least-squared regression model, inputting PET data, D2/D0, and D4/D0 to generate an exponential decay curve. This model was then used to estimate the fraction of glucose remaining in the dialysate at a particular dwell time t (Dt/D0). Daily glucose absorption was calculated by multiplying 1−Dt/D0 with the amount of glucose the patient was exposed to in 24 hours. Results We observed the mean glucose absorption (89.7±28.8 g/d), as measured from the effluent, very close to our estimate (88.12±28.9 g/d), and the difference between the glucose estimation and actual absorption was not statistically significant (P>0.05), with "W" value of 8. After validating our hypothesis, we randomly selected an independent cohort of 11 patients with ESKD who were on various PD modalities and analyzed their data. We observed that the mean daily glucose absorption of 62.7±24.5 g (27.98–110.35 g), much lower than that reported in the literature, depends on dwell times and membrane characteristics in addition to the amount of glucose absorption in the cohort. Conclusions Our model provides a simple tool for estimating glucose absorption and caloric load in contemporary patients on PD. Hopefully, the accurate estimation of caloric load and the incorporation of it into the daily caloric intake of the individual will help to reduce metabolic consequences of hyperglycemia and weight gain and improve overall outcomes of PD.

Purpose: Most ALK-positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. MET 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 (n = 101) or plasma (n = 106) specimens from patients with ALK-positive lung cancer to detect MET genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with MET alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 patients with MET-driven resistance. Results: MET 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 MET amplification than those who had received next-generation ALK inhibitors after crizotinib (P = 0.019). Two tumor specimens harbored an identical ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET 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 ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET 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 MET alterations may derive clinical benefit from therapies that target both ALK and MET.

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.

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

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 .

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.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.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]; p0·0001). 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.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.AstraZeneca.

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. Nanyang Technological University Submitted/Accepted version This study was supported by the SingHealth-NTU collaborative research grant (Grant number: SHS-NTU/014/2016).

Background: Recent epidemiological and experimental studies have shown that obesity is a major risk factor for Colorectal Cancer (CRC). Regular intake of high fat-containing diet can promote obesity and metabolic syndrome by increasing the insulin resistance and inflammatory response which contribute to carcinogenesis. Previously, we have shown that inhibition of polyol pathway enzyme aldose reductase (AR) prevents carcinogens- and inflammatory growth factorsinduced CRC. However, the effect of AR inhibition on a high-fat diet (HFD)-induced formation of intestinal polyps in Apc-deficient Min (multiple intestinal neoplasia; ApcMin/+) mice is not known. Methods: We examined the effect of AR inhibitor, fidarestat on the HFD-induced formation of preneoplastic intestinal polyps in ApcMin/+ mice which is an excellent model of colon cancer. Results: APCMin/+ mice fed for 12 weeks of HFD caused a significant increase in the formation of polyps in the small and large intestines and fidarestat given along with the HFD prevented the number of intestinal polyps. Fidarestat also decreased the size of the polyps in the intestines of HFDtreated APC Min mice. Further, the expression levels of beta-catenin, PCNA, PKC-β2, P-AKT, Pp65, COX-2, and iNOS in the small and large intestines of HFD-treated mice significantly increased, and AR inhibitor prevented it. Conclusion: Our results thus suggest that fidarestat could be used as a potential chemopreventive drug for intestinal cancers due to APC gene mutations.

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.

A Japan Society of Clinical Oncology (JSCO)-hosted expert meeting was held in Japan on 27 October 2019, which comprised experts from the JSCO, the Japanese Society of Medical Oncology (JSMO), the European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the Taiwan Oncology Society (TOS). The purpose of the meeting was to focus on what we have learnt from both microsatellite instability (MSI)/deficient mismatch repair (dMMR) biomarkers in predicting the efficacy of anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) immunotherapy, and the neurotrophic tyrosine receptor kinase (NTRK) gene fusions in predicting the efficacy of inhibitors of the tropomyosin receptor kinase (TRK) proteins across a range of solid tumour types. The recent regulatory approvals of the anti-PD-1 antibody pembrolizumab and the TRK inhibitors larotrectinib and entrectinib, based on specific tumour biomarkers rather than specific tumour type, have heralded a paradigm shift in cancer treatment approaches. The purpose of the meeting was to develop international expert consensus recommendations on the use of such tumour-agnostic treatments in patients with solid tumours. The aim was to generate a reference document for clinical practice, for pharmaceutical companies in the design of clinical trials, for ethics committees in the approval of clinical trial protocols and for regulatory authorities in relation to drug approvals, with a particular emphasis on diagnostic testing and patient selection. Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

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

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. QC 20201009

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.

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.

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+, CD11b+F4/80+, Ly6C+CCR2high, and Ly6C+CD11b+ 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.

// Trang Nguyen-Vu 1, * , Jun Wang 1, * , Fahmi Mesmar 1 , Srijita Mukhopadhyay 1 , Ashish Saxena 1 , Catherine W. McCollum 1 , Jan-Ake Gustafsson 1, 2 , Maria Bondesson 1, 3 , Cecilia Williams 1, 2, 4 1 Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA 2 Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden 3 Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA 4 Science for Life Laboratory, School of Biotechnology, KTH The Royal Institute of Technology, Solna, Sweden * These authors have contributed equally to this work Correspondence to: Cecilia Williams, email: Cecilia.williams@scilifelab.se Keywords: colorectal cancer, PROX1, estrogen receptor, microRNA, metastasis Received: October 05, 2015 Accepted: May 25, 2016 Published: June 07, 2016 ABSTRACT Colon cancer is a common cause of cancer death in the Western world. Accumulating evidence supports a protective role of estrogen via estrogen receptor beta (ERβ) but the mechanism of action is not known. Here, we elucidate a molecular mechanism whereby ERβ represses the oncogenic prospero homebox 1 (PROX1) through the upregulation of miR-205. We show that PROX1 is a potential target of miR-205 and that in clinical specimens from The Cancer Genome Atlas data, ERβ and miR-205 are decreased in colorectal cancer tissue compared to non-tumorous colon, while PROX1 levels are increased. Through mechanistic studies in multiple colorectal cancer cell lines, we show that ERβ upregulates miR-205, and that miR-205 targets and represses PROX1 through direct interaction with its 3’UTR. Through the generation of intestine-specific ERβ knockout mice, we establish that this pathway is correspondingly regulated in normal intestinal epithelial cells in vivo . Functionally, we demonstrate that miR-205 decreases cell proliferation and decreases migratory and invasive potential of colon cancer cells, leading to a reduction of micrometastasis in vivo . In conclusion, ERβ in both normal and cancerous colon epithelial cells upregulates miRNA-205, which subsequently reduces PROX1 through direct interaction with its 3’UTR. This results in reduced proliferative and metastatic potential of the cells. Our study proposes a novel pathway that may be exploited using ERβ-selective agonists and/or miR-205-replacement therapy in order to improve preventive and therapeutic approaches against colon cancer.

DNA damaging agents cause rapid shrinkage of tumors and form the basis of chemotherapy for sarcomas despite significant toxicities. Drugs having superior efficacy and wider therapeutic windows are needed to improve patient outcomes. We used cell proliferation and apoptosis assays in sarcoma cell lines and benign cells; γ-H2AX expression, comet assay, immunoblot analyses and drug combination studies in vitro and in patient derived xenograft (PDX) models. BO-1055 caused apoptosis and cell death in a concentration and time dependent manner in sarcoma cell lines. BO-1055 had potent activity (submicromolar IC50) against Ewing sarcoma and rhabdomyosarcoma, intermediate activity in DSRCT (IC50 = 2-3μM) and very weak activity in osteosarcoma (IC50 >10μM) cell lines. BO-1055 exhibited a wide therapeutic window compared to other DNA damaging drugs. BO-1055 induced more DNA double strand breaks and γH2AX expression in cancer cells compared to benign cells. BO-1055 showed inhibition of tumor growth in A673 xenografts and caused tumor regression in cyclophosphamide resistant patient-derived Ewing sarcoma xenografts and A204 xenografts. Combination of BO-1055 and irinotecan demonstrated synergism in Ewing sarcoma PDX models. Potent activity on sarcoma cells and its relative lack of toxicity presents a strong rationale for further development of BO-1055 as a therapeutic agent.

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.

The development of Fusarium Basal Rot (FBR)-resistant onion cultivars through field and seedling screening approaches faces tremendous challenges due to non-uniform distribution of the disease pathogen and possible multiple mechanisms of host&ndash, plant resistance. This study compared the efficiencies of these two methods for increasing FBR resistance of short-day onion after a single selection cycle. Asymptomatic plants or bulbs of seven onion cultivars were selected using a seedling screen performed in a growth chamber or a field screening of mature bulbs. Original and selected populations were evaluated for their responses to FBR stress thereafter employing the same two methods used for screening. The field screening of mature bulbs was found unreliable in both selection and evaluation, likely due to a non-random distribution of the FBR pathogen and variable environmental factors present in the field. The seedling screening successfully increased FBR resistance in the selected cultivar populations revealed by a seedling evaluation. From the results, it is recommended to use a consistent method for both screening and evaluation to make the most selection progress.

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.

BACKGROUND: The second-generation ALK inhibitor alectinib recently demonstrated superior efficacy compared to the first-generation ALK inhibitor crizotinib in advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC), establishing alectinib as the new standard first-line therapy. Brigatinib, another second-generation ALK inhibitor, has demonstrated 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 nine patients in this study who underwent post-alectinib/pre-brigatinib biopsies, five had an ALK I1171X or V1180L resistance mutation; of these, one had a confirmed partial response and three 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.

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.

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.

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.

Multimodality imaging techniques are becoming the norm in medical imaging. Using a combination of techniques, clinicians can make a more informed diagnosis. In the case of abdominal aortic aneurysms (AAA), a combination of CT and MRI imaging techniques is used to diagnose and subsequently decide on surgical intervention. Clinicians use a maximum transverse diameter metric of 55 mm to recommend surgery in AAA patients based on the images obtained. However, the clinical metric by itself is not sufficient to prognose rupture. Hence, a mechanics-based approach can be employed to extract biomechanical parameters such as wall shear stress and principal stresses to predict rupture well in advance. With the application of computational fluid dynamics (CFD), these parameters can be estimated from a fluid–structure interaction (FSI)-based analysis of the abnormal aorta. Patient-specific geometry and boundary conditions such as velocity, pressure, and material properties are used in these methods. In this chapter, an FSI-based approach to study the rupture mechanics of AAA is discussed in detail. Subsequently, the need of studying AAA in Asian population is outlined and a case study is presented on a patient-specific model to illustrate the mechanics-based approach in predicting rupture in AAA. Results from the case study reveal that the maximum transverse diameter is not the sole determinant of AAA rupture risk. Hence, mechanics-based method supplements the image-based techniques for better patient management.

Abdominal aortic aneurysms (AAAs) occur because of dilation of the infra-renal aorta to more than 150% of its initial diameter. Progression to rupture is aided by several pathophysiological and biomechanical factors. Surgical intervention is recommended when the aneurysm maximum transverse diameter (DAAA) exceeds 55 mm. A system model that incorporates biomechanical parameters will improve prognosis and establish a relationship between AAA geometry and rupture risk. Two Asian patient-specific AAA geometries were obtained from an IRB-approved vascular database. A biomechanical model based on the fluid–structure interaction (FSI) method was developed for a small aneurysm with DAAA of 35 mm and a large aneurysm with a corresponding diameter of 75 mm. The small aneurysm (patient 1) developed a maximum principal stress (PS1) of 3.16e5 Pa and the large aneurysm (patient 2) developed a PS1 of 2.32e5 Pa. Maximum deformation of arterial wall was 0.0020 m and 0.0022 m for patients 1 and 2 respectively. Location of maximum integral wall shear stress (WSS) (fluid) was different from that of PS1. Induced WSS was also higher in patient 1 (18.74 Pa vs 12.88 Pa). An FSI model incorporating the effect of both the structural and fluid domains aids in better understanding of the mechanics of AAA rupture. Patient 1, having a lower DAAA than patient 2, developed a larger PS1 and WSS. It may be concluded that DAAA may not be the sole determinant of AAA rupture risk. Accepted version

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 mushroomT. terrestrisandT. vialis, 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-κB 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.

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 Nrf-2 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.

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. Nanyang Technological University The authors acknowledge the SingHealth-NTU collaborative research grant (Grant number: SHS-NTU/014/2016) for the funding support to carry out this project.

143 Background: There is an emerging evidence that the gut microbiome may influence anti-tumor immune response during treatment with checkpoint inhibitors (CPIs). A number of factors can cause gut microbiome dysbiosis including the use of antibiotics (ABX). We hypothesized that the use of ABX during immunotherapy can adversely affect the efficacy of CPIs. We explored the prevalence of ABX use amongst patients (pts) using CPIs, and whether the use of ABX influences the response to CPIs. Methods: We performed an institutional retrospective review of all the pts treated with CPIs from 2/2015-3/2018. A patient was considered to have used ABX if he or she was prescribed ABX within 6 months before or after, initiating CPIs. Statistical analysis was done using logistic regression with overall response rate (ORR) (CR, PR and SD) as the outcome. 9 separate analyses were done: one for each temporality (30 days, 60 days, 6 months) and use-order (before, after, neither) combination. Odds ratios for ORR as univariate analysis, and adjusted for age and sex; and adjusted for age, sex, and tumor type were calculated. Results: Out of 242 pts, 111 were lung, 36 bladder, 35 renal, 16 gastrointestinal and 44 other cancers. 50% (121) pts received nivolumab, 28% (68) pembrolizumab and 21% (52) atezolizumab. 75%, 46% and 32% of the pts received ABX within 6 months, 60 days and 30 days of starting CPIs. Only ABX use in the first 30- or 60-days following CPI initiation was associated with inferior ORR (OR 0.42 [95% CI:0.23,0.76] p = 0.005 for 60-days). ABX use prior to initiation of CPI at any time point, or ABX use in the first 6 months of CPI use did not impact CPI efficacy, Table 1. Conclusions: ABX use within the first 60 days of starting CPI therapy is prevalent (32%). This study suggests that the use of ABX within 60 days following initiation of CPIs significantly negatively impacts the ORR. Unnecessary usage of ABX should be avoided, especially during the early phase of starting CPIs. [Table: see text]

The role of single-agent nab-paclitaxel in relapsed or platinum-refractory advanced non-small cell lung cancer (NSCLC) has not been well reported in Western populations. We reviewed our own institution's experience using nab-paclitaxel in these settings. We analyzed the records of stage IV NSCLC patients with relapsed or platinum-refractory disease treated with single-agent nab-paclitaxel at Weill Cornell Medical College between October 2008 and December 2013. The primary endpoint of the study was treatment failure-free survival (TFFS), defined as the time from the start of nab-paclitaxel therapy to discontinuation of the drug for any reason. The best overall response was recorded for each patient, and overall response and disease control rates were calculated. Thirty-one stage IV NSCLC patients received a median of 4 cycles (range 1-40) of nab-paclitaxel. Dose reduction or drug discontinuation due to toxicity occurred in 10 patients, mainly because of grade 2/3 fatigue or peripheral neuropathy. The overall response rate was 16.1 %, and the disease control rate was 64.5 %. Median TFFS was 3.5 months (95 % CI 1.3-5.3 months). No statistically significant difference in TFFS based on line of therapy or prior taxane exposure was identified. There was a statistically significant decrease in TFFS for patients with non-adenocarcinoma histology, although there were only five patients in this group. There was a trend toward reduction in the risk of treatment failure with increasing age. One patient remained on nab-paclitaxel therapy for over 3 years. Single-agent nab-paclitaxel was well tolerated and demonstrated efficacy in advanced NSCLC patients with relapsed or platinum-refractory disease. Further prospective clinical trials with nab-paclitaxel in these settings are warranted.

Objective: To estimate the incidence, short-term outcome, and spatial distribution of stroke patients and to evaluate the completeness of case ascertainment in Ludhiana. Methods: This population-based prospective cohort study was conducted in Ludhiana, Punjab, Northwest India. All first-ever stroke patients (≥18 years) were included between March 2010 and March 2013 using WHO Stepwise Approach Surveillance methodology from the city. Stroke patient data were obtained from hospitals, scan centers, and general practitioners, and details of deaths from the Municipal Corporation. Results: Out of 7,199 stroke patients recruited, 3,441 were included in final analysis. The mean age was 59 ± 15 years. The annual incidence rate was 140/100,000 (95% confidence interval [CI] 133–147) and age-adjusted incidence rate was 130/100,000 (95% CI 123–137). The annual incidence rate for stroke in the young (18–49 years) was 46/100,000 (95% CI 41–51). The case fatality at 28 days was 22%. Patients above 60 years of age ( p = 0.03) and patients who were managed in public hospitals had poor survival ( p = 0.01). Hot spots for cumulative incidence were seen in central and southern parts of the city, and hot spots for poor outcome were seen in the outskirts of the city. Conclusions: The incidence rates are similar to other studies from India. Stroke patient survival is poor in public hospitals. The finding of spatial analysis is of public health significance for stroke prevention and strengthening of stroke services.