Publications by authors named "Christopher Schultz"

128 Publications

Analysis of the effects of chemical oxidation on microbial activity using .

Heliyon 2021 Dec 23;7(12):e08665. Epub 2021 Dec 23.

US Department of Agriculture, Agriculture Research Service, Northern Plains Agricultural Research Laboratory, Sidney, MT, 59270, USA.

chemical oxidation is an effective groundwater remediation approach for delivering oxidants to the subsurface environment where various contaminants of concern, natural organic matter, and other reduced species within the soil consume the oxidants. The addition of these oxidants alters microbial activity changing the physical and chemical structure of the soil. This paper studied the effects of chemical oxidation on microbial activity with and without toluene. Several oxidants were used as part of the study: sodium percarbonate, hydrogen peroxide, potassium permanganate, and sodium persulfate evaluated at low, medium, and high concentrations. A series of biometer experiments seeded with microbe and soil sample and aqueous toluene solution for each oxidant was monitored by CO production as a function of incubation days to evaluate the effects of oxidation on the microbial activity. Of the oxidants tested, permanganate oxidation resulted in the highest increase in microbial activity post oxidation based on CO production both with and without the addition of toluene. The other oxidants exhibited a direct correlation between oxidant concentration and the change in permanganate chemical oxidant demand of the soil. However, there was no correlation between oxidant concentration and microbial activity. Each of the oxidants was shown to increase CO yield except for sodium percarbonate, which had an adverse effect on microbial activity. It is likely that the increased microbial activity associated with permanganate oxidation was the result of chemical reactions between the oxidant and natural organic matter in the soil.
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http://dx.doi.org/10.1016/j.heliyon.2021.e08665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8717238PMC
December 2021

Magnetic resonance linear accelerator technology and adaptive radiation therapy: An overview for clinicians.

CA Cancer J Clin 2022 Jan 18;72(1):34-56. Epub 2021 Nov 18.

Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas.

Radiation therapy (RT) continues to play an important role in the treatment of cancer. Adaptive RT (ART) is a novel method through which RT treatments are evolving. With the ART approach, computed tomography or magnetic resonance (MR) images are obtained as part of the treatment delivery process. This enables the adaptation of the irradiated volume to account for changes in organ and/or tumor position, movement, size, or shape that may occur over the course of treatment. The advantages and challenges of ART maybe somewhat abstract to oncologists and clinicians outside of the specialty of radiation oncology. ART is positioned to affect many different types of cancer. There is a wide spectrum of hypothesized benefits, from small toxicity improvements to meaningful gains in overall survival. The use and application of this novel technology should be understood by the oncologic community at large, such that it can be appropriately contextualized within the landscape of cancer therapies. Likewise, the need to test these advances is pressing. MR-guided ART (MRgART) is an emerging, extended modality of ART that expands upon and further advances the capabilities of ART. MRgART presents unique opportunities to iteratively improve adaptive image guidance. However, although the MRgART adaptive process advances ART to previously unattained levels, it can be more expensive, time-consuming, and complex. In this review, the authors present an overview for clinicians describing the process of ART and specifically MRgART.
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http://dx.doi.org/10.3322/caac.21707DOI Listing
January 2022

Characterization of Underrepresented Populations in Modern Era Clinical Trials Involving Radiation Therapy.

Pract Radiat Oncol 2021 Nov-Dec;11(6):453-459

Departments of Radiation Oncology; Surgery, Medical College of Wisconsin.

Purpose: The demographic composition of modern radiation therapy (RT) clinical trials is incompletely studied. Understanding and minimizing disparities in clinical trials is critical to ensure health equity and the generalizability of research findings.

Methods And Materials: Clinicaltrials.gov was searched to identify RT clinical trials that occurred from 1996 to 2019. A total of 1242 trials were reviewed for patient characteristics. The demographic composition of the studies was summarized by the frequency and percentage of patients by race, gender, and ethnicity. The racial composition of the study population was compared with the 2018 US Census using a 1-sample χ test. Subgroup racial composition was compared using χ tests of independence. Analyses used a complete case approach.

Results: A total of 122 trials met the inclusion criteria, and 121 of these (99.1%) reported race. Trial subgroups included 63 trials in the United States (51.6%), 9 proton therapy trials (7.4%), 34 RT toxicity mitigation or prevention trials (27.9%), 24 trials for female cancer (19.7%), and 17 trials for male cancer (13.9%). US clinical trials overall, US RT toxicity mitigation or prevention trials, US trials for female cancer, and US trials for male cancer had significantly different racial compositions compared with the 2018 US Census data (P < .001 for all). Compared with all clinical trials, those for proton therapy had the largest magnitude of significantly lower enrollment of participants who identified their race as Black, Asian, or other (P < .001).

Conclusions: This study characterized the racial composition of prospective RT clinical trials in a modern cohort. The racial population represented across multiple categories in the United States differed significantly from US census data and was most pronounced in trials evaluating proton therapy. This is a benchmark study for future efforts to characterize and balance the participation of underrepresented populations in RT clinical trials.
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http://dx.doi.org/10.1016/j.prro.2021.03.012DOI Listing
November 2021

The FDA-Approved Anthelmintic Pyrvinium Pamoate Inhibits Pancreatic Cancer Cells in Nutrient-Depleted Conditions by Targeting the Mitochondria.

Mol Cancer Ther 2021 Nov 19;20(11):2166-2176. Epub 2021 Aug 19.

Brenden-Colson Center for Pancreatic Care, Departments of Surgery and Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal aggressive cancer, in part due to elements of the microenvironment (hypoxia, hypoglycemia) that cause metabolic network alterations. The FDA-approved antihelminthic pyrvinium pamoate (PP) has previously been shown to cause PDAC cell death, although the mechanism has not been fully determined. We demonstrated that PP effectively inhibited PDAC cell viability with nanomolar IC50 values (9-93 nmol/L) against a panel of PDAC, patient-derived, and murine organoid cell lines. , we demonstrated that PP inhibited PDAC xenograft tumor growth with both intraperitoneal (IP; < 0.0001) and oral administration (PO; = 0.0023) of human-grade drug. Metabolomic and phosphoproteomic data identified that PP potently inhibited PDAC mitochondrial pathways including oxidative phosphorylation and fatty acid metabolism. As PP treatment reduced oxidative phosphorylation ( < 0.001), leading to an increase in glycolysis ( < 0.001), PP was 16.2-fold more effective in hypoglycemic conditions similar to those seen in PDAC tumors. RNA sequencing demonstrated that PP caused a decrease in mitochondrial RNA expression, an effect that was not observed with established mitochondrial inhibitors rotenone and oligomycin. Mechanistically, we determined that PP selectively bound mitochondrial G-quadruplexes and inhibited mitochondrial RNA transcription in a G-quadruplex-dependent manner. This subsequently led to a 90% reduction in mitochondrial encoded gene expression. We are preparing to evaluate the efficacy of PP in PDAC in an IRB-approved window-of-opportunity trial (IND:144822).
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0652DOI Listing
November 2021

Patterns of Care, Tolerability, and Safety of the First Cohort of Patients Treated on a Novel High-Field MR-Linac Within the MOMENTUM Study: Initial Results From a Prospective Multi-Institutional Registry.

Int J Radiat Oncol Biol Phys 2021 11 13;111(4):867-875. Epub 2021 Jul 13.

Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, Netherlands.

Purpose: High-field magnetic resonance-linear accelerators (MR-Linacs), linear accelerators combined with a diagnostic magnetic resonance imaging (MRI) scanner and online adaptive workflow, potentially give rise to novel online anatomic and response adaptive radiation therapy paradigms. The first high-field (1.5T) MR-Linac received regulatory approval in late 2018, and little is known about clinical use, patient tolerability of daily high-field MRI, and toxicity of treatments. Herein we report the initial experience within the MOMENTUM Study (NCT04075305), a prospective international registry of the MR-Linac Consortium.

Methods And Materials: Patients were included between February 2019 and October 2020 at 7 institutions in 4 countries. We used descriptive statistics to describe the patterns of care, tolerability (the percentage of patients discontinuing their course early), and safety (grade 3-5 Common Terminology Criteria for Adverse Events v.5 acute toxicity within 3 months after the end of treatment).

Results: A total 943 patients participated in the MOMENTUM Study, 702 of whom had complete baseline data at the time of this analysis. Patients were primarily male (79%) with a median age of 68 years (range, 22-93) and were treated for 39 different indications. The most frequent indications were prostate (40%), oligometastatic lymph node (17%), brain (12%), and rectal (10%) cancers. The median number of fractions was 5 (range, 1-35). Six patients discontinued MR-Linac treatments, but none due to an inability to tolerate repeated high-field MRI. Of the 415 patients with complete data on acute toxicity at 3-month follow-up, 18 (4%) patients experienced grade 3 acute toxicity related to radiation. No grade 4 or 5 acute toxicity related to radiation was observed.

Conclusions: In the first 21 months of our study, patterns of care were diverse with respect to clinical utilization, body sites, and radiation prescriptions. No patient discontinued treatment due to inability to tolerate daily high-field MRI scans, and the acute radiation toxicity experience was encouraging.
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http://dx.doi.org/10.1016/j.ijrobp.2021.07.003DOI Listing
November 2021

Novel and Highly Potent ATR Inhibitor M4344 Kills Cancer Cells With Replication Stress, and Enhances the Chemotherapeutic Activity of Widely Used DNA Damaging Agents.

Mol Cancer Ther 2021 08 27;20(8):1431-1441. Epub 2021 May 27.

Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, Bethesda, Maryland.

Although several ATR inhibitors are in development, there are unresolved questions regarding their differential potency, molecular signatures of patients with cancer for predicting activity, and most effective therapeutic combinations. Here, we elucidate how to improve ATR-based chemotherapy with the newly developed ATR inhibitor, M4344 using and models. The potency of M4344 was compared with the clinically developed ATR inhibitors BAY1895344, berzosertib, and ceralasertib. The anticancer activity of M4344 was investigated as monotherapy and combination with clinical DNA damaging agents in multiple cancer cell lines, patient-derived tumor organoids, and mouse xenograft models. We also elucidated the anticancer mechanisms and potential biomarkers for M4344. We demonstrate that M4344 is highly potent among the clinically developed ATR inhibitors. Replication stress (RepStress) and neuroendocrine (NE) gene expression signatures are significantly associated with a response to M4344 treatment. M4344 kills cancer cells by inducing cellular catastrophe and DNA damage. M4344 is highly synergistic with a broad range of DNA-targeting anticancer agents. It significantly synergizes with topotecan and irinotecan in patient-derived tumor organoids and xenograft models. Taken together, M4344 is a promising and highly potent ATR inhibitor. It enhances the activity of clinical DNA damaging agents commonly used in cancer treatment including topoisomerase inhibitors, gemcitabine, cisplatin, and talazoparib. RepStress and NE gene expression signatures can be exploited as predictive markers for M4344.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-1026DOI Listing
August 2021

Splenic-vasculature involvement is associated with poor prognosis in resected distal pancreatic cancer.

Gastroenterol Rep (Oxf) 2021 Apr 24;9(2):139-145. Epub 2020 Nov 24.

Department of Pathology, Immunology and Lab Medicine, University of Florida, Gainesville, FL, USA.

Background: Distal pancreatic carcinoma is one of the most lethal cancers largely due to its high incidence of distant metastasis. This study aims to assess the prognostic value of splenic-vasculature involvement in resected distal pancreatic carcinoma.

Methods: In this retrospective study, we collected the clinicopathologic information of 454 patients with pancreatic cancer and performed univariate and multivariate analyses to identify factors associated with progression-free survival (PFS) and overall survival (OS), with an emphasis on the prognostic value of splenic-artery and -vein involvement.

Results: Univariate analysis revealed that larger tumor size, non-intraductal papillary mucinous neoplasm (non-IPMN)-associated adenocarcinoma, poor differentiation, stage pT3, nodal metastasis, lymphovascular invasion, perineural invasion, and pathologic and radiographic evidence of splenic-vein invasion were significantly associated with shorter PFS and OS (all  < 0.05). Multivariate analysis confirmed non-IPMN-associated adenocarcinoma, stage pT3, stage pN1-2, and post-operative adjuvant chemotherapy as independent risk factors for both PFS and OS, and larger tumor size and radiographic evidence of splenic-artery invasion as predictors of PFS only.

Conclusion: Guidelines should be developed for a uniform approach with regard to the examination and reporting of the status of the splenic vasculature when dealing with distal-pancreatic-cancer specimens.
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http://dx.doi.org/10.1093/gastro/goaa084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128010PMC
April 2021

BRCA1 Protein Expression Predicts Survival in Glioblastoma Patients from an NRG Oncology RTOG Cohort.

Oncology 2021 6;99(9):580-588. Epub 2021 May 6.

Department of Radiation Oncology, Weill Cornell Medicine, New York, New York, USA.

Purpose: Glioblastoma, the most common malignant brain tumor, was associated with a median survival of <1 year in the pre-temozolomide (TMZ) era. Despite advances in molecular and genetic profiling studies identifying several predictive biomarkers, none has been translated into routine clinical use. Our aim was to investigate the prognostic significance of a panel of diverse cellular molecular markers of tumor formation and growth in an annotated glioblastoma tissue microarray (TMA).

Methods And Materials: A TMA composed of archived glioblastoma tumors from patients treated with surgery, radiation, and non-TMZ chemother-apy, was provided by RTOG. RAD51, BRCA-1, phosphatase and tensin homolog tumor suppressor gene (PTEN), and miRNA-210 expression levels were assessed using quantitative in situ hybridization and automated quantitative protein analysis. The objectives of this analysis were to determine the association of each biomarker with overall survival (OS), using the Cox proportional hazard model. Event-time distributions were estimated using the Kaplan-Meier method and compared by the log-rank test.

Results: A cohort of 66 patients was included in this study. Among the 4 biomarkers assessed, only BRCA1 expression had a statistically significant correlation with survival. From univariate analysis, patients with low BRCA1 protein expression showed a favorable outcome for OS (p = 0.04; hazard ratio = 0.56) in comparison with high expressors, with a median survival time of 18.9 versus 4.8 months.

Conclusions: BRCA1 protein expression was an important survival predictor in our cohort of glioblastoma patients. This result may imply that low BRCA1 in the tumor and the consequent low level of DNA repair cause vulnerability of the cancer cells to treatment.
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http://dx.doi.org/10.1159/000516168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491475PMC
September 2021

Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress.

Cancer Cell 2021 04;39(4):566-579.e7

Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Small cell neuroendocrine cancers (SCNCs) are recalcitrant cancers arising from diverse primary sites that lack effective treatments. Using chemical genetic screens, we identified inhibition of ataxia telangiectasia and rad3 related (ATR), the primary activator of the replication stress response, and topoisomerase I (TOP1), nuclear enzyme that suppresses genomic instability, as synergistically cytotoxic in small cell lung cancer (SCLC). In a proof-of-concept study, we combined M6620 (berzosertib), first-in-class ATR inhibitor, and TOP1 inhibitor topotecan in patients with relapsed SCNCs. Objective response rate among patients with SCLC was 36% (9/25), achieving the primary efficacy endpoint. Durable tumor regressions were observed in patients with platinum-resistant SCNCs, typically fatal within weeks of recurrence. SCNCs with high neuroendocrine differentiation, characterized by enhanced replication stress, were more likely to respond. These findings highlight replication stress as a potentially transformative vulnerability of SCNCs, paving the way for rational patient selection in these cancers, now treated as a single disease.
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http://dx.doi.org/10.1016/j.ccell.2021.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048383PMC
April 2021

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

J Geriatr Oncol 2021 07 2;12(6):937-944. Epub 2021 Apr 2.

Stanford University, United States of America.

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

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

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

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

Selecting the optimal parameters for sonoporation of pancreatic cancer in a pre-clinical model.

Cancer Biol Ther 2021 03 10;22(3):204-215. Epub 2021 Mar 10.

Department of Radiology, Thomas Jefferson University, Philadelphia, PA, USA.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the modern world, in part due to poor delivery of chemotherapeutics. Sonoporation can be used to enhance the efficacy of standard of care therapies for PDAC. Using xenograft models of PDAC we investigate sonoporation using four ifferent ultrasound contrast agents (UCAs) and two ultrasound regimens to identify the ideal parameters to increase therapeutic efficacy. MIA-PaCa2 xenografts in over 175 immunodeficient mice were treated with gemcitabine and paclitaxel and subjected to low or high power ultrasound (60 and 200 mW/cm respectively) in conjunction with one of four different UCAs. The UCAs investigated were Definity®, SonoVue®, Optison™ or Sonazoid™. Tumor volumes, vascularity, hemoglobin, and oxygenation were measured and compared to controls. High power treatment in conjunction with Sonazoid sonoporation led to significantly smaller tumors when started early (tumors ~50mm; = .0105), while no UCAs significantly increased efficacy in the low power cohort. This trend was also found in larger tumors (~250mm) where all four UCA agents significantly increased therapeutic efficacy in the high power group ( < .01), while only Definity and SonoVue increased efficacy in the low power cohort ( < .03). Overall, the higher power ultrasound treatment modality was more consistently effective at decreasing tumor volume and increasing vascularity characteristics. In conclusion, Sonazoid was the most consistently effective UCA at decreasing tumor volume and increasing vascularity. Thus, we are pursuing a larger phase II clinical trial to validate the increased efficacy of sonoporation in conjunction with chemotherapy in PDAC patients.
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http://dx.doi.org/10.1080/15384047.2021.1881026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043187PMC
March 2021

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

Oral Oncol 2021 05 25;116:105241. Epub 2021 Feb 25.

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

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

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

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

Conclusions: We have developed and validated easy-to-use nomograms for LSCC outcomes using prospective cooperative group trial data.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144062PMC
May 2021

In Reply to Peñagarícano.

Int J Radiat Oncol Biol Phys 2021 02;109(2):641

Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.

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http://dx.doi.org/10.1016/j.ijrobp.2020.08.066DOI Listing
February 2021

Observations of lightning in relation to transitions in volcanic activity during the 3 June 2018 Fuego Eruption.

Sci Rep 2020 Oct 22;10(1):18015. Epub 2020 Oct 22.

Earth System Science Center, The University of Alabama in Huntsville, Huntsville, AL, USA.

Satellite and ground-based remote sensing are combined to characterize lightning occurrence during the 3 June 2018 Volcán de Fuego eruption in Guatemala. The combination of the space-based Geostationary Lightning Mapper (GLM) and ground-based Earth Networks Total Lightning Network observed two distinct periods of lightning during this eruption totaling 75 unique lightning flash occurrences over five hours (57 in cloud, 18 cloud-to-ground). The first period of lightning coincided with the rapid growth of the ash cloud, while the second maxima occurred near the time of a deadly pyroclastic density current (PDC) and thunderstorm. Ninety-one percent of the lightning during the event was observed by only one of the lightning sensors, thus showing the importance of combining lightning datasets across multiple frequencies to characterize electrical activity in volcanic eruptions. GLM flashes during the event had a median total optical energy and flash length of 16 fJ, and 12 km, respectively. These median GLM flash energies and lengths observed in the volcanic plume are on the lower end of the flash spectrum because flashes observed in surrounding thunderstorms on 3 June had larger median total optical energy values (130 fJ) and longer median flash lengths (20 km). All 18 cloud-to-ground flashes were negative polarity, supportive of net negative charge within the plume. Mechanisms for the generation of the secondary lightning maxima are discussed based on the presence and potential interaction between ash plume, thunderstorm, and PDC transport during this secondary period of observed lightning.
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http://dx.doi.org/10.1038/s41598-020-74576-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582158PMC
October 2020

The MOMENTUM Study: An International Registry for the Evidence-Based Introduction of MR-Guided Adaptive Therapy.

Front Oncol 2020 7;10:1328. Epub 2020 Sep 7.

Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, Netherlands.

MR-guided Radiation Therapy (MRgRT) allows for high-precision radiotherapy under real-time MR visualization. This enables margin reduction and subsequent dose escalation which may lead to higher tumor control and less toxicity. The Unity MR-linac (Elekta AB, Stockholm, Sweden) integrates a linear accelerator with a 1.5T diagnostic quality MRI and an online adaptive workflow. A prospective international registry was established to facilitate the evidence-based implementation of the Unity MR-linac into clinical practice, to systemically evaluate long-term outcomes, and to aid further technical development of MR-linac-based MRgRT. In February 2019, the Multi-OutcoMe EvaluatioN of radiation Therapy Using the MR-linac study (MOMENTUM) started within the MR-linac Consortium. The MOMENTUM study is an international academic-industrial partnership between several hospitals and industry partner Elekta. All patients treated on the MR-linac are eligible for inclusion in MOMENTUM. For participants, we collect clinical patient data (e.g., patient, tumor, and treatment characteristics) and technical patient data which is defined as information generated on the MR-linac during treatment. The data are captured, pseudonymized, and stored in an international registry at set time intervals up to two years after treatment. Patients can choose to provide patient-reported outcomes and consent to additional MRI scans acquired on the MR-linac. This registry will serve as a data platform that supports multicenter research investigating the MR-linac. Rules and regulations on data sharing, data access, and intellectual property rights are summarized in an academic-industrial collaboration agreement. Data access rules ensure secure data handling and research integrity for investigators and institutions. Separate data access rules exist for academic and industry partners. This study is registered at ClinicalTrials.gov with ID: NCT04075305 (https://clinicaltrials.gov/ct2/show/NCT04075305). The multi-institutional MOMENTUM study has been set up to collect clinical and technical patient data to advance technical development, and facilitate evidenced-based implementation of MR-linac technology with the ultimate purpose to improve tumor control, survival, and quality of life of patients with cancer.
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http://dx.doi.org/10.3389/fonc.2020.01328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505056PMC
September 2020

Improving Structure Delineation for Radiation Therapy Planning Using Dual-Energy CT.

Front Oncol 2020 28;10:1694. Epub 2020 Aug 28.

Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, United States.

Purpose: We present the advantages of using dual-energy CT (DECT) for radiation therapy (RT) planning based on our clinical experience.

Methods: DECT data acquired for 20 representative patients of different tumor sites and/or clinical situations with dual-source simultaneous scanning (Drive, Siemens) and single-source sequential scanning (Definition, Siemens) using 80 and 140-kVp X-ray beams were analyzed. The data were used to derive iodine maps, fat maps, and mono-energetic images (MEIs) from 40 to 190 keV to exploit the energy dependence of X-ray attenuation. The advantages of using these DECT-derived images for RT planning were investigated.

Results: When comparing 40 keV MEIs to conventional 120-kVp CT, soft tissue contrast between the duodenum and pancreatic head was enhanced by a factor of 2.8. For a cholangiocarcinoma patient, contrast between tumor and surrounding tissue was increased by 96 HU and contrast-to-noise ratio was increased by up to 60% for 40 keV MEIs compared to conventional CT. Simultaneous dual-source DECT also preserved spatial resolution in comparison to sequential DECT as evidenced by the identification of vasculature in a pancreas patient. Volume of artifacts for five patients with titanium implants was reduced by over 95% for 190 keV MEIs compared to 120-kVp CT images. A 367-cm region of photon starvation was identified by low CT numbers in the soft tissue of a mantle patient in a conventional CT scan but was eliminated in a 190 keV MEI. Fat maps enhanced image contrast as demonstrated by a meningioma patient.

Conclusion: The use of DECT for RT simulation offers clinically meaningful advantages through improved simulation workflow and enhanced structure delineation for RT planning.
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http://dx.doi.org/10.3389/fonc.2020.01694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484725PMC
August 2020

Simulated shift work during pregnancy does not impair progeny metabolic outcomes in sheep.

J Physiol 2020 12 28;598(24):5807-5819. Epub 2020 Sep 28.

Robinson Research Institute, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.

Key Points: Maternal shift work increases the risk of pregnancy complications, although its effects on progeny health after birth are not clear. We evaluated the impact of a simulated shift work protocol for one-third, two-thirds or all of pregnancy on the metabolic health of sheep progeny. Simulated shift work had no effect on growth, body size, body composition or glucose tolerance in pre-pubertal or young adult progeny. Glucose-stimulated insulin secretion was reduced in adult female progeny and insulin sensitivity was increased in adult female singleton progeny. The results of the present study do not support the hypothesis that maternal shift work exposure impairs metabolic health of progeny in altricial species.

Abstract: Disrupted maternal circadian rhythms, such as those experienced during shift work, are associated with impaired progeny metabolism in rodents. The effects of disrupted maternal circadian rhythms on progeny metabolism have not been assessed in altricial, non-litter bearing species. We therefore assessed postnatal growth from birth to adulthood, as well as body composition, glucose tolerance, insulin secretion and insulin sensitivity, in pre-pubertal and young adult progeny of sheep exposed to control conditions (CON: 10 males, 10 females) or to a simulated shift work (SSW) protocol for the first one-third (SSW0-7: 11 males, 9 females), the first two-thirds (SSW0-14: 8 males, 11 females) or all (SSW0-21: 8 males, 13 females) of pregnancy. Progeny growth did not differ between maternal treatments. In pre-pubertal progeny (12-14 weeks of age), adiposity, glucose tolerance and insulin secretion during an i.v. glucose tolerance test and insulin sensitivity did not differ between maternal treatments. Similarly, in young adult progeny (12-14 months of age), food intake, adiposity and glucose tolerance did not differ between maternal treatments. At this age, however, insulin secretion in response to a glucose bolus was 30% lower in female progeny in the combined SSW groups compared to control females (P = 0.031), and insulin sensitivity of SSW0-21 singleton females was 236% compared to that of CON singleton female progeny (P = 0.025). At least in this model, maternal SSW does not impair progeny metabolic health, with some evidence of greater insulin action in female young adult progeny.
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http://dx.doi.org/10.1113/JP280341DOI Listing
December 2020

Margin-Positive Pancreatic Ductal Adenocarcinoma during Pancreaticoduodenectomy: Additional Resection Does Not Improve Survival.

Ann Surg Oncol 2021 Mar 10;28(3):1552-1562. Epub 2020 Aug 10.

Department of Surgery, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.

Background: The impact of resecting positive margins during pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDA) remains debated. Additionally, the survival benefit of resecting multiple positive margins is unknown.

Methods: We identified patients with PDA who underwent PD from 2006 to 2015. Pancreatic neck, bile duct, and uncinate frozen section margins were assessed before and after resection of positive margins. Survival curves were compared with log-rank tests. Multivariable Cox regression assessed the effect of margin status on overall survival.

Results: Of 501 patients identified, 17.3%, 5.3%, and 19.7% had an initially positive uncinate, bile duct, or neck margin, respectively. Among initially positive bile duct and neck margins, 77.8% and 67.0% were resected, respectively. Although median survival was decreased among patients with any positive margins (15.6 vs. 20.9 months; p = 0.006), it was similar among patients with positive bile duct or neck margins with or without R1 to R0 resection (17.0 vs. 15.6 months; p = 0.20). Median survival with and without positive uncinate margins was 13.8 vs. 19.7 months (p = 0.04). Uncinate margins were never resected. Resection of additional margins when the uncinate was concurrently positive was not associated with improved survival (p = 0.37). Patients with positive margins who received adjuvant therapy had improved survival, regardless of margin resection (p = 0.03). Adjuvant therapy was independently protective against death (hazard ratio 0.6, 95% CI 0.5-0.7).

Conclusions: Positive PD margins at any position are associated with reduced overall survival; however, resection of additional margins may not improve survival, particularly with concurrently positive uncinate margins. Adjuvant chemotherapy improves survival with positive margins, regardless of resection.
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http://dx.doi.org/10.1245/s10434-020-09000-9DOI Listing
March 2021

Early anthropometry, strength, and function in survivors of critical illness.

Aust Crit Care 2021 01 26;34(1):33-37. Epub 2020 Jul 26.

Intensive Care Unit, Royal Adelaide Hospital, Port Road, Adelaide, South Australia, 5000, Australia. Electronic address:

Background: Critically ill patients experience acute muscle wasting and long-term functional impairments, yet this has been inadequately categorised early in recovery.

Objective: This observational study aimed to evaluate anthropometry, strength, and muscle function after intensive care unit discharge.

Methods: Adult patients able to complete study measures after prolonged intensive care unit stay (≥5 d) were eligible. Demographic and clinical data were collected, and bodyweight, height, triceps skinfold, trunk length, handgrip strength, 6-minute walk test, whole-body dual-energy x-ray absorptiometry, and mid-thigh, knee, and above-ankle circumferences were measured. Body cell mass was calculated from these data. Data are presented as mean (standard deviation) or median [interquartile range].

Results: Fourteen patients (50% male; 57 [10.5] years) were assessed 11.1 (6.9) d after intensive care unit discharge. Patients lost 4.76 (6.66) kg in the intensive care unit. Triceps skinfold thickness (17.00 [8.65] mm) and handgrip strength (12.60 [8.57] kg) were lower than normative data. No patient could commence the 6-minute walk test. Dual-energy x-ray absorptiometry-derived muscle mass correlated with handgrip strength (R = 0.57; 95% confidence interval = 0.06-0.85; p = 0.03), but body cell mass did not.

Conclusions: Anthropometry and strength in intensive care unit survivors are below normal. Muscle mass derived from dual-energy x-ray absorptiometry correlates with handgrip strength but body cell mass does not.
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http://dx.doi.org/10.1016/j.aucc.2020.05.007DOI Listing
January 2021

Comprehensive Genomic Analysis in NRG Oncology/RTOG 9802: A Phase III Trial of Radiation Versus Radiation Plus Procarbazine, Lomustine (CCNU), and Vincristine in High-Risk Low-Grade Glioma.

J Clin Oncol 2020 10 24;38(29):3407-3417. Epub 2020 Jul 24.

The Ohio State University, Columbus, OH.

Purpose: NRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802.

Methods: mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates.

Results: Of the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were wild type, 43 (41%) were mutant/non-codeleted, and 37(35%) were mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; = .003; HR, 0.13; < .001) and OS (HR, 0.38; = .013; HR, 0.21; = .029) in the mutant/non-codeleted and mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the wild-type subgroup.

Conclusion: This study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with -mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.
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http://dx.doi.org/10.1200/JCO.19.02983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527157PMC
October 2020

Pulsed Reduced Dose Rate Radiotherapy in Conjunction With Bevacizumab or Bevacizumab Alone in Recurrent High-grade Glioma: Survival Outcomes.

Int J Radiat Oncol Biol Phys 2020 11 27;108(4):979-986. Epub 2020 Jun 27.

Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.

Purpose: Dismal prognosis and limited treatment options for recurrent high-grade glioma have provoked interest in various forms of reirradiation. Pulsed reduced dose rate radiation therapy (pRDR) is a promising technique that exploits low-dose hyper-radiosensitivity of proliferating tumor cells while sparing adjacent nonproliferating normal brain tissue. Large radiation treatment volumes can thus be used to target both contrast-enhancing and FLAIR abnormalities thought to harbor recurrent gross and microscopic disease, respectively. The aim of this retrospective study was to determine whether the addition of pRDR to bevacizumab improves survival over bevacizumab alone for recurrent high-grade glioma.

Methods And Materials: Eighty patients with recurrent high-grade glioma were included in this study; 47 patients received bevacizumab monotherapy (BEV), and 33 patients received pRDR with bevacizumab (BEV/pRDR). Progression-free survival (PFS) and overall survival were compared between the BEV and BEV/pRDR groups. Regression analysis was performed to identify and control for confounding influences on survival analyses.

Results: Significant (P < .05) advantages in PFS (12 vs 4 months; hazard ratio = 2.37) and OS (16 vs. 9 months; hazard ratio = 1.68) were observed with BEV/pRDR compared with BEV alone.

Conclusions: This retrospective analysis suggests that treatment with pRDR in addition to bevacizumab could significantly prolong PFS and overall survival compared with bevacizumab alone for recurrent high-grade glioma.
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http://dx.doi.org/10.1016/j.ijrobp.2020.06.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8655709PMC
November 2020

Validation of American Joint Committee on Cancer 8 edition of TNM staging in resected distal pancreatic cancer.

World J Gastrointest Pharmacol Ther 2020 Jun;11(2):25-39

Department of Pathology, Immunology and Lab Medicine, University of Florida, Gainesville, FL 32610, United States.

Background: In order to improve risk stratification and clinical management of the pancreatic ductal adenocarcinoma (PDAC), the American Joint Committee on Cancer (AJCC) has published its eighth edition staging manual. Some major changes have been introduced in the new staging system for both T and N categories. Given the rarity of resectable disease, distal pancreatic cancer is likely underrepresented in the published clinical studies, and how the impact of the staging system actually reflects on to clinical outcomes remain unclear.

Aim: To validate the AJCC 8 edition of TNM staging in distal PDAC.

Methods: A retrospective cohort study was performed in seven academic medical centers in the United States. Clinicopathological prognostic factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated through univariate and multivariate analyses.

Results: Overall, 454 patients were enrolled in the study, and were divided into 2 subgroups: Invasive intraductal papillary mucinous neoplasms (IPMN) (115 cases) and non-IPMN associated adenocarcinoma (339 cases). Compared to invasive IPMN, non-IPMN associated adenocarcinomas are more common in relatively younger patients, have larger tumor size, are more likely to have positive lymph nodes, and are associated with a higher tumor (T) stage and nodal (N) stage, lymphovascular invasion, perineural invasion, tumor recurrence, and a worse PFS and OS. The cohort was predominantly categorized as stage 3 per AJCC 7 edition staging manual, and it's more evenly distributed based on 8 edition staging manual. T and N staging of both 7 and 8 edition sufficiently stratify PFS and OS in the entire cohort, although dividing into N1 and N2 according to the 8 edition does not show additional stratification. For PDAC arising in IPMN, T staging of the 7 edition and N1/N2 staging of the 8 edition appear to further stratify PFS and OS. For PDAC without an IPMN component, T staging from both versions fails to stratify PFS and OS.

Conclusion: The AJCC 8 edition TNM staging system provides even distribution for the T staging, however, it does not provide better risk stratification than previous staging system for distal pancreatic cancer.
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http://dx.doi.org/10.4292/wjgpt.v11.i2.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288727PMC
June 2020

4D-MRI driven MR-guided online adaptive radiotherapy for abdominal stereotactic body radiation therapy on a high field MR-Linac: Implementation and initial clinical experience.

Clin Transl Radiat Oncol 2020 Jul 15;23:72-79. Epub 2020 May 15.

Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, United States.

Background And Purpose: In this report, we describe our implementation and initial clinical experience using 4D-MRI driven MR-guided online adaptive radiotherapy (MRgOART) for abdominal stereotactic body radiotherapy (SBRT) on the Elekta Unity MR-Linac.

Materials And Methods: Eleven patients with abdominal malignancies were treated with free-breathing SBRT in three to five fractions on a 1.5 T MR-Linac. Online adaptive plans were generated using Adapt-To-Position (ATP) or Adapt-To-Shape (ATS) workflows based on motion averaged or mid-position images derived from a pre-beam 4D-MRI. A high performance server positioned on the local MR-Linac machine network was utilized for 4D-MR image reconstruction. A parallel contour editing approach was employed in the ATS workflow. Intravoxel incoherent motion (IVIM) and T2 mapping sequences were acquired during adaptive planning in both ATP and ATS workflows for treatment response monitoring. Adaptive plans were delivered under real-time cine image motion monitoring.

Results: The shortest 4D-MRI time-to-image was the motion averaged image, followed by mid position and respiratory binned images. In this cohert of patients, 50% of treatments utilized the ATS workflow; the remaining treatments utilized the ATP workflow. Mid-position images were utilized as daily planning images for two of the eleven patients. The mean daily adaptive plan secondary dose calculation and ArcCheck 3D Gamma passing rates were 97.5% (92.1-100.0%) and 99.3% (96.2-100.0%), respectively. The median overall treatment times for abdominal SBRT was 46 and 62 min for ATP and ATS workflows, respectively.

Conclusion: We have successfully implemented and utilized a 4D-MRI driven MRgOART process with ATP and ATS workflows for free-breathing abdominal SBRT on a 1.5 T Elekta Unity MR-Linac.
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http://dx.doi.org/10.1016/j.ctro.2020.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256110PMC
July 2020

HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis.

J Clin Invest 2020 07;130(7):3848-3864

Department of Pathology, University of Chicago, Chicago, Illinois, USA.

Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumor growth, and strongly suppressed metastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to its ability to simultaneously regulate multiple essential oncogenic pathways in MPNST cells, including the Wnt/β-catenin, YAP/TAZ, RB/E2F, and BET pathways, which converge on key transcriptional networks. Given the exceptional dependency of MPNST cells on HuR for survival, proliferation, and dissemination, we propose that HuR represents a promising therapeutic target for MPNST treatment.
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http://dx.doi.org/10.1172/JCI130379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324187PMC
July 2020

Effect of Hypercapnia, an Element of Obstructive Respiratory Disorder, on Pancreatic Cancer Chemoresistance and Progression.

J Am Coll Surg 2020 04 11;230(4):659-667. Epub 2020 Feb 11.

Jefferson Pancreas, Biliary, and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, PA.

Background: Chronic obstructive respiratory disorders (ORDs) are linked to increased rates of cancer-related deaths. Little is known about the effects of hypercapnia (elevated CO) on development of pancreatic ductal adenocarcinoma (PDAC) and drug resistance.

Study Design: Two PDAC cell lines were exposed to normocapnic (5% CO) and hypercapnic (continuous/intermittent 10% CO) conditions, physiologically similar to patients with active ORD. Cells were assessed for proliferation rate, colony formation, and chemo-/radiotherapeutic efficacy. In a retrospective clinical study design, patients with PDAC who had undergone pancreatic resection between 2002 and 2014 were reviewed. Active smokers were excluded to remove possible smoking-related protumorigenic influence. Clinical data, pathologic findings, and survival end points were recorded. Kaplan-Meier and Cox regression analyses were performed.

Results: Exposure to hypercapnia resulted in increased colony formation and proliferation rates in vitro in both cell lines (MIA-PaCa-2: 111% increase and Panc-1: 114% increase; p < 0.05). Hypercapnia exposure induced a 2.5-fold increase in oxaliplatin resistance (p < 0.05) in both cell lines and increased resistance to ionizing radiation in MIA-PaCa-2 cells (p < 0.05). Five hundred and seventy-eight patients were included (52% were male, median age was 68.7 years [interquartile range 60.6 to 76.8 years]). Cox regression analysis, assessing TNM staging, age, sex, and ORD status, identified ORD as an independent risk factor for both overall survival (hazard ratio 1.64; 95% CI, 1.2 to 2.3; p < 0.05) and disease-free survival (hazard ratio 1.68; 95% CI, 1.06 to 2.67).

Conclusions: PDAC cells exposed to hypercapnic environments, which is common in patients with ORD, showed tumor proliferation, radioresistance, and chemoresistance. Patients with a history of ORD had a worse overall prognosis, suggesting that hypercapnic conditions play a role in the development and progression of PDAC and stressing the need for patient-tailored care.
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http://dx.doi.org/10.1016/j.jamcollsurg.2019.12.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498306PMC
April 2020

Understanding and targeting the disease-related RNA binding protein human antigen R (HuR).

Wiley Interdiscip Rev RNA 2020 05 23;11(3):e1581. Epub 2020 Jan 23.

Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.

Altered gene expression is a characteristic feature of many disease states such as tumorigenesis, and in most cancers, it facilitates cancer cell survival and adaptation. Alterations in global gene expression are strongly impacted by post-transcriptional gene regulation. The RNA binding protein (RBP) HuR (ELAVL1) is an established regulator of post-transcriptional gene regulation and is overexpressed in most human cancers. In many cancerous settings, HuR is not only overexpressed, but it is "overactive" as denoted by increased subcellular localization within the cytoplasm. This dysregulation of HuR expression and cytoplasmic localization allows HuR to stabilize and increase the translation of various prosurvival messenger RNA (mRNAs) involved in the pathogenesis of numerous cancers and various diseases. Based on almost 20 years of work, HuR is now recognized as a therapeutic target. Herein, we will review the role HuR plays in the pathophysiology of different diseases and ongoing therapeutic strategies to target HuR. We will focus on three ongoing-targeted strategies: (1) inhibiting HuR's translocation from the nucleus to the cytoplasm; (2) inhibiting the ability of HuR to bind target RNA; and (3) silencing HuR expression levels. In an oncologic setting, HuR has been demonstrated to be critical for a cancer cell's ability to survive a variety of cancer relevant stressors (including drugs and elements of the tumor microenvironment) and targeting this protein has been shown to sensitize cancer cells further to insult. We strongly believe that targeting HuR could be a powerful therapeutic target to treat different diseases, particularly cancer, in the near future. This article is categorized under: RNA in Disease and Development > RNA in Disease NRA Turnover and Surveillance > Regulation of RNA Stability Translation > Translation Regulation.
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http://dx.doi.org/10.1002/wrna.1581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482136PMC
May 2020

The association between BMI and BSA-temozolomide-induced myelosuppression toxicities: a correlative analysis of NRG oncology RTOG 0525.

Neurooncol Pract 2019 Dec 6;6(6):473-478. Epub 2019 Apr 6.

Baptist Hospital of Miami, FL.

Background: Fearing increased myelotoxicity, many practitioners adjust the body surface area (BSA)-calculated doses in obese patients. Regarding temozolomide (TMZ), a prior study suggested men with a BSA >2 m may experience increased toxicity; however, surprisingly, the inverse observation was noted in women, ie, BSA <2 m was associated with higher toxicity. To further clarify this issue, data derived from a large clinical trial were analyzed.

Methods: The incidence of grade 3 and 4 myelotoxicity in a newly diagnosed glioblastoma phase 3 trial (RTOG 0525) was statistically correlated with BMI and separately with BSA. All patients received radiation and TMZ followed by adjuvant standard dose TMZ vs dose-dense TMZ; dosing regimen-associated myelotoxicity and BMI/BSA were analyzed separately. was defined as a BMI ≥30.

Results: There was no statistically significant correlation between gender and BSA and the occurrence of myotoxicities. For the standard arm, surprisingly the incidence of grade 3/4 myotoxicities in patients with a BMI <30 was significantly higher than in patients with a BMI ≥30 (12% vs 1%, odds ratio [OR] 12.5, < .001). There was no significant difference between obese and nonobese patients (BMI "cut-point" of 30) in the dose-dense arm (OR = 0.9, 95% confidence interval: 0.4-1.6). The grade hematological 3/4 toxicity rate was significantly higher in women vs men (14% vs 8%) = .009 in spite of the lack of association between gender and BSA or BMI.

Conclusion: TMZ dosing based on actual BSA is recommended with the caveat that woman are likely at higher toxicity risk.
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http://dx.doi.org/10.1093/nop/npz006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899045PMC
December 2019

Dynamic trafficking and turnover of JAM-C is essential for endothelial cell migration.

PLoS Biol 2019 12 2;17(12):e3000554. Epub 2019 Dec 2.

Centre for Microvascular Research, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.

Junctional complexes between endothelial cells form a dynamic barrier that hinders passive diffusion of blood constituents into interstitial tissues. Remodelling of junctions is an essential process during leukocyte trafficking, vascular permeability, and angiogenesis. However, for many junctional proteins, the mechanisms of junctional remodelling have yet to be determined. Here, we used receptor mutagenesis, horseradish peroxidase (HRP), and ascorbate peroxidase 2 (APEX-2) proximity labelling, alongside light and electron microscopy (EM), to map the intracellular trafficking routes of junctional adhesion molecule-C (JAM-C). We found that JAM-C cotraffics with receptors associated with changes in permeability such as vascular endothelial cadherin (VE-Cadherin) and neuropilin (NRP)-1 and 2, but not with junctional proteins associated with the transmigration of leukocytes. Dynamic JAM-C trafficking and degradation are necessary for junctional remodelling during cell migration and angiogenesis. By identifying new potential trafficking machinery, we show that a key point of regulation is the ubiquitylation of JAM-C by the E3 ligase Casitas B-lineage lymphoma (CBL), which controls the rate of trafficking versus lysosomal degradation.
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http://dx.doi.org/10.1371/journal.pbio.3000554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907879PMC
December 2019

ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications.

Mol Cancer Ther 2019 11;18(11):1899-1908

The University of Texas MD Anderson Cancer Center, Houston, Texas.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid malignancies with very few therapeutic options to treat advanced or metastatic disease. The utilization of genomic sequencing has identified therapeutically relevant alterations in approximately 25% of PDAC patients, most notably in the DNA damage response and repair (DDR) genes, rendering cancer cells more sensitive to DNA-damaging agents and to DNA damage response inhibitors, such as PARP inhibitors. ATM is one of the most commonly mutated DDR genes, with somatic mutations identified in 2% to 18% of PDACs and germline mutations identified in 1% to 34% of PDACs. ATM plays a complex role as a cell-cycle checkpoint kinase, regulator of a wide array of downstream proteins, and responder to DNA damage for genome stability. The disruption of ATM signaling leads to downstream reliance on ATR and CHK1, among other DNA-repair mechanisms, which may enable exploiting the inhibition of downstream proteins as therapeutic targets in -mutated PDACs. In this review, we detail the function of ATM, review the current data on ATM deficiency in PDAC, examine the therapeutic implications of ATM alterations, and explore the current clinical trials surrounding the ATM pathway.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830515PMC
November 2019
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