tbuckley/cabot-search huggingface dataset:
Steric Inhibition of 5′ UTR Regulatory Elements Results in Upregulation of Human CFTR
Authors: Shruti Sasaki, Rachel Sun, Huynh-Hoa Bui, Jeff R. Crosby, Brett P. Monia, Shuling Guo
Journal: Molecular Therapy (2019)

Cystic fibrosis (CF) is an autosomal recessive monogenic disease caused by mutations in the CFTR gene. Therapeutic approaches that are focused on correcting CFTR protein face the challenge of the heterogeneity in CFTR mutations and resulting defects. Thus, while several small molecules directed at CFTR show benefit in the clinic for subsets of CF patients, these drugs cannot treat all CF patients. Additionally, the clinical benefit from treatment with these modulators could be enhanced with novel therapies.To address this unmet need, we utilized an approach to increase CFTR protein levels through antisense oligonucleotide (ASO)-mediated steric inhibition of 5′ UTR regulatory elements. We identified ASOs to upregulate CFTR protein expression and confirmed the regulatory role of the sites amenable to ASO-mediated upregulation. Two ASOs were investigated further, and both increased CFTR protein expression and function in cell lines and primary human bronchial epithelial cells with distinct CF genotypes. ASO treatment further increased CFTR function in almost all CF genotypes tested on top of treatment with the FDA approved drug Symdeko (ivacaftor and tezacaftor). Thus, we present a novel approach to CFTR therapeutic intervention, through ASO-mediated modulation of translation. Cystic fibrosis (CF) is an autosomal recessive monogenic disease caused by mutations in the CFTR gene. Therapeutic approaches that are focused on correcting CFTR protein face the challenge of the heterogeneity in CFTR mutations and resulting defects. Thus, while several small molecules directed at CFTR show benefit in the clinic for subsets of CF patients, these drugs cannot treat all CF patients. Additionally, the clinical benefit from treatment with these modulators could be enhanced with novel therapies. To address this unmet need, we utilized an approach to increase CFTR protein levels through antisense oligonucleotide (ASO)-mediated steric inhibition of 5′ UTR regulatory elements. We identified ASOs to upregulate CFTR protein expression and confirmed the regulatory role of the sites amenable to ASO-mediated upregulation. Two ASOs were investigated further, and both increased CFTR protein expression and function in cell lines and primary human bronchial epithelial cells with distinct CF genotypes. ASO treatment further increased CFTR function in almost all CF genotypes tested on top of treatment with the FDA approved drug Symdeko (ivacaftor and tezacaftor). Thus, we present a novel approach to CFTR therapeutic intervention, through ASO-mediated modulation of translation.
68Ga-PSMA PET/CT Uptake in the Ureter Caused by Ligand Expression in Urothelial Cancer
Authors: Helle D. Zacho, Sine H. Pedersen, Astrid Petersen, Lars J. Petersen
Journal: Clinical Nuclear Medicine (2019)

Abstract 68 Ga-PSMA PET/CT has become a well-established imaging modality to detect prostate cancer (PCa) metastases in biochemical recurrence. Despite its claimed specificity for PCa, 68 Ga-PSMA uptake in tissues unrelated to PCa, particularly in the neovascular tissue of other cancers, has been reported in numerous studies. A 73-year-old man underwent 68 Ga-PSMA PET/CT for biochemical recurrence of PCa 7 years after radical prostatectomy. The 68 Ga-PSMA PET/CT showed 1 lesion with PSMA uptake in the distal left ureter. Histology revealed a low-grade noninvasive papillary urothelial carcinoma. By immunohistochemistry, PSMA expression was observed in the neoplastic urothelial cells and in the vessels of the papillary structures.
First-in class selective AXL inhibitor bemcentinib (BGB324) in combination with LDAC or decitabine exerts anti-leukaemic activity in AML patients unfit for intensive chemotherapy: Phase II open-label study.
Authors: Sonja Loges, Michael Heuser, Jörg Chromik, Carlos Enrique Vigil, Peter Paschka, Francesca RE, Nicola Di Renzo, Roberto Lemoli, Daniele Mattei, Isabel Ben Batalla, Monica Hellesøy, David Micklem, Robert J Holt, Katherine Lorens, James B. Lorens, Muhammad Shoaib, Hassan Aly, Walter M. Fiedler, Jorge E. Cortes, Bjorn T. Gjertsen
Journal: Journal of Clinical Oncology (2019)

7043 Background: The RTK AXL represents a therapeutic target promoting AML cell proliferation and survival by pleiotropic mechanisms and is a negative regulator of anti-tumour immunity. Bemcentinib is a first-in-class, highly selective, oral AXL inhibitor that has previously shown encouraging anti-leukaemic activity as a monotherapy in r/r AML and hr-MDS. Methods: A monotherapy dose-escalation and expansion part of this trial is complete. In this second, phase II part of the study, 11 and 15 AML pts unfit for intensive chemotherapy received bemcentinib at RP2D (200 mg po/d) in combination with low-dose cytarabine (LDAC) and decitabine, respectively. Median age was 77 yr (range: 50-83), median screen myeloblast count 39% (3-95%) and 2/19 (11%) of pts evaluable for FLT3 were FLT3+. Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) at screen and following treatment. Results: The most common TRAEs (≥ 15% of pts) were ECG QT prolongation (35%) and diarrhoea (15%). Among these, 3 were Grade 3, and none 4 or 5. All TRAEs were manageable and/or reversible. As of Feb ‘19, 9 pts (2 de novo, 1 secondary, 6 r/r) in the bemcentinib + LDAC group were evaluable for response and 4 (44%; 2 de novo + 2 relapsed) achieved rapid CRi at C2D1. Responses were durable (range: 7 – 11 cycles) in 3 of the 4 responders. A further 2 pts (22%, 1 secondary + 1 relapsed) achieved durable SD (5 and 6 cycles). mPFS among the 5 pts with durable CRi or SD was 5 months (range: 3.5-7.7). Further, at the time of writing, 11 pts (8 de novo, 3 r/r) in the bemcentinib + decitabine group were evaluable for response of which 4 (36%, all de novo) achieved CRi after ≥ 4 cycles. One additional de novo pt achieved durable SD lasting for 5 cycles. Conclusions: Bemcentinib in combination with LDAC exerted early durable responses in patients with both de novo and relapsed AML whilst the combination of bemcentinib + decitabine exerted comparably fewer and later responses in de novo AML. Soluble biomarker correlations will be presented at the meeting. Both combinations were generally well-tolerated and further exploration is warranted. Clinical trial information: NCT02488408.
Myocardial Infarction Risk Stratification With a Single Measurement of High-Sensitivity Troponin I
Authors: Yader Sandoval, Richard Nowak, Christopher R. deFilippi, Robert H. Christenson, W. Frank Peacock, James McCord, Alexander T. Limkakeng, Anne Sexter, Fred S. Apple
Journal: Journal of the American College of Cardiology (2019)
Report on the AASLD/EASL Joint Workshop on Clinical Trial Endpoints in NAFLD
Authors: Mary E. Rinella, Frank Tacke, Arun J. Sanyal, Quentin M. Anstee
Journal: Hepatology (2019)

Nonalcoholic fatty liver disease (NAFLD) is a global public health concern. Its natural history, the development of nonalcoholic steatohepatitis (NASH) and fibrosis, is highly variable, prone to endogenous (e.g., genetics, microbiota) and exogenous (e.g., nutrition, alcohol, physical activity) disease modifiers, and can fluctuate over time. The complexity of its pathophysiology is reflected by the multitude of pharmacological targets in development. NASH clinical trials have provided valuable insight that is applicable to future trial design. Endpoints for NASH have evolved over the past decade and will continue to be refined. Currently accepted endpoints for conditional approval include resolution of NASH without worsening of fibrosis and/or improvement in fibrosis without worsening of NASH by standardized evaluation of paired liver histology. In pediatric NASH, practical obstacles, pubertal hormonal changes, and stringent safety requirements mandate adaptations in trial design. In adult patients with NASH‐related cirrhosis, clinical events (e.g. decompensation, hepatocellular carcinoma, transplantation, death) are more prevalent and thereby are viable primary endpoints. Consideration of the natural fluctuation of disease, the clinical implication of the chosen primary endpoint, and factors that may affect placebo response will facilitate an accurate determination of efficacy of emerging therapeutics for NASH. Conclusion : The June 2018 American Association for the Study of Liver Diseases and European Association for the Study of the Liver joint workshop on NAFLD endpoints summarized important findings from ongoing and completed trials, defined the scientific evidence supporting distinct endpoints, and provided guidance for future trial design.
Changes in Myocardial Native T1 and T2 After Exercise Stress
Authors: Shiro Nakamori, Ahmed Fahmy, Jihye Jang, Hossam El-Rewaidy, Ulf Neisius, Sophie Berg, Beth Goddu, Patrick Pierce, Jennifer Rodriguez, Thomas Hauser, Long H. Ngo, Warren J. Manning, Reza Nezafat
Journal: JACC. Cardiovascular imaging (2019)
Phase I/II dose-escalation and expansion study of FLX475 alone and in combination with pembrolizumab in advanced cancer.
Authors: John D. Powderly, Bartosz Chmielowski, Julie R. Brahmer, Sarina Anne Piha-Paul, Samantha Elizabeth Bowyer, Patricia LoRusso, Daniel V.T. Catenacci, Christina Wu, Minal A. Barve, Michael Jon Chisamore, Nicole Nasrah, Dan Johnson, William Ho
Journal: Journal of Clinical Oncology (2020)

TPS3163 Background: Regulatory T cells (T reg ) can dampen anti-tumor immune responses in the tumor microenvironment (TME). The predominant chemokine receptor on human T reg is CCR4, the receptor for the chemokines CCL17 and CCL22, which are produced by tumor cells, tumor-associated macrophages and dendritic cells, as well as by effector T cells (T eff ) in the setting of an inflammatory anti-tumor response. Preclinical studies with orally-available CCR4 antagonists have demonstrated potent inhibition of T reg migration into tumors, an increase in the intratumoral T eff /T reg ratio, and anti-tumor efficacy as a single agent and in combination with checkpoint inhibitors. In a first-in-human trial conducted in healthy volunteers, the oral CCR4 antagonist FLX475 was demonstrated to be well tolerated with outstanding PK properties. A robust PD assay measuring receptor occupancy on circulating T reg demonstrated the ability to safely achieve exposure levels predicted to maximally inhibit T reg recruitment into tumors via CCR4 signaling. These human PK, PD, and safety data have enabled a streamlined design of a Phase 1/2 study of FLX475 in cancer patients both as monotherapy and in combination with checkpoint inhibitor. Methods: This clinical trial is a Phase 1/2, open-label, dose-escalation and cohort expansion study to determine the safety and preliminary anti-tumor activity of FLX475 as monotherapy and in combination with pembrolizumab. The study is being conducted in 2 parts, a dose-escalation phase (Part 1) and a cohort expansion phase (Part 2). In Part 1 (Phase 1) of the study, at least 3 to 6 eligible subjects are being enrolled in sequential cohorts treated with successively higher doses of FLX475 as monotherapy (Part 1a) or in combination with pembrolizumab (Part 1b). In Part 2 (Phase 2) of the study, expansion cohorts of both checkpoint-naïve and checkpoint-experienced patients with tumor types predicted to be enriched for T reg and/or CCR4 ligand expression (i.e. “charged tumors”) -- including both EBV + and HPV + tumors and NSCLC, HNSCC, and TNBC -- will be enrolled using a Simon 2-stage design. As of February 4, 2020, Phase 1 dose escalation has been completed and a recommended Phase 2 dose chosen for both FLX475 monotherapy and combination therapy with pembrolizumab. Enrollment into Phase 2 expansion cohorts has been initiated. Clinical trial information: NCT03674567 .
Tumor mutation burden and circulating tumor DNA in combined CTLA-4 and PD-1 antibody therapy in metastatic melanoma – results of a prospective biomarker study
Authors: Andrea Forschner, Florian Battke, Dirk Hadaschik, Martin Schulze, Stephanie Weißgraeber, Chung-Ting Han, Maria Kopp, Maximilian Frick, Bernhard Klumpp, Nicola Tietze, Teresa Amaral, Peter Martus, Tobias Sinnberg, Thomas Eigentler, Ulrike Keim, Claus Garbe, Dennis Döcker, Saskia Biskup
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Metastasized or unresectable melanoma has been the first malignant tumor to be successfully treated with checkpoint inhibitors. Nevertheless, about 40–50% of the patients do not respond to these treatments and severe side effects are observed in up to 60%. Therefore, there is a high need to identify reliable biomarkers predicting response. Tumor Mutation Burden (TMB) is a debated predictor for response to checkpoint inhibitors and early measurement of ctDNA can help to detect treatment failure to immunotherapy in selected melanoma patients. However, it has not yet been clarified how TMB and ctDNA can be used to estimate response to combined CTLA-4 and PD-1 antibody therapy in metastatic melanoma. <h3>Patients and methods</h3> In this prospective biomarker study, we included 35 melanoma patients with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) therapy. In all patients, a tumor panel of 710 tumor-associated genes was applied (tumor vs. reference tissue comparison), followed by repetitive liquid biopsies. Cell-free DNA was extracted and at least one driver mutation was monitored. Treatment response was evaluated after&nbsp;about three months of therapy. <h3>Results</h3> TMB was significantly higher in responders than in nonresponders and TMB &gt; 23.1 Mut/Mb (TMB-high) was associated with a survival benefit compared to TMB ≤ 23.1 Mut/Mb (TMB-low or TMB-intermediate). Furthermore, a &gt; 50% decrease of cell-free DNA concentration or undetectable circulating tumor DNA (ctDNA), measured by tumor-specific variant copies/ml of plasma at first follow-up three weeks after treatment initiation were significantly associated with response to combined immunotherapy and improved overall survival, respectively. It is noticeable that no patient with TMB ≤ 23.1 Mut/Mb and detectable or increasing ctDNA at first follow-up responded to immunotherapy. <h3>Conclusion</h3> High TMB, &gt; 50% decrease of cell-free DNA concentration, and undetectable ctDNA at first follow-up seem to be associated with response and overall survival under combined immunotherapy. The evaluation of ctDNA and cell-free DNA three weeks after treatment initiation may be suitable for early assessment of efficacy of immunotherapy.
Improving Treatment for Advanced Prostate Cancer
Authors: Ian F. Tannock
Journal: New England Journal of Medicine (2019)

For about 75 years, the primary treatment for men with metastatic prostate cancer has been with androgen-deprivation therapy, by either surgical or medical castration. About 90% of men respond to such therapy with an improvement in symptoms and a reduction in serum levels of prostate-specific antigen (PSA), with a median response duration of approximately 18 months. Subsequent treatments with first-generation inhibitors of the androgen receptor, such as flutamide and bicalutamide, and chemotherapy with docetaxel or other drugs can provide short-term palliation for some men. The median duration of survival with these treatments is approximately 2.5 years. Additional research has shown . . .
The role of postoperative radiotherapy (PORT) in the management of parotid gland malignancy (PGM).
Authors: Louis Benjamin Harrison, Kenneth Hu, Rania Ayman Shourbaji, Bruce Culliney, Zujun Li, Mark Urken, Mark Persky, Waleed Fouad Mourad
Journal: Journal of Clinical Oncology (2012)

5581 Background: To report the role of PORT in the management of PGM and to analyze the prognostic factors for optimal locoregional (LRC) and distant control (DC) Methods: This is a single institution retrospective study. From March 2001-2011, a total of 118 patients with PGM were treated with surgery and PORT (100%) of which 75% were treated with IMRT, 20 and 10% received concurrent carboplatin and CDDP respectively. Indications for PORT were: recurrent or gross residual disease, +ve or close margins, nerve invasion and +ve lymph nodes (LN). PORT fields comprehended parotid bed and ipsilateral neck. Median PORT doses delivered were 70, 63, 54 Gy (at 1.8-2 Gy/fraction) for gross, microscopic disease, and ipsilateral neck respectively. All PORT was delivered via 4-6 MV photons with daily 3-5 mm bolus. The median age was 52 (18-89). Females and Caucasian made up 56% and 64% of the population, respectively. Histologic findings were adenoid cystic carcinoma 20%, mucoepidermoid carcinoma 19%, adenocarcinoma 18%, pleomorphic carcinoma 16%, salivary duct carcinoma 9%, acinic cell carcinoma 8%, ex-pleomorphic carcinoma 7%, and sarcoma 3%. Pathological stages I, II, III, IV were 10, 30, 20 and 40% respectively Results: With a median follow up of 56 months (12-124), the LRC and DC for the whole cohort were 96% (5/118) and 93% (8/118) respectively. The median duration of PORT was 45 days (40-60). The median time to LR failure (LRF) and distant metastases were 16 (12 - 30) and 28 months (24-48) respectively. Late RT toxicity was; grade I xerostomia 30%, altered taste 15%, trismus 6%, dysphagia and neck stiffness 2%. Kaplan-Meier curve shows the 5-year cause-specific survival to be 100%. Chi square and regression analysis tests show significant relationship (P=0.001) between salivary duct ca (70%) and distant metastases (DM), also males are at higher risk (17%) to develop LRF and DM, compared to females (6%). Poor prognostic features for DM and LRF were salivary duct ca, stage IV, PNI, and multiple LN involvement. Conclusions: Our data show that surgery followed by PORT to the tumor bed and ipsilateral neck provide excellent long standing oncologic and functional outcomes. Further studies are warranted to optimize the management of patients at higher risk of DM despite LRC and RT ± chemotherapy administered.
Abstract 14585: Contrast Induced Acute Kidney Injury and Clinical Outcome after Intra-Arterial and Intravenous Contrast Administration: Risk Assessment Adjusted for Patient Characteristics by Design
Authors: Judith Kooiman, Pum A Le Haen, Gülcin Gezgin, Jean-Paul P de Vries, Doeke Boersma, Harald F Brulez, Yvo W Sijpkens, Aart J van der Molen, Suzanne C Cannegieter, Jaap F Hamming, Menno V Huisman
Journal: Circulation (2012)

Purpose To analyze the relative risk and clinical course of contrast induced acute kidney injury (CI-AKI) after intra-arterial (IA) versus intravenous (IV) contrast administration in patients who u...
Hollow, Rough, and Nitric Oxide‐Releasing Cerium Oxide Nanoparticles for Promoting Multiple Stages of Wound Healing
Authors: Xiaomin Ma, Yan Cheng, Hui Jian, Yanlin Feng, Yun Chang, Runxiao Zheng, Xiaqing Wu, Li Wang, Xi Li, Haiyuan Zhang
Journal: Advanced Healthcare Materials (2019)

Wound healing is a complex and sequential biological process that involves multiple stages. Although various nanomaterials are applied to accelerate the wound healing process, only a single stage is promoted during the process, lacking hierarchical stimulation. Herein, hollow CeO2 nanoparticles (NPs) with rough surface and l-arginine inside (Ah CeO2 NPs) are developed as a compact and programmable nanosystem for sequentially promoting the hemostasis, inflammation, and proliferation stages. The rough surface of Ah CeO2 NPs works as a nanobridge to rapidly closure the wounds, promoting the hemostasis stage. The hollow structure of Ah CeO2 NPs enables the multireflection of light inside particles, significantly enhancing the light harvest efficiency and electron-hole pair abundance. Simultaneously, the porous shell of Ah CeO2 NPs facilitates the electron-hole separation and reactive oxygen species production, preventing wound infection and promotion wound healing during the inflammation stage. The enzyme mimicking property of Ah CeO2 NPs can alleviate the oxidative injury in the wound, and the released l-arginine can be converted into nitric oxide (NO) under the catalysis of inducible NO synthase, both of which promote the proliferation stage. A series of in vitro and in vitro biological assessments corroborate the effectiveness of Ah CeO2 NPs in the wound healing process.
Long-acting or extended-release antiretroviral products for HIV treatment and prevention in infants, children, adolescents, and pregnant and breastfeeding women: knowledge gaps and research priorities
Authors: Sharon Nachman, Claire L Townsend, Elaine J Abrams, Moherndren Archary, Edmund Capparelli, Polly Clayden, Shahin Lockman, Patrick Jean-Philippe, Kenneth Mayer, Mark Mirochnick, Jane McKenzie-White, Kimberly Struble, Heather Watts, Charles Flexner
Journal: The Lancet HIV (2019)

Antiretroviral agents with long-acting properties have potential to improve treatment outcomes substantially for people living with HIV. In November 2017, the Long acting/Extended Release Antiretroviral Resource Program (LEAP) convened a workshop with the aim of shaping the research agenda and promoting early development of long-acting or extended release products for key populations: pregnant and lactating women, children aged up to 10 years, and adolescents aged 10-19 years. Goals included strategies and principles to ensure that the needs of children, adolescents, and pregnant and lactating women are considered when developing long-acting formulations. Research should focus not only on how best to transition long-acting products to these populations, but also on early engagement across sectors and among stakeholders. A parallel rather than sequential approach is needed when establishing adult, adolescent, and paediatric clinical trials and seeking regulatory approval. Pregnant and lactating women should be included in adult clinical trials. Adolescent-friendly trial design is needed to improve recruitment and retention of young people.
Randomized Comparison of Clinical Effectiveness of Pharmacologic SPECT and PET MPI in Symptomatic CAD Patients
Authors: Krishna K. Patel, Firas Al Badarin, Paul S. Chan, John A. Spertus, Staci Courter, Kevin F. Kennedy, James A. Case, A. Iain McGhie, Gary V. Heller, Timothy M. Bateman
Journal: JACC. Cardiovascular imaging (2019)
Results of REARRANGE trial: A randomized phase 2 study comparing different dosing approaches for regorafenib (REG) during the first cycle of treatment in patients (pts) with metastatic colorectal cancer (mCRC)
Authors: G. Argiles, N. Mulet Margalef, M. Valladares-Ayerbes, J. Vieitez de Prado, C. Grávalos, P. García Alfonso, C. Santos, M. Tobeña, J. Sastre, M. Benavides, T. Cano, F. Loupakis, M. Rodriguez Garrote, F. Rivera, R. Goldberg, A. Falcone, J. Bennouna, F. Ciardiello, J. Tabernero, E. Aranda
Journal: Annals of Oncology (2019)