tbuckley/cabot-search huggingface dataset:
Microneedle‐Based Generation of Microbubbles in Cancer Tumors to Improve Ultrasound‐Assisted Drug Delivery
Authors: Ashkan Zandi, Mohammad Ali Khayamian, Mohammad Saghafi, Shahriar Shalileh, Pouyan Katebi, Sepanta Assadi, Ali Gilani, Mohammad Salemizadeh Parizi, Shohreh Vanaei, Mohammad Reza Esmailinejad, Fereshteh Abbasvandi, Parisa Hoseinpour, Mohammad Abdolahad
Journal: Advanced Healthcare Materials (2019)

Production of local microbubbles (MBs) with dense distribution in tumor environment is achieved by developing an integrated electrochemical stimulator on a microfabricated silicon needle covered by zinc-oxide nanowires (ZnONWs). MBs are then exploded by external ultrasonic actuation, which induce microcavitations in tumor cells followed by direct entrance of anticancer drugs into cancer cells. This system, named ZnO nanowire-based microbubble generator probe (ZnONW-MGP), is tested on tumorized mice models (by MC4L2 breast cell lines). Mice treated by ZnONW-MGP have ≈82% reduction in tumor size within 10 days with just 25% of conventional dose of paclitaxel while in the absence of the system, they have just a 15% reduction in tumor size. Presence of ZnO nanostructures on microneedles strongly reduces the size of MBs and enhances the efficacy of the sonoporation.
Phorbol ester induced ex vivo expansion of rigorously-defined phenotypic but not functional human cord blood hematopoietic stem cells: a cautionary tale demonstrating that phenotype does not always recapitulate stem cell function
Authors: Yandan Chen, Chunxu Yao, Yincheng Teng, Rongzhen Jiang, Xinxin Huang, Sheng Liu, Jun Wan, Hal E. Broxmeyer, Bin Guo
Journal: Leukemia (2019)
Diabetes is associated with unique pathological mechanisms in heart failure.
Authors: J. Jasper Tromp, A. A. Voors, A. Sharma, J. P. Ferreira, W. Ouwerkerk, H. L. Hillege, P. Van der Harst, D. J. Van Veldhuisen, P. Van der Meer, I. Sama
Journal: European Journal of Heart Failure (2019)
Supramolecular Toxin Complexes for Targeted Pharmacological Modulation of Polymorphonuclear Leukocyte Functions
Authors: Astrid Johanna Heck, Theresa Ostertag, Leonie Schnell, Stephan Fischer, Bikram Keshari Agrawalla, Pia Winterwerber, Eva Wirsching, Michael Fauler, Manfred Frick, Seah Ling Kuan, Tanja Weil, Holger Barth
Journal: Advanced Healthcare Materials (2019)

Abstract The targeted pharmacological modulation of polymorphonuclear leukocytes (PMNs) is of major medical interest. These innate immune cells play a central role in the defense against pathogenic microorganisms. However, their excessive chemotactic recruitment into tissues after traumatic injury is detrimental due to local and systemic inflammation. Rho‐GTPases, being the master regulators of the actin cytoskeleton, regulate migration and chemotaxis of PMNs, are attractive pharmacological targets. Herein, supramolecular protein complexes are assembled in a “mix‐and‐match” approach containing the specific Rho‐inhibiting clostridial C3 enzyme and three PMN‐binding peptides using an avidin platform. Selective delivery of the C3 Rho‐inhibitor with these complexes into the cytosol of human neutrophil‐like NB‐4 cells and primary human PMNs ex vivo is demonstrated, where they catalyze the adenosine diphosphate (ADP) ribosylation of Rho and induce a characteristic change in cell morphology. Notably, the complexes do not deliver C3 enzyme into human lung epithelial cells, A549 lung cancer cells, and immortalized human alveolar epithelial cells (hAELVi), demonstrating their cell type‐selectivity. The supramolecular complexes represent attractive molecular tools to decipher the role of PMNs in infection and inflammation or for the development of novel therapeutic approaches for diseases that are associated with hyperactivity and reactivity of PMNs such as post‐traumatic injury.
The Innate Immune Sensor Sting Can Augment or Ameliorate Graft-Versus-Host Disease Dependent on the Genetic Disparity between Donors and Recipients
Authors: Cameron S. Bader, Henry Barreras, Casey O. Lightbourn, Sabrina Copsel, Jeonghyun Ahn, Glen N. Barber, Robert B. Levy
Journal: Blood (2017)
Patient-reported neurotoxicity with FULV versus FLOX in patients with stage II or III carcinoma of the colon: Results of NSABP Protocol C-07
Authors: S. R. Land, J. Kopec, R. Cecchini, P. A. Ganz, H. Wieand, L. Colangelo, S. Sharif, J. P. Kuebler, J. Costantino, N. Wolmark
Journal: Journal of Clinical Oncology (2006)

3564 Background: NSABP Phase III Protocol C-07 compared the efficacy of FULV versus FLOX in patients with stage II or III colon cancer. The definitive analysis revealed an increase in 3-year disease-free survival from 71.6% to 76.5% (HR=0.79, p=0.004) in favor of FLOX. The present study compares patient-reported neurotoxicity between the treatment groups. Methods: Patients were randomized to either FULV (5-FU, 500 mg/m 2 iv bolus weekly x 6; LV, 500 mg/m 2 iv weekly x 6, each 8-week cycle x 3) or FLOX (FULV with oxaliplatin 85 mg/m 2 iv administered on weeks 1, 3 and 5 of each 8-week cycle x 3). A subset of patients (planned sample size 400) at select institutions completed the validated FACT/GOG Oxaliplatin-Specific Neurotoxicity Scale (NTX-12) at baseline, week 4 of cycle 2, and at 6, 12 and 18 months. Mean NTX-12 scores were compared between treatments at 18 months using a t-test and longitudinally with mixed effects modeling. Item responses were compared between treatments with logistic regression. Results: From February 2000 to July 2001, 395 patients with follow-up (206 FULV, 189 FLOX) were enrolled in the neurotoxicity study. They were comparable by disease stage and site, age, and sex to the 759 concurrently accrued C-07 patients not in the sub-study (data not shown). NTX-12 form submission rates were high (with a low of 77% at 12 months). Mean neurotoxicity was higher in the oxaliplatin arm throughout the period of study (p&lt;0.0001) and remained higher at 18 months (p=0.009). During therapy, FLOX patients experienced significant increases in hand/foot neuropathy and overall weakness, and an improvement in hearing ( Table ). At 18 months, hand neurotoxicity resolved, but patients who received oxaliplatin experienced ringing in the ears and continued foot discomfort. Conclusions: This presentation provides the first public review of the severity and persistence of neurotoxicity associated with oxaliplatin in this study. [Table: see text] [Table: see text]
Development of Complex Renal Cysts during Crizotinib Treatment and Also during Alectinib Treatment: A Possible Drug Class Effect?
Authors: Vito Longo, Anna Maria Catino, Michele Montrone, Francesco Pesola, Pamela Pizzutilo, Gabriela Delbene, Pietro Gatti, Annunziata Ferrante, Domenico Galetta
Journal: Journal of Thoracic Oncology (2019)
Letter to the Editor: Hepatectomy for Hepatocellular Carcinoma Patients With Portal Vein Tumor Thrombus: Benefit or Not
Authors: Fang Luo, Rui Liao
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. SEE ARTICLE ON PAGE XXXX. To The Editor: We read with interest the study by Zhang et al., which developed an Eastern Hepatobiliary Surgery Hospital/Portal Vein Tumor Thrombus (EHBH/PVTT) scoring system to predict the prognosis and evaluate the benefit of hepatocellular carcinoma (HCC) patients with PVTT after R0 hepatectomy.1 They reported that it could select appropriate HCC patients with type 1 and type 2 PVTT for hepatectomy. While applauding the authors' efforts, we have some doubts. In this study, overall survival (OS) was set as the primary study endpoint. However, in our opinion, disease‐free survival was more important than OS here. First, the PVTT was resected en bloc with the liver specimen after surgery. Second, once recurrent HCC was diagnosed, patients were actively treated with different treatments. Therefore, the death of some patients may not be directly associated with PVTT after surgery. After recurrence, other effective treatment could influence the prognosis of HCC patients after liver regeneration (LR). Early recurrence represents a true metastasis and is associated with the dissemination of primary HCC tumor cells that may come from PVTT. Moreover, it appears that these HCC patients with PVTT have not received transarterial chemoembolization (TACE) after surgery. Previously, one of the authors in this study (Min‐Shan Chen) confirmed that TACE plus LR could provide survival benefits for HCC patients with PVTT.2 Furthermore, there is no information on whether the patients had antiviral therapy after surgery, because most patients (75.6%‐89.3%) did not receive preoperative antiviral treatment. It is well known that antiviral treatment could benefit the prognosis of HCC.3 We are confused why alpha‐fetoprotein of at least 20 ng/mL = 2 rather than 1, which also may greatly affect the final surgical evaluation on HCC patients with PVTT, as the threshold of the EHBH‐PVTT score is only 3. So far, it is unclear whether EHBH‐PVTT scores could be suitable for HCC patients with PVTT in western countries. Despite these limitations, this study provides a valuable tool to guide the selection of subgroups of patients who could benefit from LR. According to this study, PVTT is not the absolute surgical contraindication for HCC patients as long as they could benefit from hepatectomy.
Clinical and Molecular Predictors of Response to Immune Checkpoint Inhibitors in Patients with Advanced Esophagogastric Cancer
Authors: Megan Greally, Joanne F. Chou, Walid K. Chatila, Matthew Margolis, Marinela Capanu, Jaclyn F. Hechtman, Yaelle Tuvy, Ritika Kundra, Foysal Daian, Marc Ladanyi, David P. Kelsen, David H. Ilson, Michael F. Berger, Laura H. Tang, David B. Solit, Luis A. Diaz, Nikolaus Schultz, Yelena Y. Janjigian, Geoffrey Y. Ku
Journal: Clinical Cancer Research (2019)

Immune checkpoint inhibitors (ICI) are effective in only a minority of patients with esophagogastric cancer (EGC). Here, we aimed to identify predictors of durable clinical benefit to ICI in EGC.Patients with advanced EGC treated with ICIs at Memorial Sloan Kettering Cancer Center (New York, NY) were identified. Clinicopathologic variables were assessed. In patients profiled by MSK-IMPACT-targeted sequencing, outcomes were correlated with tumor genomic features.One-hundred sixty-one patients were treated with ICIs (110 with anti-PD-1/PD-L1 antibodies and 51 with anti-CTLA-4 and PD-1/PD-L1 antibodies). The median progression-free survival (PFS) and overall survival (OS) were 1.7 and 4.9 months, respectively. Greater number of disease sites (≥3), liver metastases, treatment with ≥3 prior therapies and ECOG performance status ≥2 were associated with poorer PFS and OS. Patients treated with combination ICI and those with PD-L1-positive tumors had improved outcomes. There was no difference in outcomes between patients treated with antibiotics during or in the 2 months preceding ICI treatment versus those who were not. Occurrence of irAEs was associated with improved OS. In genomically profiled tumors (n = 89), survival was associated with increasing tumor mutation burden (TMB). However, in multivariable analyses and when microsatellite unstable (MSI) patients were excluded, a significant association was no longer observed.In patients with advanced EGC, heavily pretreated patients, those with high-volume disease and/or poor PS were less likely to benefit from ICI. irAEs were associated with improved OS. TMB correlated with improved survival, but this association was not observed when MSI-high patients were excluded.
DIS3L2 Promotes Progression of Hepatocellular Carcinoma via hnRNP U-Mediated Alternative Splicing
Authors: Songge Xing, Zhaoyong Li, Wenhao Ma, Xiaoping He, Shengqi Shen, Haoran Wei, Shi-Ting Li, Ying Shu, Linchong Sun, Xiuying Zhong, Yuhao Huangfu, Lanhong Su, Junru Feng, Xiaozhang Zhang, Ping Gao, Wei-Dong Jia, Huafeng Zhang
Journal: Cancer Research (2019)

Abstract DIS3-like 3′-5′ exoribonuclease 2 (DIS3L2) degrades aberrant RNAs, however, its function in tumorigenesis remains largely unexplored. Here, aberrant DIS3L2 expression promoted human hepatocellular carcinoma (HCC) progression via heterogeneous nuclear ribonucleoproteins (hnRNP) U-mediated alternative splicing. DIS3L2 directly interacted with hnRNP U through its cold-shock domains and promoted inclusion of exon 3b during splicing of pre-Rac1 independent of its exonuclease activity, yielding an oncogenic splicing variant, Rac1b, which is known to stimulate cellular transformation and tumorigenesis. DIS3L2 regulated alternative splicing by recruiting hnRNP U to pre-Rac1. Rac1b was critical for DIS3L2 promotion of liver cancer development both in vitro and in vivo. Importantly, DIS3L2 and Rac1b expression highly correlated with HCC progression and patient survival. Taken together, our findings uncover an oncogenic role of DIS3L2, in which it promotes liver cancer progression through a previously unappreciated mechanism of regulating hnRNP U-mediated alterative splicing. Significance: These findings establish the role and mechanism of the 3′-5′ exoribonuclease DIS3L2 in hepatocellular carcinoma carcinogenesis.
A phase II study of neoadjuvant chemotherapy with docetaxel and bevacizumab in patients (pts) with high-risk localized prostate cancer: A Prostate Cancer Clinical Trials Consortium trial
Authors: W. K. Oh, P. G. Febbo, J. P. Richie, F. M. Fennessy, G. Scibelli, J. H. Hayes, T. K. Choueiri, C. M. Tempany, M. E. Taplin, R. W. Ross
Journal: Journal of Clinical Oncology (2009)

5060 Background: Treatment options for high-risk localized prostate cancer remain inadequate, with the majority of pts relapsing despite surgery or radiation therapy. We conducted a phase II multicenter trial of neoadjuvant docetaxel and bevacizumab prior to radical prostatectomy in pts with high risk localized prostate cancer. Methods: Eligibility included any of the following: PSA &gt; 20 ng/ml or PSA velocity &gt; 2 ng/ml/yr, cT3 disease, any biopsy Gleason 8–10, Gleason 7 with T3 disease by endorectal (er) MRI. Also, &gt;50% biopsy cores involved and either Gleason 7 or PSA &gt;10 or cT2 disease were eligible. Pts were treated with docetaxel 70 mg/m2 q 3weeks x 6 cycles and bevacizumab 15 mg/m2 q 3 weeks x 5 cycles. The primary endpoint was erMRI partial response (PR, defined here as &gt;50% decrease in tumor volume) in a single target lesion after chemotherapy. Results: 42 pts were registered and treated with 220 cycles so far. Median age was 55 yrs (range 41–67). Median Gleason score was 8 (69% with Gleason 8–10 cancer). Median PSA was 10.5 ng/ml (range 2.1–72.5). Clinical stage was T2 in 46% and T3 in 32%. Of 23 evaluable pts to date, the median decline in the maximal tumor volume by erMRI was -45% (range -84% to 110%). 9/23 (39%) patients had PR, and only 1 pt had radiographic progression. Any PSA decline was noted in 22/34 (65%) evaluable pts, with 18% having a &gt;50% decline. Treatment was well-tolerated: 2 pts had grade 3 allergic reactions requiring discontinuation, 3 had febrile neutropenia and 1 had grade 3 hyperglycemia. Mild fatigue was common. Only 1 pt stopped treatment because of a rising PSA. To date, 31 pts have had radical prostatectomy. One had intraoperative bladder neck injury and was treated instead with radiation + hormone therapy. A second pt had an intraoperative rectal injury but completed surgery. Conclusions: Neoadjuvant docetaxel and bevacizumab demonstrates clinical evidence of activity in men with high-risk localized prostate cancer, with a 39% PR rate by erMRI and PSA declines noted in 65%. Treatment was well-tolerated. The study is ongoing and updated data on response, toxicity and pathology will be presented. [Table: see text]
Employing Macrophage-Derived Microvesicle for Kidney-Targeted Delivery of Dexamethasone: An Efficient Therapeutic Strategy against Renal Inflammation and Fibrosis
Authors: Tao-Tao Tang, Lin-Li Lv, Bin Wang, Jing-Yuan Cao, Ye Feng, Zuo-Lin Li, Min Wu, Feng-Mei Wang, Yi Wen, Le-Ting Zhou, Hai-Feng Ni, Ping-Sheng Chen, Ning Gu, Steven D Crowley, Bi-Cheng Liu
Journal: Theranostics (2019)

Although glucocorticoids are the mainstays in the treatment of renal diseases for decades, the dose dependent side effects have largely restricted their clinical use. Microvesicles (MVs) are small lipid-based membrane-bound particles generated by virtually all cells. Here we show that RAW 264.7 macrophage cell-derived MVs can be used as vectors to deliver dexamethasone (named as MV-DEX) targeting the inflamed kidney efficiently. Methods: RAW macrophages were incubated with dexamethasone and then MV-DEX was isolated from the supernatants by centrifugation method. Nanoparticle tracking analysis, transmission electron microscopy, western blot and high-performance liquid chromatography were used to analyze the properties of MV-DEX. The LC-MS/MS was applied to investigate the protein compositions of MV-DEX. Based on the murine models of LPS- or Adriamycin (ADR)-induced nephropathy or in-vitro culture of glomerular endothelial cells, the inflammation-targeting characteristics and the therapeutic efficacy of MV-DEX was examined. Finally, we assessed the side effects of chronic glucocorticoid therapy in MV-DEX-treated mice. Results: Proteomic analysis revealed distinct integrin expression patterns on the MV-DEX surface, in which the integrin αLβ2 (LFA-1) and α4β1 (VAL-4) enabled them to adhere to the inflamed kidney. Compared to free DEX treatment, equimolar doses of MV-DEX significantly attenuated renal injury with an enhanced therapeutic efficacy against renal inflammation and fibrosis in murine models of LPS- or ADR-induced nephropathy. In vitro, MV-DEX with about one-fifth of the doses of free DEX achieved significant anti-inflammatory efficacy by inhibiting NF-κB activity. Mechanistically, MV-DEX could package and deliver glucocorticoid receptors to renal cells, thereby, increasing cellular levels of the receptor and improving cell sensitivity to glucocorticoids. Notably, delivering DEX in MVs significantly reduced the side effects of chronic glucocorticoid therapy (e.g., hyperglycemia, suppression of HPA axis). Conclusion: In summary, macrophage-derived MVs efficiently deliver DEX into the inflamed kidney and exhibit a superior capacity to suppress renal inflammation and fibrosis without apparent glucocorticoid adverse effects. Our findings demonstrate the effectiveness and security of a novel drug delivery strategy with promising clinical applications.
Dengue and Zika Virus Domain III-Flagellin Fusion and Glycan-Masking E Antigen for Prime-Boost Immunization
Authors: Hsiao-Han Lin, Shao-Ping Yang, Meng-Ju Tsai, Guan-Cheng Lin, Han-Chung Wu, Suh-Chin Wu
Journal: Theranostics (2019)

The viral E proteins of dengue virus (DENV) and Zika virus (ZIKV) are the major viral proteins involved in receptor binding and fusion, and for the induction of protective antibodies against viral infections. DIII of the E proteins is an independent domain and stretches out on the virion surface that can elicit type-specific neutralizing antibodies. For recombinant DIII vaccine development, prime-boost immunizations can provide an advantage of eliciting more type-specific neutralizing antibodies by recalling DIII antigens after DIII booster to improve protection. Methods: The DIII of the E genes of DENV and ZIKV were fused with bacterial fliC gene for the expression of flagellin-DIII (FliC-DIII) fusion proteins. Prime-boost immunization strategies by the second-dose booster of four DENV serotype or ZIKV FliC-DIII fusion proteins were used to investigate the induction of neutralizing antibodies and protection against viral infections. Cross-reactive non-neutralizing antibodies in each group of antisera were also examined using in vitro antibody-dependent enhancement (ADE) assay. A series of glycan-masking E antigens were finally constructed for prime-boost immunizations to abolish the elicitation of cross-reactive non-neutralizing antibodies for ADE activity. Results: We showed that inclusion of a bivalent live-attenuated vaccine with a FliC-DIII booster is superior in eliciting neutralization titers and protection in vivo against all four-serotype DENVs. We also demonstrated that recombinant adenovirus vectors encoding four-serotype DENV prMEs with a FliC-DIII prime-boost scheme is capable of eliciting good antibody responses. In contract, recombinant adenovirus vector of ZIKV prME gene priming, followed by ZIKV FliC-DIII booster did not improve vaccine efficacy. The glycan-masking mutation on the ZIKV E protein ij loop (E-248NHT), but not on DENV2 E protein ij loop (E-242NHT), resulted in abolishing the elicitation of cross-reactive antibodies for DENV and ZIKV infection enhancements. Conclusions: Our findings can provide useful information for designing novel immunogens and vaccination strategies in an attempt to develop a safe and efficacious DENV or ZIKV vaccine.
Classifying Patients with Amyotrophic Lateral Sclerosis by Changes in FVC. A Group-based Trajectory Analysis
Authors: Jason Ackrivo, John Hansen-Flaschen, Bobby L. Jones, E. Paul Wileyto, Richard J. Schwab, Lauren Elman, Steven M. Kawut
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

A model for stratifying progression of respiratory muscle weakness in amyotrophic lateral sclerosis (ALS) would identify disease mechanisms and phenotypes suitable for future investigations. This study sought to categorize progression of FVC after presentation to an outpatient ALS clinic.
Selective Targeting of Myoblast Fusogenic Signaling and Differentiation-Arrest Antagonizes Rhabdomyosarcoma Cells
Authors: Valerie A. Granados, Usha Avirneni-Vadlamudi, Pooja Dalal, Samuel R. Scarborough, Kathleen A. Galindo, Priya Mahajan, Rene L. Galindo
Journal: Cancer Research (2019)

Rhabdomyosarcoma (RMS) is an aggressive soft tissue malignancy comprised histologically of skeletal muscle lineage precursors that fail to exit the cell cycle and fuse into differentiated syncytial muscle-for which the underlying pathogenetic mechanisms remain unclear. In contrast to myogenic transcription factor signaling, the molecular machinery that orchestrates the discrete process of myoblast fusion in mammals is poorly understood and unexplored in RMS. The fusogenic machinery in Drosophila, however, is understood in much greater detail, where myoblasts are divided into two distinct pools, founder cells (FC) and fusion competent myoblasts (fcm). Fusion is heterotypic and only occurs between FCs and fcms. Here, we interrogated a comprehensive RNA-sequencing database and found that human RMS diffusely demonstrates an FC lineage gene signature, revealing that RMS is a disease of FC lineage rhabdomyoblasts. We next exploited our Drosophila RMS-related model to isolate druggable FC-specific fusogenic elements underlying RMS, which uncovered the EGFR pathway. Using RMS cells, we showed that EGFR inhibitors successfully antagonized RMS RD cells, whereas other cell lines were resistant. EGFR inhibitor-sensitive cells exhibited decreased activation of the EGFR intracellular effector Akt, whereas Akt activity remained unchanged in inhibitor-resistant cells. We then demonstrated that Akt inhibition antagonizes RMS-including RMS resistant to EGFR inhibition-and that sustained activity of the Akt1 isoform preferentially blocks rhabdomyoblast differentiation potential in cell culture and in vivo. These findings point towards selective targeting of fusion- and differentiation-arrest via Akt as a broad RMS therapeutic vulnerability. SIGNIFICANCE: EGFR and its downstream signaling mediator AKT1 play a role in the fusion and differentiation processes of rhabdomyosarcoma cells, representing a therapeutic vulnerability of rhabdomyosarcoma.
Abstract 14953: Serial Measurement of an Ultrasensitive Cardiac Troponin-I Predicts Cardiovascular Outcomes and Ventricular Remodeling in Chronic Heart Failure
Authors: Shweta R Motiwala, Jackie Szymonifka, Hanna K Gaggin, Anju Bhardwaj, Arianna Belcher, Rory B Weiner, Aaron L Baggish, James L Januzzi
Journal: Circulation (2013)

Introduction: Cardiac troponin-I (cTnI) concentrations are prognostically important in patients with heart failure (HF). Newer generation assays have increased sensitivity for detection and discrim...