bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Ratio of Toxic-to-Nontoxic miRNAs Predicts Platinum Sensitivity in Ovarian Cancer
Authors: Patel Monal , Wang Yinu , Bartom Elizabeth T. , Dhir Rohin , Nephew Kenneth P. , Matei Daniela , Murmann Andrea E. , Lengyel Ernst , Peter Marcus E. 
Published: July 2021

AbstractOvarian cancer remains one of the deadliest gynecologic malignancies affecting women, and development of resistance to platinum remains a major barrier to achieving a cure. Multiple mechanisms have been identified to confer platinum resistance. Numerous miRNAs have been linked to platinum sensitivity and resistance in ovarian cancer. miRNA activity occurs mainly when the guide strand of the miRNA, with its seed sequence at position 2–7/8, is loaded into the RNA-induced silencing complex (RISC) and targets complementary short seed matches in the 3′ untranslated region of mRNAs. Toxic 6mer seeds, which target genes critical for cancer cell survival, have been found in tumor-suppressive miRNAs. Many siRNAs and short hairpin RNAs (shRNA) can also kill cancer cells via toxic seeds, the most toxic of which carry G-rich 6mer seed sequences. We showed here that treatment of ovarian cancer cells with platinum led to increased RISC-bound miRNAs carrying toxic 6mer seeds and decreased miRNAs with nontoxic seeds. Platinum-tolerant cells did not exhibit this toxicity shift but retained sensitivity to cell death mediated by siRNAs carrying toxic 6mer seeds. Analysis of RISC-bound miRNAs in tumors from patients with ovarian cancer revealed that the ratio between miRNAs with toxic versus nontoxic seeds was predictive of treatment outcome. Application of the 6mer seed toxicity concept to cancer relevant miRNAs provides a new framework for understanding and predicting cancer therapy responses.Significance:These findings demonstrate that the balance of miRNAs that carry toxic and nontoxic 6mer seeds contributes to platinum resistance in ovarian cancer.
Effects of Exercise on Cancer Treatment Efficacy: A Systematic Review of Preclinical and Clinical Studies
Authors: Yang Lin , Morielli Andria R. , Heer Emily , Kirkham Amy A. , Cheung Winson Y. , Usmani Nawaid , Friedenreich Christine M. , Courneya Kerry S. 
Published: July 2021

Abstract
We systematically reviewed and synthesized evidence on the impact of physical activity/exercise on cancer treatment efficacy. We included six preclinical and seven clinical studies. Exercise significantly enhanced the efficacy of chemotherapy and tamoxifen in seven of eight rodent models in either an additive, sensitizing, or synergistic manner. In clinical studies, preliminary evidence indicates that exercise during neoadjuvant, primary, and adjuvant treatment may enhance efficacy of cancer therapies; however, no clinical study was designed for this purpose. Here we discuss the biological mechanisms of exercise-associated enhancement of therapeutic efficacy and propose future research directions to definitively examine the effects of exercise on cancer treatment and patient outcomes.
SENTI-101, a Preparation of Mesenchymal Stromal Cells Engineered to Express IL12 and IL21, Induces Localized and Durable Antitumor Immunity in Preclinical Models of Peritoneal Solid Tumors
Authors: Gonzalez-Junca Alba , Liu Frances D. , Nagaraja Archana S. , Mullenix Alyssa , Lee Chen-Ting , Gordley Russell M. , Frimannsson Daniel O. , Maller Ori , Garrison Brian S. , Iyer Dharini , Benabbas Anissa , Truong Tiffany A. , Quach Allison , Tian Mengxi , Martinez Rowena , Savur Rishi , Perry-McNamara Alyssa , Nguyen Denny , Almudhfar Niran , Blanco Carmina , Huynh Christina , Nand Asish , Lay Yu-An E. , Magal Ashita , Mangalampalli Sravani , Lee Philip J. , Lu Timothy K. , Lee Gary 
Published: July 2021

Abstract

Advanced peritoneal carcinomatosis including high-grade ovarian cancer has poor prognoses and a poor response rate to current checkpoint inhibitor immunotherapies; thus, there is an unmet need for effective therapeutics that would provide benefit to these patients. Here we present the preclinical development of SENTI-101, a cell preparation of bone marrow-derived mesenchymal stromal (also known as stem) cells (MSC), which are engineered to express two potent immune-modulatory cytokines, IL12 and IL21. Intraperitoneal administration of SENTI-101 results in selective tumor-homing and localized and sustained cytokine production in murine models of peritoneal cancer. SENTI-101 has extended half-life, reduced systemic distribution, and improved antitumor activity when compared with recombinant cytokines, suggesting that it is more effective and has lower risk of systemic immunotoxicities. Treatment of tumor-bearing immune-competent mice with a murine surrogate of SENTI-101 (mSENTI-101) results in a potent and localized immune response consistent with increased number and activation of antigen presenting cells, T cells and B cells, which leads to antitumor response and memory-induced long-term immunity. Consistent with this mechanism of action, co-administration of mSENTI-101 with checkpoint inhibitors leads to synergistic improvement in antitumor response. Collectively, these data warrant potential clinical development of SENTI-101 for patients with peritoneal carcinomatosis and high-grade ovarian cancer.
Graphical abstract: SENTI-101 schematic and mechanism of action
SENTI-101 is a novel cell-based immunotherapeutic consisting of bone marrow–derived mesenchymal stromal cells (BM-MSC) engineered to express IL12 and IL21 intended for the treatment of peritoneal carcinomatosis including high-grade serous ovarian cancer. Upon intraperitoneal administration, SENTI-101 homes to peritoneal solid tumors and secretes IL12 and IL21 in a localized and sustained fashion. The expression of these two potent cytokines drives tumor infiltration and engagement of multiple components of the immune system: antigen-presenting cells, T cells, and B cells, resulting in durable antitumor immunity in preclinical models of cancer.
Abstract 10: Endothelial FGF Protects Against Pulmonary Hypertension
Authors: Woo Kel Vin , Weinheimer Carla , Kovacs Attila , Ornitz David 
Published: July 2021

Pulmonary hypertension (PH) is a debilitating disease where 1 in 4 patients will die within five years of diagnosis. Pathologic changes of endothelial cell function, together with smooth muscle and adventitial hyperplasia increase pulmonary vascular resistance. Consequent elevation in right ventricular pressure ultimately causes right heart failure.
Expression of Fibroblast Growth Factor Receptors (FGFRs), FGFR1 and FGFR2, are elevated in lung samples from PH patients; however, the impact of these receptors on endothelial cell function, and endothelial to smooth muscle interaction is poorly understood.
We hypothesize that activation of endothelial FGFR1 and FGFR2 promotes endothelial cell survival, elaborating signals that protect against pulmonary hypertension via inhibition of smooth muscle cell recruitment.

We used the
Tie2-Cre
transgene to conditionally inactivate
Fgfr1
and
Fgfr2
in endothelial cells. Experimental mice with genotype

Tie2-Cre; Fgfr1
f/f
; Fgfr2
f/f

(DCKO) and control

Fgfr1
f/f
; Fgfr2
f/f

(DFF) were challenged with 10% hypoxia for 2 weeks. At the end, right ventricular pressure (RVp) was measured by cardiac catheterization. Compared to mice in normoxia, control littermates in hypoxia demonstrated significant increases in RVp, and RV to left ventricle + septum (LV+S) weight ratio, consistent with development of PH. DCKO mice demonstrate further elevation in RVp and an increase in the RV to LV+S weight ratio, demonstrating worsening PH. We also observed formation of plexiform lesions in DCKO mice, suggestive of a severe pathology. We found a previously unreported involvement of FGF10 in pulmonary hypertension. FGF10 expression was decreased in hypoxia-challenged DCKO mice as compared to both DCKO littermates on room air, and to hypoxia challenged DFF control mice.

Our data suggests that endothelial FGFR1 and FGFR2 activation may protect against pulmonary hypertension. Further studies are underway to elucidate the role of FGF10 and its mechanism in the pathology. We will also further identify associated FGF ligands, associated signaling mechanisms, and endothelial to smooth muscle interactions.
Abstract 101: Dipeptidylpeptidase-iv Inhibition Using MK626 Attenuates BAPB/AT2 Induced Murine Aneurysm
Authors: Byrne John S , Chen Emily , Husain Mansoor , Ouzounian Maral , Robbins Clint , Lindsay Thomas 
Published: July 2021

The dearth of effective treatments to diminish aneurysm progression is a recognized clinical challenge. Modulation of the glucagon-like peptide-1 (GLP-1) pathway is a recent addition to anti-diabetic management regimes, and has pleiotropic effects to inhibit arterial wall macrophage infiltration, a key pathological event in aneurysmal disease. We therefore hypothesized that inhibition of endogenous breakdown of GLP-1, using the dipeptidylpeptidase-IV inhibitor MK626, would attenuate BAPN/AT2 induced murine aneurysm.
Eight-week-old C57/Bl6 mice received two weeks of oral beta-aminopropriononitrile (BAPN) and four weeks of angiotensin-2 (AT2) via mini-osmotic pump. MK626 3mg/kg in methylcellulose vehicle was administered daily and compared to control methylcellulose vehicle. At four weeks, whole aortas were dissected and photomicrographed. Cross sections of aorta were stained using H&E and EVG.
Compared to wild-type, BAPN/AT2 caused dilatation of the aorta from the ascending to the suprarenal segment (p<0.002) with infrarenal sparing (p=0.77). Focal aneurysmal dilatation reproducibly occurred in the suprarenal aorta (wild-type diameter 0.93±0.03mm, n=8; BAPN/AT2 diameter 2.26±0.12, n=8; p<0.0001). Treatment with MK626 attenuated dilatation of the descending aorta compared to controls (BAPN/AT2 control 1.26±0.05mm, n=8; MK626 1.07±0.05mm, n=10; p=0.03). The focal suprarenal aneurysmal dilatation was significantly reduced by treatment with MK626 (BAPN AT2 control 2.26±0.34mm, n=8; MK626 1.66±0.32mm, n=10; p=0.0001). BAPN/AT2 induced aortic aneurysm was associated with excess matrix deposition, increased medial thickness, and elastic fibre fragmentation.
Modulation of the GLP pathway using the dipeptidylpeptidase-IV inhibitor MK626 attenuates aneurysm in a BAPN/AT2 induced murine model.
Abstract 438: Macrophages in a BAPN/AT2 Induced Model of Murine Aneurysm are Predominantly Lyve-1 and Tim-4 Negative
Authors: Byrne John S , Besla Rickvinder , Li Angela , Al-chami Edouard , Legg Karen , Chen Emily , Ouzounian Maral , Lindsay Thomas , Robbins Clint 
Published: July 2021

Macrophages are key effector cells in aneurysm progression. Aneurysm macrophages may derive from monocyte recruitment and turnover of resident cells. We tested the hypothesis that aneurysm macrophages have a non-resident (lyve-1/tim-4 negative) phenotype.
C57/Bl6 mice were administered beta-aminopropriononitrile (BAPN) and angiotensin-2 (AT2). At four weeks, whole aortas were excised, photomicrographed, and single cell suspensions created for immunophenotyping with flow cytometry. Results were compared to wild-type controls.
BAPN/AT2 causes aortic dilatation (p<0.01) with maximal aneurysmal degeneration at the suprarenal aorta (wild-type control aortic diameter 0.93±0.03mm, n=8; BAPN/AT2 2.00±0.10mm, n=23; p<0.0001). BAPN/AT2 significantly increased aortic cd45+ myeloid-lymphoid cells and cd11b+ f4/80+ macrophages (p<0.02). Maximal aneurysm diameter correlated positively with aortic cell numbers of cd45+ myeloid-lymphoid cells (R=0.8168, p<0.001) and macrophages (R=0.5977, p=0.02). In wild-type, aortic macrophages are predominantly lyve-1 positive (67±3%, n=10). Whilst overall macrophage numbers are increased in aneurysm, the percentage of lyve-1 positive macrophages is significantly reduced (40±3%, n=18; p<0.001). The number of lyve-1 negative macrophages (R=0.6875, p=0.02), correlated with maximal suprarenal aortic diameter. In controls and aneurysm, lyve-1 positive, but not lyve-1 negative, macrophages are also tim-4 positive.
In a BAPN/AT2 murine aneurysm model, aortic cd45+ myeloid-lymphoid cells and macrophages are increased and cell counts correlate with maximal aortic dilatation. Wild-type murine aortic macrophages are predominantly lyve-1/tim4 positive, with a significant relative increase in lyve-1/tim4 negative macrophages in aneurysm, suggesting lyve-1/tim-4 may indicate a resident macrophage phenotype.
Abstract 165: Diacylglycerol kinase α Exacerbates Cardiac Injury After Ischemia/reperfusion In Transgenic Mouse Hearts
Authors: Sasaki Toshiki , Takeishi Yasuchika , Kitahara Tatsuro , Koyama Yo , Niizeki Takeshi , Suzuki Satoshi , Kubota Isao 
Published: July 2021

Background: Activation of the diacylglycerol-protein kinase C (DAG-PKC) cascade has been implicated in cardiac dysfunction after ischemia/reperfusion (I/R). DAG kinase (DGK) terminates DAG signaling by converting it to phosphatidic acid, and thus may act as a regulator of DAG-PKC signaling. It has been reported that α, ϵ, and &#03B6; isoforms of DGK have been identified in the heart. We examined the functional role of DGKα in cardiac injury after I/R.
Methods and Results: We generated transgenic mice with cardiac specific overexpression of DGKα (DGKα-TG) using α-myosin heavy chain promoter. Left anterior descending coronary artery was transiently occluded for 30 min and reperfused for 24 hr in DGKα-TG and wild type littermate (WT) mice. After 24 hr, echocardiography was performed, mice were sacrificed, and the hearts were removed. Areas at risk and infarct size were assessed by Evans blue/TTC double staining. Left ventricular chamber dilatation after I/R was more pronounced in DGKα-TG mice than in WT mice (left ventricular end-diastolic dimension: 3.44 +/− 0.41 mm vs. 3.05 +/−0.24 mm, P < 0.01). Left ventricular systolic function was more severely depressed in DGKα-TG mice than in WT mice (left ventricular fractional shortening: 34.3 +/− 3.6% vs. 42.2 +/− 4.0%, P < 0.01). The ratio of infarct size/area at risk at 24 hr after I/R was larger in DGKα-TG mice than in WT mice (17.9 +/− 4.2% vs. 11.3 +/− 3.3%, P < 0.01). The phosphorylation activity of extracellular-signal regulated kinase (ERK) was increased after I/R in WT mouse hearts (2.58 +/−0.52-fold increase, P<0.0001). However in DGKα-TG mice, activation of ERK after I/R was abolished (1.77+/−0.67-fold increase, P<0.01 vs. WT).
Conclusion: DGKα exacerbates cardiac injury by inhibiting cardio-protective effect of ERK activation.
Abstract 3381: Usefulness of Carperitide as an Adjunctive Therapy for Acute Myocardial Infarction in Patients with Chronic Kidney Disease -Subgroup Analysis of J-WIND-ANP trial
Authors: Asakura Masanori , Kim Jiyoong , Asanuma Hiroshi , Myoishi Masafumi , Seguchi Osamu , Shintani Yasunori , Tomoike Hitonobu , Kitakaze Masafumi 
Published: July 2021

Background Chronic kidney disease (CKD) is highly prevalent in patients with cardiovascular disease. Recent investigation suggests that nesiritide (human brain natriuretic peptide) increases the risk of worsening renal function in patients with acute heart failure, whereas carperitide (human atrial natriuretic peptide) has beneficial effects on renal function.
Methods We evaluated the usefulness of carperitide as an adjunctive therapy for acute myocardial infarction (AMI) in 158 patients with low eGRF (<60ml/min) estimated by the modified MDRD equation in J-WIND-ANP trial. Of 158 patients, 78 received carperitide (67±9 years old, male 54 patients) and 80 received placebo (67±9 years old, male 54 patients). Other risk factors such as hypertension, diabetes mellitus, and smoking were comparable between two groups. There was no difference in elapsed time between carperitide group (3.6hr 95%CI 3.0hr–5.9hr) and placebo group (3.5hr 95%CI 2.5hr-5.5hr). We analyzed the effects of carperitide on AUC of CK, ejection fraction (EF) at 6 months, and cardiac events.
Results Carperitide administration reduced AUC of CK compared with placebo (carperitide group 65,040 mg/dl vs placebo group 79,286 mg/dl, p<0.05). Carperitide increased EF at 6 months after the onset of AMI compared with placebo (carperitide group 48.1±7.6% vs placebo group 44.0±10.0%, p<0.05). We found no significant difference in total death, cardiac events and reperfusion injury between both groups.
Conclusions Carperitide reduced infarct size and improved chronic left ventricular function in AMI patients with CKD. These results suggest that carperitide is useful as an adjunctive therapy for AMI in AMI patients with CKD.
Abstract 1707: Murine γHerpesvirus-68 Infection Induces Pulmonary Vascular Disease in S100A4 Overexpressing Mice Associated with Elastase Activity and Altered MicroRNA Expression
Authors: Kim Yu-Mee , Spiekerkoetter Edda , Wang Lingli , Rabinovitch Marlene 
Published: July 2021

Human γ herpesvirus infection is linked to idiopathic pulmonary arterial hypertension (IPAH). S100A4, a metastasis gene, is highly expressed in the plexiform lesions of IPAH patients. Previously, we reported that murine γherpesvirus-68 (M1-MHV-68) infection in S100A4 overexpressing but not in C57 wild-type (WT) mice induced mild neointimal formation in pulmonary arteries (PA) associated with heightened serine elastase activity. We hypothesized that these neointimal lesions would progress during an extended reactivation phase, in the S100A4 mice in association with ongoing elastolysis and that the susceptibility in S100A4 mice was related either to viral load, inflammation or differential induction of host miRNAs in response to infection. We now report that the % of vessels with neointimal lesions progressively increased from 25 to 40%, between 3 and 6 mo after viral infection (P < 0.05) in S100A mice but were not observed in WT. The extent of neointimal lesions correlated with progressive fragmentation of the elastic laminae, (P < 0.001). Interestingly, these features were not sufficient to induce elevated RVSP or RVH, in the absence of muscularization or loss of distal PAs. Susceptibilty of S100A4 mice was not related to an increase in viral DNA in intra-pulmonary arteries assessed by laser capture microscopy, nor could we establish a relationship with the severity of perivascular inflammation or cytokine expression (IFN-γ and TNF-α). However, we confirmed higher lung serine elastase activity in S100A4 vs. C57 mice as early as 1 wk after viral infection. Since expression of miRNAs may be responsible for host susceptibility, we compared lungs of C57 and S100A4 mice at 6 mo using microArrays followed by qRT-PCR. Induction of miR-466 in WT mice infected with virus (P < 0.01), was not observed in S100A4 mice. miR-466 can target the 3′ UTR of RUNX1, a transcription factor for serine elastase, and reduce its expression. The inability to reduce RUNX1 in S100A4 mice in response to viral infection may be related to elevated serine elastase activity. Our studies show that viral infection can lead to progressive neointimal formation and that the susceptibility of S100A4 mice associated with heightened elastase may be linked to differential expression of miR-466.
This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).
Abstract 1779: Autophagy is an Important Survival Response to Bnip3-Mediated Mitochondrial Injury
Authors: Rikka Shivaji , Quinsay Melissa N , Gustafsson Asa B 
Published: July 2021

Myocardial ischemia and reperfusion (I/R) is associated with increased autophagy and cell death. We previously found that the mitochondrial death protein Bnip3 contributes to I/R injury and induces autophagy in cardiac cells. However, the role of Bnip3-mediated autophagy is not clear and has been reported to be a protective, as well as a detrimental process. In this study, we investigated the functional role of Bnip3-mediated autophagy by utilizing adenoviral infections of cells coupled with fluorescence deconvolution microscopy for the analysis of autophagy and Bnip3 function. Imaging of cells infected with adenoviruses expressing GFP-LC3 and Bnip3 or beta-galactosidase (beta-gal) allowed us to monitor the formation of autophagosomes in live cells. Cell death was measured by assessing LDH activity in the media. Monitoring of GFP-LC3 incorporation into autophagosomes confirmed that overexpression of Bnip3 induced upregulation of autophagy in HL-1 myocytes and neonatal myocytes. We previously found that Bnip3 mediates cell death via Bax/Bak and that mouse embryonic fibroblasts (MEFs) lacking Bax and Bak are resistant to Bnip3-mediated cell death. Bnip3 still caused significant upregulation of autophagy in Bax/Bak−/− MEFs and imaging using high resolution fluorescence microscopy showed that a majority of the cells mitochondria were sequestered in autophagosomes. These results were confirmed by electron microscopy which also revealed the presence of a number of giant mitochondria in the cytosol, suggesting stimulation of mitochondrial biogenesis. Although Bnip3 alone did not cause cell death in Bax/Bak−/− MEFs, addition of 3-methyladenine (3-MA), an inhibitor of autophagy induced significant cell death in cells infected with Bnip3 but had no effect on cells overexpressing beta-gal. Overexpression of Bnip3 caused significant cell death in wild type MEFs, which was enhanced when inhibiting autophagy with 3-MA. These results suggest that Bnip3 stimulates autophagy to remove damaged mitochondria and mitochondrial biogenesis to synthesize new functional mitochondria. Since Bnip3 is upregulated in heart failure, stimulation of autophagy and mitochondrial biogenesis might represent potential therapeutic targets to treat heart disease.
This research has received full or partial funding support from the American Heart Association, AHA National Center.
Abstract 3084: Bare Metal Stenting versus Percutaneous Pulmonary Valve Implantation for Treatment of Right Ventricular Outflow Tract Obstruction - Utilization of a Catheter/Magnetic Resonance Hybrid Lab for Acute Physiological Comparison
Authors: Lurz Philipp , Nordmeyer Johannes , Khambadkone Sachin , Derrick Graham , Yates Rob , Muthurangu Vivek , Jones Rod , Bonhoeffer Philipp , Taylor Andrew M 
Published: July 2021

Background: Treatment of right ventricular outflow tract obstruction (RVOTO) is possible with a bare metal stent (BMS), though this causes pulmonary regurgitation (PR). In this study, we sought to assess the acute physiological effects of BMS vs. percutaneous pulmonary valve implantation (PPVI) using a catheter/ magnetic resonance (MR) hybrid lab (Siemens).
Methods: 12 consecutive children (median age 12.9) with significant RVOTO (echo gradient > 50 mmHg) were included. Patients were initially placed in the MR scanner and the ventricular volumes and great vessel blood flow assessed under general anaesthetic (GA). Patients were then transferred into the bi-plane catheter lab (under the same GA, on a sliding table) and a BMS inserted. Catheters and wires were removed and patients were transferred back to MR for repeat assessment. This whole process was repeated for a PPVI, which was placed into the BMS. MR and pressure data were compared with repeated measures ANOVA and post-hoc testing between the 3 physiological states.

Results (see Table

): BMS placement significantly reduced RV pressures and caused free PR. The increased PR was partially compensated for by a decrease in RV ESV and an increase in RV EF. There was no improvement in effective RV SV after BMS placement. Re-valvulation with PPVI resulted in a significant increase in effective RV SV, with consequent heart rate reduction at maintained cardiac output.

Conclusion: Utilisation of a catheter/MR hybrid lab offers new opportunities for the assessment of acute physiology following percutaneous interventions. Using this method we have demonstrated the superior acute haemodynamic effects of PPVI over BMS in patients with RVOTO.