bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of redox imbalance and apoptosis in multiple myeloma cells by the novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid
Authors: Ikeda Takashi , Nakata Yukiko , Kimura Fumihiko , Sato Ken , Anderson Kenneth , Motoyoshi Kazuo , Sporn Michael , Kufe Donald 
Published: June 2022

Abstract
The synthetic oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its chemical derivatives induce differentiation and apoptosis of human leukemia cells. The precise mechanisms responsible for the effects of CDDO, however, remain unclear. In the present study, we examined the effects of CDDO and its C-28 imidazolide ester (CDDO-Im) on apoptosis of multiple myeloma (MM) cells. The results show that both CDDO and CDDO-Im are potent inducers of MM cell apoptosis and that CDDO-Im is more active than CDDO. CDDO-Im treatment was associated with (a) depletion of glutathione, (b) increases in reactive oxygen species, (c) a reduction of the Fas-associated death domain (FADD)-like interleukin-1-converting enzyme (FLICE) inhibitory protein, (d) activation of caspase-8, and (e) a decrease of the mitochondrial transmembrane potential. The reducing agents, N-acetyl-l-cysteine, DTT, and catalase inhibited each of these CDDO-Im-induced proapoptotic signals. Inhibition of caspase-8 with z-IETD-fmk also abrogated CDDO-Im-induced decreases of the mitochondrial transmembrane potential and inhibited apoptosis. These results demonstrate that CDDO-Im disrupts intracellular redox balance and thereby activates the extrinsic caspase-8-dependent apoptotic pathway. We further show that CDDO-Im induces apoptosis of primary MM cells at submicromolar concentrations and that MM cells are more sensitive to this agent than normal bone marrow mononuclear cells. These results suggest that CDDO compounds have potential as new agents for the treatment of MM.
Combined inhibition of epidermal growth factor receptor and JAK/STAT pathways results in greater growth inhibition in vitro than single agent therapy
Authors: Dowlati Afshin , Nethery David , Kern Jeffrey A. 
Published: June 2022

Abstract
Epidermal growth factor receptor (EGFR) inhibition with small molecule tyrosine kinase inhibitors results in antitumor activity in only a minority of patients whose tumors express EGFR. One hypothesis to explain this suboptimal clinical activity is that multiple growth regulatory pathways are abnormal in most EGFR-expressing cancers. Given the importance of Stat-3 signaling pathway in epidermoid tumors, we hypothesized that blocking complementary pathways in an epidermal growth factor (EGF)-driven model of proliferation in the A431 cell line would demonstrate improved antiproliferative activity. Exposure of A431 cells to the EGF results in a significant increase in EGFR and Stat-3 phosphorylation. However, inhibition of EGFR by AG1478 fails to decrease EGF-induced Stat-3 phosphorylation. This suggests that EGF continues to drive Stat-3 phosphorylation through other receptors. Our study suggests that residual ErbB2 activation by EGF, despite EGFR blockade, is responsible for persistent downstream activation of Stat-3. In this setting, combined exposure to an EGFR blocker and Stat-3 blocker (AG490) results in significantly greater tumor growth inhibition than either agent alone. We conclude that targeting multiple pathways (EGFR and JAK/STAT pathways) in EGF-driven tumors may result in greater antiproliferative activity than blocking EGFR alone.
Antisense oligonucleotides directed at the bcl-xl gene product augment chemotherapy response in mesothelioma
Authors: Ozvaran Mustafa K. , Cao Xiaobo X. , Miller Steven D. , Monia Brett A. , Hong Waun Ki , Smythe W. Roy 
Published: June 2022

Abstract
Objective: Malignant pleural mesothelioma (MPM) is resistant to both conventional chemotherapy and apoptosis. The bcl-2 family proteins are major determinants of apoptotic homeostasis. MPM lines and tumors routinely overexpress the anti-apoptotic protein BCL-XL. We have previously shown that antisense inhibition of BCL-XL in MPM cells leads to apoptosis. We sought to determine whether antisense oligonucleotides directed at the bcl-xl gene product would augment response to a conventional chemotherapeutic agent in human mesothelioma cell lines.
Methods: The human MPM cell lines REN and I-45 were exposed to two bcl-xl antisense oligonucleotides (15999, 16009) and one sense oligonucleotide (113529) construct at varying doses, followed by IC50 cisplatin. Cellular viability was assessed by a calorimetric assay, and apoptosis was evaluated by Hoechst staining, Annexin V staining, and sub-G1 fluorescence-activated cell sorter analysis. Western blot analysis of BCL-2 family proteins was performed following single agent and combined treatment. Isobologram mathematical analysis was used to determine whether or not combination therapies were additive or synergistic.
Results: Cell viability was most affected with the 15999 antisense oligonucleotides plus IC50 cisplatin combination (70% of I-45 and 90% of REN cells killed), and apoptosis was markedly increased with this combination by all measures. Western blot demonstrated 15999 antisense oligonucleotides construct down-regulation of BCL-XL, but no further effect on expression of BCL-2 proteins with cisplatin. Isobologram analysis demonstrated 15999 + cisplatin synergistic effect.
Conclusions: Exposure of human MPM cells to bcl-xl antisense oligonucleotides sensitizes human mesothelioma cells to the conventional chemotherapeutic agent cisplatin. Similar approaches using a combination of molecular and conventional treatment may have clinical utility for this tumor.
Disulfide-constrained peptides that bind to the extracellular portion of the prostate-specific membrane antigen
Authors: Lupold Shawn E. , Rodriguez Ronald 
Published: June 2022

Abstract
The prostate-specific membrane antigen (PSMA) is a well-characterized surface antigen, overexpressed in the most advanced, androgen-resistant human prostate cancer cells. We sought to exploit PSMA cell surface properties as a target for short peptides that will potentially guide protein-based therapeutics, such as viral vectors, to prostate cancer cells. Two separate phage display peptide strategies were applied, in parallel, to purified PSMA protein bound to two separate substrates. We reasoned that peptide sequences common to both substrate selections would be specific binders of PSMA. Additionally, the design allowed for stringent cross-selections, where phage populations from one selection condition could be applied to the alternative substrate. These strategies resulted in a series of phage displayed peptides able to bind to PSMA by ELISA and direct binding assays, both with purified protein and in prostate cancer cells. Cell binding is competitively inhibited by purified PSMA. The synthesized peptides are capable of enhancing PSMA carboxypeptidase enzymatic activity, suggesting protein folding stabilization. The discovery of these peptides provides the foundation for subsequent development of peptide targeted therapeutics against prostate cancer.
Hypoxia inducible factor-1α as a cancer drug target
Authors: Powis Garth , Kirkpatrick Lynn 
Published: June 2022

Abstract
The hypoxia inducible factor 1 (HIF-1) is a heterodimeric transcription factor that is an important regulator of the growing tumor's response to hypoxia. HIF-1 activity in tumors depends on the availability of the HIF-1α subunit, the levels of which increase under hypoxic conditions and through the activation of oncogenes and/or inactivation of tumor suppressor genes. HIF-1 activates genes that allow the cancer cell to survive and grow in the hostile hypoxic tumor environment. Increased tumor HIF-1α has been correlated with increased angiogenesis, aggressive tumor growth, and poor patient prognosis, leading to the current interest in HIF-1α as a cancer drug target. A number of anticancer agents have been reported to decrease HIF-1α or HIF-1 transactivating activity in cells in culture. However, more relevant to the agents' antitumor activity is whether HIF-1 is inhibited in tumors in vivo. This has been demonstrated for only a few of the reported HIF-1 inhibitors. Some of the agents are moving toward clinical trial where it will be important to demonstrate that the agents inhibit HIF-1α in patient tumors or, failing this, the downstream consequences of HIF-1 inhibition such as decreased vascular endothelial growth factor formation, and relate this inhibition to antitumor activity. Only in this way will it be possible to determine if HIF-1α is a valid cancer drug target in humans.
Human apurinic endonuclease 1 (APE1) expression and prognostic significance in osteosarcoma: Enhanced sensitivity of osteosarcoma to DNA damaging agents using silencing RNA APE1 expression inhibition
Authors: Wang Dong , Luo Meihua , Kelley Mark R. 
Published: June 2022

Abstract
Osteosarcoma is the most common highly malignant bone tumor with primary appearance during the second and third decade of life. It is associated with a high risk of relapse, possibly resulting from a developed resistance to chemotherapy agents. As a means to overcome osteosarcoma tumor cell resistance and/or to sensitize tumor cells to currently used chemotherapeutic treatments, we examined the role of human apurinic endonuclease 1 (APE1) in osteosarcoma tumor cell resistance and prognosis. Sixty human samples of archived conventional (intramedullary) osteosarcoma were analyzed. APE1 protein was elevated in 72% of these tissues and among those with a known clinical outcome, there was a significant correlation between high APE1 expression levels and reduced survival times. The remaining 28% of samples showed low expression of APE1. Given that APE1 was overexpressed in osteosarcoma, we decreased APE1 levels using silencing RNA (siRNA) targeting technology in the osteosarcoma cell line, human osteogenic sarcoma (HOS), to enhance chemo- and radiation sensitivity. Using siRNA targeted technology of APE1, protein levels were reduced by more than 90% within 24 hours, remained low for 72 hours, and returned to normal levels at 96 hours. There was also a clear loss of APE1 endonuclease activity following APE1-siRNA treatment. A decrease in APE1 levels in siRNA-treated human osteogenic sarcoma cells led to enhanced cell sensitization to the DNA damaging agents: methyl methanesulfonate, H2O2, ionizing radiation, and chemotherapeutic agents. The findings presented here have both prognostic and therapeutic implications for treating osteosarcoma. The APE1-siRNA results demonstrate the feasibility for the therapeutic modulation of APE1 using a variety of molecules and approaches.
SB-431542, a small molecule transforming growth factor-β-receptor antagonist, inhibits human glioma cell line proliferation and motility
Authors: Hjelmeland Mark D. , Hjelmeland Anita B. , Sathornsumetee Sith , Reese Elizabeth D. , Herbstreith Michael H. , Laping Nicholas J. , Friedman Henry S. , Bigner Darell D. , Wang Xiao-Fan , Rich Jeremy N. 
Published: June 2022

AbstractTransforming growth factor-β (TGF-β) is a multifunctional cytokine that promotes malignant glioma invasion, angiogenesis, and immunosuppression. Antisense oligonucleotide suppression of TGF-β2 ligand expression has shown promise in preclinical and clinical studies but at least two ligands mediate the effects of TGF-β in gliomas. Therefore, we examined the effects of SB-431542, a novel, small molecule inhibitor of the type I TGF-β receptor, on a panel of human malignant glioma cell lines. SB-431542 blocked the phosphorylation and nuclear translocation of the SMADs, intracellular mediators of TGF-β signaling, with decreased TGF-β–mediated transcription. Furthermore, SB-431542 inhibited the expression of two critical effectors of TGF-β-vascular endothelial growth factor and plasminogen activator inhibitor-1. SB-431542 treatment of glioma cultures inhibited proliferation, TGF-β–mediated morphologic changes, and cellular motility. Together, our results suggest that small molecule inhibitors of TGF-β receptors may offer a novel therapy for malignant gliomas by reducing cell proliferation, angiogenesis, and motility.
Preclinical validation of anti-TMEFF2-auristatin E–conjugated antibodies in the treatment of prostate cancer
Authors: Afar Daniel E.H. , Bhaskar Vinay , Ibsen Eric , Breinberg Danna , Henshall Susan M. , Kench James G. , Drobnjak Marija , Powers Rick , Wong Melanie , Evangelista Ferdinand , O'Hara Chris , Powers David , DuBridge Robert B. , Caras Ingrid , Winter Ruth , Anderson Terri , Solvason Nanette , Stricker Phillip D. , Cordon-Cardo Carlos , Scher Howard I. , Grygiel John J. , Sutherland Robert L. , Murray Richard , Ramakrishnan Vanitha , Law Debbie A. 
Published: June 2022

Abstract
Current treatments for advanced stage, hormone-resistant prostate cancer are largely ineffective, leading to high patient mortality and morbidity. To fulfill this unmet medical need, we used global gene expression profiling to identify new potential antibody-drug conjugate (ADC) targets that showed maximal prostate cancer-specific expression. TMEFF2, a gene encoding a plasma membrane protein with two follistatin-like domains and one epidermal growth factor–like domain, had limited normal tissue distribution and was highly overexpressed in prostate cancer. Immunohistochemistry analysis using a specific monoclonal antibody (mAb) to human TMEFF2 showed significant protein expression in 74% of primary prostate cancers and 42% of metastatic lesions from lymph nodes and bone that represented both hormone-naïve and hormone-resistant disease. To evaluate anti-TMEFF2 mAbs as potential ADCs, one mAb was conjugated to the cytotoxic agent auristatin E via a cathepsin B–sensitive valine-citrulline linker. This ADC, Pr1-vcMMAE, was used to treat male severe combined immunodeficient mice bearing xenografted LNCaP and CWR22 prostate cancers expressing TMEFF2. Doses of 3 to 10 mg/kg of this specific ADC resulted in significant and sustained tumor growth inhibition, whereas an isotype control ADC had no significant effect. Similar efficacy and specificity was shown with huPr1-vcMMAE, a humanized anti-TMEFF2 ADC. No overt in vivo toxicity was observed with either murine or human ADC, despite significant cross-reactivity of anti-TMEFF2 mAb with the murine TMEFF2 protein, implying minimal toxicity to other body tissues. These data support the further evaluation and clinical testing of huPr1-vcMMAE as a novel therapeutic for the treatment of metastatic and hormone-resistant prostate cancer.
Use of Freeze-dried Watercress for Detoxification of Carcinogens and Toxicants in Smokers: Implications of the Findings and Potential Opportunities
Authors: El-Bayoumy Karam , Stoner Gary 
Published: June 2022

AbstractBonorden and colleagues designed a clinical trial to test the hypothesis that daily consumption of freeze-dried watercress, a rich source of the chemopreventive agent phenethyl isothiocyanate, can enhance the detoxification of well-known tobacco and environmental carcinogens and toxicants. Initial results have validated subject compliance and a positive outcome of this study would further support the use of watercress as a whole food-based approach to cancer chemoprevention. On the basis of the design of the clinical trial and the various biological samples to be collected, we discuss potential opportunities to test future hypotheses.See related article, p. 143
Endothelial Natriuretic Peptide Receptor 1 Play Crucial Role for Acute and Chronic Blood Pressure Regulation by Atrial Natriuretic Peptide
Authors: Tokudome Takeshi , Otani Kentaro , Mao Yuanjie , Jensen Lars Jørn , Arai Yuji , Miyazaki Takahiro , Sonobe Takashi , Pearson James T. , Osaki Tsukasa , Minamino Naoto , Ishida Junji , Fukamizu Akiyoshi , Kawakami Hayato , Onozuka Daisuke , Nishimura Kunihiro , Miyazato Mikiya , Nishimura Hirohito 
Published: June 2022

Background:
ANP (atrial natriuretic peptide), acting through NPR1 (natriuretic peptide receptor 1), provokes hypotension. Such hypotension is thought to be due to ANP inducing vasodilation via NPR1 in the vasculature; however, the underlying mechanism remains unclear. Here, we investigated the mechanisms of acute and chronic blood pressure regulation by ANP.

Methods and Results:

Immunohistochemical analysis of rat tissues revealed that NPR1 was abundantly expressed in endothelial cells and smooth muscle cells of small arteries and arterioles. Intravenous infusion of ANP significantly lowered systolic blood pressure in wild-type mice. ANP also significantly lowered systolic blood pressure in smooth muscle cell–specific
Npr1
–knockout mice but not in endothelial cell–specific
Npr1
–knockout mice. Moreover, ANP significantly lowered systolic blood pressure in
Nos3
-knockout mice. In human umbilical vein endothelial cells, treatment with ANP did not influence nitric oxide production or intracellular Ca
2+
concentration, but it did hyperpolarize the cells. ANP-induced hyperpolarization of human umbilical vein endothelial cells was inhibited by several potassium channel blockers and was also abolished under knockdown of RGS2 (regulator of G-protein signaling 2), an GTPase activating protein in G-protein α-subunit. ANP increased
Rgs2
mRNA expression in human umbilical vein endothelial cells but failed to lower systolic blood pressure in
Rgs2
-knockout mice. Endothelial cell–specific
Npr1
-overexpressing mice exhibited lower blood pressure than did wild-type mice independent of RGS2, and showed dilation of arterial vessels on synchrotron radiation microangiography.

Conclusions:
Together, these results indicate that vascular endothelial NPR1 plays a crucial role in ANP-mediated blood pressure regulation, presumably by a mechanism that is RGS2-dependent in the acute phase and RGS2-independent in the chronic phase.
Sex Differences in Diurnal Sodium Handling During Diet-Induced Obesity in Rats
Authors: Soliman Reham H. , Jin Chunhua , Taylor Crystal M. , Moura Coelho da Silva Emile , Pollock David M. 
Published: June 2022

Background:
Emerging evidence over the past several years suggests that diurnal control of sodium excretion is sex dependent and involves the renal endothelin system. Given recent awareness of disruptions of circadian function in obesity, we determined whether diet-induced obesity impairs renal handling of an acute salt load at different times of day and whether this varies by sex and is associated with renal endothelin dysfunction.

Methods:
Male and female Sprague-Dawley rats were placed on a high-fat diet for 8 weeks before assessing renal sodium handling and blood pressure.

Results:

Male, but not female, rats on high fat had a significantly reduced natriuretic response to acute NaCl injection at the beginning of their active period that was associated with lower endothelin 1 (ET-1) excretion, lower ET-1 mRNA expression in the cortex and outer medulla as well as lower ET
B
receptor expression in the outer medulla of the high-fat rats. Obese males also had significantly higher blood pressure (telemetry) that was exacerbated by adding high salt to the diet during the last 2 weeks. While female rats developed hypertension with a high-fat diet, they were not salt sensitive and ET-1 excretion was unchanged.

Conclusions:
These data identify diet-induced obesity as a sex-specific disruptive factor for maintaining proper sodium handling. Although high-fat diets induce hypertension in both sexes, these data reveal that males are at greater risk of salt-dependent hypertension and further suggest that females have more redundant systems that can be productive against salt-sensitive hypertension in at least some circumstances.
The Influence of Transdiagnostic Vulnerability Factors on PTSD Symptom Clusters in a Veteran Sample
Authors: Kreminski Michael A. , Courtney James A. , Drummond Sean P. A. , Norton Peter J. 
Published: June 2022

Background: There is continuing debate as to the latent structure underpinning posttraumatic stress disorder symptomatology. The transdiagnostic vulnerability factors of negative affect, anxiety sensitivity (and subcomponents) and intolerance of uncertainty have previously demonstrated the ability to explain symptom clusters in a range of anxiety and depressive disorders, and may give further understanding of PTSD symptomatology. Method: Within an Australian Defence Force veteran population, structural equation modeling is utilized to assess whether a hierarchical Original Model containing negative affect as the general cognitive factor, anxiety sensitivity and intolerance of uncertainty as mid-level factors, can explain variability among posttraumatic stress disorder symptom clusters as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. A further hierarchical Anxiety Sensitivity Extended model consisting of the general cognitive factor of negative affect and the three sub-factors of anxiety sensitivity as mid-level factors was also tested upon PTSD symptom clusters. Results: Both the hierarchical Original and Anxiety Sensitivity Extended models fit the data well. Within both models, negative affect consistently showed significant direct effects upon the posttraumatic stress disorder symptom clusters. In the Original Model, anxiety sensitivity served as a significant mediator of negative affect for several symptom clusters, while intolerance of uncertainty was non-significant both as a direct effect and as a mediator of negative affect. In the Anxiety Sensitivity Extended Model, the cognitive concerns sub-factor of anxiety sensitivity served as a significant mediator of negative affect for several symptom clusters, while the social and physical concerns sub-factors did not have significant direct or mediating effects. Conclusions: This study demonstrates a transdiagnostic hierarchical model significantly explains the severity of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition posttraumatic stress disorder symptom constructs within a subclinical population. Negative affect and anxiety sensitivity can each be targeted with specific interventions, suggesting new avenues to augment current gold standard psychotherapeutic interventions.
Sustained Virologic Response Rates Before and After Removal of Sobriety Restriction for Hepatitis C Virus Treatment Access
Authors: Martin Michelle T. , Waring Nicole , Forrest Jasmine , Nazari Jonathan L. , Abdelaziz Abdullah I. , Lee Todd A. 
Published: June 2022

Objectives: Until November 1, 2018, Illinois Medicaid restricted coverage of hepatitis C virus (HCV) medication to patients with sobriety from alcohol and illicit substances for ≥12 months. This policy limited treatment access for patients with a high risk of HCV transmission, despite clinical trial and real-world data demonstrating high sustained virologic response (SVR) rates among patients with substance use. The objective of this study was to compare HCV SVR rates between patients treated before and after removal of the Illinois Medicaid sobriety restriction. Methods: We performed a retrospective cohort study of Medicaid-insured patients who completed direct-acting antiviral treatment at an urban, academic medical center in Illinois from January 1, 2014, through October 21, 2020. The primary endpoint was SVR. We compared group characteristics using χ2 or Fisher exact tests for categorical variables and Wilcoxon rank-sum tests for continuous variables. We used logistic regression to compare SVR rates before and after the policy change, adjusting for differences between groups. Results: A total of 496 patients (348 pre–policy change; 148 post–policy change) started treatment; excluding loss to follow-up/early discontinuation, SVR rates were 95.4% (309 of 324) pre–policy change and 97.1% (134 of 138) post–policy change. SVR rates did not differ after adjusting for the use of historic HCV regimens and the higher cirrhosis rate in the pre–policy change group compared with the post–policy change group (odds ratio = 0.98; 95% CI, 0.32-3.67). Conclusion: HCV SVR rates were similar before and after removal of the Illinois Medicaid sobriety restriction, regardless of group differences. Results support HCV treatment regardless of documented sobriety to facilitate progress toward HCV elimination.