Publications by authors named "Weining Ma"

23 Publications

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PKA-RIIβ autophosphorylation modulates PKA activity and seizure phenotypes in mice.

Commun Biol 2021 Mar 1;4(1):263. Epub 2021 Mar 1.

State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.

Temporal lobe epilepsy (TLE) is one of the most common and intractable neurological disorders in adults. Dysfunctional PKA signaling is causally linked to the TLE. However, the mechanism underlying PKA involves in epileptogenesis is still poorly understood. In the present study, we found the autophosphorylation level at serine 114 site (serine 112 site in mice) of PKA-RIIβ subunit was robustly decreased in the epileptic foci obtained from both surgical specimens of TLE patients and seizure model mice. The p-RIIβ level was negatively correlated with the activities of PKA. Notably, by using a P-site mutant that cannot be autophosphorylated and thus results in the released catalytic subunit to exert persistent phosphorylation, an increase in PKA activities through transduction with AAV-RIIβ-S112A in hippocampal DG granule cells decreased mIPSC frequency but not mEPSC, enhanced neuronal intrinsic excitability and seizure susceptibility. In contrast, a reduction of PKA activities by RIIβ knockout led to an increased mIPSC frequency, a reduction in neuronal excitability, and mice less prone to experimental seizure onset. Collectively, our data demonstrated that the autophosphorylation of RIIβ subunit plays a critical role in controlling neuronal and network excitabilities by regulating the activities of PKA, providing a potential therapeutic target for TLE.
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http://dx.doi.org/10.1038/s42003-021-01748-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921646PMC
March 2021

Changes in the expression of endothelial monocyte‑activating polypeptide II in the rat hippocampus following status epilepticus.

Int J Mol Med 2021 Feb 3;47(2):699-707. Epub 2020 Dec 3.

Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.

Endothelial monocyte‑activating polypeptide II (EMAP II) is a sensitive marker of neurotoxic injury, the expression of which increases significantly under conditions of stress, such as hypoxia or apoptosis. Studies have confirmed the extensive apoptosis of nerve cells in the brain following status epilepticus (SE), and the occurrence of SE can confer a hypoxic state on cells. The purpose of the present study was to observe the changes in the expression of EMAP II, and in the numbers and tight junction protein levels of microvascular endothelial cells in the hippocampus of rats with pilocarpine‑induced SE. The protein expression levels of EMAP II, CD31, zonula occludens 1 (ZO‑1) and occludin in the hippocampus were determined by immunofluorescence and western blot analyses. It was found that almost 75.6% of the rats in the SE group developed Racine stage IV‑V seizures at approximately 44.7±18.8 min after the pilocarpine administration, and the 24‑h mortality rate was almost 10.4%. The weight of the rats in the SE group was significantly decreased within 24 h following SE. Immunofluorescence staining revealed a low EMAP II expression in the hippocampus of the rats in the control group; however, the numbers of EMAP II‑positive cells were significantly increased in the SE group from 2 h to 21 days. The trend of EMAP II protein expression was consistent with that obtained with immunofluorescence staining. The numbers of CD31‑positive microvascular endothelial cells were significantly increased from 24 h to 21 days compared with the levels in the control group. The protein expression of ZO‑1 and occludin was most significantly decreased in the SE group. On the whole, the present study demonstrated that the expression of EMAP II in the rat hippocampus was upregulated in the SE model, which may promote angiogenesis and alter the TJ integrity of brain microvascular endothelial cells, with an increased number of CD31‑positive microvascular endothelial cells and a decreased expression of ZO‑1 and occludin.
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http://dx.doi.org/10.3892/ijmm.2020.4808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797450PMC
February 2021

Measuring Tumor Epichaperome Expression Using [I] PU-H71 Positron Emission Tomography as a Biomarker of Response for PU-H71 Plus Nab-Paclitaxel in HER2-Negative Metastatic Breast Cancer.

JCO Precis Oncol 2020 17;4. Epub 2020 Nov 17.

Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Epichaperome network maintenance is vital to survival of tumors that express it. PU-H71 is an epichaperome inhibitor that binds to the ATP-binding site of HSP90 and has demonstrated antitumor activity in breast cancer xenograft models and clinical safety in patients. PU-positron emission tomography (PET) is a theragnostic imaging tool that allows visualization of the epichaperome target. In this phase Ib trial, we present safety and tolerability for PU-H71 plus nab-paclitaxel in HER2-negative patients with metastatic breast cancer (MBC) and the utility of PU-PET as a noninvasive predictive biomarker.

Methods: We performed a 3 + 3 dose-escalation study with escalating PU-H71 doses and standard nab-paclitaxel. The primary objective was to establish safety and determine maximum tolerated dose (MTD)/recommended phase 2 dose. Secondary objectives were to assess pharmacokinetics and clinical efficacy. Patients could enroll in a companion PU-PET protocol to measure epichaperome expression before treatment initiation to allow exploratory correlation with treatment benefit.

Results: Of the 12 patients enrolled, dose-limiting toxicity occurred in one patient (G3 neutropenic fever) at dose level 1; MTD of PU-H71 was 300 mg/m plus nab-paclitaxel 260 mg/m administered every 3 weeks. Common toxicities included diarrhea, fatigue, peripheral neuropathy, and nausea. PU-H71 systemic exposure was not altered by nab-paclitaxel administration. Two of 12 patients had partial response (overall response rate, 17%) and the clinical benefit rate was 42% (5 of 12). Time to progression was associated with baseline epichaperome positivity and PU-H71 peak standard uptake value (SUV), with more durable disease control observed with high epichaperome levels.

Conclusion: The combination of PU-H71 and nab-paclitaxel was well tolerated, with evidence of clinical activity. More durable disease control without progression was observed in patients with high baseline epichaperome expression. A phase II trial of this combination with PU-PET as a companion diagnostic for patient selection is currently planned.
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http://dx.doi.org/10.1200/PO.20.00273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713524PMC
November 2020

Early neurological deterioration in cardiogenic cerebral embolism due to nonvalvular atrial fibrillation: Predisposing factors and clinical implications.

Authors:
Lin Cong Weining Ma

Brain Behav 2021 Feb 4;11(2):e01985. Epub 2020 Dec 4.

Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.

Purpose: The aim of the study was to investigate factors which may predispose patients to early neurological deterioration (END) and explore peripheral biomarkers for the prediction of END in cardiogenic cerebral embolism (CCE) patients.

Methods: Patients diagnosed with CCE within 24 hr of onset between January 2017 and January 2019 were included in this study. END was defined as an increase of ≥2 on the National Institutes of Health Stroke Scale (NIHSS) or the emergence of new neurological symptoms within 3 days of admission. Binary logistic regression was used to investigate the factors associated with END. Receiver operating characteristic (ROC) curves were then generated to determine the predictive value of the potential biomarkers and the optimal cutoff values.

Results: Of the 129 (male, 55.81%; mean age 71.85 ± 11.99 years) CCE patients, 55 patients with END were identified. Hemorrhage transformation (HT), coronary heart disease (CHD), diastolic blood pressure, cystatin C levels, NIHSS score, and platelet-to-lymphocyte ratio (PLR) at admission were independently associated with END. A peripheral cystatin C level ≥ 1.41 mg/L and a PLR ≥ 132.97 were predictive factors for END in CCE patients. The lymphocyte-to-monocyte ratio (LMR) was negatively independently associated with HT, and LMR < 2.31 may predict the occurrence of HT in patients with CCE.

Conclusions: Of the potential predisposing factors considered, increased cystatin C and PLR were associated with END within 3 days of CCE, and a decreased LMR may have predictive value for HT in CCE patients.
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http://dx.doi.org/10.1002/brb3.1985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882173PMC
February 2021

Effects of Boldine on Antioxidants and Allied Inflammatory Markers in Mouse Models of Asthma.

J Environ Pathol Toxicol Oncol 2020 ;39(3):225-234

Department of Pediatrics, Shanghai General Hospital, Shanghai, China.

Asthma is marked by chronic irritation in the airway lumen of the lungs due to the accretion of inflammatory cells that influence the regular inhalation process. An extended buildup of inflammation leads to oxidative pressure and the repression of antioxidant functions. In the current study, a potential compound, boldine, was tested for the containment of provocative markers along the path of antiasthmatic activity in an ovalbumin (OVA)-induced asthmatic mice model. As an effect, the boldine (10 and 20 mg/kg) treatment suppressed inflammatory cells such as eosinophil, macrophage, neutrophil, lymphocyte, and other inflammatory markers in the bronchoalveolar lavage fluid (BALF) of OVA-induced mice. Likewise, immunoglobulin E (IgE) levels were drastically condensed in the serum of boldine-treated animals. Levels of enzymatic and nonenzymatic antioxidants, such as superoxide dismutase (SOD) and glutathione (GSH), were upregulated in the boldine treatment group compared to the asthmatic control group, which displays the antioxidant effects of boldine on asthmatic animals. Interestingly, the reactive oxygen species (ROS) and malonaldehyde (MDA) levels were repressed in the BALF of boldine-treated mice groups. Therefore, the effects of boldine are significant for the management of asthma, reducing the accrual of inflammatory cells, along with other inflammatory markers, while improving antioxidant markers and containing ROS. Hence, boldine may be an option for clinical trials of chronic asthma management.
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http://dx.doi.org/10.1615/JEnvironPatholToxicolOncol.2020034039DOI Listing
September 2020

The FDP/FIB Ratio and Blood FDP Level May Be Related to Seizures After Fever in Young Children.

Front Pediatr 2020 31;8:439. Epub 2020 Jul 31.

Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.

To evaluate the relationship of the blood fibrinogen (FIB) degradation product (FDP) level and FDP/FIB ratio with seizure in young children with fever. A total of 35 children with simple febrile seizures and 80 children with fever but no seizure were selected. First, the differences in white blood cell (WBC), platelets (PLT), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), FIB, FDP, FDP/FIB ratio, and C-reactive protein (CRP) between 35 children with simple febrile seizures and 40 randomly selected children with fever but no seizure were retrospectively analyzed. Then, an ROC curve was used to determine the diagnostic utility of the FDP level, FDP/FIB ratio, and FDP+FDP/FIB ratio, and the best diagnostic cutoff points were selected. Finally, the diagnostic specificities of the three diagnostic indicators were verified by comparison with the results of all 80 children with fever but no seizure. The FDP level and FDP/FIB ratio were significantly different between the two groups ( < 0.0001) and there was a positive correlation between the FDP and FIB levels. Both the FDP level and FDP/FIB ratio had good diagnostic value. An FDP ≥ 2.0 mg/L and FDP/FIB ratio ≥ 0.5 had good diagnostic specificities. Combined application of an FDP ≥ 2.0 mg/L and FDP/FIB ratio ≥ 0.5 improved the diagnostic power. The blood FDP level and FDP/FIB ratio may be related to seizures after fever, and an FDP ≥ 2.0 mg/L + FDP/FIB ratio ≥ 0.5 has good diagnostic specificity.
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http://dx.doi.org/10.3389/fped.2020.00439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412868PMC
July 2020

A multimodality triage algorithm to improve cytoreductive outcomes in patients undergoing primary debulking surgery for advanced ovarian cancer: A Memorial Sloan Kettering Cancer Center team ovary initiative.

Gynecol Oncol 2020 09 6;158(3):608-613. Epub 2020 Jun 6.

Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Obstetrics & Gynecology, Weill Cornell Medical College, New York, NY, USA. Electronic address:

Objective: To describe outcomes using a multimodal algorithm to triage patients with advanced epithelial ovarian cancer (EOC) to primary debulking surgery (PDS) versus neoadjuvant chemotherapy (NACT).

Methods: All patients with EOC treated at our institution from 04/2015-08/2018 were identified. We included patients without contraindication to PDS who underwent prospective calculation of a Resectability (R)-score. A low risk score for suboptimal cytoreduction was defined as ≤6, and a high risk score ≥7. Patients were triaged to laparotomy/PDS, laparoscopic evaluation of resectability (LSC), or NACT depending on R-score.

Results: Among 299 participants, 226 (76%) had a low risk score and 73 (24%) a high risk score. For patients with a low risk score, management included laparotomy/PDS, 181 (80%); LSC, 43 (19%) (with subsequent triage: PDS, 31; NACT, 12); and NACT, 2 (1%). For patients with a high risk score, management included laparotomy/PDS, 9 (12%); LSC, 51 (70%) (with subsequent triage: PDS, 28; NACT, 23); and NACT, 13 (18%). Overall, 83% underwent PDS, with a 75% CGR rate and 94% optimal cytoreduction rate. Use of the algorithm resulted in a 31% LSC rate and a 6% rate of suboptimal PDS.

Conclusions: The multimodal algorithm led to excellent surgical results; 94% of patients achieved an optimal resection, with a very low rate of suboptimal cytoreduction.
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http://dx.doi.org/10.1016/j.ygyno.2020.05.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487016PMC
September 2020

Prognostic Relationship Between Peripheral Red Cell Distribution Width and Acute Cerebral Infarction in Patients with rtPA Thrombolysis.

Neurotox Res 2020 06 11;38(1):211-218. Epub 2020 Mar 11.

Department of Neurosurgery, Shengjing Hospital of China Medical University, No. 39 Huaxiang Road, Tiexi District, Shenyang, 110000, Liaoning, People's Republic of China.

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http://dx.doi.org/10.1007/s12640-020-00186-0DOI Listing
June 2020

Quantitative Serum Proteomic Study Reveals that Fibrinogen-Related Proteins May Participate in the Pathophysiological Process of Simple Febrile Convulsion.

J Am Soc Mass Spectrom 2020 Mar 19;31(3):666-674. Epub 2020 Feb 19.

Department of Pediatric, Shengjing Hospital of China Medical University, Shenyang 110004, China.

Simple febrile convulsion (SFC) is a common disease that is mainly caused by fever from extracranial infections. In this study, we used proteomic approaches involving discovery and validation cohorts to examine the proteomes of serum from children who were diagnosed with SFC, children with fever but without convulsion, and healthy children (normal controls). We identified 86 proteins involved in different biological pathways that were significantly different between the SFC and normal control groups. Of these 86 proteins, 35 had higher expression in the SFC group compared with the normal control group, whereas 51 had lower expression. Notably, fibrinogen-related proteins involved in the coagulation system pathway were markedly decreased in the SFC group. Targeted and absolute quantification of fibrinogen-related proteins was performed and validated the potential of these proteins as biomarkers. Thus, fibrinogen-related proteins may participate in the pathophysiological process of SFC and may be potential biomarkers for the diagnosis of SFC.
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http://dx.doi.org/10.1021/jasms.9b00100DOI Listing
March 2020

Pre-Operative Interictal Discharge Patterns and Magnetic Resonance Imaging Findings Affect Prognosis of Temporal Lobe Epilepsy Surgery.

Eur Neurol 2019 3;81(3-4):152-162. Epub 2019 Jul 3.

Department of Neurosurgery, Shengjing Hospital Affiliated to China Medical University, Shenyang, China,

Objective: This study investigated whether pre-operative interictal discharge patterns detected by electroencephalogram (EEG) and magnetic resonance imaging (MRI) findings affect the surgical prognosis in temporal lobe epilepsy (TLE) patients.

Methods: A retrospective analysis of 115 cases of patients with refractory TLE was carried out from October 2010 to 2014 based on the classification of pre-operative interictal discharge patterns in EEG and MRI findings. The patients were followed up for 4 years after surgery. The ILAE method was used to assess differences in seizure-free rate among different types of interictal discharge pattern as well as in MRI findings.

Results: A total of 115 cases were classified according to interictal discharge patterns in EEG, including normal cases, unilateral anterior discharge, unilateral multi-region discharge, and bilateral discharge. MRI findings were classified into negative results and positive results. Unilateral anterior and bilateral discharges showed statistically significant differences in post-operative seizure-free rates (p< 0.001). MRI-positive cases showed good overall post-operative outcome, irrespective of interictal discharge pattern in the EEG, whereas MRI-negative cases showed good overall prognosis if the interictal discharge pattern in EEG occurred in the unilateral anterior region.

Conclusion: If the pre-operative interictal discharge pattern in EEG is confined to the unilateral anterior region, prognosis is good. If there are abnormalities in MRI findings, post-operative prognosis is good, regardless of pre-operative interictal discharge patterns in EEG. Surgical intervention is highly recommended for TLE patients with normal MRI findings and interictal discharge confined to the unilateral anterior region.
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http://dx.doi.org/10.1159/000501002DOI Listing
June 2020

ERG3 potassium channel-mediated suppression of neuronal intrinsic excitability and prevention of seizure generation in mice.

J Physiol 2018 10 7;596(19):4729-4752. Epub 2018 Sep 7.

State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China.

Key Points: ERG3 channels have a high expression level in the central nervous system. Knockdown of ERG3 channels enhances neuronal intrinsic excitability (caused by decreased fast afterhyperpolarization, shortened delay time to the generation of an action potential and enhanced summation of somatic excitatory postsynaptic potentials) in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. The expression of ERG3 protein is reduced in human and mouse hippocampal epileptogenic foci. Knockdown of ERG3 channels in hippocampus enhanced seizure susceptibility, while mice treated with the ERG channel activator NS-1643 were less prone to epileptogenesis. The results provide strong evidence that ERG3 channels have a crucial role in the regulation of neuronal intrinsic excitability in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells and are critically involved in the onset and development of epilepsy.

Abstract: The input-output relationship of neuronal networks depends heavily on the intrinsic properties of their neuronal elements. Profound changes in intrinsic properties have been observed in various physiological and pathological processes, such as learning, memory and epilepsy. However, the cellular and molecular mechanisms underlying acquired changes in intrinsic excitability are still not fully understood. Here, we demonstrate that ERG3 channels are critically involved in the regulation of intrinsic excitability in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Knock-down of ERG3 channels significantly increases neuronal intrinsic excitability, which is mainly caused by decreased fast afterhyperpolarization, shortened delay time to the generation of an action potential and enhanced summation of somatic excitatory postsynaptic potentials. Interestingly, the expression level of ERG3 protein is significantly reduced in human and mouse brain tissues with temporal lobe epilepsy. Moreover, ERG3 channel knockdown in hippocampus significantly enhanced seizure susceptibility, while mice treated with the ERG channel activator NS-1643 were less prone to epileptogenesis. Taken together, our results suggest ERG3 channels play an important role in determining the excitability of hippocampal neurons and dysregulation of these channels may be involved in the generation of epilepsy. ERG3 channels may thus be a novel therapeutic target for the prevention of epilepsy.
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http://dx.doi.org/10.1113/JP275970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166062PMC
October 2018

CDYL suppresses epileptogenesis in mice through repression of axonal Nav1.6 sodium channel expression.

Nat Commun 2017 08 25;8(1):355. Epub 2017 Aug 25.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.

Impairment of intrinsic plasticity is involved in a range of neurological disorders such as epilepsy. However, how intrinsic excitability is regulated is still not fully understood. Here we report that the epigenetic factor Chromodomain Y-like (CDYL) protein is a critical regulator of the initiation and maintenance of intrinsic neuroplasticity by regulating voltage-gated ion channels in mouse brains. CDYL binds to a regulatory element in the intron region of SCN8A and mainly recruits H3K27me3 activity for transcriptional repression of the gene. Knockdown of CDYL in hippocampal neurons results in augmented Nav1.6 currents, lower neuronal threshold, and increased seizure susceptibility, whereas transgenic mice over-expressing CDYL exhibit higher neuronal threshold and are less prone to epileptogenesis. Finally, examination of human brain tissues reveals decreased CDYL and increased SCN8A in the temporal lobe epilepsy group. Together, our findings indicate CDYL is a critical player for experience-dependent gene regulation in controlling intrinsic excitability.Alterations in intrinsic plasticity are important in epilepsy. Here the authors show that the epigenetic factor CDYL regulates the gene expression of the voltage gated sodium channel, Nav1.6, which contributes to seizures in a rat model of epilepsy.
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http://dx.doi.org/10.1038/s41467-017-00368-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572458PMC
August 2017

Causes of Avascular Hypoechoic Testicular Lesions Detected at Scrotal Ultrasound: Can They Be Considered Benign?

AJR Am J Roentgenol 2017 Jul;209(1):110-115

1 Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065.

Objective: The purposes of this study were to determine the cause of avascular hypoechoic lesions detected at scrotal ultrasound and to assess usefulness of sonographic and clinical features in differentiating benign from malignant etiologic factors.

Materials And Methods: This retrospective study included 58 patients with avascular hypoechoic lesions detected at testicular ultrasound. The sonographic features recorded were lesion size and margins and presence of peripheral vascularity and focal calcifications. Also recorded were patient age, symptoms, risk factors, lesion palpability, and levels of serum tumor markers. The reference standard was pathologic results or at least 2-year stability documented with serial follow-up ultrasound studies. Features associated with malignant, including burnt-out, lesions and benign lesions were examined by Fisher exact test, Wilcox-on rank sum test, and the generalized estimating equations method for multivariable models.

Results: Sixty-three lesions were identified in 58 patients; 40 of the 63 (63.5%) were benign. Patients with malignant lesions had elevated serum tumor marker levels more often than patients who had benign lesions (26.1% versus 5.7%, p = 0.043). The clinical palpability of lesions and history of testicular cancer were not statistically significantly different between patients with malignant and those with benign lesions. Poorly defined margins of a lesion and focal calcification within the lesion were more often found in malignant lesions. Maximal size of a lesion and peripheral vascularity were not associated with either the benign or the malignant nature of a lesion.

Conclusion: Although most avascular hypoechoic testicular lesions are benign, a substantial proportion are malignant. The ultrasound characteristics of a lesion, the patient's clinical presentation, and serum tumor marker status may be useful in differentiating malignant from benign lesions.
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http://dx.doi.org/10.2214/AJR.16.17333DOI Listing
July 2017

Ginsenoside Rh2 inhibits invasiveness of glioblastoma through modulation of VEGF-A.

Tumour Biol 2015 Jul 29. Epub 2015 Jul 29.

Department of Neurosurgery, Shengjing Hospital of China Medical University, 36 Sanhaojie, Shenyang, 110004, China,

The malignancy of glioblastoma multiforme (GBM) is largely due to its local invasion and the presence of the tumor in the relatively restrained region in the brain. Hence, effective prevention of the cancer cell invasion is substantially critical for controlling the growth and deterioration of GBM. We have recently reported the role of ginsenoside Rh2 (GRh2) in suppressing the growth of GBM through EGFR/PI3k/Akt/mTor signaling pathways. Here, we further showed that GRh2 efficiently inhibited the cancer vascularization in vivo. In vitro, GRh2 dose-dependently inhibited the protein, but not messenger RNA (mRNA) of vascular endothelial growth factor A (VEGF-A) in GBM cells. We then examined the underlying mechanisms and found that GRh2 increased the levels of miR-497, which bound to 3'UTR of VEGF-A mRNA to inhibit its translation. Together, our data demonstrate a previously unappreciated role for GRh2 in inhibition of GBM-associated cancer vascularization, which may contribute to the effects of GRh2 on suppression of GBM cancer growth and invasion.
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http://dx.doi.org/10.1007/s13277-015-3759-6DOI Listing
July 2015

Ovarian vein thrombosis after debulking surgery for ovarian cancer: epidemiology and clinical significance.

Am J Obstet Gynecol 2015 Aug 2;213(2):208.e1-4. Epub 2015 Mar 2.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Objective: Ovarian vein thrombosis is associated with pregnancy and pelvic surgery. Postpartum ovarian vein thrombosis is associated with infection and a high morbidity rate and is treated with anticoagulant and intravenous antibiotic therapy. The natural history of such thrombotic events after debulking surgery for ovarian cancer has not been well described. Our objective was to characterize the presentation and outcomes for patients with this condition at our institution.

Study Design: We conducted a retrospective study of patients who underwent surgical debulking for ovarian cancer at Memorial Sloan Kettering Cancer Center between the years 2001 and 2010. Patients were included if contrast computed tomography scans of both the abdomen and pelvis were performed within 12 weeks before and 12 weeks after the surgery. The images were reviewed to assess for the presence and extent of a new postoperative ovarian vein thrombosis. When available, subsequent studies were assessed for thrombus progression. Medical records were reviewed to determine whether anticoagulation was used for treatment of the thrombotic episode and to record the occurrence of any new significant venous thromboembolic event in the next year.

Results: One hundred fifty-nine patients had satisfactory imaging. New ovarian vein thrombosis was a common complication of debulking surgery, as found in 41 of patients (25.8%). Only 5 women with ovarian vein thrombosis were started on anticoagulation, of which 2 individuals had an independent venous thromboembolic event as indication for treatment. Only 2 of the ovarian vein thromboses (4.9%) progressed to the inferior vena cava or left renal vein on subsequent scan. The estimated cumulative incidence of venous thromboembolism 1 year after the first postoperative scan was 17.1% for patients in the new ovarian vein thrombosis group vs 15.3% of individuals for the group without a postoperative ovarian vein thrombosis (P = .78).

Conclusion: Ovarian vein thrombosis is commonly encountered after debulking surgery for ovarian cancer. Anticoagulation is usually not indicated, and clinically meaningful thrombus progression rarely occurs.
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http://dx.doi.org/10.1016/j.ajog.2015.02.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863445PMC
August 2015

EGFR signaling-dependent inhibition of glioblastoma growth by ginsenoside Rh2.

Tumour Biol 2014 Jun 21;35(6):5593-8. Epub 2014 Feb 21.

Department of Neurosurgery, Shengjing Hospital of China Medical University, 36 Sanhaojie, Shenyang, 110004, Liaoning Province, China,

Glioblastoma is the most common and most aggressive malignant primary brain tumor in humans, accounting for 52 % of all functional tissue brain tumor cases and 20 % of all intracranial tumors. The typical treatment involves a combination of chemotherapy, radiation, and surgery, whereas it still achieves fairly poor patient survival. Ginsenoside Rh2 has been reported to have a therapeutic effect on some tumors, but its effect on glioblastoma has not been extensively evaluated. Here, we show that ginsenoside Rh2 can substantially inhibit the growth of glioblastoma in vitro and in vivo in a mouse model. Moreover, the inhibition of the tumor growth appears to result from combined effects on decreased tumor cell proliferation and increased tumor cell apoptosis. Further analyses suggest that ginsenoside Rh2 may have its antiglioblastoma effect through inhibition of the epidermal growth factor receptor (EGFR) signaling pathway in tumor cells. In a lose-of-function experiment, recombinant EGFR was given together with ginsenoside Rh2 to the tumor cells in vitro and in vivo, which completely blocked the antitumor effects of ginsenoside Rh2. Thus, our data not only reveal an anti-glioblastoma effect of ginsenoside Rh2 but also demonstrate that this effect may function via inhibition of EGFR signaling in glioblastoma cells.
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http://dx.doi.org/10.1007/s13277-014-1739-xDOI Listing
June 2014

Enhancement of ovarian malignancy on clinical contrast enhanced MRI studies.

ISRN Obstet Gynecol 2013 13;2013:979345. Epub 2013 Feb 13.

Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Purpose. To assess if there is a significant difference in enhancement of high grade serous carcinoma of the ovary compared with other ovarian malignancies on clinically performed contrast enhanced MRI studies. Methods. In this institutional-review-board-approved study, two radiologists reviewed contrast enhanced MRI scans in 37 patients with ovarian cancer. Readers measured the signal intensity (SI) of ovarian mass and gluteal fat pre- and postcontrast administration. Percentage enhancement (PE) was calculated as [(post-pre)/precontrast SI] × 100. Results. Pathology revealed 19 patients with unilateral and 18 patients with bilateral malignancies for a total of 55 malignant ovaries-high grade serous carcinoma in 25/55 ovaries (45%), other epithelial carcinomas in 12 ovaries (22%), nonepithelial cancers in 8 ovaries (14%), and borderline tumors in 10 ovaries (18%). Enhancement of high grade serous carcinoma was not significantly different from other invasive ovarian malignancies (Reader 1 P = 0.865; Reader 2 P = 0.353). Enhancement of invasive ovarian malignancies was more than borderline tumors but did not reach statistical significance (Reader 1P = 0.102; Reader 2 P = 0.072). Conclusion. On clinically performed contrast enhanced MRI studies, enhancement of high grade serous ovarian carcinoma is not significantly different from other ovarian malignancies.
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http://dx.doi.org/10.1155/2013/979345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586516PMC
March 2013

A phase I dose-escalation trial of trastuzumab and alvespimycin hydrochloride (KOS-1022; 17 DMAG) in the treatment of advanced solid tumors.

Clin Cancer Res 2012 Sep 10;18(18):5090-8. Epub 2012 Jul 10.

Memorial Sloan-Kettering Cancer Center; Weill Cornell Medical College, New York, NY 10032, USA.

Purpose: We conducted a phase I dose-escalation study to define the maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics of alvespimycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, given in combination with trastuzumab.

Experimental Design: Patients were treated with trastuzumab followed by intravenous alvespimycin on a weekly schedule. Hsp90 client proteins were measured at baseline and serially in peripheral blood lymphocytes (PBL) during cycle 1. Patients with advanced solid tumors progressing on standard therapy were eligible.

Results: Twenty-eight patients (25, breast; 3, ovarian) were enrolled onto three dose cohorts: 60 (n = 9), 80 (n = 13), and 100 mg/m(2) (n = 6). Dose-limiting toxicities (DLT) were: grade III left ventricular systolic dysfunction presenting as congestive heart failure in 1 patient (100 mg/m(2)), and reversible grade III keratitis in two patients (80 mg/m(2)). Drug-related grade III toxicity included one episode each of fatigue, diarrhea, myalgia, and back pain. Common mild to moderate toxicities included diarrhea, fatigue, myalgia, arthralgia, nausea, blurry vision, headache, back pain, and dry eyes. There was one partial response and seven cases of stable disease (range, 4-10 months), all in HER2+ MBC. In addition, an ovarian cancer patient had complete resolution of ascites and pleural effusion that lasted 24.8 months. There was no change in PK upon weekly dosing. Hsp70 effect continued to increase across four weeks and was most pronounced at 80 and 100 mg/m(2).

Conclusion: The combination of alvespimycin and trastuzumab is safe and tolerable at MTD. Antitumor activity was seen in patients with refractory HER2+ MBC and ovarian cancer. The recommended dose of alvespimycin for further study in this combination is 80 mg/m(2) weekly.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-3200DOI Listing
September 2012

Gemcitabine for advanced endometrial cancer: a retrospective study of the Memorial sloan-Kettering Cancer Center experience.

Int J Gynecol Cancer 2012 Jun;22(5):807-11

Gynecologic Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Background: Gemcitabine is active in several gynecologic malignancies including ovarian cancer, cervical cancer, and uterine leiomyosarcoma. It has been used in an off-label setting for the treatment of advanced endometrial cancer, despite lack of published data showing efficacy. We performed a retrospective study to determine the progression-free survival and response rate of endometrial cancer patients treated with gemcitabine at Memorial Sloan-Kettering Cancer Center.

Methods: Eligible patients had histologically confirmed advanced (stage IV or recurrent) endometrial cancer that was treated with single-agent gemcitabine at Memorial Sloan-Kettering Cancer Center between 1999 and 2009. Response to therapy was determined by review of computed tomography imaging by Response Evaluation Criteria in Solid Tumors 1.1 criteria.

Results: Forty-six patients were included in the analysis. Median age was 66 years (range, 52-87 years). All patients were previously treated with chemotherapy. The median number of prior lines of chemotherapy was 2 (range, 1-8). Median dose of gemcitabine administered was 800 mg/m infused on days 1 and 8 of a 21-day cycle. Predominant histology was endometrioid (48%, n = 22) followed by serous (35%, n = 16), clear cell (15%, n = 7), and undifferentiated (2%, n = 1). Overall response rate was 10.9% (95% confidence interval, 1.9%-19.9%); 5 patients (11%) achieved a partial response. Thirteen patients (28%) displayed stable disease lasting at least 3 months. Of note, 5 (71%) of the 7 patients with clear cell histology displayed stable disease or partial response (n = 5). The median progression-free survival was 3.0 months (95% confidence interval, 2.1-3.3 months). Nonhematologic grades 3 and 4 toxicities were rare. Ten patients (22%) were treated with granulocyte colony-stimulating factor during treatment. Grade 3 thrombocytopenia was seen in 4 patients (9%). There were no cases of grade 4 thrombocytopenia.

Conclusions: In a mixed population of patients with previously treated advanced endometrial cancer, gemcitabine was well tolerated and showed modest activity. Patients with clear cell histology appeared to have greater likelihood of benefit.
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http://dx.doi.org/10.1097/IGC.0b013e31824a33a2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904291PMC
June 2012

HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab.

Clin Cancer Res 2011 Aug 10;17(15):5132-9. Epub 2011 May 10.

Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Purpose: HSP90 is a chaperone protein required for the stability of a variety of client proteins. 17-Demethoxygeldanamycin (17-AAG) is a natural product that binds to HSP90 and inhibits its activity, thereby inducing the degradation of these clients. In preclinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. On the basis of these data and activity in a phase I study, we conducted a phase II study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2-positive breast cancer.

Experimental Design: We enrolled patients with metastatic HER2(+) breast cancer whose disease had previously progressed on trastuzumab. All patients received weekly treatment with tanespimycin at 450 mg/m(2) intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

Results: Thirty-one patients were enrolled with a median age of 53 years and a median Karnofsky performance status (KPS) of 90%. The most common toxicities, largely grade 1, were diarrhea, fatigue, nausea, and headache. The overall response rate was 22%, the clinical benefit rate [complete response + partial response + stable disease] was 59%, the median progression-free survival was 6 months (95% CI: 4-9), and the median overall survival was 17 months (95% CI: 16-28).

Conclusions: This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors. Tanespimycin plus trastuzumab has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously progressing on trastuzumab. Further research exploring this therapeutic interaction and the activity of HSP90 inhibitors is clearly warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-0072DOI Listing
August 2011

HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab.

Clin Cancer Res 2011 Aug 10;17(15):5132-9. Epub 2011 May 10.

Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Purpose: HSP90 is a chaperone protein required for the stability of a variety of client proteins. 17-Demethoxygeldanamycin (17-AAG) is a natural product that binds to HSP90 and inhibits its activity, thereby inducing the degradation of these clients. In preclinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. On the basis of these data and activity in a phase I study, we conducted a phase II study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2-positive breast cancer.

Experimental Design: We enrolled patients with metastatic HER2(+) breast cancer whose disease had previously progressed on trastuzumab. All patients received weekly treatment with tanespimycin at 450 mg/m(2) intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

Results: Thirty-one patients were enrolled with a median age of 53 years and a median Karnofsky performance status (KPS) of 90%. The most common toxicities, largely grade 1, were diarrhea, fatigue, nausea, and headache. The overall response rate was 22%, the clinical benefit rate [complete response + partial response + stable disease] was 59%, the median progression-free survival was 6 months (95% CI: 4-9), and the median overall survival was 17 months (95% CI: 16-28).

Conclusions: This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors. Tanespimycin plus trastuzumab has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously progressing on trastuzumab. Further research exploring this therapeutic interaction and the activity of HSP90 inhibitors is clearly warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-0072DOI Listing
August 2011

Imaging appearance of granulomatous disease after intravesical Bacille Calmette-Guerin (BCG) treatment of bladder carcinoma.

AJR Am J Roentgenol 2009 Jun;192(6):1494-500

Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY 10022, USA.

Objective: The purpose of our study is to present the radiographic findings in a series of 16 patients with complications associated with intravesical bacille Calmette-Guérin (BCG) treatment of bladder cancer.

Conclusion: Intravesical BCG-related complications such as granulomatous disease may show imaging findings mimicking primary or metastatic tumors in patients with bladder cancer. Radiologists should consider this possibility when imaging abnormalities are encountered in bladder cancer patients treated with intravesical BCG so that appropriate management can be administered and unnecessary procedures avoided.
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http://dx.doi.org/10.2214/AJR.08.1962DOI Listing
June 2009

Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer: a phase I dose-escalation study.

J Clin Oncol 2007 Dec;25(34):5410-7

Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

Purpose: This phase I study examined whether a heat shock protein (Hsp) 90 inhibitor tanespimycin (17-AAG; KOS-953) could be administered safely in combination with trastuzumab at a dose that inhibits Hsp90 function in vivo in lymphocytes.

Patients And Methods: Patients with an advanced solid tumor progressing during standard therapy were eligible. Patients were treated with weekly trastuzumab followed by intravenous tanespimycin, assessed in escalating dose levels.

Results: Twenty-five patients were enrolled onto four tanespimycin dose levels: 225 (n = 4), 300 (n = 3), 375 (n = 8), and 450 mg/m2 (n = 10). Dose-limiting toxicity (DLT) was observed at the third and fourth cohort (1 patient each): more than 2-week delay for grade 4 fatigue/grade 2 nausea and anorexia (375 mg/m2); more than 2-week delay for thrombocytopenia (450 mg/m2). Drug-related grade 3 toxicity included emesis, increased ALT, hypersensitivity reactions (two patients each), and drug-induced thrombocytopenia (n = 1). Common mild to moderate toxicities included fatigue, nausea, diarrhea, emesis, headache, rash/pruritus, increased AST/ALT, and anorexia. Pharmacokinetic analysis demonstrated no difference in tanespimycin kinetics with or without trastuzumab. Pharmacodynamic testing showed reactive induction of Hsp70 (a marker of Hsp90 inhibition) in lymphocytes at all dose levels. Antitumor activity was noted (partial response, n = 1; minor response, n = 4; stable disease > or = 4 months, n = 4). Tumor regressions were seen only in patients with human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer.

Conclusion: Tanespimycin plus trastuzumab is well tolerated and has antitumor activity in patients with HER-2+ breast cancer whose tumors have progressed during treatment with trastuzumab. These data suggest that Hsp90 function can be inhibited in vivo to a degree sufficient to cause inhibition of tumor growth.
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http://dx.doi.org/10.1200/JCO.2007.11.7960DOI Listing
December 2007