Publications by authors named "Jiaxin Niu"

31 Publications

Epidemiology and analysis of potential risk factors of high-risk human papillomavirus (HPV) in Shanghai China: A cross-sectional one-year study in non-vaccinated women.

J Med Virol 2021 Nov 12. Epub 2021 Nov 12.

Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Data regarding human papillomavirus (HPV) prevalence, its associated risk factors, and women's knowledge about this disease before the HPV vaccine was approved are limited in Shanghai, China. Therefore, we investigated these questions among females in Shanghai and aimed to provide comprehensive data to guide HPV vaccination and present the biopsychosocial risk factors that impact high-risk HPV infection, and evaluate the level of knowledge and awareness of this disease among women aged 21-65 years old. A total of 6619 (aged from 21 to 65) women from different communities volunteered to participate in the HPV screening and complete questionnaires from December 2016 to December 2017 in the Department of Obstetrics and Gynecology of nine hospitals in Shanghai. Data were analyzed using sample logistic regression to assess biopsychosocial risk factors that impact high-risk HPV infection and knowledge of HPV infection. A total of 632 (9.5%) cases were positive for high-risk HPV test, 22.6% of them were HPV 16/18 infection, 77.4% of them were non HPV 16/18 infection. 40 potential risk factors may be related to high-risk HPV infection, and there were 19 factors' p value < 0.1 from single factor logistic analysis. Finally, multivariable regression revealed education level, type of vaginitis, history of hyperlipidemias, family history of cancer, number of pregnancies, number of sex partners were independent risk factors for high-risk HPV infection (p < 0.05). When stratified by education level, women who finished graduate school had significantly greater knowledge of cervical cancer, cervical screening, and the relationship between HPV and cervical cancer than other groups (p < 0.05). The prevalence rate of high-risk HPV was a little lower than other regions in China and other countries, which may be related to regions, races, living habits, and economy. A less reported finding is that the history of vaginitis and the history of hyperlipidemias in our study were related to HPV infection. The majority of the participants had poor knowledge regarding cervical cancer, cervical screening, and the relationship between HPV and cervical cancer. Hence, these results should be served as a wake-up call for the government to increase knowledge and awareness via the media and doctors.
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http://dx.doi.org/10.1002/jmv.27453DOI Listing
November 2021

N NMR as a General Tool to Characterize the Nitrogen-Containing Species and Monitor the Nitration Process.

J Org Chem 2021 Dec 11;86(23):16699-16706. Epub 2021 Nov 11.

School of Materials Science and Engineering, Experimental Center for Advanced Materials, Beijing Institute of Technology, Beijing 100081, China.

The usefulness of N NMR spectroscopy was highly underestimated compared with N NMR, which usually required tedious and expensive N-labeling manipulations. It is of great significance to make the N NMR spectroscopy convenient and useful considering N nuclei's high natural abundance of 99.6%. Herein, lots of efforts have been made to generalize routine N NMR to characterize nitrogen-containing species by tuning the balance between the solubility and viscosity of the samples. Satisfactory N NMR spectra of more than 60 nitrogen-containing compounds have been recorded, and the chemical shifts and the peaks' full width at half-maxima of more than 10 nitrogen-based functionalities have been summarized. Successful monitoring of the ortho-selective nitration of aniline has been demonstrated using the N NMR protocol developed in this paper, which will help realize the visualization of nitration processes in the industry.
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http://dx.doi.org/10.1021/acs.joc.1c01954DOI Listing
December 2021

Clinical evaluation of a real-time optoelectronic device in cervical cancer screening.

Eur J Obstet Gynecol Reprod Biol 2021 Nov 28;266:182-186. Epub 2021 Sep 28.

Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Objective: Early screening and intervention are crucial for the prevention and treatment of cervical cancer. TruScreen is a real-time, intelligent, pathological diagnostic technology designed for cervical cancer screening. The aim of this study was to evaluate the clinical value of TruScreen in screening for cervical lesions.

Study Design: A total of 458 women aged between 25 and 65 years were recruited to receive cervical cancer screening, including human papillomavirus (HPV) testing, cytological testing using the ThinPrep cytology test (TCT), and TruScreen from December 2018 to January 2020. The clinical performance of TruScreen, alone and in combination with HPV testing, was evaluated to detect cervical intraepithelial neoplasia grade 2 or worse (CIN2+ or CIN3+).

Results: For detection of CIN2+, the sensitivity and specificity of TruScreen were 83.78% and 78.86%, respectively. The specificity of TruScreen was significantly higher than those of HPV testing (50.59%, P < 0.001) and TCT (55.58%, P < 0.001). In high-risk HPV-positive women, the specificity of HPV testing combined with TruScreen was significantly higher than that of HPV testing combined with TCT (50% vs 39.9%, P = 0.004). The sensitivity of HPV testing combined with TruScreen was comparable to that of HPV testing combined with TCT (93.94% vs 87.88%, P = 0.625). Similar patterns were also observed for CIN3+ cases.

Conclusion: TruScreen has the potential for screening high-grade cervical precancerous lesions and may replace cytological tests as a cervical cancer screening method in China to avoid subjectivity in the interpretation of cytological tests and requirements by pathologists.
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http://dx.doi.org/10.1016/j.ejogrb.2021.09.027DOI Listing
November 2021

The effect of 5-Aminolaevulinic Acid Photodynamic Therapy versus CO laser in the Treatment of Cervical Low-grade Squamous Intraepithelial Lesions with High-Risk HPV Infection: A non-randomized, controlled pilot study.

Photodiagnosis Photodyn Ther 2021 Sep 23;36:102548. Epub 2021 Sep 23.

Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiaotong University School of Medicine; Shanghai Key Laboratory of Gynecologic Oncology, Renji Hospital, Shanghai Jiaotong University School of Medicine; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine. Electronic address:

Background: There are insufficient studies comparing the efficacy of 5-aminolaevulinic acid (ALA) photodynamic therapy (PDT) against CO laser therapy in the treatment of cervical low-grade squamous intraepithelial lesion (LSIL) with high-risk human papillomavirus (HR-HPV), especially for long-term efficacy.

Methods: Patients with cervical LSIL and HR-HPV infection were divided into two treatment groups based on their own choice. All patients had a follow-up test including HPV testing, cytology and colposcopy at 4-6 months and 12 months after the treatment.

Results: (1) Among 277 patients, 176 patients received 5-ALA PDT and 101 patients received CO laser therapy. (2) 4-6 months after treatment, there was no significant difference between two groups in the complete remission (CR) rates of cervical LSIL and the clearance rate of HR-HPV infection. (3) 12 months after treatment, compared with the CO laser group, the CR rates of cervical LSIL in the 5-ALA PDT group was significantly higher than the CO laser group. There was no statistical difference in the clearance rate of HR-HPV infection between the two groups. (4) 12 months after treatment, the recurrence rate of cervical lesions and the reinfection rate of HR-HPV infection in 5-ALA PDT group were significantly lower than those in CO laser group.

Conclusion: The effect of 5-ALA PDT is similar to CO laser at 4-6 months. The long-term efficacy of 5-ALA PDT appears better than CO laser. As a non-invasive treatment, 5-ALA PDT is a highly effective therapeutic procedure for cervical LSIL with HR-HPV infection.
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http://dx.doi.org/10.1016/j.pdpdt.2021.102548DOI Listing
September 2021

Anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody quavonlimab in combination with pembrolizumab: Safety and efficacy from a phase I study in previously treated extensive-stage small cell lung cancer.

Lung Cancer 2021 09 18;159:162-170. Epub 2021 Jul 18.

Chaim Sheba Medical Center at Tel HaShomer, Derech Sheba 2, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel. Electronic address:

Objectives: This first-in-human phase I study (NCT03179436) investigated anti-cytotoxic T-lymphocyte-associated protein 4 monoclonal antibody quavonlimab and anti-programmed death 1 monoclonal antibody pembrolizumab in patients with advanced solid tumors. The study was conducted in two parts: dose-escalation (part 1) and dose-confirmation (part 2). First-line treatment with quavonlimab + pembrolizumab conferred encouraging antitumor activity (objective response rate [ORR], 28%-40%) and was generally well tolerated (grade ≥ 3 treatment-related adverse events [TRAEs] were lowest with quavonlimab 25 mg every 6 weeks [Q6W] at 30% and highest with quavonlimab 75 mg Q3W at 57%) in non-small cell lung cancer. We present data from patients with extensive-stage small cell lung cancer (SCLC) receiving second-line or later therapy.

Materials And Methods: Patients with stage III/IV SCLC received quavonlimab 75 mg Q6W plus pembrolizumab 200 mg Q3W for ≤ 2 years. Primary endpoints were safety and tolerability; ORRs as assessed by blinded independent central review per Response Evaluation Criteria In Solid Tumorsv1.1 was a secondary endpoint. Progression-free survival (PFS), overall survival (OS), and the correlation of response with PD-L1 expression were exploratory endpoints.

Results: Forty patients with extensive-stage SCLC received treatment; median follow-up was 13 months. Dose-limiting toxicity occurred in 4 patients (10%). TRAEs occurred in 80% of patients; grade 3 events occurred in 33% of patients and no grade 4/5 events were reported. Confirmed ORRs (95% CI) were 18% (7-33) among all patients, 7% (<1-34) for PD-L1-positive tumors (n = 14), and 19% (5-42) for PD-L1-negative tumors (n = 21). Response duration ranged from 2.9 to 19.1+ months. Median PFS was 2.0 months; 6-month PFS rate was 26%. Median OS was 11.0 months; 6-month OS rate was 66%.

Conclusions: Encouraging antitumor activity was observed with quavonlimab + pembrolizumab in patients with extensive-stage SCLC; responses were observed in PD-L1-positive and PD-L1-negative tumors. The combination was tolerable with manageable toxicities.
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http://dx.doi.org/10.1016/j.lungcan.2021.07.009DOI Listing
September 2021

A phase I/II study of rovalpituzumab tesirine in delta-like 3-expressing advanced solid tumors.

NPJ Precis Oncol 2021 Aug 5;5(1):74. Epub 2021 Aug 5.

UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.

Delta-like protein 3 (DLL3) is highly expressed in solid tumors, including neuroendocrine carcinomas/neuroendocrine tumors (NEC/NET). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Patients with NECs and other advanced DLL3-expressing tumors were enrolled in this phase I/II study (NCT02709889). The primary endpoint was safety. Two hundred patients were enrolled: 101 with NEC/NET (large-cell NEC, gastroenteropancreatic NEC, neuroendocrine prostate cancer, and other NEC/NET) and 99 with other solid tumors (melanoma, medullary thyroid cancer [MTC], glioblastoma, and other). The recommended phase II dose (RP2D) was 0.3 mg/kg every 6 weeks (q6w) for two cycles. At the RP2D, grade 3/4 adverse events included anemia (17%), thrombocytopenia (15%), and elevated aspartate aminotransferase (8%). Responses were confirmed in 15/145 patients (10%) treated at 0.3 mg/kg, including 9/69 patients (13%) with NEC/NET. Rova-T at 0.3 mg/kg q6w had manageable toxicity, with antitumor activity observed in patients with NEC/NET, melanoma, MTC, and glioblastoma.
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http://dx.doi.org/10.1038/s41698-021-00214-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342450PMC
August 2021

Anti-angiogenesis Revisited: Combination with Immunotherapy in Solid Tumors.

Curr Oncol Rep 2021 07 16;23(9):100. Epub 2021 Jul 16.

Department of Medical Oncology, Banner MD Anderson Cancer Center, Gilbert, AZ, 85234, USA.

Purpose Of Review: Both anti-angiogenesis and immunotherapy are well-established therapeutic options in solid tumors. Here, we review the rationale as well as clinical evidence of combining these two approaches.

Recent Findings: There is strong rationale and substantial preclinical and clinical evidence that anti-angiogenesis plays a pivotal role in overcoming immunotherapy resistance. The combination of an anti-angiogenic agent and a checkpoint inhibitor offers a more robust treatment option in many clinical trials in a wide variety of solid tumor types. Combination of anti-angiogenesis and immunotherapy has emerged as a standard of care in some tumor types and the indication is expected to expand to more tumor types in the years to come.
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http://dx.doi.org/10.1007/s11912-021-01099-7DOI Listing
July 2021

Hemophagocytic lymphohistiocytosis in pregnancy: a case report and review of the literature.

J Obstet Gynaecol 2020 Feb 19;40(2):153-159. Epub 2019 Jun 19.

Department of Gynecology and Obstetrics, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.

Hemophagocytic lymphohistiocytosis (HLH) during pregnancy is rare and seldom reported in literature. Here we report a case of pregnancy-associated HLH. A patient was admitted at 26 weeks and 2 days pregnancy complaining of cough and fever was admitted. She was found having bi-cytopenia, elevated ferritin and hypertriglyceridaemia. HLH was not confirmed because of the negative results from the first bone marrow biopsy. As the situation worsened, a timely termination of pregnancy was carried out. The second bone marrow biopsy did reveal hemophagocytosis and then pregnant-related HLH was confirmed. Prompt treatment of dexamethasone and etoposide have the puerpernat in a better situation. From this case, we learned HLH can be likely ignored and not be diagnosed promptly in a pregnant patient. In order to confirm this disease, a bone marrow biopsy should be performed promptly or repeatly for suspicious HLH. The time of termination and treatment is both essential for the foetus and the puerperant. Given the high morbidity and mortality of this disease in recent years, an expert consensus or clinical guideline should be developed.
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http://dx.doi.org/10.1080/01443615.2019.1601168DOI Listing
February 2020

Reaction yield model of nitrocellulose alkaline hydrolysis.

J Hazard Mater 2019 06 11;371:603-608. Epub 2019 Mar 11.

School of Human Settlement and Civil Engineering, Xi'an Jiaotong University, Xi'an, Shannxi Province, 710049, PR China.

Military nitrocellulose waste is flammable and explosive, and thus requires safe disposal and resource utilization. The alkaline hydrolysis process is a potential treatment method for nitrocellulose waste. In this study, a reaction yield model of nitrocellulose alkaline hydrolysis reaction was studied. For this purpose, a theoretical reaction yield model of nitrocellulose alkaline hydrolysis was developed based on Fick's law and scanning electron microscopy analysis. Additionally, the reaction yield model was experimentally validated. The results revealed a linear relationship between the nitrocellulose alkaline hydrolysis rate of x and the reaction time of t, which is given by t/t = x. The limiting step of the alkaline hydrolysis of nitrocellulose is the rate of diffusion of OH through the large pore channels. Accordingly, the reaction rate of the nitrocellulose alkaline hydrolysis can be increased by increasing the KOH concentration, reaction temperature, and reducing the size of the nitrocellulose granules. Thus, this model provides theoretical and technical support for the safe disposal and resource utilization of nitrocellulose waste.
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http://dx.doi.org/10.1016/j.jhazmat.2019.03.044DOI Listing
June 2019

Mechanisms of resistance to BRAF and MEK inhibitors and clinical update of US Food and Drug Administration-approved targeted therapy in advanced melanoma.

Onco Targets Ther 2018 17;11:7095-7107. Epub 2018 Oct 17.

TW Lewis Melanoma Center of Excellence, Banner MD Anderson Cancer Center, Gilbert, AZ, USA,

Approximately 50% of melanomas harbor an activating mutation. Combined BRAF and MEK inhibitors such as dabrafenib and trametinib, vemurafenib and cobimetinib, and encorafenib and binimetinib are US Food and Drug Administration (FDA)-approved to treat patients with -mutated advanced melanoma. Both genetic and epigenetic alterations play a major role in resistance to BRAF inhibitors by reactivation of the MAPK and/or the PI3K-Akt pathways. The role of BRAF inhibitors in modulating the immunomicroenvironment and perhaps enhancing the efficacy of checkpoint inhibitors is gaining interest. This article provides a comprehensive review of mechanisms of resistance to BRAF and MEK inhibitors in melanoma and summarizes landmark trials that led to the FDA approval of BRAF and MEK inhibitors in metastatic melanoma.
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http://dx.doi.org/10.2147/OTT.S182721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200076PMC
October 2018

PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma.

N Engl J Med 2018 07 4;379(4):341-351. Epub 2018 Jun 4.

From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).

Background: No systemic therapies have been approved for the treatment of advanced cutaneous squamous-cell carcinoma. This cancer may be responsive to immune therapy, because the mutation burden of the tumor is high and the disease risk is strongly associated with immunosuppression. In the dose-escalation portion of the phase 1 study of cemiplimab, a deep and durable response was observed in a patient with metastatic cutaneous squamous-cell carcinoma.

Methods: We report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic-disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg per kilogram of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase 2 study, the primary end point was the response rate, as assessed by independent central review.

Results: In the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval [CI], 30 to 70). In the metastatic-disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic-disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event.

Conclusions: Among patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT02383212 and NCT02760498 .).
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http://dx.doi.org/10.1056/NEJMoa1805131DOI Listing
July 2018

Treatment of Leptomeningeal Metastases in a Patient with Non-Small Cell Lung Cancer Harboring EGFR T790M Mutation.

Case Rep Oncol 2017 Sep-Dec;10(3):840-845. Epub 2017 Sep 20.

Department of Medical Oncology, Banner MD Anderson Cancer Center, Gilbert, AZ, USA.

Background: Leptomeningeal metastasis (LM) is an uncommon complication in patients with solid tumors, associated with poor survival. However, LM appears to be more frequent in lung cancer patients with EGFR mutations, posing a unique clinical challenge to treating physicians.

Case Presentation: We report the case of a 68-year-old Asian man with metastatic lung adenocarcinoma harboring an EGFR L858R mutation, which was initially treated with gefitinib. He developed disease progression 1 year later. Re-biopsy of the right lower lobe primary lesion revealed only an EGFR L858R mutation in the absence of a T790M mutation. The patient also experienced persistent confusion and generalized fatigue, and magnetic resonance imaging (MRI) of the brain demonstrated extensive LM. At this time, a liquid biopsy revealed an EGFR T790M mutation. Following initiation of treatment with osimertinib, the patient exhibited a rapid response with MRI of the brain showing substantial improvement of the LM after 6 months. Unfortunately, the LM recurred after 1 year at which time the patient declined further systemic chemotherapy.

Conclusion: To our knowledge, this is the second reported case of LM in a patient with lung cancer harboring an EGFR T790M mutation that was successfully treated with osimertinib.
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http://dx.doi.org/10.1159/000480452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649226PMC
September 2017

A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced cancer (PembroPlus).

Br J Cancer 2017 Jun 6;117(1):33-40. Epub 2017 Jun 6.

Western Regional Medical Center, Cancer Treatment Centers of America, 14200 W Celebrate Life Way, Goodyear, AZ 85338, USA.

Background: Pembrolizumab (P) is an anti-PD-1 antibody that blocks the interaction between programmed cell death protein 1 (PD-1) on T-cells and PD-L1 and PD-L2 on tumour cells. A phase Ib trial of P plus chemotherapy was undertaken to evaluate the safety and efficacy.

Methods: Patients with advanced, metastatic solid tumours were enrolled onto one of six treatment arms. Pembrolizumab was given: with gemcitabine (G), G+docetaxel (D), G+nab-paclitaxel (NP), G+vinorelbine (V) or irinotecan (I) until progression or toxicity, or with liposomal doxorubicin (LD) for up to 15 cycles, progression or toxicity. Safety monitoring and response assessments were conducted.

Results: Forty-nine patients were enrolled and treated. The most common adverse events were transaminitis, cytopenias, rash, diarrhoea, fatigue, nausea and vomiting. Arm 2 was closed due to poor accrual. The recommended phase II dose (RP2D) was determined for Arms 1, 3a, 4, 5 and 6. There were eight partial responses across multiple tumour types.

Conclusions: Standard dose P can be safely combined with G, G+NP, G+V, I and LD. Efficacy was observed in multiple tumour types and evaluation to determine if response and duration of response are more robust than what would be expected for chemotherapy or immunotherapy alone requires further validation.
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http://dx.doi.org/10.1038/bjc.2017.145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520208PMC
June 2017

Incidence and clinical significance of ESR1 mutations in heavily pretreated metastatic breast cancer patients.

Onco Targets Ther 2015 11;8:3323-8. Epub 2015 Nov 11.

CTCA Medicine and Science, Philadelphia, PA, USA.

Background: ESR1 mutation has recently emerged as one of the important mechanisms involved in endocrine resistance. The incidence and clinical implication of ESR1 mutation has not been well evaluated in heavily pretreated breast cancer patients.

Methods: We conducted a retrospective review of advanced breast cancer patients with tumors who underwent next-generation sequencing genomic profiling using Foundation One test at Cancer Treatment Centers of America(®) regional hospitals between November 2012 and November 2014.

Results: We identified a total of 341 patients including 217 (59%) estrogen receptor (ER)+, 177 (48%) progesterone receptor (PR)+, 30 (8%) hormone receptor+/HER2 positive, and 119 (32%) triple negative patients. ESR1 mutation was noted in 27/222 (12.1%) ER+ or PR+ breast cancer patients. All ER+ patients received at least one line of an aromatase inhibitor. All 28 patients were found to harbor ESR1 mutations affecting ligand-binding domain with the most common mutations affecting Y537 (17/28, 60.7%) and D538 (9/28, 32.1%). In this cohort, 19 (67.9%) patients carried three or more, seven (25%) patients had one or two additional genomic alterations and one (3.6%) patient had an ESR1 mutation only. Of 28 patients, three patients were treated with fulvestrant immediately before and two patients were treated after next-generation sequencing testing; only one patient achieved stable disease for 8 months and the other four patients had progression of disease. In all, 3/3 (100%) patients before testing and 2/4 (50%) after testing treated with exemestane and everolimus achieved stable disease for at least 6 months.

Conclusion: ESR1 mutation was found in 12.1% of a large cohort of advanced breast cancer patients. Exemestane in combination with everolimus might be a reasonable option. Prospective studies are warranted to validate these findings.
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http://dx.doi.org/10.2147/OTT.S92443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648593PMC
December 2015

Albumin-bound paclitaxel in solid tumors: clinical development and future directions.

Drug Des Devel Ther 2015 24;9:3767-77. Epub 2015 Jul 24.

Department of Medical Oncology, Cancer Treatment Centers of America, Goodyear, AZ, USA.

Albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free formulation of paclitaxel that was initially developed more than a decade ago to overcome toxicities associated with the solvents used in the formulation of standard paclitaxel and to potentially improve efficacy. Nab-paclitaxel has demonstrated an advantage over solvent-based paclitaxel by being able to deliver a higher dose of paclitaxel to tumors and decrease the incidence of serious toxicities, including severe allergic reactions. To date, nab-paclitaxel has been indicated for the treatment of three solid tumors in the USA. It was first approved for the treatment of metastatic breast cancer in 2005, followed by locally advanced or metastatic non-small-cell lung cancer in 2012, and most recently for metastatic pancreatic cancer in 2013. Nab-paclitaxel is also under investigation for the treatment of a number of other solid tumors. This review highlights key clinical efficacy and safety outcomes of nab-paclitaxel in the solid tumors for which it is currently indicated, discusses ongoing trials that may provide new data for the expansion of nab-paclitaxel's indications into other solid tumors, and provides a clinical perspective on the use of nab-paclitaxel in practice.
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http://dx.doi.org/10.2147/DDDT.S88023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521678PMC
April 2016

Metastatic Breast Cancer with Extensive Osseous Metastasis Presenting with Symptomatic Immune Thrombocytopenic Purpura and Anemia: A Case Report and Review of the Literature.

Case Rep Oncol 2015 May-Aug;8(2):256-63. Epub 2015 Jun 5.

Department of Medical Oncology, Western Regional Medical Center at Cancer Treatment Centers of America, Goodyear, Ariz., USA.

Background: Immune thrombocytopenic purpura (ITP) is a rare acquired bleeding disorder with an estimated incidence of 1 in 10,000 people in the general population. The association of ITP with breast cancer is an even rarer entity with very limited reports in the English literature.

Case Presentation: We report a case of a 51-year-old female with no significant past medical history who presented with sudden onset of malaise, syncope, gingival bleed and epistaxis. She was found to have severe thrombocytopenia (platelet count 6,000/μl) and anemia (hemoglobin 7.2 g/dl). Her workup led to the diagnosis of metastatic ductal breast cancer with extensive bone metastasis. Bone marrow biopsy demonstrated myelophthisis which was initially thought to be consistent with her presentation of thrombocytopenia and anemia. Therefore, the patient was started on hormonal therapy for the treatment of her metastatic breast cancer. After 3 months of therapy, she did not improve and developed severe mucosal bleeding. Her clinical presentation was suspicious for ITP and immune-mediated anemia, and hence she was started on steroids and intravenous immunoglobulin. The patient had a dramatic response to therapy with normalization of her platelet count and hemoglobin within 2 weeks.

Conclusion: To our knowledge, this is the first reported case of metastatic breast cancer presenting with symptomatic ITP and anemia, and both symptoms are postulated to be immune-mediated.
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http://dx.doi.org/10.1159/000431213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478340PMC
June 2015

The effect of sign language structure on complex word reading in Chinese deaf adolescents.

PLoS One 2015 23;10(3):e0120943. Epub 2015 Mar 23.

Department of Psychology, Fudan University, Shanghai, China.

The present study was carried out to investigate whether sign language structure plays a role in the processing of complex words (i.e., derivational and compound words), in particular, the delay of complex word reading in deaf adolescents. Chinese deaf adolescents were found to respond faster to derivational words than to compound words for one-sign-structure words, but showed comparable performance for two-sign-structure words. For both derivational and compound words, response latencies to one-sign-structure words were shorter than to two-sign-structure words. These results provide strong evidence that the structure of sign language affects written word processing in Chinese. Additionally, differences between derivational and compound words in the one-sign-structure condition indicate that Chinese deaf adolescents acquire print morphological awareness. The results also showed that delayed word reading was found in derivational words with two signs (DW-2), compound words with one sign (CW-1), and compound words with two signs (CW-2), but not in derivational words with one sign (DW-1), with the delay being maximum in DW-2, medium in CW-2, and minimum in CW-1, suggesting that the structure of sign language has an impact on the delayed processing of Chinese written words in deaf adolescents. These results provide insight into the mechanisms about how sign language structure affects written word processing and its delayed processing relative to their hearing peers of the same age.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120943PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370692PMC
December 2015

HER2-positive, trastuzumab-resistant metastatic esophageal cancer presenting with brain metastasis after durable response to dual HER2 blockade: a case report.

J Gastrointest Oncol 2014 Dec;5(6):E103-8

1 Department of Medical Oncology, 2 Department of Pathology, 3 Department of Radiology, Western Regional Medical Center at Cancer Treatment Centers of America, Goodyear, AZ, USA ; 4 Department of Medical Oncology, Cancer Treatment Centers of America, 5 Drexel University College of Medicine, Philadelphia, PA, USA.

We here report a case of a patient diagnosed with human epithelial growth factor receptor 2 (HER2)-amplified esophageal adenocarcinoma. The patient responded well to trastuzumab-based chemotherapy initially, but progressed with liver metastases. Her treatment was then switched to dual HER2 blockade with both trastuzumab and lapatinib in combination with capecitabine. She tolerated therapy and responded remarkably well with radiographic resolution of liver metastases. Unfortunately, she developed multiple brain metastases in the absence of extracranial progression. Discordant negative expression of HER2 and subclonal mutations in brain lesions were discovered, which, at least in part, explained her brain metastases in the presence of capecitabine and lapatinib, as both agents are known to be able to cross the blood brain barrier. The potential mechanism for dual HER2 blockade is discussed in the context of HER2-positive, trastuzumab-resistant, advanced esophageal cancer. The incidence of brain metastasis in advanced gastro-esophageal cancer has been reported to be extremely low, but is expected to increase with more effective systemic therapy. The intratumoral heterogeneity between the metastases, local recurrences and the primary tumor is definitely noteworthy.
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http://dx.doi.org/10.3978/j.issn.2078-6891.2014.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226817PMC
December 2014

Cyclophosphamide-induced severe acute hyponatremic encephalopathy in patients with breast cancer: report of two cases.

Case Rep Oncol 2014 May 31;7(2):550-4. Epub 2014 Jul 31.

Departments of Medical Oncology, Western Regional Medical Center, Cancer Treatment Centers of America, Goodyear, Ariz., USA.

Background: Cyclophosphamide is an alkylating agent widely used in antineoplastic and immunosuppressive therapies. Symptomatic hyponatremia can be a rare but life-threatening complication in patients treated with cyclophosphamide.

Case Presentations: We report 2 patients who presented with severe acute hyponatremic encephalopathy after receiving their first cycles of a low-dose cyclophosphamide-containing regimen for breast cancer. In case 1, a 58-year-old female received the combination of docetaxel and cyclophosphamide, and in case 2, a 56-year-old female received the combination of doxorubicin and cyclophosphamide. Both patients recovered after correction of their serum sodium concentration without neurological deficits. Future cycles of chemotherapy were well tolerated without recurrence of hyponatremia after cyclophosphamide was discontinued from the respective regimens.

Conclusion: Clinicians must always keep in mind that acute hyponatremic encephalopathy can be induced by low-dose cyclophosphamide.
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http://dx.doi.org/10.1159/000365832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164106PMC
May 2014

Pegylated liposomal Doxorubicin-induced acute transient encephalopathy in a patient with breast cancer: a case report.

Case Rep Oncol 2014 Jan 21;7(1):228-32. Epub 2014 Mar 21.

Department of Medical Oncology, Western Regional Medical Center at Cancer Treatment Centers of America, Goodyear, Ariz., America.

Background: Pegylated liposomal doxorubicin (PLD) has a unique pharmacokinetic profile and is widely used to treat a variety of malignancies, alone or in combination with other agents.

Case Report: A 57-year-old female patient with metastatic breast cancer developed dural metastases to the brain and underwent craniotomy and whole-brain radiation. She continued to receive chemotherapy with carboplatin without any serious complications. Four months later, there was evidence of progression leading to the institution of PLD. During the first course of PLD, there was evidence of acute encephalopathy which resolved after 18 h with discontinuation of this agent. Interestingly, she did well when she was rechallenged with conventional doxorubicin in the following cycles.

Conclusion: We hereby report, to the best of our knowledge, the first case of acute transient encephalopathy induced by PLD. We postulate that partial disruption of the blood-brain barrier may have been responsible for PLD-induced encephalopathy.
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http://dx.doi.org/10.1159/000362101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000299PMC
January 2014

Laparoscopic Splenectomy in Colorectal Cancer Patients with Chemotherapy-Associated Thrombocytopenia due to Hypersplenism.

Case Rep Oncol 2012 Sep 14;5(3):601-7. Epub 2012 Sep 14.

Department of Surgery, Cancer Treatment Centers of America at Western Regional Medical Center, Goodyear, Ariz., USA.

Background: Hypersplenism due to chemotherapy-related liver injury has been associated with severe thrombocytopenia that may preclude continuation of systemic therapy for cancer patients. Patients treated for metastatic colorectal cancer (mCRC) are among the most common patients affected by hypersplenism. Cessation of systemic therapy invariably leads to progression of disease. While partial splenic embolization has been employed successfully to reverse the effects of hypersplenism, the role of laparoscopic splenectomy for this problem has not been completely defined.

Methods: A retrospective review was conducted of mCRC patients treated with laparoscopic splenectomy at our institution to reverse severe thrombocytopenia due to chemotherapy-related hypersplenism. An endpoint assessed was the ability to resume therapy after splenectomy.

Results: Six patients with mCRC and hypersplenism requiring cessation of systemic therapy underwent laparoscopic splenectomy. All (6) patients had a postsurgical platelet count >150 × 10(3)/μl and resumed chemotherapy after surgery. Median platelet count prior to surgery was 66 × 10(3)/μl, and just prior to resuming systemic therapy it was 399.5 × 10(3)/μl. Median spleen size was 14.0 cm. There were no surgical complications. Mean hospital stay was 2.8 days and the median time from surgery to resumption of therapy was 23.5 days.

Conclusions: Laparoscopic splenectomy appears to offer selected patients with mCRC the opportunity to resume systemic therapy that otherwise would be discontinued due to thrombocytopenia from hypersplenism.
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http://dx.doi.org/10.1159/000345413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531924PMC
September 2012

Change of HER2 status in metastatic esophageal adenocarcinoma: heterogeneity of the disease? Case report and review of literature.

J Gastrointest Oncol 2012 Dec;3(4):358-61

Department of Medical Oncology, Cancer Treatment Centers of America at Western Regional Medical Center, Goodyear, AZ, USA;

A case report is presented of a patient diagnosed with esophageal adenocarcinoma with an extremely aggressive clinical course. Discordant expression of HER2 in longitudinally-collected biopsies was noted, with the original biopsy testing negative and a follow up biopsy testing positive. Upon retest of the original biopsy however, heterogeneity of HER2 expression was found among tumor clones across three distinct fields. The patient did not survive long enough to receive chemotherapy with trastuzumab, which has shown efficacy in tumors with HER2 positive expression. Understanding of the biological heterogeneity of HER2 expression in the primary tumor is crucial to detect HER2 positive clones, which may yield improved patient outcomes.
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http://dx.doi.org/10.3978/j.issn.2078-6891.2012.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492485PMC
December 2012

Oxaliplatin-induced thrombotic thrombocytopenic purpura: case report and literature review.

J Clin Oncol 2012 Nov 17;30(31):e312-4. Epub 2012 Sep 17.

Department of Medical Oncology, Cancer Treatment Centers of America at Western Regional Medical Center, 14200 W Fillmore St, Goodyear, AZ 85338, USA.

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http://dx.doi.org/10.1200/JCO.2012.42.5082DOI Listing
November 2012

Zyxin is involved in thrombin signaling via interaction with PAR-1 receptor.

FASEB J 2009 Dec 18;23(12):4193-206. Epub 2009 Aug 18.

Department of Pharmacology (MC 868), University of Illinois at Chicago, 909 S. Wolcott Ave., Chicago, IL 60612, USA.

Protease-activated receptor 1 (PAR-1) mediates thrombin signaling in human endothelial cells. As a G-protein-coupled receptor, PAR-1 transmits thrombin signal through activation of the heterotrimeric G proteins, Gi, Gq, and G12/13. In this study, we demonstrated that zyxin, a LIM-domain-containing protein, is involved in thrombin-mediated actin cytoskeleton remodeling and serum response element (SRE)-dependent gene transcription. We determined that zyxin binds to the C-terminal domain of PAR-1, providing a possible mechanism of involvement of zyxin as a signal transducer in PAR-1 signaling. Data showing that disruption of PAR-1-zyxin interaction inhibited thrombin-induced stress fiber formation and SRE activation supports this hypothesis. Similarly, depletion of zyxin using siRNA inhibited thrombin-induced actin stress fiber formation and SRE-dependent gene transcription. In addition, depletion of zyxin resulted in delay of endothelial barrier restoration after thrombin treatment. Notably, down-regulation of zyxin did not affect thrombin-induced activation of RhoA or Gi, Gq, and G12/13 heterotrimeric G proteins, implicating a novel signaling pathway regulated by PAR-1 that is not mediated by G-proteins. The observation that zyxin targets VASP, a partner of zyxin in regulation of actin assembly and dynamics, to focal adhesions and along stress fibers on thrombin stimulation suggests that zyxin may participate in thrombin-induced cytoskeletal remodeling through recruitment of VASP. In summary, this study establishes a crucial role of zyxin in thrombin signaling in endothelial cells and provides evidence for a novel PAR-1 signaling pathway mediated by zyxin.
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http://dx.doi.org/10.1096/fj.09-131862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812041PMC
December 2009

RhoGDI-1 modulation of the activity of monomeric RhoGTPase RhoA regulates endothelial barrier function in mouse lungs.

Circ Res 2007 Jul 24;101(1):50-8. Epub 2007 May 24.

University of Illinois College of Medicine, Department of Pharmacology, 835 S. Wolcott Ave, Chicago, IL 60612, USA.

Rho family GTPases have been implicated in the regulation of endothelial permeability via their actions on actin cytoskeletal organization and integrity of interendothelial junctions. In cell culture studies, activation of RhoA disrupts interendothelial junctions and increases endothelial permeability, whereas activation of Rac1 and Cdc42 enhances endothelial barrier function by promoting the formation of restrictive junctions. The primary regulators of Rho proteins, guanine nucleotide dissociation inhibitors (GDIs), form a complex with the GDP-bound form of the Rho family of monomeric G proteins, and thus may serve as a nodal point regulating the activation state of RhoGTPases. In the present study, we addressed the in vivo role of RhoGDI-1 in regulating pulmonary microvascular permeability using RhoGDI-1(-/-) mice. We observed that basal endothelial permeability in lungs of RhoGDI-1(-/-) mice was 2-fold greater than wild-type mice. This was the result of opening of interendothelial junctions in lung microvessels which are normally sealed. The activity of RhoA (but not of Rac1 or Cdc42) was significantly increased in RhoGDI-1(-/-) lungs as well as in cultured endothelial cells on downregulation of RhoGDI-1 with siRNA, consistent with RhoGDI-1-mediated modulation RhoA activity. Thus, RhoGDI-1 by repressing RhoA activity regulates lung microvessel endothelial barrier function in vivo. In this regard, therapies augmenting endothelial RhoGDI-1 function may be beneficial in reestablishing the endothelial barrier and lung fluid balance in lung inflammatory diseases such as acute respiratory distress syndrome.
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http://dx.doi.org/10.1161/CIRCRESAHA.106.145847DOI Listing
July 2007

A novel mechanism of G protein-dependent phosphorylation of vasodilator-stimulated phosphoprotein.

J Biol Chem 2005 Sep 26;280(38):32866-76. Epub 2005 Jul 26.

Department of Pharmacology, College of Medicine, University of Illinois, Chicago, Illinois 60612, USA.

Vasodilator-stimulated phosphoprotein (VASP) is a major substrate of protein kinase A (PKA). Here we described the novel mechanism of VASP phosphorylation via cAMP-independent PKA activation. We showed that in human umbilical vein endothelial cells (HUVECs) alpha-thrombin induced phosphorylation of VASP. Specific inhibition of Galpha13 protein by the RGS domain of a guanine nucleotide exchange factor, p115RhoGEF, inhibited thrombin-dependent phosphorylation of VASP. More importantly, Galpha13-induced VASP phosphorylation was dependent on activation of RhoA and mitogen-activated protein kinase kinase kinase, MEKK1, leading to the stimulation of the NF-kappaB signaling pathway. alpha-Thrombin-dependent VASP phosphorylation was inhibited by small interfering RNA-mediated knockdown of RhoA, whereas Galpha13-dependent VASP phosphorylation was inhibited by a specific RhoA inhibitor botulinum toxin C3 and by a dominant negative mutant of MEKK1. We determined that Galpha13-dependent VASP phosphorylation was also inhibited by specific PKA inhibitors, PKI and H-89. In addition, the expression of phosphorylation-deficient IkappaB and pretreatment with the proteasome inhibitor MG-132 abolished Galpha13- and alpha-thrombin-induced VASP phosphorylation. In summary, we have described a novel pathway of Galpha13-induced VASP phosphorylation that involves activation of RhoA and MEKK1, phosphorylation and degradation of IkappaB, release of PKA catalytic subunit from the complex with IkappaB and NF-kappaB, and subsequent phosphorylation of VASP.
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http://dx.doi.org/10.1074/jbc.M501361200DOI Listing
September 2005

LIM kinase 1 coordinates microtubule stability and actin polymerization in human endothelial cells.

J Biol Chem 2005 Jul 16;280(28):26533-42. Epub 2005 May 16.

Department of Pharmacology, College of Medicine, University of Illinois, Chicago, Illinois 60612, USA.

Microtubule (MT) destabilization promotes the formation of actin stress fibers and enhances the contractility of cells; however, the mechanism involved in the coordinated regulation of MTs and the actin cytoskeleton is poorly understood. LIM kinase 1 (LIMK1) regulates actin polymerization by phosphorylating the actin depolymerization factor, cofilin. Here we report that LIMK1 is also involved in the MT destabilization. In endothelial cells endogenous LIMK1 co-localizes with MTs and forms a complex with tubulin via the PDZ domain. MT destabilization induced by thrombin or nocodazole resulted in a decrease of LIMK1 colocalization with MTs. Overexpression of wild type LIMK1 resulted in MT destabilization, whereas the kinase-dead mutant of LIMK1 (KD) did not affect MT stability. Importantly, down-regulation of endogenous LIMK1 by small interference RNA resulted in abrogation of the thrombin-induced MTs destabilization and the inhibition of thrombin-induced actin polymerization. Expression of Rho kinase 2, which phosphorylates and activates LIMK1, dramatically decreases the interaction of LIMK1 with tubulin but increases its interaction with actin. Interestingly, expression of KD-LIMK1 or small interference RNA-LIMK1 prevents thrombin-induced microtubule destabilization and F-actin formation, suggesting that LIMK1 activity is required for thrombin-induced modulation of microtubule destabilization and actin polymerization. Our findings indicate that LIMK1 may coordinate microtubules and actin cytoskeleton.
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http://dx.doi.org/10.1074/jbc.M502921200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1403832PMC
July 2005

G Protein betagamma subunits stimulate p114RhoGEF, a guanine nucleotide exchange factor for RhoA and Rac1: regulation of cell shape and reactive oxygen species production.

Circ Res 2003 Oct 25;93(9):848-56. Epub 2003 Sep 25.

Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, Ill 60612, USA.

Rho GTPases integrate the intracellular signaling in a wide range of cellular processes. Activation of these G proteins is tightly controlled by a number of guanine nucleotide exchange factors (GEFs). In this study, we addressed the functional role of the recently identified p114RhoGEF in in vivo experiments. Activation of endogenous G protein-coupled receptors with lysophosphatidic acid resulted in activation of a transcription factor, serum response element (SRE), that was enhanced by p114RhoGEF. This stimulation was inhibited by the functional scavenger of Gbetagamma subunits, transducin. We have determined that Gbetagamma subunits but not Galpha subunits of heterotrimeric G proteins stimulated p114RhoGEF-dependent SRE activity. Using coimmunoprecipitation assay, we have determined that Gbetagamma subunits interacted with full-length and DH/PH domain of p114RhoGEF. Similarly, Gbetagamma subunits stimulated SRE activity induced by full-length and DH/PH domain of p114RhoGEF. Using in vivo pull-down assays and dominant-negative mutants of Rho GTPases, we have determined that p114RhoGEF activated RhoA and Rac1 but not Cdc42 proteins. Functional significance of RhoA activation was established by the ability of p114RhoGEF to induce actin stress fibers and cell rounding. Functional significance of Rac1 activation was established by the ability of p114RhoGEF to induce production of reactive oxygen species (ROS) followed by activation of NADPH oxidase enzyme complex. In summary, our data showed that the novel guanine nucleotide exchange factor p114RhoGEF regulates the activity of RhoA and Rac1, and that Gbetagamma subunits of heterotrimeric G proteins are activators of p114RhoGEF under physiological conditions. The findings help to explain the integrated effects of LPA and other G-protein receptor-coupled agonists on actin stress fiber formation, cell shape change, and ROS production.
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http://dx.doi.org/10.1161/01.RES.0000097607.14733.0CDOI Listing
October 2003

G alpha 13-mediated transformation and apoptosis are permissively dependent on basal ERK activity.

Am J Physiol Cell Physiol 2003 Oct 7;285(4):C922-34. Epub 2003 May 7.

Department of Pharmacology, University of Illinois, Chicago, IL 60612, USA.

We previously reported that the alpha-subunit of heterotrimeric G13 protein induces either mitogenesis and neoplastic transformation or apoptosis in a cell-dependent manner. Here, we analyzed which signaling pathways are required for G alpha 13-induced mitogenesis or apoptosis using a novel mutant of G alpha 13. We have identified that in human cell line LoVo, the mutation encoding substitution of Arg260 to stop codon in mRNA of G alpha 13 subunit produced a mutant protein (G alpha 13-T) that lacks a COOH terminus and is endogenously expressed in LoVo cells as a polypeptide of 30 kDa. We found that G alpha 13-T lost its ability to promote proliferation and transformation but retained its ability to induce apoptosis. We found that full-length G alpha 13 could stimulate Elk1 transcription factor, whereas truncated G alpha 13 lost this ability. G alpha 13-dependent stimulation of Elk1 was inhibited by dominant-negative extracellular signal-regulated kinase (MEK) but not by dominant-negative MEKK1. Similarly, MEK inhibitor PD-98059 blocked G alpha 13-induced Elk1 stimulation, whereas JNK inhibitor SB-203580 was ineffective. In Rat-1 fibroblasts, G alpha 13-induced cell proliferation and foci formation were also inhibited by dominant-negative MEK and PD-98059 but not by dominant-negative MEKK1 and SB-203580. Whereas G alpha 13-T alone did not induce transformation, coexpression with constitutively active MEK partially restored its ability to transform Rat-1 cells. Importantly, full-length but not G alpha 13-T could stimulate Src kinase activity. Moreover, G alpha 13-dependent stimulation of Elk1, cell proliferation, and foci formation were inhibited by tyrosine kinase inhibitor, genistein, or by dominant-negative Src kinase, suggesting the involvement of a Src-dependent pathway in the G alpha 13-mediated cell proliferation and transformation. Importantly, truncated G alpha 13 retained its ability to stimulate apoptosis signal-regulated kinase ASK1 and c-Jun terminal kinase, JNK. Interestingly, the apoptosis induced by G alpha 13-T was inhibited by dominant-negative ASK1 or by SB-203580.
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http://dx.doi.org/10.1152/ajpcell.00115.2003DOI Listing
October 2003

Functional significance of protein kinase A activation by endothelin-1 and ATP: negative regulation of SRF-dependent gene expression by PKA.

Cell Signal 2003 Jun;15(6):597-604

Section of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, MC 6076, Chicago, IL 60637, USA.

Endothelin-1 (ET1) and ATP stimulate contraction and hypertrophy of vascular smooth muscle cells (VSMC) by activating diverse signalling pathways. In this study, we show that in VSMC, ET1 and ATP stimulate transient and sustained activation of protein kinase A (PKA), respectively. Using a dominant negative PKA mutant (PKA-DN), we examined the functional significance of PKA activation in the signalling of ET1 and ATP. Overexpression of PKA-DN did not alter the ET1- or ATP-induced phosphorylation of the extracellular signal-regulated protein kinase, Erk2. ATP stimulated a profound, PKA-dependent activation of cAMP-response element (CRE), whereas the effect of ET1 was negligible. Both ET1 and ATP stimulated serum response factor (SRF)-dependent gene expression. Overexpression of PKA-DN potentiated the effects of ET1 and ATP on SRF activity, whereas stimulation of PKA by isoproterenol, forskolin or by overexpression of the PKA catalytic subunit decreased SRF activity. These data demonstrate that (i) PKA negatively regulates SRF activity and (ii) ET1 and ATP stimulate opposing pathways, whose balance determines the net activity of SRF.
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http://dx.doi.org/10.1016/s0898-6568(02)00148-1DOI Listing
June 2003
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