Publications by authors named "Sha Guan"

6 Publications

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Fruquintinib with gefitinib as first-line therapy in patients carrying EGFR mutations with advanced non-small cell lung cancer: a single-arm, phase II study.

Transl Lung Cancer Res 2021 Feb;10(2):839-854

Hutchison MediPharma, Shanghai, China.

Background: Fruquintinib is an oral vascular endothelial growth factor receptor inhibitor. Previous gefitinib studies with anti-angiogenics show promising efficacy. This phase II trial assessed efficacy and safety of fruquintinib in combination with gefitinib, in patients with advanced non-small cell lung cancer (NSCLC).

Methods: Fifty patients with stage IIIB/IV NSCLC and an epidermal growth factor receptor (EGFR) exon-19 deletion or exon-21 L858R mutation were enrolled between January 2017 and June 2019. Per protocol (version 1.0), patients received 4 mg fruquintinib once daily (qd) Days 1-21 of Cycle 1, using a 3-week-on/1-week-off schedule, plus continuous gefitinib 250 mg qd. If tolerated, patients proceeded to fruquintinib 5 mg qd (fruquintinib 5 mg group, n=26). Following protocol updates, dose escalation of fruquintinib from 4 mg qd to 5 mg qd was not allowed. The primary efficacy endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), disease control rate (DCR), time to response, duration of response and adverse events (AEs).

Results: ORR was 73.5% (95% CI, 58.9-85.1) and DCR was 98.0% (95% CI, 89.2-100.0). Median PFS was 14.7 months for both groups; PFS was highest for patients with exon-19 deletion (16.5 months; 95% CI, 12.9-21.2). Grade ≥3 treatment-emergent AEs occurred in 17 (65.3%; fruquintinib 5 mg,) and 11 patients (45.8%; 4 mg). Serious AEs were recorded for nine patients (fruquintinib 5 mg, six patients; 4 mg, three).

Conclusions: Fruquintinib and gefitinib treatment showed an acceptable safety profile and promising efficacy in patients with NSCLC.
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http://dx.doi.org/10.21037/tlcr-20-1028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947379PMC
February 2021

A Phase III, randomized, double-blind, placebo-controlled, multicenter study of fruquintinib in Chinese patients with advanced nonsquamous non-small-cell lung cancer - The FALUCA study.

Lung Cancer 2020 08 20;146:252-262. Epub 2020 Jun 20.

The Fifth People's Hospital of Shanghai, China.

Objectives: Fruquintinib is an orally active kinase inhibitor that selectively targets the vascular endothelial growth factor (VEGF) receptor. A Phase II trial has demonstrated a significant benefit in progression-free survival (PFS) for fruquintinib-treated patients with locally advanced/metastatic nonsquamous non-small-cell lung cancer (NSCLC) who have progressed after second-line chemotherapy. This Phase III trial is a randomized, double-blind, multicenter trial to confirm fruquintinib's efficacy in the same patient population.

Materials And Methods: From December 2015 to February 2018, 730 patients were screened, of whom 527 were enrolled into the study. Participants were randomized 2:1 to receive fruquintinib (n = 354) or placebo (n = 173) once daily for 3 weeks on-treatment, and 1 week off-treatment. Patients were stratified according to epidermal growth factor receptor mutation status and prior use of VEGF inhibitors. Primary endpoint was overall survival (OS).

Results: Median OS was 8.9 months for the fruquintinib group and 10.4 months for placebo group (hazard ratio [HR] 1.02; 95 % confidence interval [CI], 0.82-1.28; P = 0.841), with median PFS of 3.7 months and 1.0 months, respectively (HR 0.34; 95 % CI, 0.28-0.43; P < 0.001). Objective response rate and disease control rate were 13.8 % and 66.7 % for fruquintinib, and 0.6 % and 24.9 % for placebo, respectively (P < 0.001). Hypertension was the most frequent treatment-emergent adverse event (≥grade 3) observed in fruquintinib-treated patients (21.0 %). Post hoc analysis revealed that fruquintinib prolonged the median OS for patients who did not receive subsequent antitumor therapy: 7.0 months versus 5.1 months for placebo (HR 0.65; 95 % CI, 0.46-0.91; P = 0.012). Patients receiving fruquintinib also reported improvements in quality of life for most functional scales measured by EORTC QLQ-C30 and LC13 questionnaires.

Conclusion: Although the study did not meet its primary endpoint, fruquintinib could be effective in combination with other agents for the treatment of patients with NSCLC who have failed second-line chemotherapy.
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http://dx.doi.org/10.1016/j.lungcan.2020.06.016DOI Listing
August 2020

Clathrin-dependent entry and vesicle-mediated exocytosis define insulin transcytosis across microvascular endothelial cells.

Mol Biol Cell 2015 Feb 24;26(4):740-50. Epub 2014 Dec 24.

Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada Keenan Research Centre, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada Department of Microbiology and Immunology, University of Western Ontario, London, ON N6A 5C1, Canada Interdepartmental Division of Critical Care, Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada

Transport of insulin across the microvasculature is necessary to reach its target organs (e.g., adipose and muscle tissues) and is rate limiting in insulin action. Morphological evidence suggests that insulin enters endothelial cells of the microvasculature, and studies with large vessel-derived endothelial cells show insulin uptake; however, little is known about the actual transcytosis of insulin and how this occurs in the relevant microvascular endothelial cells. We report an approach to study insulin transcytosis across individual, primary human adipose microvascular endothelial cells (HAMECs), involving insulin uptake followed by vesicle-mediated exocytosis visualized by total internal reflection fluorescence microscopy. In this setting, fluorophore-conjugated insulin exocytosis depended on its initial binding and uptake, which was saturable and much greater than in muscle cells. Unlike its degradation within muscle cells, insulin was stable within HAMECs and escaped lysosomal colocalization. Insulin transcytosis required dynamin but was unaffected by caveolin-1 knockdown or cholesterol depletion. Instead, insulin transcytosis was significantly inhibited by the clathrin-mediated endocytosis inhibitor Pitstop 2 or siRNA-mediated clathrin depletion. Accordingly, insulin internalized for 1 min in HAMECs colocalized with clathrin far more than with caveolin-1. This study constitutes the first evidence of vesicle-mediated insulin transcytosis and highlights that its initial uptake is clathrin dependent and caveolae independent.
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http://dx.doi.org/10.1091/mbc.E14-08-1307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325843PMC
February 2015

Influence of human myasthenia gravis thymus on the differentiation of human cord blood stem cells in SCID mice.

Neurol Sci 2014 Feb 27;35(2):191-7. Epub 2013 Jun 27.

Department of Immunology and Microbiology, Basic Medical College, Zhengzhou University, No.100 of Science Road, Zhengzhou, 450001, China.

The normal thymus contributes to T lymphocytes differentiation and induction of tolerance to self-antigens. Myasthenia gravis (MG) is characterized by abnormal thymic hyperplasia. To assess the potential influence of MG-thymus on the differentiation of T lymphocytes differentiation, we used the MG-thymus transplanted severe combined immunodeficiency (SCID) mice model to evaluate the human cord blood stem cells differentiation. Thymus fragments from MG patient and human cord blood stem cells were transplanted into SCID mice successively. SCID mice were observed to develop sustained human T lymphocytes and a functional anti-tumor immune. The levels of various T cell subsets in SCID mice with MG-thymus were different from that of control group. Among that, the frequency of CD4(+)CD25(+) T cells was significant lower in SCID mice with MG-thymus. The deficiency of CD4(+)CD25(+) T cells seens to contribute to the pathogenesis of MG.
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http://dx.doi.org/10.1007/s10072-013-1476-8DOI Listing
February 2014

Peritumoral lymphatic microvessel density is related to poor prognosis in lung adenocarcinoma: A retrospective study of 65 cases.

Exp Ther Med 2012 Apr 3;3(4):636-640. Epub 2012 Feb 3.

Department of Oncology, Wuhan General Hospital of Guangzhou Command, People's Liberation Army, Wuhan 430070, P.R. China.

Although recent investigations have identified that lymphangiogenesis is associated with regional lymph node metastasis and tumor prognosis in non-small cell lung cancer (NSCLC), peritumoral lymphatic microvessel density (LMVD) and its prognostic significance in lung adenocarcinoma remain unknown. In the present study, we assessed peritumoral LMVD in lung adenocarcinoma and investigated its correlation with patient prognosis. Using immunohistochemistry (SP method), the D2-40-positive peritumoral LMVD count in lung adenocarcinoma was found to be 11.56±10.73, which was higher than intratumoral LMVD (P<0.001), and was found to be associated with lymphatic metastasis (P=0.003) and pTNM staging (P=0.046). Furthermore, a significant difference in the patient overall survival time was demonstrated between tumors with a high peritumoral LMVD and those with a low peritumoral LMVD (P=0.005). Finally, using multivariate analysis, it was determined that peritumoral LMVD, lymphatic metastasis and pTNM staging were independent prognostic factors. In conclusion, the results suggest that D2-40-positive peritumoral LMVD may predict the prognosis of lung adenocarcinoma.
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http://dx.doi.org/10.3892/etm.2012.470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3438604PMC
April 2012

Interleukin(IL)-4 promotion of CXCL-8 gene transcription is mediated by ERK1/2 pathway in human pulmonary artery endothelial cells.

Mol Immunol 2011 Sep 6;48(15-16):1784-92. Epub 2011 Jun 6.

Department of Respiratory Diseases, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.

Interleukin-4 is central to allergic pulmonary inflammatory responses, but its contribution to airway neutrophilia remains controversial. The endothelium plays a critical role in regulating leukocyte recruitment and migration during inflammation. However, its response to IL-4 is reported to either increase or decrease the production of neutrophil chemotactic factors. We hypothesized that these conflicting findings may be due to the tissue and the size of the vessels from which endothelial cells have been derived. The expression of CXCL-8 by human primary culture umbilical veins endothelial cells (HUVECs), human pulmonary artery endothelial cells (HPAECs), and human pulmonary microvascular endothelial cells (HPMECs) when stimulated with recombinant human IL-4 (rhIL-4) was studied. The chemoattractant property of the cells' supernatants for neutrophils was evaluated using Boyden chambers. The role of the nuclear factor-κB (NF-κB), and mitogen-activated protein kinases (MAPK) in IL-4-induced HPAECs was studied using Western blotting and electrophoretic mobility shift assay (EMSA). We demonstrated that IL-4 increased the mRNA expression and the protein production of CXCL-8 in HPAECs, but not in HUVECs and HPMECs. The supernatants of HAPECs stimulated by IL-4 significantly promoted neutrophils migration in a dose-dependent manner, and was significantly attenuated by an inhibitor of CXCL-8. We also found that extracellular-regulated protein kinase1/2 (ERK1/2) is activated by IL-4 in HPAECs, but not JUN-N-terminal protein kinase (JNK) or p38 MAPK pathway. Furthermore, NF-κB-DNA binding activity, phosphorylation of IκBα and p65 levels were not affected by rhIL-4 in HAPECs. These findings indicate marked functional differences in the response of micro and macro-ECs to IL-4. ERK1/2, rather than NF-κB, JNK and p38 MAPK signaling, plays a role in IL-4 induced chemokine activation. Our results suggest that inhibition of ERK1/2 may be a possible target for airway neutrophilia in allergic lung diseases.
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http://dx.doi.org/10.1016/j.molimm.2011.05.003DOI Listing
September 2011
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