Publications by authors named "Keda Yu"

21 Publications

  • Page 1 of 1

Targeting PGC1α to wrestle cancer: a compelling therapeutic opportunity.

J Cancer Res Clin Oncol 2022 Jan 15. Epub 2022 Jan 15.

Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.

Metabolic adaptation is an emerging hallmark of cancer, as it provides tumor cells sufficient energy and metabolic intermediates. Although tumor cells are believed to highly rely on Warburg effect to satisfy their energy demand, more studies have pointed out that various types of tumor cells are highly dependent on oxidative phosphorylation to drive the tumorigenesis. Peroxisome proliferator-activated receptor-c coactivator 1α (PGC1α), the crucial member of PGC1 family, is aberrantly expressed in several cancer types, implicating its role in tumor proliferation, migration, invasion, metastasis, and chemoresistance. Numerous studies have reported that PGC1α participates in the regulation of tumor development by altering the transcriptional programs as well as the metabolic phenotypes. Thus, PGC1α-targeted therapy is therapeutically exploitable to target the metabolic vulnerabilities in tumor cells. This review mainly focuses on the current underlying mechanisms for its roles in regulating metabolic adaptation of tumor cells and its upstream regulators; how PGC1α participates in the regulation of the tumor proliferation, migration, invasion, metastasis, therapy resistance; and the feasibility of PGC1α-targeted therapy for cancer treatment.
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http://dx.doi.org/10.1007/s00432-021-03912-zDOI Listing
January 2022

Biomimetic porous scaffolds containing decellularized small intestinal submucosa and Sr/Feco-doped hydroxyapatite accelerate angiogenesis/osteogenesis for bone regeneration.

Biomed Mater 2022 Jan 13. Epub 2022 Jan 13.

Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei, 430000, CHINA.

The design of bone scaffolds is predominately aimed to well reproduce the natural bony environment by imitating the architecture/composition of host bone. Such biomimetic biomaterials are gaining increasing attention and acknowledged quite promising for bone tissue engineering. Herein, novel biomimetic bone scaffolds containing decellularized small intestinal submucosa matrix (SIS-ECM) and Sr/Feco-doped hydroxyapatite (SrFeHA) are fabricated for the first time by the sophisticated self-assembled mineralization procedure, followed by cross-linking and lyophilization post-treatments. The results indicate the constructed SIS/SrFeHA scaffolds are characterized by highly porous structures, rough microsurface and improved mechanical strength, as well as efficient releasing of bioactive Sr/Feand ECM components. These favorable physico-chemical properties endow SIS/SrFeHA scaffolds with an architectural/componential biomimetic bony environment which appears to be highly beneficial for inducing angiogenesis/osteogenesis both in vitro and in vivo. In particular, the cellular functionality and bioactivity of endotheliocytes/osteoblasts are significantly enhanced by SIS/SrFeHA scaffolds, and the cranial defects model further verifies the potent ability of SIS/SrFeHA to accelerate in vivo vascularization and bone regeneration following implantation. In this view these results highlight the considerable angiogenesis/osteogenesis potential of biomimetic porous SIS/SrFeHA scaffolds for inducing bone regeneration and thus may afford a new promising alternative for bone tissue engineering.
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http://dx.doi.org/10.1088/1748-605X/ac4b45DOI Listing
January 2022

Delayed initiation of radiation therapy is associated with inferior outcomes for breast cancer patients with hormone receptor-negative tumors after breast-conserving surgery.

Gland Surg 2021 Sep;10(9):2631-2643

Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: To investigate whether the interval between adjuvant chemotherapy (CT) completion and postoperative radiation therapy initiation (ICR) after breast-conserving surgery (BCS) affects ipsilateral breast tumor recurrence (IBTR) or survival.

Methods: All women who were diagnosed with invasive breast cancer and underwent BCS between 2005 and 2014 were included. In total, 1,472 patients underwent adjuvant CT followed by postoperative radiation therapy (RT) (CT+), whereas 402 patients received postoperative RT alone (CT-). Analyses were stratified by ICR and the interval between surgery and the initiation of postoperative RT (ISR) in these two cohorts. The cutoff points for treatment delay were 47 days in the CT+ cohort and 69 days in the CT- cohort. IBTR, local-regional failure (LRF), disease-free survival (DFS), and overall survival (OS) were assessed through Kaplan-Meier (K-M) analysis. Univariate and multivariate regression analyses were performed to determine the prognostic factors of survival outcomes.

Results: The median follow-up duration was 56 months. There was an association between a delay in ICR and an increase in IBTR in the CT+ group (P=0.014 for intervals ≤47 >47 days). This association was confirmed by multivariate analyses [hazard ratio (HR) of 2.766; P=0.046] in the hormone receptor-negative subgroup. The 5-year cumulative incidence rates of IBTR were 1.3% and 3.3% (≤47 >47 days, respectively) in the CT+ cohort. For patients in the CT- cohort, a longer delay of initiation of postoperative RT (≤69 >69 days) significantly decreased DFS (HR of 6.430; P=0.002). The 5-year cumulative incidence rates of disease recurrence were 3.0% for RT starting ≤69 days after surgery and 12.6% for RT starting >69 days after surgery.

Conclusions: A high IBTR rate was related to an ICR beyond 47 days. Delay of RT after CT or surgery among patients who undergo BCS should be avoided, especially among patients in the hormone receptor-negative subgroup.
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http://dx.doi.org/10.21037/gs-20-717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514317PMC
September 2021

Corrigendum: Bioactive Sr/Feco-substituted hydroxyapatite in cryogenically 3D printed porous scaffolds for bone tissue engineering (202113035007).

Biofabrication 2021 Oct 13;14(1). Epub 2021 Oct 13.

Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China.

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http://dx.doi.org/10.1088/1758-5090/ac278aDOI Listing
October 2021

The advance of adjuvant treatment for triple-negative breast cancer.

Cancer Biol Med 2021 Aug 27. Epub 2021 Aug 27.

Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by its highly aggressive behavior, early recurrence, and poor outcomes, when compared with other subtypes. Due to the absence of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, TNBC lacks meaningful biomarkers and an effective therapeutic strategy. Chemotherapy remains the main adjuvant treatment for patients with TNBC. Anthracycline/taxane-based regimens are the standard of care in adjuvant settings. The addition of capecitabine or platinum may offer extra benefits to patients with TNBC, but at the cost of increased toxicity or adverse events. Dose-dense chemotherapy may enhance treatment efficacy in patients who are able to tolerate the treatment regimen, especially in high-risk patients. As a heterogenous disease, TNBC can be classified into several molecular subtypes according to genomic or transcriptional features, which may indicate potential targets for more precise and individualized treatment strategies. With our increased understanding of signal pathways associated with TNBC, as well as the discovery of novel biomarkers indicative of TNBC prognosis, several new therapeutic options are under investigation, and some have already reported good results. In this review, we summarized the current conventional therapeutic strategies and emerging clinical trials regarding adjuvant treatment for TNBC. Furthermore, we evaluated the prognostic value of several potential targets and the progress of targeted therapy in TNBC, both in neoadjuvant and adjuvant settings.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0752DOI Listing
August 2021

Associations of Estrogen Receptor, Progesterone Receptor, Human Epidemic Growth Factor Receptor-2 and Ki-67 with Ultrasound Signs and Prognosis of Breast Cancer Patients.

Cancer Manag Res 2021 9;13:4579-4586. Epub 2021 Jun 9.

Department of Mammary Gland, Fudan University Cancer Hospital, Taiyuan City, Shanxi Province, 030000, People's Republic of China.

Objective: The functions of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki-67 in breast cancer have been explored. This study was carried out to explore ER, PR, HER-2 and Ki-67 expression levels in breast cancer patients and their relationship with ultrasound signs and prognosis.

Patients And Methods: A total of 274 female primary breast cancer patients received preoperative ultrasound examination. ER, PR, HER-2 and Ki-67 expression levels in breast cancer tissues were detected by immunohistochemical staining after surgery. The correlations of ER, PR, HER-2 and Ki-67 expression with ultrasound signs and prognosis of breast cancer patients were analyzed.

Results: The positive expression rate of ER, PR and HER-2 and Ki-67 high expression in 274 breast cancer patients was 73.36% (201/274), 59.85% (164/274), 24.09% (66/274) and 66.06% (181/274), respectively. ER-positive expression had association with lymph node metastasis (LNM) and blood flow grading; HER-2-positive expression was associated with LNM, while Ki-67-positive expression was related to the tumor diameter, LNM, and blood flow grading. LNM and Ki-67 high expression were risk factors for OS; PR-positive was a protective factor for OS; TNM stage, tumor diameter, LNM and Ki-67 high expression were risk factors for DFS in breast cancer patients.

Conclusion: ER, PR, HER-2 and Ki-67 in breast cancer are related to the ultrasound signs and prognosis of breast cancer patients. The joint detection of multiple indicators provides a reference for the individualized treatment of targeted drugs.
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http://dx.doi.org/10.2147/CMAR.S276422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200160PMC
June 2021

Controlled delivery of bone morphogenic protein-2-related peptide from mineralised extracellular matrix-based scaffold induces bone regeneration.

Mater Sci Eng C Mater Biol Appl 2021 Jul 13;126:112182. Epub 2021 May 13.

Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address:

Ideal bone tissue engineering scaffolds composed of extracellular matrix (ECM) require excellent osteoconductive ability to imitate the bone environment. We developed a mineralised tissue-derived ECM-modified true bone ceramic (TBC) scaffold for the delivery of aspartic acid-modified bone morphogenic protein-2 (BMP-2) peptide (P28) and assessed its osteogenic capacity. Decellularized ECM from porcine small intestinal submucosa (SIS) was coated onto the surface of TBC, followed by mineralisation modification (mSIS/TBC). P28 was subsequently immobilised onto the scaffolds in the absence of a crosslinker. The alkaline phosphatase activity and other osteogenic differentiation marker results showed that osteogenesis of the P28/mSIS/TBC scaffolds was significantly greater than that of the TBC and mSIS/TBC groups. In addition, to examine the osteoconductive capability of this system in vivo, we established a rat calvarial bone defect model and evaluated the new bone area and new blood vessel density. Histological observation showed that P28/mSIS/TBC exhibited favourable bone regeneration efficacy. This study proposes the use of mSIS/TBC loaded with P28 as a promising osteogenic scaffold for bone tissue engineering applications.
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http://dx.doi.org/10.1016/j.msec.2021.112182DOI Listing
July 2021

bone regeneration with sequential delivery of aptamer and BMP2 from an ECM-based scaffold fabricated by cryogenic free-form extrusion.

Bioact Mater 2021 Nov 24;6(11):4163-4175. Epub 2021 Apr 24.

Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

tissue engineering is a powerful strategy for the treatment of bone defects. It could overcome the limitations of traditional bone tissue engineering, which typically involves extensive cell expansion steps, low cell survival rates upon transplantation, and a risk of immuno-rejection. Here, a porous scaffold polycaprolactone (PCL)/decellularized small intestine submucosa (SIS) was fabricated via cryogenic free-form extrusion, followed by surface modification with aptamer and PlGF-2*-fused BMP2 (pBMP2). The two bioactive molecules were delivered sequentially. The aptamer Apt19s, which exhibited binding affinity to bone marrow-derived mesenchymal stem cells (BMSCs), was quickly released, facilitating the mobilization and recruitment of host BMSCs. BMP2 fused with a PlGF-2 peptide, which showed "super-affinity" to the ECM matrix, was released in a slow and sustained manner, inducing BMSC osteogenic differentiation. results showed that the sequential release of PCL/SIS-pBMP2-Apt19s promoted cell migration, proliferation, alkaline phosphatase activity, and mRNA expression of osteogenesis-related genes. The results demonstrated that the sequential release system of PCL/SIS-pBMP2-Apt19s evidently increased bone formation in rat calvarial critical-sized defects compared to the sequential release system of PCL/SIS-BMP2-Apt19s. Thus, the novel delivery system shows potential as an ideal alternative for achieving cell-free scaffold-based bone regeneration .
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http://dx.doi.org/10.1016/j.bioactmat.2021.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099605PMC
November 2021

Surface modified small intestinal submucosa membrane manipulates sequential immunomodulation coupled with enhanced angio- and osteogenesis towards ameliorative guided bone regeneration.

Mater Sci Eng C Mater Biol Appl 2021 Feb 17;119:111641. Epub 2020 Oct 17.

Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address:

Constructing bioactive guided bone regeneration (GBR) membranes that possess biological multifunctionality is becoming increasingly attractive and promising to meet higher requirements for bone healing. Given the biological responses following implantation, GBR process originates from an early inflammation-driven reaction adjacent to implanted membranes surface. However, to date there is relatively little attention paid to the critical immunoregulatory functions in traditionally designed GBR membranes. Herein, for the first time, we manipulate immunomodulatory properties of the widely-used native small intestinal submucosa (SIS) membrane by incorporating strontium-substituted nanohydroxyapatite coatings and/or IFN-γ to its surface. In vitro results reveal the obtained novel membrane SIS/SrHA/IFN-γ not only promote functions of endothelial cells and osteoblasts directly, but also energetically mediate a sequential M1-M2 macrophages transition to concurrently facilitate angiogenesis and osteogenesis. Moreover, in vivo outcomes of subcutaneous implantation and cranial defects repair further confirm its superior capacity to promote vascularization and in situ bone regeneration than pristine SIS through immunomodulation. These results demonstrate a sequential immunomodulatory strategy renders modified SIS membranes acting as a robust immunomodulator rather than a traditional barrier to significantly ameliorate in vivo GBR outcomes and hence provide important implications that may facilitate concerns on immunomodulatory properties for future GBR developments.
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http://dx.doi.org/10.1016/j.msec.2020.111641DOI Listing
February 2021

Bioactive Sr/Feco-substituted hydroxyapatite in cryogenically 3D printed porous scaffolds for bone tissue engineering.

Biofabrication 2021 04 2;13(3). Epub 2021 Apr 2.

Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China.

Developing multi-doped bioceramics that possess biological multifunctionality is becoming increasingly attractive and promising for bone tissue engineering. In this view innovative Sr/Feco-substituted nano-hydroxyapatite with gradient doping concentrations fixed at 10 mol% has been deliberately designed previously. Herein, to evaluate their therapeutic potentials for bone healing, novel gradient SrFeHA/PCL scaffolds are fabricated by extrusion cryogenic 3D printing technology with subsequent lyophilization. The obtained scaffolds exhibit desired 3D interconnected porous structure and rough microsurface, along with appreciable release of bioactive Sr/Fefrom SrFeHA components. These favorable physicochemical properties render printed scaffolds realizing effective biological applications bothand, particularly the moderate co-substituted Sr7.5Fe2.5HA and Sr5Fe5HA groups exhibit remarkably enhanced bioactivity that not only promotes the functions of MC3T3 osteoblasts and HUVECs directly, but also energetically manipulates favorable macrophages activation to concurrently facilitate osteogenesis/angiogenesis. Moreover,subcutaneous implantation and cranial defects repair outcomes further confirm their superior capacity to dictate immune reaction, implants vascularization andbone regeneration, mainly dependent on the synergetic effects of released Sr/Fe. Accordingly, for the first time, present study highlights the great potential of Sr7.5Fe2.5HA and Sr5Fe5HA for ameliorating bone regeneration process by coupling of immunomodulation with enhanced angio- and osteogenesis and hence may provide a new promising alternative for future bone tissue engineering.
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http://dx.doi.org/10.1088/1758-5090/abcf8dDOI Listing
April 2021

Developmental Potential of Abnormally Fertilized Oocytes and the Associated Clinical Outcomes.

Front Physiol 2020 4;11:528424. Epub 2020 Nov 4.

Reproductive Medicine Center, Jinhua People's Hospital, Jinhua, China.

This study aims to investigate the embryo development potential of extending the culture of abnormally fertilized zygotes with no pronuclear (0PN), monopronuclear (1PN), and poor-quality day 3 embryos and to determine the associated clinical outcomes. This is a retrospective study performed between January 2014 and May 2018 at Jinhua People's Hospital. The normal developed embryos and the abnormal 0PN, 1PN, and poor-quality day 3 embryos were cultured to day 5 or 6 for embryo transfer. Clinical outcomes resulting from abnormal embryos and normally developed embryos were compared. A total of 6466 embryos (1542 0PN, 852 1PN, and 4072 poor-quality day 3 embryos) from 831 treatment cycles were cultured to the blastocyst stage. The total blastulation rate was 17.3% (1121/6466) with 18.2% in 0PN, 26.1% in 1PN, and 15.2% in poor-quality day 3 embryos. The rate for good-quality blastocyst formation was 9.5% (616/6466) with 11.2% in 0PN group, 14.8% in 1PN group, and 7.8% in poor-quality day 3 embryos, respectively. Blastulation rates of 0PN and 1PN derived from intracytoplasmic sperm injection (ICSI) were significantly lower compared with the fertilization group. A total of 243 cycles were transferred with blastocysts originating from abnormal embryos, resulting in 109 (44.9%) clinical pregnancies and 19 (17.4%) miscarriages; in the control group, a total of 350 cycles resulted in 214 (61.1%) clinical pregnancies and 18 (8.4%) miscarriages. The live birth rate was significantly lower in the abnormal embryo group than that in the control group. Collectively, conventional fertilization derived 0PN and 1PN zygotes, not ICSI, together with day 3 embryos with poor quality, that were able to reach the blastocyst stage and produce a fair pregnancy rate and live birth rate.
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http://dx.doi.org/10.3389/fphys.2020.528424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672117PMC
November 2020

Creation of Bony Microenvironment with Extracellular Matrix Doped-Bioactive Ceramics to Enhance Osteoblast Behavior and Delivery of Aspartic Acid-Modified BMP-2 Peptides.

Int J Nanomedicine 2020 29;15:8465-8478. Epub 2020 Oct 29.

Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China.

Introduction: Decellularized matrix from porcine small intestinal submucosa (SIS) endows scaffolds with an ECM-like surface, which enhances stem cell self-renewal, proliferation, and differentiation. Mesoporous bioactive glass (MBG) is extensively recognized as an excellent bio-ceramic for fabricating bone grafts.

Materials And Methods: In the current study, SIS was doped on an MBG scaffold (MBG/SIS) using polyurethane foam templating and polydopamine chemistry method. To mimic the bony environment of a natural bone matrix, an ECM-inspired delivery system was constructed by coupling the BMP2-related peptide P28 to a heparinized MBG/SIS scaffold (MBG/SIS-H-P28). The release of P28 from MBG/SIS-H-P28 and its effects on the proliferation, viability, and osteogenic differentiation of bone marrow stromal stem cells were investigated in vitro and in vivo.

Results: Our research indicated that the novel tissue-derived ECM scaffold MBG/SIS has a hierarchical and interconnected porous architecture, and superior biomechanical properties. MBG/SIS-H-P28 released P28 in a controlled manner, with the long-term release time of 40 d. The results of in vitro experiments showed improvements in cell proliferation, cell viability, alkaline phosphatase activity, and mRNA expression levels of osteogenesis-related genes (, and ) compared to those of MBG/SIS or MBG/SIS-P28 and MBG/SIS-H-P28. The in vivo results demonstrated that MBG/SIS-H-P28 scaffolds evidently increased bone formation in rat calvarial critical-sized defect compared to that in controls.

Conclusion: MBG/SIS-H-P28 scaffolds show potential as ideal platforms for delivery of P28 and for providing a bony environment for bone regeneration.
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http://dx.doi.org/10.2147/IJN.S272571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605642PMC
November 2020

HER2-positive pure mucinous breast carcinoma: A case report and literature review.

Medicine (Baltimore) 2020 Aug;99(33):e20996

Department of Mammary Gland, Fudan University Cancer Hospital, Shanghai, China.

Introduction: Pure mucinous carcinoma is a rare type of breast carcinoma, but it usually has a favorable prognosis. Tumors of pure mucinous carcinoma are typically positive for both estrogen receptor (ER) and progesterone receptor (PR), and they do not commonly overexpress human epidermal growth factor receptor 2 (HER2). However, when tumors have HER2 overexpression and are progesterone receptor negative, the prognosis is worse.

Patient Concerns: A 59-year-old female reported a slow growth mass of 3 years, which was radiologically diagnosed as fibroadenoma at another institution. The patient came to our institution for treatment and follow-up. She had no salient past history.

Diagnosis: Excisional biopsy revealed a pure mucinous breast carcinoma that was ER (100%, moderate-strong intensity), PR(-), 5% Ki-67 (+), and HER2(3+) by immunohistochemistry. The HER2 gene was found to be amplified by fluorescence in situ hybridization (FISH). The clinical staging was T2N0M0, with pathological grade I, subtype luminal B.

Interventions: After a modified radical mastectomy, she received four 21-day cycles of intravenous docetaxel (75 mg/m), intravenous cyclophosphamide (600 mg/m), and intravenous trastuzumab (8 mg/kg) (loading dose) on day 1 followed by 6 mg/kg every 3 weeks to complete a full year of treatment. She then received 2.5 mg of letrozole daily for 5 years.

Outcomes: After following up for 2 years, the patient's outcome was survival without recurrence. Cardiac ultrasounds were performed every 3 months and there was no change in the left ventricular ejection fraction (LEVF).

Conclusion: It is essential to correctly diagnose the ER(+), PR(-) HER2(+) subtype in mucinous carcinoma. This type should be treated with chemotherapy and anti-HER2 therapy, as well as aromatase inhibitor endocrine therapy.
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http://dx.doi.org/10.1097/MD.0000000000020996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437824PMC
August 2020

Adjuvant Capecitabine With Docetaxel and Cyclophosphamide Plus Epirubicin for Triple-Negative Breast Cancer (CBCSG010): An Open-Label, Randomized, Multicenter, Phase III Trial.

J Clin Oncol 2020 06 10;38(16):1774-1784. Epub 2020 Apr 10.

Department of Breast Surgery, The Second Affiliated Hospital of Zhongshan University, Guangzhou, Guangdong, People's Republic of China.

Purpose: Standard adjuvant chemotherapy for triple-negative breast cancer (TNBC) includes a taxane and an anthracycline. Concomitant capecitabine may be beneficial, but robust data to support this are lacking. The efficacy and safety of the addition of capecitabine into the TNBC adjuvant treatment regimen was evaluated.

Patients And Methods: This randomized, open-label, phase III trial was conducted in China. Eligible female patients with early TNBC after definitive surgery were randomly assigned (1:1) to either capecitabine (3 cycles of capecitabine and docetaxel followed by 3 cycles of capecitabine, epirubicin, and cyclophosphamide) or control treatment (3 cycles of docetaxel followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide). Randomization was centralized without stratification. The primary end point was disease-free survival (DFS).

Results: Between June 2012 and December 2013, 636 patients with TNBC were screened, and 585 were randomly assigned to treatment (control, 288; capecitabine, 297). Median follow-up was 67 months. The 5-year DFS rate was higher for capecitabine than for control treatment (86.3% 80.4%; hazard ratio, 0.66; 95% CI, 0.44 to 0.99; = .044). Five-year overall survival rates were numerically higher but not significantly improved (capecitabine, 93.3%; control, 90.7%). Overall, 39.1% of patients had capecitabine dose reductions, and 8.4% reported grade ≥ 3 hand-foot syndrome. The most common grade ≥ 3 hematologic toxicities were neutropenia (capecitabine, 136 [45.8%]; control, 118 [41.0%]) and febrile neutropenia (capecitabine, 50 [16.8%]; control, 46 [16.0%]). Safety data were similar to the known capecitabine safety profile and generally comparable between arms.

Conclusion: Capecitabine when added to 3 cycles of docetaxel followed by 3 cycles of a 3-drug anthracycline combination containing capecitabine instead of fluorouracil significantly improved DFS in TNBC without new safety concerns.
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http://dx.doi.org/10.1200/JCO.19.02474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255982PMC
June 2020

The prognostic and predictive potential of Ki-67 in triple-negative breast cancer.

Sci Rep 2020 01 14;10(1):225. Epub 2020 Jan 14.

Department of Oncology, Shanghai Medical College, Fudan University, 130 Dong-An Road, Shanghai, 200032, P.R. China.

As a cell proliferation biomarker, Ki-67 is principally used in ER+/HER2- breast cancer. However, the importance and the best cutoff point of Ki-67 in triple-negative breast cancer (TNBC) remains unclear and was evaluated in this study.A total of 1800 patients with early invasive TNBC between 2011 and 2016 at Fudan University Shanghai Cancer Center were consecutively recruited for this study. The optimal cutoff for Ki-67 was assessed by Cutoff Finder. Propensity score matching (PSM, ratio = 1:2) was performed to match the Ki-67 group with the Ki-67 group. Overall survival (OS) and disease-free survival (DFS) were compared between the two groups using the Kaplan-Meier method and Cox regression model. The most relevant cutoff value for Ki-67 for prognosis was 30% (p = 0.008). At the cutoff point of 30%, worse DFS and OS were observed in the Ki-67 group. In multivariate analyses, N-stage (p < 0.001), T-stage (p = 0.038), and Ki-67 at the 30% threshold (p = 0.020) were independently linked to OS. In subgroup analysis, Ki-67 cutoff at 30% had prognostic and predictive potential for DFS with either tumor size ≤2 cm (p = 0.008) or lymph node-negative (N-) (p = 0.038) and especially with TNM (stage I) TNBCs. For 945 N- TNBC patients, adjuvant chemotherapy (CT) was associated with better OS in the Ki-67 group (p = 0.017) than in the Ki-67 group (p = 0.875). For stage I/Ki-67 patients, adjuvant CT did not affect DFS (p = 0.248). Thus, Ki-67 cutoff at 30% had early independent prognostic and predictive potential for OS and DFS in TNBCs, and Ki-67 > 30% was significantly associated with worse prognosis, especially for stage I patients. For stage I/Ki-67 TNBC patients, the advantage of CT is unclear, providing the basis for future de-escalation therapy.
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http://dx.doi.org/10.1038/s41598-019-57094-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959292PMC
January 2020

Idiopathic Granulomatous Mastitis with Skin Rupture: A Retrospective Cohort Study of 200 Patients Who Underwent Surgical and Nonsurgical Treatment.

J Invest Surg 2021 Jul 10;34(7):810-815. Epub 2019 Dec 10.

Shanxi Medical University, Shanxi, China.

Background: Idiopathic granulomatous mastitis (IGM) can clinically and radiographically mimic an abscess or breast cancer. Although IGM is benign, it can cause the breast skin to appear "riddled with holes" and can even result in the loss of the breast. The optimal treatment has not been established.

Methods: We retrospectively studied the medical records of 200 patients with IGM who were treated for skin rupture from June 2015 to June 2017 in our institute. The patients' treatment modalities (including surgery after steroid therapy and steroid therapy alone), outcomes, and scores of satisfaction questionnaires were analyzed. The time to healing and recurrence rate were compared with a focus on the treatment modalities to identify the most effective treatments for IGM.

Results: The median follow-up time was 15.64 months (range, 12-36 months). In total, 156 patients were treated with surgery after steroid therapy and 44 were treated with steroid therapy alone. The median times to healing in the surgical and nonsurgical groups were 25 and 258 days, respectively ( = 0.003). Four of 156 (2.56%) patients developed post-excision wound complications. Eight of 156 patients (5.1%) in the surgical group and 10 of 44 (22.7%) patients in the nonsurgical group developed recurrence ( < 0.01). The scores of the satisfaction questionnaire were 36 ± 4.28 in the surgical group and 24 ± 8.62 in the nonsurgical group ( = 0.017).

Conclusion: IGM is a benign disease but can have serious consequences. Surgery after steroid therapy is an effective and more satisfactory treatment than steroid therapy alone.
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http://dx.doi.org/10.1080/08941939.2019.1696905DOI Listing
July 2021

LncRNA WT1-AS Inhibits Triple-Negative Breast Cancer Cell Migration and Invasion by Downregulating Transforming Growth Factor β1.

Cancer Biother Radiopharm 2019 Dec 17;34(10):671-675. Epub 2019 Oct 17.

Department of General Surgery, Shanxi Provincial People's Hospital, Taiyuan City, P.R. China.

Long noncoding RNA WT1-AS has been demonstrated as a potential tumor suppressor in gastric cancer. However, the functions of WT1-AS in other types of cancer remain unclear. Our study was therefore performed to explore the role of WT1-AS in triple-negative breast cancer (TNBC). Tissue specimens were obtained from 62 TNBC patients included in this study. A TNBC cell line BT-549 was used as the cell model of TNBC. Gene expression was detected by qPCR and Western blot. Overexpression experiments were used to analyze gene interactions. Transwell assays were used to explore the effects of transfections on cell invasion and migration. We found that WT1-AS was downregulated in TNBC tissues than in nontumor tissues and decreased with increase in clinical stages. Transforming growth factor β1 (TGF-β1) was upregulated in TNBC tissues and inversely correlated with WT1-AS. TGF-β1 overexpression did not significantly affect WT1-AS in BT-549 cells, but WT1-AS negatively regulated the expression of TGF-β1. WT1-AS overexpression caused inhibited migration and invasion of TNBC cells. TGF-β1 overexpression showed opposite functions and reduced the effects of WT1-AS overexpression. WT1-AS may downregulate TGF-β to inhibit the migration and invasion of TNBC cells.
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http://dx.doi.org/10.1089/cbr.2019.2925DOI Listing
December 2019

Neddylation Inactivation Facilitates FOXO3a Nuclear Export to Suppress Estrogen Receptor Transcription and Improve Fulvestrant Sensitivity.

Clin Cancer Res 2019 06 4;25(12):3658-3672. Epub 2019 Mar 4.

Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China.

Purpose: How the neddylation pathway functions in breast tumor and regulation of estrogen receptor (ER) expression is rarely reported. The purpose of this study was to identify the role of neddylation in breast cancer and ER expression, and further explore the underlying mechanisms.

Experimental Design: Expression patterns of nedd8-activating enzyme (NAE) and nedd8, two key proteins in the neddylation pathway, were examined in human breast specimens. ER-α expression was investigated using animal 18F-FES-PET/CT and immunoblotting upon NAE inhibitor MLN4924 treatment. Chromatin immunoprecipitation assay, luciferase reporter promoter assay, and the CRISPR-Cas9 system were used to elucidate the mechanism of ER-α regulation by MLN4924. The ER-positive breast cancer mouse model was used to determine the synergetic effect of MLN4924 and fulvestrant on tumor growth. All statistical tests were two-sided.

Results: Both NAE1 and nedd8 expressions were higher in the ER-positive subgroup. Higher expressions of NAE1 and nedd8 indicated poorer prognosis. Importantly, ER-α expression was significantly downregulated upon MLN4924 treatment and . Mechanistically, MLN4924 treatment delayed serum and glucocorticoid-induced protein kinase (SGK) degradation and induced Forkhead box O3a (FOXO3a) nuclear export as well as decreased binding to the promoter. Importantly, MLN4924 single or synergized with fulvestrant significantly suppressed the growth of ER-positive breast cancer and .

Conclusions: Our proof-of-principle study determines the activation of neddylation in breast tumor tissues for the first time and reveals a new ER-α regulatory mechanism, as well as further explores an effective approach to improve fulvestrant sensitivity through a neddylation inactivation combination.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2434DOI Listing
June 2019

LGR5 acts as a target of miR-340-5p in the suppression of cell progression and drug resistance in breast cancer via Wnt/β-catenin pathway.

Gene 2019 Jan 6;683:47-53. Epub 2018 Oct 6.

Reproductive Medicine Center, Jinhua People's Hospital, Jinhua 321000, Zhejiang, China; Zhejiang Normal University, Jinhua People's Hospital Joint Center for Biomedical Research, Jinhua 321000, Zhejiang, China. Electronic address:

Breast cancer is one of the most common malignant tumors among females. Recent studies demonstrated that microRNAs (miRNAs) played an important role in the regulation of tumor progression. In our present study, we firstly detected miR-340-5p expression in breast cancer cell lines and found lower expression of miR-340-5p in breast cancer cell lines (MCF-7, MDA-MB-231, BT-549, ZR-75-1) through qRT-PCR. Overexpressed miR-340-5p inhibited cell proliferation and drug resistance to docetaxel with enhanced cell apoptosis of breast cancer cells. Through bioinformatic prediction, we found that LGR5 was a potential target of miR-340-5p. LGR5 was highly expressed in breast cancer cells. Relative expression of LGR5 was negatively regulated by miR-340-5p. Knockdown of LGR5 also inhibited cell proliferation and drug resistance to docetaxel with enhanced cell apoptosis of breast cancer cells. Moreover, knockdown of LGR5 decreased the expression of β-catenin, c-myc, Survivin. The activation of Wnt/β-catenin pathway contracted the effects of LGR5 siRNA, indicating that LGR5 siRNA inhibited cell proliferation and drug resistance with induced apoptosis via suppressing Wnt/β-catenin signaling pathway in breast cancer. Taken together, our study demonstrated that overexpressed miR-340-5p inhibited cell proliferation and drug resistance with increased apoptosis of breast cancer cells through down-regulating LGR5 expression via Wnt/β-catenin pathway. The miR-340-5p/LGR5 axis may provide a new perspective for treatment for breast cancer.
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http://dx.doi.org/10.1016/j.gene.2018.10.014DOI Listing
January 2019

The effect of synthetic fragment 31-44 of human growth hormone on glucose uptake by isolated adipose tissue.

Biochem Biophys Res Commun 1983 Feb;110(3):866-72

Synthetic tetradecapeptide corresponding to amino acid sequence 31-44 of human growth hormone molecule and possessing a lipotropic activity was tested for the ability to stimulate glucose uptake by isolated epididymal fat pads of fed rats. Tetradecapeptide 31-44 (1 microgram/ml), growth hormone (1 microgram/ml) and insulin (50 microU/ml) stimulated in about equal degree the uptake of [U-14C]glucose by adipose tissue. Tissue samples were preliminary incubated for 3-4 hours in the absence of hormones to eliminate the refractoriness to the insulin-like effects of growth hormone. Without preincubation the tissue was refractory to the action of growth hormone and tetradecapeptide 31-44, but was sensitive to insulin. The data obtained together with the findings of Lewis et al., which showed that 20K structural variant of human growth hormone having the deletion of residues 32-46 cannot stimulate glucose uptake and lipolysis in rats, make it possible to suggest that both activities are associated with fragment 31-44.
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http://dx.doi.org/10.1016/0006-291x(83)91041-0DOI Listing
February 1983
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