Publications by authors named "Shenglin Ma"

147 Publications

Integrated Analysis of Genomic and Immunological Features in Lung Adenocarcinoma With Micropapillary Component.

Front Oncol 2021 17;11:652193. Epub 2021 Jun 17.

Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou, China.

Background: Micropapillary adenocarcinoma is one of the most aggressive histologic subtypes of lung adenocarcinoma (LADC), and even a minor proportion of micropapillary component (MPC) within the LADC could contribute to poor prognosis. Comprehensive analysis of genetic and immunological features of LADC with different percentages of MPC would help better understand cancer biology of this LADC subtype and direct future treatments.

Methods: We performed next-generation sequencing (NGS) for a discovery cohort of 43 LADC patients whose tumors were micro-dissected to separate MPC and non-MPC lesions and a reference cohort of 113 LADC patients. MPC-enriched genetic alterations that were detected in the discovery cohort were then confirmed using a validation cohort of 183 LADC patients. Immunological staining was also conducted on the MPC-containing samples in the discovery cohort.

Results: Tumors with a higher percentage of MPC tended to harbor more tumor mutation burdens (TMBs) and chromosome instability (CIN). Some rare genetic events may serve as the genetic landscape to drive micropapillary tumor progression. Specifically, alterations in transcription termination factor 1 (), brain-specific angiogenesis inhibitor 3 (), mammalian target of rapamycin (), and cyclin-dependent kinase inhibitor 2A () were cross-validated to be enriched in MPC-contained LADC. Additionally, tumors with a higher percentage of MPC were associated with a higher percentage of CD4+, CD8+, and PD-L1+ staining, and some genetic changes that were enriched in MPC, including amplification and mutation, were correlated with increased PD-L1 expression.

Conclusion: We identified multiple novel MPC-enriched genetic changes that could help us understand the nature of this aggressive cancer subtype. High MPC tumors tended to have elevated levels of TMBs, T cell infiltration, and immunosuppression than low MPC tumors, implying the potential link between MPC content and sensitivity to immunotherapy.
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http://dx.doi.org/10.3389/fonc.2021.652193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248503PMC
June 2021

Targeting androgen receptor (AR) with antiandrogen Enzalutamide increases prostate cancer cell invasion yet decreases bladder cancer cell invasion via differentially altering the AR/circRNA-ARC1/miR-125b-2-3p or miR-4736/PPARγ/MMP-9 signals.

Cell Death Differ 2021 Jul 14;28(7):2145-2159. Epub 2021 Jun 14.

George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.

Androgen-deprivation therapy (ADT) via targeting androgens/androgen receptor (AR) signals may suppress cell proliferation in both prostate cancer (PCa) and bladder cancer (BCa), yet its impact on the cell invasion of these two urological cancers remains unclear. Here we found targeting androgens/AR with either the recently developed antiandrogen Enzalutamide (Enz) or AR-shRNAs led to increase PCa cell invasion, yet decrease BCa cell invasion. Mechanistic dissection revealed that suppressing androgens/AR signals could result in differential alterations of the selective circular RNAs (circRNAs) as a result of differential endogenous AR transcription. A negative autoregulation in PCa, yet a positive autoregulation in BCa, as a result of differential binding of AR to different androgen-response elements (AREs) and a discriminating histone H3K4 methylation, likely contributes to this outcome between these two urological tumors. Further mechanistic studies indicated that AR-encoded circRNA-ARC1 might sponge/alter the availability of the miRNAs miR-125b-2-3p and/or miR-4736, to impact the metastasis-related PPARγ/MMP-9 signals to alter the PCa vs. BCa cell invasion. The preclinical study using the in vivo mouse model confirms in vitro cell lines data, showing that Enz treatment could increase PCa metastasis, which can be suppressed after suppressing circRNA-ARC1 with sh-circRNA-ARC1. Together, these in vitro/in vivo results demonstrate that antiandrogen therapy with Enz via targeting AR may lead to either increase PCa cell invasion or decrease BCa cell invasion. Targeting these newly identified AR/circRNA-ARC1/miR-125b-2-3p and/or miR-4736/PPARγ/MMP-9 signals may help in the development of new therapies to better suppress the Enz-altered PCa vs. BCa metastasis.
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http://dx.doi.org/10.1038/s41418-021-00743-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257744PMC
July 2021

Decitabine Sensitizes the Radioresistant Lung Adenocarcinoma to Pemetrexed Through Upregulation of Folate Receptor Alpha.

Front Oncol 2021 17;11:668798. Epub 2021 May 17.

Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Cancer Center, Zhejiang University, Hangzhou, China.

Chemotherapy is the backbone of subsequent treatment for patients with lung adenocarcinoma (LUAD) exhibiting radiation resistance, and pemetrexed plays a critical role in this chemotherapy. However, few studies have assessed changes in the sensitivity of LUAD cells to pemetrexed under radioresistant circumstances. Therefore, the objectives of this study were to delineate changes in the sensitivity of radioresistant LUAD cells to pemetrexed and to elucidate the related mechanisms and then develop an optimal strategy to improve the cytotoxicity of pemetrexed in radioresistant LUAD cells. Our study showed a much lower efficacy of pemetrexed in radioresistant cells than in parental cells, and the mechanism of action was the significant downregulation of folate receptor alpha (FRα) by long-term fractionated radiotherapy, which resulted in less cellular pemetrexed accumulation. Interestingly, decitabine effectively reversed the decrease in FRα expression in radioresistant cells through an indirect regulatory approach. Thereafter, we designed a combination therapy of pemetrexed and decitabine and showed that the activation of FRα by decitabine sensitizes radioresistant LUAD cells to pemetrexed both and in xenografts. Our findings raised a question regarding the administration of pemetrexed to patients with LUAD exhibiting acquired radioresistance and accordingly suggested that a combination of pemetrexed and decitabine would be a promising treatment strategy.
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http://dx.doi.org/10.3389/fonc.2021.668798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165306PMC
May 2021

Pemetrexed-Platinum With or Without Bevacizumab for Chinese Chemo-Naive Advanced Lung Adenocarcinoma Patients: A Real-World Study.

Front Pharmacol 2021 7;12:649222. Epub 2021 May 7.

Department of Thoracic Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Despite recent advances in the treatment of advanced non-small-cell lung cancer (NSCLC), bevacizumab plus platinum-based doublet chemotherapy remains a commonly used first-line regimen. This study was conducted to compare the efficacy and safety of pemetrexed-platinum with or without bevacizumab in Chinese chemo-naive advanced lung adenocarcinoma patients in a real-world setting. We retrospectively collected 100 patients who received pemetrexed-platinum with or without bevacizumab (PP, = 46; Bev+PP, = 54) until disease progression or unacceptable toxicity. Clinical characteristics of patients were balanced, except for the proportion of stage IV b+c (Bev+PP and PP: 67.4 vs. 37.0%, = 0.0066). Bev+PP significantly improved the objective response rate (ORR, 65 vs. 30%, = 0.0004) and progression-free survival (PFS, 7.4 vs. 6.8 months, = 0.009), but not overall survival (OS, 17.5 vs. 15.0 months, = 0.553) compared with PP. Treatment ( = 0.001), gender ( = 0.008), adrenal metastasis ( = 0.001), and liver metastasis ( = 0.013) were independent risk factors for PFS. Patients with adrenal metastasis tended to be at the highest risk of not benefiting from bevacizumab addition (HR [95% CI]: 2.244 [0.6495-7.753]). The safety profile was acceptable, and grade ≥3 toxicity occurred similarly. This study showed that pemetrexed-platinum plus bevacizumab was effective compared to chemotherapy alone in Chinese patients with advanced NSCLC.
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http://dx.doi.org/10.3389/fphar.2021.649222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138310PMC
May 2021

Cancer-associated fibroblasts in non-small cell lung cancer: Recent advances and future perspectives.

Cancer Lett 2021 Aug 18;514:38-47. Epub 2021 May 18.

Hangzhou Cancer Institution, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China; Zhejiang University Cancer Center, Hangzhou, 310058, China. Electronic address:

Non-small cell lung cancer (NSCLC) constitutes the majority of lung cancer, which is the leading cause of cancer-related deaths in the world. Nearly 70% of NSCLC patients were diagnosed at advanced stage with only 15% of five-year survival rate. Cancer-associated fibroblasts (CAFs) are the major component of tumor microenvironment and account for almost 70% of the cells in tumor tissues. By the crosstalk with cancer cells, CAFs reprogrammed cancer cell metabolism, remodeled extracellular matrix (ECM) and created a supportive niche for cancer stem cells. CAFs lead collective invasion of tumor cells and shape tumor immune microenvironment, promoting tumor metastasis and immune escape. In this review, we have summarized the progress of studies regarding CAFs influences on NSCLC in recent five years from the aspects of cell growth, metabolism, therapy resistance, invasion and metastasis and immune suppression. We have discussed the involved mechanisms and implications for the development of anti-NSCLC therapies. The current strategies of CAFs targeting and elimination have also been generalized. Only better understanding of the molecular biology of CAFs may contribute to the development of novel anti-NSCLC strategies.
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http://dx.doi.org/10.1016/j.canlet.2021.05.009DOI Listing
August 2021

Thoracic radiotherapy and concurrent almonertinib for unresectable stage III EGFR-mutated non-small-cell lung cancer: a phase 2 study.

BMC Cancer 2021 May 7;21(1):511. Epub 2021 May 7.

Department of Thoracic Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, People's Republic of China.

Background: Concurrent chemo-radiotherapy remains the standard treatment in unresectable stage III non-small-cell lung cancer (NSCLC) patients. Several studies have shown a potential value of concurrent epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) with thoracic radiotherapy in EGFR-mutated population, but a high risk of radiation pneumonitis raised a major concern. This study intends to explore the safety and efficacy of concurrent almonertinib, a new third-generation EGFR-TKI, with radiotherapy in locally advanced EGFR-mutated NSCLC patients.

Methods: Locally advanced NSCLC patients harboring sensitive EGFR mutation will be included in this study. A radiotherapy plan will be made for each patient before treatment, and the lung V20 will be calculated. Patients with lung V20 ≥ 28% were enrolled in induction group (arm A), which almonertinib was given for 2 months followed by concurrent radiotherapy; patients with lung V20 < 28% were enrolled in concurrent group (arm B), which almonertinib was given concurrent with thoracic radiotherapy. The primary endpoint is the incidence of grade ≥ 3 radiation pneumonitis within 6 months post-radiotherapy, and the secondary endpoints are local control rate, progression-free survival, and overall survival.

Discussion: The safety and efficacy of third-generation EGFR-TKI concurrent with thoracic radiotherapy in locally advanced EGFR-mutated NSCLC is still unknown. We propose to conduct this phase 2 study evaluating the safety especially the radiation pneumonitis within 6 months post-radiotherapy. This trial protocol has been approved by the Ethics committee of Hangzhou cancer hospital. The ethics number is HZCH-2020-030.

Trial Registration: clinicaltrials.gov, NCT04636593 . Registered 19 November 2020 - Retrospectively registered.
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http://dx.doi.org/10.1186/s12885-021-08266-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103745PMC
May 2021

Capilliposide C from Restores Radiosensitivity in Ionizing Radiation-Resistant Lung Cancer Cells Through Regulation of ERRFI1/EGFR/STAT3 Signaling Pathway.

Front Oncol 2021 1;11:644117. Epub 2021 Apr 1.

Department of Thoracic Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Zhejiang University Cancer Center, Hangzhou, China.

Aims: Radiation therapy is used as the primary treatment for lung cancer. Unfortunately, radiation resistance remains to be the major clinic problem for lung cancer patients. capilliposide C (LC-C), an extract from LC Hemsl, has demonstrated multiple anti-cancer effects in several types of cancer. Here, we investigated the potential therapeutic impacts of LC-C on radiosensitivity in lung cancer cells and their underlying mechanisms.

Methods: Non-small cell lung cancer cell lines were initially irradiated to generate ionizing radiation (IR)-resistant lung cancer cell lines. RNA-seq analysis was used to examine the whole-transcriptome alteration in IR-resistant lung cancer cells treated with or without LC-C, and the differentially expressed genes with most significance were verified by RT-qPCR. Colony formation assays were performed to determine the effect of LC-C and the target gene ErbB receptor feedback inhibitor 1 (ERRFI1) on radiosensitivity of IR-resistant lung cancer cells. In addition, effects of ERRFI1 on cell cycle distribution, DNA damage repair activity were assessed by flow cytometry and -H2AX immunofluorescence staining respectively. Western blotting was performed to identify the activation of related signaling pathways. Tumor xenograft experiments were conducted to observe the effect of LC-C and ERRFI1 on radiosensitivity of IR-resistant lung cancer cells .

Results: Compared with parental cells, IR-resistant lung cancer cells were more resistant to radiation. LC-C significantly enhanced the effect of radiation in IR-resistant lung cancer cells both and and validated ERRFI1 as a candidate downstream gene by RNA-seq. Forced expression of ERRFI1 alone could significantly increase the radiosensitivity of IR-resistant lung cancer cells, while silencing of ERRFI1 attenuated the radiosensitizing function of LC-C. Accordingly, LC-C and ERRFI1 effectively inhibited IR-induced DNA damage repair, and ERRFI1 significantly induced G2/M checkpoint arrest. Additional investigations revealed that down-regulation of EGFR/STAT3 pathway played an important role in radiosensitization between ERRFI1 and LC-C. Furthermore, the high expression level of ERRFI1 was associated with high overall survival rates in lung cancer patients.

Conclusions: Treatment of LC-C may serve as a promising therapeutic strategy to overcome the radiation resistance and ERRFI1 may be a potential therapeutic target in NSCLC.
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http://dx.doi.org/10.3389/fonc.2021.644117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047471PMC
April 2021

A Novel Ultrasonic TOF Ranging System Using AlN Based PMUTs.

Micromachines (Basel) 2021 Mar 8;12(3). Epub 2021 Mar 8.

School of Electronic and Computer Engineering Bldg. A, Peking University Shenzhen Graduate School, University Town, Xili, Nanshan, Shenzhen 518055, China.

This paper presents a high-accuracy complementary metal oxide semiconductor (CMOS) driven ultrasonic ranging system based on air coupled aluminum nitride (AlN) based piezoelectric micromachined ultrasonic transducers (PMUTs) using time of flight (TOF). The mode shape and the time-frequency characteristics of PMUTs are simulated and analyzed. Two pieces of PMUTs with a frequency of 97 kHz and 96 kHz are applied. One is used to transmit and the other is used to receive ultrasonic waves. The Time to Digital Converter circuit (TDC), correlating the clock frequency with sound velocity, is utilized for range finding via TOF calculated from the system clock cycle. An application specific integrated circuit (ASIC) chip is designed and fabricated on a 0.18 μm CMOS process to acquire data from the PMUT. Compared to state of the art, the developed ranging system features a wide range and high accuracy, which allows to measure the range of 50 cm with an average error of 0.63 mm. AlN based PMUT is a promising candidate for an integrated portable ranging system.
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http://dx.doi.org/10.3390/mi12030284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999705PMC
March 2021

A COVID-19 risk score combining chest CT radiomics and clinical characteristics to differentiate COVID-19 pneumonia from other viral pneumonias.

Aging (Albany NY) 2021 03 13;13(7):9186-9224. Epub 2021 Mar 13.

Medical Physics Program, University of Nevada, Las Vegas, NV 89154, USA.

With the continued transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) throughout the world, identification of highly suspected COVID-19 patients remains an urgent priority. In this study, we developed and validated COVID-19 risk scores to identify patients with COVID-19. In this study, for patient-wise analysis, three signatures, including the risk score using radiomic features only, the risk score using clinical factors only, and the risk score combining radiomic features and clinical variables, show an excellent performance in differentiating COVID-19 from other viral-induced pneumonias in the validation set. For lesion-wise analysis, the risk score using three radiomic features only also achieved an excellent AUC value. In contrast, the performance of 130 radiologists based on the chest CT images alone without the clinical characteristics included was moderate as compared to the risk scores developed. The risk scores depicting the correlation of CT radiomics and clinical factors with COVID-19 could be used to accurately identify patients with COVID-19, which would have clinically translatable diagnostic and therapeutic implications from a precision medicine perspective.
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http://dx.doi.org/10.18632/aging.202735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064216PMC
March 2021

The mechanisms and reversal strategies of tumor radioresistance in esophageal squamous cell carcinoma.

J Cancer Res Clin Oncol 2021 May 9;147(5):1275-1286. Epub 2021 Mar 9.

Hangzhou Cancer Institution, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China.

Esophageal squamous cell carcinoma (ESCC) is one of most lethal malignancies with high aggressive potential in the world. Radiotherapy is used as one curative treatment modality for ESCC patients. Due to radioresistance, the 5-year survival rates of patients after radiotherapy is less than 20%. Tumor radioresistance is very complex and heterogeneous. Cancer-associated fibroblasts (CAFs), as one major component of tumor microenvironment (TME), play critical roles in regulating tumor radioresponse through multiple mechanisms and are increasingly considered as important anti-cancer targets. Cancer stemness, which renders cancer cells to be extremely resistant to conventional therapies, is involved in ESCC radioresistance due to the activation of Wnt/β-catenin, Notch, Hedgehog and Hippo (HH) pathways, or the induction of epithelial-mesenchymal transition (EMT), hypoxia and autophagy. Non-protein-coding RNAs (ncRNAs), which account for more than 90% of the genome, are involved in esophageal cancer initiation and progression through regulating the activation or inactivation of downstream signaling pathways and the expressions of target genes. Herein, we mainly reviewed the role of CAFs, cancer stemness, non-coding RNAs as well as others in the development of radioresistance and clarify the involved mechanisms. Furthermore, we summarized the potential strategies which were reported to reverse radioresistance in ESCC. Together, this review gives a systematic coverage of radioresistance mechanisms and reversal strategies and contributes to better understanding of tumor radioresistance for the exploitation of novel intervention strategies in ESCC.
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http://dx.doi.org/10.1007/s00432-020-03493-3DOI Listing
May 2021

Multi-omics analysis identifies potential mechanisms of AURKB in mediating poor outcome of lung adenocarcinoma.

Aging (Albany NY) 2021 02 17;13(4):5946-5966. Epub 2021 Feb 17.

Nanjing Medical University, Nanjing, China.

Aurora kinases B (AURKB), which plays a critical role in chromosomal segmentation and mitosis, greatly promotes cell cycle progression and aggressive proliferation of cancers. So far, its role and underlying mechanisms in mediating poor outcome of lung adenocarcinoma (LUAD) remained largely unclear. Analyses on multiple omics data of lung adenocarcinoma cohort in The Cancer Genome Atlas (TCGA) were performed based on AURKB expression, and demonstrated its association with clinical characteristics and the potential of using AURKB as a biomarker in predicting patients' survival. This study found aberrant alterations of genomics and epigenetics, including up-regulation and down-regulation of oncogenic genes and tumor suppressors, pathways involved in the cell cycle, DNA repair, spliceosome, and proteasome, hypermethylation enrichments around transcriptional start sites, which are all related to AURKB expression. We further discovered the possible role of tumor suppressors DLC1 and HLF in AURKB-mediated adverse outcome of LUAD. To conclude, this study proved AURKB as a potential prognostic factor and therapeutic target for lung adenocarcinoma treatment and provide a future research direction.
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http://dx.doi.org/10.18632/aging.202517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950220PMC
February 2021

The prognostic value of longitudinal circulating tumor DNA profiling during osimertinib treatment.

Transl Lung Cancer Res 2021 Jan;10(1):326-339

Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.

Background: Serial profiling of circulating tumor DNA (ctDNA) could reflect dynamic molecular changes in response to treatment and potentially predict impending disease progression (PD). Herein, we investigated the molecular factors and dynamic changes in ctDNA that can serve as predictors of survival outcomes of patients with epidermal growth factor receptor ()-mutated advanced non-small cell lung cancer (NSCLC) who received osimertinib therapy after progression from prior EGFR inhibitor regimen.

Methods: Capture-based targeted sequencing was performed on the baseline and longitudinal plasma samples collected from 72 and 57 patients, respectively, using a 168-gene panel.

Results: Analysis revealed that inferior overall survival (OS) was correlated with various baseline molecular features including high allelic fraction (AF) of sensitizing mutations (P=0.045), high maximum AF (maxAF, P=0.060), or harboring concurrent genomic alterations such as copy number amplification (CNA) in (P=0.026) or in other genes (P=0.026), and genes involved in the cell cycle (P=0.004) or TP53 signaling pathway (P=0.032). Moreover, ctDNA clearance at first follow-up after 6 weeks of osimertinib therapy was correlated with significantly longer progression-free survival (PFS) (P=0.022) and OS (P=0.009). Molecular PD, reflected by the emergence of new mutation or increased AF of existing mutations, was detected at an average lead time of 2.5 months prior to radiological PD. Patients with molecular PD were more likely to harbor CNA (P=0.035) and mutations (P=0.023).

Conclusions: Molecular factors derived from serial ctDNA profiling can serve as predictive and prognostic markers, which could allow early detection of PD, preceding imaging modalities by 2.5 months.
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http://dx.doi.org/10.21037/tlcr-20-371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867761PMC
January 2021

A RF Redundant TSV Interconnection for High Resistance Si Interposer.

Micromachines (Basel) 2021 Feb 8;12(2). Epub 2021 Feb 8.

Chengdu Ganide Technology Co., Ltd, Chengdu 610000, China.

Through Silicon Via (TSV) technology is capable meeting effective, compact, high density, high integration, and high-performance requirements. In high-frequency applications, with the rapid development of 5G and millimeter-wave radar, the TSV interposer will become a competitive choice for radio frequency system-in-package (RF SIP) substrates. This paper presents a redundant TSV interconnect design for high resistivity Si interposers for millimeter-wave applications. To verify its feasibility, a set of test structures capable of working at millimeter waves are designed, which are composed of three pieces of CPW (coplanar waveguide) lines connected by single TSV, dual redundant TSV, and quad redundant TSV interconnects. First, HFSS software is used for modeling and simulation, then, a modified equivalent circuit model is established to analysis the effect of the redundant TSVs on the high-frequency transmission performance to solidify the HFSS based simulation. At the same time, a failure simulation was carried out and results prove that redundant TSV can still work normally at 44 GHz frequency when failure occurs. Using the developed TSV process, the sample is then fabricated and tested. Using L-2L de-embedding method to extract S-parameters of the TSV interconnection. The insertion loss of dual and quad redundant TSVs are 0.19 dB and 0.46 dB at 40 GHz, respectively.
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http://dx.doi.org/10.3390/mi12020169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914721PMC
February 2021

Suberoylanilide hydroxamic acid enhances the radiosensitivity of lung cancer cells through acetylated wild-type and mutant p53-dependent modulation of mitochondrial apoptosis.

J Int Med Res 2021 Feb;49(2):300060520981545

Department of Thoracic Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China.

Objective: Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, has shown potential as a candidate radiosensitizer for many types of cancers. This study aimed to explore the radiosensitization mechanism of SAHA in lung cancer cells.

Methods: Mutations in p53 were generated by site-directed mutagenesis using polymerase chain reaction. Transfection was performed to generate H1299 cells carrying wild-type or mutant p53. The radiosensitizing enhancement ratio was determined by clonogenic assays. Mitochondrial apoptosis was detected using JC-1 staining and flow cytometry analysis.

Results: Our results showed that SAHA induced radiosensitization in H1299 cells expressing wild-type p53, p53 or p53, but this enhanced clonogenic cell death was not observed in parental H1299 (p53-null) cells or H1299 cells expressing p53 with K120R, A161T and V274R mutations. In SAHA-sensitized cells, mitochondrial apoptosis was induced following exposure to irradiation. Additionally, we observed that a secondary mutation at K120 (K120R) could eliminate p53-mediated radiosensitization and mitochondrial apoptosis.

Conclusions: The results of this study suggest that wild-type and specific mutant forms of p53 mediate SAHA-induced radiosensitization by regulating mitochondrial apoptosis, and the stabilization of K120 acetylation by SAHA is the molecular basis contributing to radiosensitization in lung cancer cells.
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http://dx.doi.org/10.1177/0300060520981545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876760PMC
February 2021

Glucosuric, renal and haemodynamic effects of licogliflozin, a dual inhibitor of sodium-glucose co-transporter-1 and sodium-glucose co-transporter-2, in patients with chronic kidney disease: A randomized trial.

Diabetes Obes Metab 2021 05 16;23(5):1182-1190. Epub 2021 Feb 16.

Novartis Institutes for BioMedical Research, Basel, Switzerland.

Aim: To investigate the glucosuric, renal and haemodynamic effects of licogliflozin, a dual sodium-glucose co-transporter-1 and sodium-glucose co-transporter-2 inhibitor, in patients with chronic kidney disease (CKD).

Methods: This multiple-dose, parallel-group, phase II mechanistic study randomized 53 participants (aged 18-78 years, body mass index ≤ 50 kg/m ) with varying degrees of CKD or normal renal function to treatment with licogliflozin (50 mg once daily) or placebo for 7 days. The effects of licogliflozin on 24-h urinary glucose excretion (UGE ), renal function, haemodynamics, pharmacokinetics and safety were assessed.

Results: Licogliflozin treatment for 7 days significantly (p < .01) increased UGE from baseline in participants with normal renal function (adjusted mean change: 41.8 [33.6, 49.9] g) or with mild (32.6 [24.1, 41.0] g), moderate A (35.7 [28.6, 42.9] g) or moderate B (20.3 [13.1, 27.5] g) CKD, but not in severe (6.2 [-0.71, 13.18] g) CKD. Licogliflozin reduced urinary electrolytes (sodium, potassium and chloride), blood pressure and urinary volume to varying extents among different groups. Significant increases in renin (p < .05), angiotensin II (p < .05) and aldosterone (p < .01) levels were observed. Adverse events were generally mild, and most commonly included diarrhoea (94%), flatulence (68%) and abdominal pain (21%).

Conclusion: Licogliflozin treatment results in significantly increased UGE and favourable changes in urinary electrolytes and haemodynamics in patients with varying degrees of CKD (estimated glomerular filtration rate ≥ 45 mL/min/1.73 m ).
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http://dx.doi.org/10.1111/dom.14327DOI Listing
May 2021

Downregulation of breast cancer resistance protein by long-term fractionated radiotherapy sensitizes lung adenocarcinoma to SN-38.

Invest New Drugs 2021 Apr 21;39(2):458-468. Epub 2021 Jan 21.

Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.

Chemotherapy is usually the subsequent treatment for non-small cell lung cancer patients with acquired radioresistance after long-term fractionated radiotherapy. However, few studies have focused on the selection of chemotherapeutic drugs to treat lung adenocarcinoma patients with radioresistance. Our study compared the sensitivity changes of lung adenocarcinoma cells to conventional chemotherapeutic drugs under radioresistant circumstances by using three lung adenocarcinoma cell models, which were irradiated with fractionated X-rays at a total dose of 60 Gy. The results showed that the toxicities of paclitaxel, docetaxel and SN-38 were increased in radioresistant cells. The IC values of docetaxel and SN-38 decreased 0 ~ 3 times and 3 ~ 36 times in radioresistant cells, respectively. Notably, the A549 radioresistant cells were approximately 36 times more sensitive to SN-38 than the parental cells. Further results revealed that the downregulation of the efflux transporter BCRP by long-term fractionated irradiation was an important factor contributing to the increased cytotoxicity of SN-38. In addition, the reported miRNAs and transcriptional factors that regulate BCRP did not participate in the downregulation. In conclusion, these results presented important data on the sensitivity changes of lung adenocarcinoma cells to chemotherapeutic drugs after acquiring radioresistance and suggested that irinotecan (the prodrug of SN-38) might be a promising drug candidate for lung adenocarcinoma patients with acquired radioresistance.
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http://dx.doi.org/10.1007/s10637-020-01003-3DOI Listing
April 2021

Deep learning-based automatic delineation of the hippocampus by MRI: geometric and dosimetric evaluation.

Radiat Oncol 2021 Jan 14;16(1):12. Epub 2021 Jan 14.

Department of Radiation Oncology, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, China.

Background: Whole brain radiotherapy (WBRT) can impair patients' cognitive function. Hippocampal avoidance during WBRT can potentially prevent this side effect. However, manually delineating the target area is time-consuming and difficult. Here, we proposed a credible approach of automatic hippocampal delineation based on convolutional neural networks.

Methods: Referring to the hippocampus contouring atlas proposed by RTOG 0933, we manually delineated (MD) the hippocampus on the MRI data sets (3-dimensional T1-weighted with slice thickness of 1 mm, n = 175), which were used to construct a three-dimensional convolutional neural network aiming for the hippocampus automatic delineation (AD). The performance of this AD tool was tested on three cohorts: (a) 3D T1 MRI with 1-mm slice thickness (n = 30); (b) non-3D T1-weighted MRI with 3-mm slice thickness (n = 19); (c) non-3D T1-weighted MRI with 1-mm slice thickness (n = 11). All MRIs confirmed with normal hippocampus has not been violated by any disease. Virtual radiation plans were created for AD and MD hippocampi in cohort c to evaluate the clinical feasibility of the artificial intelligence approach. Statistical analyses were performed using SPSS version 23. P < 0.05 was considered significant.

Results: The Dice similarity coefficient (DSC) and Average Hausdorff Distance (AVD) between the AD and MD hippocampi are 0.86 ± 0.028 and 0.18 ± 0.050 cm in cohort a, 0.76 ± 0.035 and 0.31 ± 0.064 cm in cohort b, 0.80 ± 0.015 and 0.24 ± 0.021 cm in cohort c, respectively. The DSC and AVD in cohort a were better than those in cohorts b and c (P < 0.01). There is no significant difference between the radiotherapy plans generated using the AD and MD hippocampi.

Conclusion: The AD of the hippocampus based on a deep learning algorithm showed satisfying results, which could have a positive impact on improving delineation accuracy and reducing work load.
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http://dx.doi.org/10.1186/s13014-020-01724-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807715PMC
January 2021

Vertically-Oriented TiCT MXene Membranes for High Performance of Electrokinetic Energy Conversion.

ACS Nano 2020 Nov 24. Epub 2020 Nov 24.

College of Energy, Xiamen University, Xiamen, Fujian 361005, P. R. China.

The electrokinetic effect to convert the mechanical energy from ambient has gained sustained research attention because it is free of moving parts and easy to be miniaturized for microscale applications. The practical application is constrained by the limited electrokinetic energy conversion performance. Herein, we report vertically oriented MXene membranes (VMMs) with ultrafast permeation as well as high ion selectivity, in which the permeation is several thousand higher than the largely researched horizontally stacked MXene membranes (HMMs). The VMMs can achieve a high streaming current of 8.17 A m driven by the hydraulic pressure, largely outperforming all existing materials. The theoretical analysis and numerical calculation reveal the underlying mechanism of the ultrafast transport in VMMs originates from the evident short migration paths, the low energy loss during the ionic migration, and the large effective inlet area on the membrane surface. The orientation of the 2D lamella in membranes, the long-overlooked element in the existing literatures, is identified to be an essential determinant in the performance of 2D porous membranes. These understandings can largely promote the development of electrokinetic energy conversion devices and bring advanced design strategy for high-performance 2D materials.
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http://dx.doi.org/10.1021/acsnano.0c02202DOI Listing
November 2020

Erlotinib Versus Etoposide/Cisplatin With Radiation Therapy in Unresectable Stage III Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer: A Multicenter, Randomized, Open-Label, Phase 2 Trial.

Int J Radiat Oncol Biol Phys 2021 04 19;109(5):1349-1358. Epub 2020 Nov 19.

Department of Radiation Oncology and Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, China. Electronic address:

Purpose: This study aimed to compare erlotinib (E) and etoposide/cisplatin (EP) with concurrent radiation therapy (RT) for patients with stage IIIA/B unresectable advanced non-small cell lung cancer with activating epidermal growth factor receptor mutation (EGFRm+).

Methods And Patients: This was a multicenter, randomized, open-label, phase 2 trial conducted across 19 institutions in China (December 2012 to January 2016). Enrolled patients were randomized (1:1) to E + RT (oral erlotinib 150 mg/d for 2 years or until disease progression or intolerable toxicity and RT 200 cGy/d, 5 d/wk for 6 weeks from the first day of erlotinib) or EP + RT (etoposide 50 mg/m intravenously on days 1-5 and 29-33; cisplatin 50 mg/m intravenously on days 1, 8, 29 and 36; and RT as for E + RT). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate and safety.

Results: Two hundred fifty-two patients were screened, and 20 patients with EGFRm+ in each group received the allocated E + RT or EP + RT treatment. Patient characteristics were well balanced between groups. Compared with EP + RT, median PFS with E + RT was significantly longer (24.5 vs 9.0 months [hazard ratio, 0.104; 95% confidence interval, 0.028-0.389; P < .001]). Objective response rate in the E + RT and EP + RT groups was 70% and 61.9%, respectively (P = .744). The incidence of adverse events (any grade) was similar between E + RT and EP + RT groups (88.9% and 84.2%).

Conclusions: The primary endpoint of PFS was met, and the data showed that E + RT might provide PFS improvement compared with EP + RT, with similar tolerability. However, definitive statements regarding the efficacy of concurrent E + RT in patients with unresectable stage III non-small cell lung cancer with activating EGFRm+ cannot be made, and slow patient accrual will likely make it infeasible to conduct a phase 3 study.
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http://dx.doi.org/10.1016/j.ijrobp.2020.11.026DOI Listing
April 2021

[Pathological and Molecular Features of Lung Micropapillary Adenocarcinoma].

Zhongguo Fei Ai Za Zhi 2020 Nov;23(11):1007-1013

Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 
Hangzhou 310006, China.

Lung micropapillary adenocarcinoma is characterized by frequent metastasis, lymph node infiltration, high recurrence rate and low overall survival rate as a high-grade lung adenocarcinoma. Special oncogenic pathway is activated and immune microenvironment is established in this subtype of tumor. This article reviews the Pathological phenomena and molecular features of micropapillary adenocarcinoma studied in recent years, aiming to deepen the understanding of micropapillary lesions and lay the foundation for formulating specific treatment strategies.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2020.102.37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679217PMC
November 2020

Anticorrosive non-crystalline coating prepared by plasma electrolytic oxidation for ship low carbon steel pipes.

Sci Rep 2020 Sep 24;10(1):15675. Epub 2020 Sep 24.

College of Marine Engineering, Dalian Maritime University, Dalian, 116026, China.

A corrosion-resistant non-crystalline coating was fabricated by plasma electrolytic oxidation (PEO) on Q235 low carbon steel for ship pipes. The distribution and composition of chemical elements and phases of PEO coatings were analyzed by an orthogonal experiment, and the formation mechanism of PEO coatings was discussed. The corrosion current densities and corrosion potentials were measured. The results indicated that the formation of a transition layer mainly containing FeO was crucial for achieving an excellent coating quality. Furthermore, the corrosion current density of coated steel was reduced by 78% compared with the bare steel.
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http://dx.doi.org/10.1038/s41598-020-72787-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515860PMC
September 2020

The impact of respiratory motion and CT pitch on the robustness of radiomics feature extraction in 4DCT lung imaging.

Comput Methods Programs Biomed 2020 Dec 27;197:105719. Epub 2020 Aug 27.

Medical Physics Program, University of Nevada, Las Vegas, NV 89154, USA. Electronic address:

Purpose/objective(s): The precise radiomics analysis on thoracic 4DCT data is easily compromised by the respiratory motion and CT scan parameter setting, thus leading to the risk of overfitting and/or misinterpretation of data in AI-enabled therapeutic model building. In this study, we investigated the impact of respiratory amplitudes, frequencies and CT scan pitch settings within the thoracic 4DCT scan on robust radiomics feature selection.

Materials/methods: A Three-dimensional QUSAR lung tumor phantom was used to simulate different respiratory amplitudes and frequencies along with different CT scan pitch settings. A total of 43 tumor respiratory patterns extracted from 43 patients with non-small cell lung cancer were used to drive the QUSAR lung tumor phantom to mimic the human tumor motion. The 4DCT images of the QUSAR lung tumor phantom with different respiratory patterns and different CT scan pitch setups were acquired for radiomics feature extraction. A static high-quality CT images of the phantom acquired were also used as a reference for radiomics feature extraction. The range of respiratory amplitudes was mimicked at 3mm at left and right (LR) and anterior and posterior (AP) directions and 3mm - 15 mm at the superior and inferior (SI) direction with an interval of 2 mm. The respiratory frequencies were set at 10, 11, 12, 13, 14, 15 and 20 beats per minute (BPMs), respectively. The CT scan pitches were set at 0.025, 0.048, 0.071, 0.93, 0.108, 0.14, 0.16, 0.18, 0.21, 0.23, and 0.25, respectively, which was based on a procedure described in Med. Phys. 30(1):88-97. The pairwise Concordance Correlation Coefficient (CCC) was used to determine the robustness of radiomics feature extraction via comparing the agreement in feature values between 1766 radiomics features extracted from each image acquired under different combinations of respiratory amplitudes and frequencies and CT scan pitches of 4DCT and those extracted from the static CT images.

Results: (1) When the respiratory amplitudes were at 3, 5, 7, 9, 12 and 15mm in the SI direction, the maximum CCC index could be achieved at the reconstructed 4DCT phase images of 60%, 70%, 30%, 20%, 60%~70% and 10%, respectively. Under these six amplitudes, the maximum intensity projection (MIP) and average intensity projection (AIP) images reconstructed show mean CCC values of 0.778 and 0.609, respectively, in pairwise radiomics feature extraction comparison between 4DCT and static CT. (2) When the respiratory amplitude was set at 12 mm in the SI direction, the maximum CCC index could be consistently achieved at the reconstructed 4DCT phase of 90% for the seven respiratory frequencies of 10, 11, 12, 13, 14, 15 and 20 BPMs, respectively. Under these respiratory states, the MIP and AIP images reconstructed show mean CCC values of 0.702 and 0.562, respectively. (3) When the respiratory amplitude was set at 12 mm and the respiratory frequency was set at 13 BPM, the maximum CCC index could be obtained at the reconstructed 4DCT phase of 90% for all scan pitches used except the 0% phase which was obtained at the pitch setting of 0.048. Under these CT scan pitch settings, the MIP and AIP images reconstructed show mean CCC values of 0.558 and 0.782, respectively. (4) The total number of robust features were 50, 34 and 35 with different respiratory amplitudes and phases and CT scanning pitch used (CCC values ≥ 0.99).

Conclusion: In 4DCT, the respiratory amplitude, frequency and CT scan pitch are three limiting factors that greatly affect the robustness of radiomics feature extraction. The reconstructed 4DCT phases with better robustness along with suitable respiratory amplitude, frequency and CT scan pitch determined could be used to guide the breathing training for patients with lung cancer for radiation therapy to improve the robust radiomics feature extraction process.
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http://dx.doi.org/10.1016/j.cmpb.2020.105719DOI Listing
December 2020

Prophylactic chemotherapeutic hyperthermic intraperitoneal perfusion reduces peritoneal metastasis in gastric cancer: a retrospective clinical study.

BMC Cancer 2020 Aug 31;20(1):827. Epub 2020 Aug 31.

Department of Oncology, Zhejiang Hospital, Hangzhou, Zhejiang, 310013, P.R. China.

Background: Peritoneal metastasis is the most frequent failure in gastric cancer. This study evaluated the role of prophylactic chemotherapeutic hyperthermic intraperitoneal perfusion (CHIP) in patients after D2 dissection.

Methods: Gastric cancer patients after D2 dissection were enrolled in this study. Patients received either chemotherapy (IV group) or CHIP (CHIP group). Sites of recurrence or metastasis, disease-free survival (DFS), overall survival (OS) and adverse events were evaluated.

Results: Twenty-two patients received CHIP treatment, and 21 patients received chemotherapy alone. The median DFS time was 24.5 and 36.5 months in the IV group and CHIP group (P = 0.044), respectively. The median OS time was 33.1 months in the IV group and not reached in the CHIP group (P = 0.037). We also found that CHIP could reduce the total recurrence/metastasis rate, especially that of peritoneal metastasis. In the subgroup analysis, DFS and OS were both superior in deficient mismatch repair (dMMR) patients than in proficient MMR (pMMR) patients.

Conclusion: This hypothesis-generating study indicates that CHIP might be feasible for gastric cancer patients after D2 resection.
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http://dx.doi.org/10.1186/s12885-020-07339-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461269PMC
August 2020

[Research Advances and Obstacles of CT-based Radiomics in Diagnosis and Treatment of Lung Cancer].

Zhongguo Fei Ai Za Zhi 2020 Oct 17;23(10):904-908. Epub 2020 Aug 17.

Department of Oncology, Hangzhou First People's Hospital, Hangzhou 310006, China.

Radiomics, a technology based on multimodal medical image processing and analysis, is able to extract automatically and analyze massive data from computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography/computed tomography (PET/CT) via high-performance computer algorithm in order to pursue early diagnosis of disease, benign and malignant tumor discrimination, dynamic evaluation of disease treatment, and individualized precision therapy. To date, many studies demonstrate that radiomics not only has great potential in early diagnosis of lung cancer and prediction of genotype, treatment efficacy, as well as prognosis but also is based on imaging methods that are noninvasive, inexpensive, and repeatable. It does demonstrate precious values in guiding the clinical diagnosis and treatment of lung cancer, especially in the personalized and precise treatments and researches of lung cancer. However, the consistency and reproducibility of radiomics and the selection of robust characteristics still warrant further researches.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2020.101.36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583873PMC
October 2020

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

Ticagrelor inhibits the NLRP3 inflammasome to protect against inflammatory disease independent of the P2Y signaling pathway.

Cell Mol Immunol 2021 May 10;18(5):1278-1289. Epub 2020 Jun 10.

Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Ticagrelor is the first reversibly binding oral P2Y receptor antagonist to inhibit platelet activation and has been approved by the Food and Drug Administration for the treatment of coronary artery disease. At present, the other pharmacological functions of ticagrelor remain poorly understood. The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome plays a critical role in the innate immune system, but its excessive activation also contributes to the pathogenesis of complex diseases. In this study, we systematically examined the effects of ticagrelor on the NLRP3 inflammasome and found that ticagrelor inhibits NLRP3 inflammasome activation in macrophages independent of its classic inhibitory effect on the P2Y signaling pathway. Further mechanistic studies demonstrate that ticagrelor attenuates the oligomerization of apoptosis-associated speck-like protein containing a CARD (ASC) by blocking chloride efflux, an effect achieved through the degradation of chloride intracellular channel proteins (CLICs) and blockade of the translocation of CLICs to the plasma membrane. Moreover, experiments on lipopolysaccharide-induced sepsis and alum-induced peritonitis in mice confirmed that ticagrelor mitigates the severity of systemic inflammation independent of P2Y receptor antagonism. Importantly, oral administration of ticagrelor rapidly and strongly inhibited NLRP3 inflammasome activation in peripheral blood mononuclear cells from patients with acute coronary syndrome. Overall, our study reveals a novel pharmacological function of ticagrelor in addition to its classic antiplatelet properties, which suggests that ticagrelor may serve as a potential therapeutic agent for use in NLRP3-associated diseases.
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http://dx.doi.org/10.1038/s41423-020-0444-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093290PMC
May 2021

s-HBEGF/SIRT1 circuit-dictated crosstalk between vascular endothelial cells and keratinocytes mediates sorafenib-induced hand-foot skin reaction that can be reversed by nicotinamide.

Cell Res 2020 09 15;30(9):779-793. Epub 2020 Apr 15.

Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China.

Hand-foot skin reaction (HFSR), among the most significant adverse effects of sorafenib, has been limiting the clinical benefits of this frontline drug in treating various malignant tumors. The mechanism underlying such toxicity remains poorly understood, hence the absence of effective intervention strategies. In the present study, we show that vascular endothelial cells are the primary cellular target of sorafenib-induced HFSR wherein soluble heparin-binding epidermal growth factor (s-HBEGF) mediates the crosstalk between vascular endothelial cells and keratinocytes. Mechanistically, s-HBEGF released from vascular endothelial cells activates the epidermal growth factor receptor (EGFR) on keratinocytes and promotes the phosphorylation of c-Jun N-terminal kinase 2 (JNK2), which stabilizes sirtuin 1 (SIRT1), an essential keratinization inducer, and ultimately gives rise to HFSR. The administration of s-HBEGF in vivo could sufficiently induce hyper-keratinization without sorafenib treatment. Furthermore, we report that HBEGF neutralization antibody, Sirt1 knockdown, and a classic SIRT1 inhibitor nicotinamide could all significantly reduce the sorafenib-induced HFSR in the mouse model. It is noteworthy that nicotinic acid, a prodrug of nicotinamide, could substantially reverse the sorafenib-induced HFSR in ten patients in a preliminary clinical study. Collectively, our findings reveal the mechanism of vascular endothelial cell-promoted keratinization in keratinocytes and provide a potentially promising therapeutic strategy for the treatment of sorafenib-induced HFSR.
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http://dx.doi.org/10.1038/s41422-020-0309-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608389PMC
September 2020

The survival benefit of radiotherapy in localized primary adult rhabdomyosarcoma.

Asia Pac J Clin Oncol 2020 Aug 14;16(4):266-272. Epub 2020 Apr 14.

Department of Radiation Oncology, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People's Hospital, Hangzhou, Zhejiang, China.

Aim: To evaluate the role of radiotherapy (RT) in the treatment of localized primary adult rhabdomyosarcoma (RMS).

Methods: This retrospective study identified 62 consecutive adult patients with localized primary RMS from January 2000 and July 2016. Local failure-free survival (LFFS), distant metastasis-free survival (DMFS) and overall survival (OS) were analyzed by the Kaplan-Meier method. Multivariate Cox proportional hazards regression models were fit to assess the ability of patient characteristics to predict survival.

Results: With a median follow-up of 33 months (range, 6-195 months), the 5-year LFFS, DMFS and OS of all patients were 64.0%, 50.0% and 45.0%, respectively. RT was administered to 28 patients (45.2%). Patients who received RT had a higher 5-year LFFS (81.7% vs 47.2%), 5-year DMFS (59.4% vs 43.1%) and 5-year OS (57.1% vs 34.8%) compared with patients who did not received RT. In mulitvariate analysis, RT retained significance as an independent predictor of improved LFFS [hazard ratio (HR) = 0.282; 95% confidence interval (CI), 0.095-0.838; P = 0.023], DMFS (HR = 0.289; 95% CI, 0.125-0.991; P = 0.004) and OS (HR = 0.334; 95% CI, 0.153-0.727; P = 0.006).

Conclusions: RT significantly reduced local recurrence, distant metastasis and tumor mortality compared with no radiotherapy for localized primary adult RMS.
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http://dx.doi.org/10.1111/ajco.13331DOI Listing
August 2020

Identification of somatic copy number variations in plasma cell free DNA correlating with intrinsic resistances to EGFR targeted therapy in T790M negative non-small cell lung cancer.

J Thorac Dis 2020 Mar;12(3):883-892

Center for Translational Medicine, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou 310006, China.

Background: About 20-30% EGFR-mutant non-small lung cancer show intrinsic resistance to EGFR targeted therapies. Compared to T790M positive in acquired resistance patients, little is known about EGFR-TKI intrinsic resistance for T790M negative patients.

Methods: Thirty-one patients with advanced stage lung cancer, including 18 patients with intrinsic resistance (PFS <6 months) and 13 patients with acquired resistance (PFS >36 months) but are negative for plasma T790M were recruited in the study. Plasma cell free DNA was profiled by low coverage whole genome sequencing with median genome coverage of 1.86X by Illumina X10. Sequencing coverage across chromosomes was summarized by samtools, and normalized by segmentation analysis as provided by R package 'DNACopy'.

Results: The most frequent chromosomal changes were found on chr7, chr1 and chr8. Among them, chr7p gains were found in 12 (66.7%) intrinsic resistance and 4 (30.7%) acquired resistance patients. The gene EGFR was found located on the focal amplification peak of chr7p. The performance of 7p gain to predict intrinsic resistance reaches AUC =0.902. Similarly, focal amplifications were also found on chromosome 5, 16 and 22, where tumor related gene PCDHA, ADAMTS18 and CRKL were located. Focal deletions were also found in chr1, 8, 10 and 16, where genes SFTPA1/2, DLC1, PTEN and CDH1 are located.

Conclusions: The results suggest cell free DNA copy number might be a useful peripheral blood tumor biomarker for predicting intrinsic resistance of EGFR targeted therapy and prognosis.
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http://dx.doi.org/10.21037/jtd.2019.12.97DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138977PMC
March 2020