Publications by authors named "Chuanwei Yang"

38 Publications

Nomograms for predicting cancer-specific survival in patients with primary central nervous system lymphoma: a population-based analysis.

Ann Transl Med 2021 Jul;9(13):1055

Department of Neurosurgery, Beijing Tiantan Hospital of Capital Medical University, Beijing Neurosurgical Institute, China National Clinical Research Center for Neurological Diseases, Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing Key Laboratory of Brain Tumor, Beijing, China.

Background: This study identified the risk factors for survival in patients with primary central nervous system lymphoma (PCNSL). Nomograms were developed and validated to predict individualized overall survival (OS) and cancer-specific survival (CSS) in this particular cohort.

Methods: Patients diagnosed with PCNSL between 1975 and 2016 were selected from the Surveillance, Epidemiology, and End Results (SEER) database for this study. The Cox regression model, the Fine and Grey's model, and the backward method were applied to determine the risk factors for OS and CSS. Nomograms were established accordingly. Internal and external validation was performed in an Asian population to examine the accuracy of the nomograms.

Results: A total of 5,900 patients with PCNSL were identified from the SEER database. A further 163 patients with PCNSL from the Beijing Tiantan Hospital between 2004 and 2018 were included. Age at diagnosis, tumor site, pathological subtype, surgery, chemotherapy, coexisting malignancies, and HIV infection were independent risk factors of CSS. In addition to the risk factors of CSS, gender, marital status, and radiation were also independent factors of OS. Nomograms were developed to estimate the 1-, 3-, and 5-year OS and CSS. The discrimination and calibration of the nomograms performed well. The C-indexes of the nomograms for OS and CSS prediction were 0.728 [95% confidence interval (CI): 0.703-0.753] and 0.726 (95% CI: 0.696-0.756), respectively. In addition, compared with previously published OS nomograms, the newly established nomograms displayed superior prediction for OS.

Conclusions: Nomograms predicting the 1-, 3- and 5-year OS and CSS of patients with PCNSL were established in this study. The validated nomograms showed relatively good performance and may be used clinically to evaluate patients' individualized risk and prognosis with PCNSL. Free software for individualized survival prediction is provided at http://www.pcnsl-survivalprediction.cn.
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http://dx.doi.org/10.21037/atm-21-753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339814PMC
July 2021

Combining MGMT promoter pyrosequencing and protein expression to optimize prognosis stratification in glioblastoma.

Cancer Sci 2021 Sep 2;112(9):3699-3710. Epub 2021 Jul 2.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Pyrosequencing (PSQ) represents the golden standard for MGMT promoter status determination. Binary interpretation of results based on the threshold from the average of several CpGs tested would neglect the existence of the "gray zone". How to define the gray zone and reclassify patients in this subgroup remains to be elucidated. A consecutive cohort of 312 primary glioblastoma patients were enrolled. CpGs 74-81 in the promoter region of MGMT were tested by PSQ and the protein expression was assessed by immunohistochemistry (IHC). Receiver operating characteristic curves were constructed to calculate the area under the curves (AUC). Kaplan-Meier plots were used to estimate the survival rate of patients compared by the log-rank test. The optimal threshold of each individual CpG differed from 5% to 11%. Patients could be separated into the hypomethylated subgroup (all CpGs tested below the corresponding optimal thresholds, n = 126, 40.4%), hypermethylated subgroup (all CpGs tested above the corresponding optimal thresholds, n = 108, 34.6%), and the gray zone subgroup (remaining patients, n = 78, 25.0%). Patients in the gray zone harbored an intermediate prognosis. The IHC score instead of the average methylation levels could successfully predict the prognosis for the gray zone (AUC for overall survival, 0.653 and 0.519, respectively). Combining PSQ and IHC significantly improved the efficiency of survival prediction (AUC: 0.662, 0.648, and 0.720 for PSQ, IHC, and combined, respectively). Immunohistochemistry is a robust method to predict prognosis for patients in the gray zone defined by PSQ. Combining PSQ and IHC could significantly improve the predictive ability for clinical outcomes.
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http://dx.doi.org/10.1111/cas.15024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409410PMC
September 2021

Corrigendum: Distinguishing Pseudoprogression From True Early Progression in Isocitrate Dehydrogenase Wild-Type Glioblastoma by Interrogating Clinical, Radiological and Molecular Features.

Front Oncol 2021 19;11:700599. Epub 2021 May 19.

Department of Neurosurgery, National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

[This corrects the article DOI: 10.3389/fonc.2021.627325.].
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http://dx.doi.org/10.3389/fonc.2021.700599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171117PMC
May 2021

Differential Predictors and Clinical Implications Associated With Long-Term Survivors in IDH Wildtype and Mutant Glioblastoma.

Front Oncol 2021 13;11:632663. Epub 2021 May 13.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Background: Glioblastoma (GBM) is the most aggressive intracranial tumor which can be divided into two subtypes based on status of isocitrate dehydrogenase (IDH). A small fraction of patients after receiving standard treatment can be long-term survivors (LTS). This study was designed to disclose the predictors and clinical implications associated with LTS in IDH wildtype and mutant GBM.

Methods: Patients who survived beyond five years after diagnosis of GBM were defined as LTS, while those with a survival less than one year were defined as short-term survivors (STS). A total of 211 patients with diagnosis of GBM in Beijing Tiantan Hospital from January 2007 to January 2015 were enrolled, including 44 (20.9%) LTS and 167 (79.1%) STS. The clinical, radiological and molecular features between groups were systematically compared.

Results: Compared with STS, LTS were a subgroup of patients with a younger age at diagnosis (=0.006), a higher KPS score (=0.011), higher rates of cystic change (=0.037), O-methylguanine-DNA methyltransferase (MGMT) promoter methylation (=0.007), and IDH mutation (=0.049), and more likely to have undergone gross total resection (<0.001). Survival analysis demonstrated that LTS with wildtype IDH conferred a longer progression-free survival (66.0 27.0 months, =0.04), but a shorter post-progression survival (46.5 months not reached, =0.0001) than those of LTS with mutant IDH. LTS with mutant IDH showed a trend towards increased survival after receiving re-operation (=0.155) and reirradiation (=0.127), while this clinical benefit disappeared in the subset of LTS with wildtype IDH (>0.05).

Conclusion: The prognostic value and therapeutic implications associated with LTS in GBM population significantly differed on the basis of IDH status. Our findings provide a new approach for physicians to better understand the two subtypes of GBM, which may assist in making more tailored treatment decisions for patients.
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http://dx.doi.org/10.3389/fonc.2021.632663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155513PMC
May 2021

Combination of Immunotherapy and Radiotherapy for Recurrent Malignant Gliomas: Results From a Prospective Study.

Front Immunol 2021 7;12:632547. Epub 2021 May 7.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Background: World Health Organization (WHO) grade IV glioma remains one of the most lethal tumors with a dismal prognosis and inevitable recurrence. We evaluated the safety and efficacy of immunotherapy with radiotherapy in this population of patients.

Methods: This study was a single-arm, open-label, phase I trial based on patients with recurrent WHO grade IV glioma. Patients were treated with intracranial and systemic immunoadjuvants in combination with low-dose reirradiation. The primary endpoint of the present trial was safety. Secondary endpoints were overall survival (OS) and progression-free survival (PFS). This trial is registered at ClinicalTrials.gov, NCT03392545.

Results: Thirty patients were enrolled. The most common adverse events (AEs) were fever (66.7%), vomiting (33.3%), headache (30.0%), and fatigue (23.3%). Only a single patient experienced grade 3 fever, and no grade 4 AEs or deaths related to treatment were observed. Of the 30 patients, 1 (3.3%) had a complete response, 5 (16.7%) had a partial response, 9 (30.0%) had stable disease, and 15 (50.0%) had progressive disease, resulting in an objective response rate of 20.0%. The median PFS of the entire cohort was 88.0 (61.0-254.0) days, and the median OS was 362.0 (197.0-601.0) days. Patients could be divided into responders and non-responders, and these groups exhibited a significant difference in terms of survival time, T lymphocyte subsets, frequency of cell division cycle 27 (CDC27) mutation status, and CD15 and CD68 expression (<0.05).

Conclusion: The combination of immunotherapy and radiotherapy is well tolerated and may provide clinical benefit for patients with recurrent WHO grade IV glioma. A prospective phase II study is needed to further validate the efficacy of our therapeutic regimen.
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http://dx.doi.org/10.3389/fimmu.2021.632547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138184PMC
September 2021

Distinguishing Pseudoprogression From True Early Progression in Isocitrate Dehydrogenase Wild-Type Glioblastoma by Interrogating Clinical, Radiological, and Molecular Features.

Front Oncol 2021 20;11:627325. Epub 2021 Apr 20.

Department of Neurosurgery, National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Pseudoprogression (PsP) mimics true early progression (TeP) in conventional imaging, which poses a diagnostic challenge in glioblastoma (GBM) patients who undergo standard concurrent chemoradiation (CCRT). This study aimed to investigate whether perioperative markers could distinguish and predict PsP from TeP in isocitrate dehydrogenase (IDH) wild-type GBM patients. New or progressive gadolinium-enhancing lesions that emerged within 12 weeks after CCRT were defined as early progression. Lesions that remained stable or spontaneously regressed were classified as PsP, otherwise persistently enlarged as TeP. Clinical, radiological, and molecular information were collected for further analysis. Patients in the early progression subgroup were divided into derivation and validation sets (7:3, according to operation date). Among 234 consecutive cases enrolled in this retrospective study, the incidences of PsP, TeP, and neither patterns of progression (nP) were 26.1% (61/234), 37.6% (88/234), and 36.3% (85/234), respectively. In the early progression subgroup, univariate analysis demonstrated female (: 2.161, = 0.026), gross total removal (GTR) of the tumor (: 6.571, < 001), located in the frontal lobe (: 2.561, = 0.008), non-subventricular zone (SVZ) infringement (: 10.937, < 0.001), and methylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter (mMGMTp) (: 9.737, < 0.001) were correlated with PsP, while GTR, non-SVZ infringement, and mMGMTp were further validated in multivariate analysis. Integrating quantitative MGMTp methylation levels from pyrosequencing, GTR, and non-SVZ infringement showed the best discriminative ability in the random forest model for derivation and validation set (AUC: 0.937, 0.911, respectively). Furthermore, a nomogram could effectively evaluate the importance of those markers in developing PsP (C-index: 0.916) and had a well-fitted calibration curve. Integrating those clinical, radiological, and molecular features provided a novel and robust method to distinguish PsP from TeP, which was crucial for subsequent clinical decision making, clinical trial enrollment, and prognostic assessment. By in-depth interrogation of perioperative markers, clinicians could distinguish PsP from TeP independent from advanced imaging.
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http://dx.doi.org/10.3389/fonc.2021.627325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093388PMC
April 2021

Two bHLH transcription factors, bHLH48 and bHLH60, associate with phytochrome interacting factor 7 to regulate hypocotyl elongation in Arabidopsis.

Cell Rep 2021 May;35(5):109054

State Key Laboratory of Genetic Engineering and Institute of Plant Biology, School of Life Sciences, Fudan University, Shanghai 200438, People's Republic of China. Electronic address:

The basic helix-loop-helix (bHLH) transcription factor PHYTOCHROME-INTERACTING FACTOR 7 (PIF7) is a central regulator that promotes stem growth by activating growth-related gene expression during shade-avoidance responses. Studying the co-factors of PIF7 can facilitate understanding of the mechanism of PIFs and light signal transduction. Here, we describe the identification of two bHLH transcription factors, bHLH48 and bHLH60 (bHLH48/bHLH60), as essential partners for PIF7-dependent modulation of hypocotyl elongation and function downstream of phytochrome B. These two bHLH factors display DNA binding activity and interact with PIF7. Genetic analysis indicated that bHLH48/bHLH60 and PIF7 are interdependent in promoting hypocotyl elongation. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis identified the substantially overlapping downstream targets of bHLH60 and PIF7. Biochemical analysis revealed that bHLH48/bHLH60 enhance the DNA binding ability of PIF7. These results provide evidence that bHLH48/bHLH60 act as positive partners of PIF7 for mutual benefit in the regulation of hypocotyl elongation.
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http://dx.doi.org/10.1016/j.celrep.2021.109054DOI Listing
May 2021

Phenotypic Study of Photomorphogenesis in Arabidopsis Seedlings.

Methods Mol Biol 2021 ;2297:41-47

State Key Laboratory of Genetic Engineering and Institute of Plant Biology, School of Life Sciences, Fudan University, Shanghai, China.

Light is one of the most important environmental factors, serving as the energy source of photosynthesis and a cue for plant developmental programs, called photomorphogenesis. Here, we provide a standardized operation to measure physiological parameters of photomorphogenesis, including in hypocotyl length, cotyledon size, and anthocyanin content.
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http://dx.doi.org/10.1007/978-1-0716-1370-2_5DOI Listing
June 2021

AtINO80 represses photomorphogenesis by modulating nucleosome density and H2A.Z incorporation in light-related genes.

Proc Natl Acad Sci U S A 2020 12 14;117(52):33679-33688. Epub 2020 Dec 14.

State Key Laboratory of Genetic Engineering and Institute of Plant Biology, Institute of Plant Biology, School of Life Sciences, Fudan University, Shanghai 200438, People's Republic of China;

Photomorphogenesis is a critical developmental process bridging light-regulated transcriptional reprogramming with morphological changes in organisms. Strikingly, the chromatin-based transcriptional control of photomorphogenesis remains poorly understood. Here, we show that the () ortholog of ATP-dependent chromatin-remodeling factor AtINO80 represses plant photomorphogenesis. Loss of AtINO80 inhibited hypocotyl cell elongation and caused anthocyanin accumulation. Both light-induced genes and dark-induced genes were affected in the mutant. Genome-wide occupancy of the H2A.Z histone variant and levels of histone H3 were reduced in In particular, AtINO80 bound the gene body of (), resulting in lower chromatin incorporations of H2A.Z and H3 at in Genetic analysis revealed that AtINO80 acts in a phytochrome B- and HY5-dependent manner in the regulation of photomorphogenesis. Together, our study elucidates a mechanism wherein AtINO80 modulates nucleosome density and H2A.Z incorporation and represses the transcription of light-related genes, such as , to fine tune plant photomorphogenesis.
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http://dx.doi.org/10.1073/pnas.2001976117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7777152PMC
December 2020

Classification of Progression Patterns in Glioblastoma: Analysis of Predictive Factors and Clinical Implications.

Front Oncol 2020 3;10:590648. Epub 2020 Nov 3.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Background: This study was designed to explore the progression patterns of IDH-wildtype glioblastoma (GBM) at first recurrence after chemoradiotherapy.

Methods: Records from 247 patients who underwent progression after diagnosis of IDH-wildtype GBM was retrospectively reviewed. Progression patterns were classified as either local, distant, subependymal or leptomeningeal dissemination based on the preoperative and serial postoperative radiographic images. The clinical and molecular characteristics of different progression patterns were analyzed.

Results: A total of 186 (75.3%) patients had local progression, 15 (6.1%) patients had distant progression, 33 (13.3%) patients had subependymal dissemination, and 13 (5.3%) patients had leptomeningeal dissemination. The most favorable survival occurred in patients with local progression, while no significant difference of survival was found among patients with distant progression, subependymal or leptomeningeal dissemination who were thereby reclassified into non-local group. Multivariable analysis showed that chemotherapy was a protective factor for non-local progression, while gender of male, subventricular zone (SVZ) involvement and O-methylguanine-DNA-methyltransferase (MGMT) promoter methylation were confirmed as risk factors for non-local progression ( < 0.05). Based on the factors screened by multivariable analysis, a nomogram was constructed which conferred high accuracy in predicting non-local progression. Patients in non-local group could be divided into long- and short-term survivors who differed in the rates of SVZ involvement, MGMT promoter methylation and reirradiation ( < 0.05), and a nomogram integrating these factors showed high accuracy in predicting long-term survivors.

Conclusion: Patients harboring different progression patterns conferred distinct clinical and molecular characteristics. Our nomograms could provide theoretical references for physicians to make more personalized and precise treatment decisions.
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http://dx.doi.org/10.3389/fonc.2020.590648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673412PMC
November 2020

LncRNA NEAT1 Regulates 5-Fu Sensitivity, Apoptosis and Invasion in Colorectal Cancer Through the MiR-150-5p/CPSF4 Axis.

Onco Targets Ther 2020 1;13:6373-6383. Epub 2020 Jul 1.

Department of Colorectal & Anal Surgery, Central Hospital of Cangzhou, Cangzhou 061000, Hebei, People's Republic of China.

Background: Colorectal cancer (CRC) is one of the most prevalent malignancies in the world. Long non-coding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) is involved in the development of many cancers. However, its role and mechanism in CRC progression still need further exploration.

Methods: The expression levels of lnc-NEAT1, microRNA-150-5p (miR-150-5p) and cleavage and polyadenylation specific factor 4 (CPSF4) were determined by quantitative real-time PCR (qRT-PCR). The sensitivity of cells to 5-fluorouracil (5-Fu) was measured by 3-(4,5-dimethyl-2 thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Cell apoptosis and invasion were evaluated by flow cytometry and transwell assays, respectively. Western blot (WB) analysis was used to assess the levels of resistance-related proteins and CPSF4 protein. Besides, dual-luciferase reporter assay was used to verify the interactions among lnc-NEAT1, miR-150-5p and CPSF4. Also, mice xenograft models were used to determine the effect of lnc-NEAT1 on CRC tumor growth in vivo.

Results: In CRC, the expression of lnc-NEAT1 was upregulated and miR-150-5p was downregulated, and the expression of both was negatively correlated. Silencing of lnc-NEAT1 promoted the 5-Fu sensitivity, enhanced the apoptosis and suppressed the invasion of CRC cells. MiR-150-5p could be sponged by lnc-NEAT1, and its inhibitors could partially reverse the effect of lnc-NEAT1 silencing on CRC progression. Besides, CPSF4 could be targeted by miR-150-5p, and its overexpression also could invert the effect of lnc-NEAT1 knockdown on CRC progression. Further, CPSF4 expression was regulated by lnc-NEAT1 and miR-150-5p. In addition, interference of lnc-NEAT1 reduced tumor volume and improved the sensitivity of CRC to 5-Fu in vivo.

Conclusion: Lnc-NEAT1 acted as an oncogene in CRC through regulating CPSF4 expression by sponging miR-150-5p. The discovery of lnc-NEAT1/miR-150-5p/CPSF4 axis provided a novel approach for CRC genomic therapy strategy.
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http://dx.doi.org/10.2147/OTT.S239432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336013PMC
July 2020

The ELF3-PIF7 Interaction Mediates the Circadian Gating of the Shade Response in Arabidopsis.

iScience 2019 Dec 20;22:288-298. Epub 2019 Nov 20.

State Key Laboratory of Genetic Engineering and Institute of Plant Biology, School of Life Sciences, Fudan University, Shanghai 200438, People's Republic of China. Electronic address:

Light filtered through dense planting initiates the shade avoidance syndrome (SAS) in plants, which helps them compete against their neighbors. Quantitative trait loci (QTL)-based analysis identified the nighttime-expressed clock component ELF3 as a new player in the SAS, but its detailed mechanism is unclear. Here, we show that the circadian clock gates shade-induced gene expression and hypocotyl elongation at night. ELF3 is involved in nighttime suppression via interaction with and inactivation of PHYTOCHROME-INTERACTING FACTOR 7 (PIF7). Loss of function of ELF3 restores the shade induction, which is largely reduced in the absence of PIF7, indicating that ELF3 acts upstream of PIF7. Finally, we found that the repressive activity of ELF3 on the shade response is stronger under short days than under long days. Our results reveal that the interaction between ELF3 and PIF7 mediates the circadian gating of the SAS, which coordinates the daily control of physiological outputs.
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http://dx.doi.org/10.1016/j.isci.2019.11.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909221PMC
December 2019

A PIF7-CONSTANS-Centered Molecular Regulatory Network Underlying Shade-Accelerated Flowering.

Mol Plant 2019 12 27;12(12):1587-1597. Epub 2019 Sep 27.

State Key Laboratory of Genetic Engineering and Institute of Plant Biology, School of Life Sciences, Fudan University, Shanghai 200438, People's Republic of China. Electronic address:

To compete with their neighbors for light and escape shaded environments, sun-loving plants have developed the shade-avoidance syndrome (SAS), a set of responses including alteration of plant architecture and initiation of early flowering and seed set. Previous studies on SAS mainly focused on dissecting molecular basis of hypocotyl elongation in seedlings under shade light; however, the molecular mechanisms underlying shade-accelerated flowering in adult plants remain unknown. In this study, we found that CONSTANS (CO) and PHYTOCHROME-INTERACTING FACTOR 7 (PIF7) have an additive effect on shade-induced flowering, but that LONG HYPOCOTYL IN FAR-RED1 (HFR1) represses early flowering by binding to CO and PIF7 and preventing the binding of CO to the promoter of FLOWERING LOCUS T (FT) and the binding of PIF7 to the promoter of pri-MIR156E/F. Under shade, de-phosphorylated PIF7 and accumulated CO, balanced by HFR1, upregulate the expression of FT, TSF, SOC1, and SPLs to accelerate flowering. Moreover, we found that the function of PIF7 in flowering time is independent of phyA. Collectively, these regulatory interactions establish a crucial link between the light signal and genetic network that regulates flowering transition under shade.
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http://dx.doi.org/10.1016/j.molp.2019.09.007DOI Listing
December 2019

Revealing dynamic regulations and the related key proteins of myeloma-initiating cells by integrating experimental data into a systems biological model.

Bioinformatics 2021 07;37(11):1554-1561

Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

Motivation: The growth and survival of myeloma cells are greatly affected by their surrounding microenvironment. To understand the molecular mechanism and the impact of stiffness on the fate of myeloma-initiating cells (MICs), we develop a systems biological model to reveal the dynamic regulations by integrating reverse-phase protein array data and the stiffness-associated pathway.

Results: We not only develop a stiffness-associated signaling pathway to describe the dynamic regulations of the MICs, but also clearly identify three critical proteins governing the MIC proliferation and death, including FAK, mTORC1 and NFκB, which are validated to be related with multiple myeloma by our immunohistochemistry experiment, computation and manually reviewed evidences. Moreover, we demonstrate that the systematic model performs better than widely used parameter estimation algorithms for the complicated signaling pathway.

Availability And Implementation: We can not only use the systems biological model to infer the stiffness-associated genetic signaling pathway and locate the critical proteins, but also investigate the important pathways, proteins or genes for other type of the cancer. Thus, it holds universal scientific significance.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz542DOI Listing
July 2021

Shade-induced nuclear localization of PIF7 is regulated by phosphorylation and 14-3-3 proteins in .

Elife 2018 06 21;7. Epub 2018 Jun 21.

State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.

Shade avoidance syndrome enables shaded plants to grow and compete effectively against their neighbors. In , the shade-induced de-phosphorylation of the transcription factor PIF7 (PHYTOCHROME-INTERACTING FACTOR 7) is the key event linking light perception to stem elongation. However, the mechanism through which phosphorylation regulates the activity of PIF7 is unclear. Here, we show that shade light induces the de-phosphorylation and nuclear accumulation of PIF7. Phosphorylation-resistant site mutations in PIF7 result in increased nuclear localization and shade-induced gene expression, and consequently augment hypocotyl elongation. PIF7 interacts with 14-3-3 proteins. Blocking the interaction between PIF7 and 14-3-3 proteins or reducing the expression of 14-3-3 proteins accelerates shade-induced nuclear localization and de-phosphorylation of PIF7, and enhances the shade phenotype. By contrast, the 14-3-3 overexpressing line displays an attenuated shade phenotype. These studies demonstrate a phosphorylation-dependent translocation of PIF7 when plants are in shade and a novel mechanism involving 14-3-3 proteins, mediated by the retention of PIF7 in the cytoplasm that suppresses the shade response.
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http://dx.doi.org/10.7554/eLife.31636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037483PMC
June 2018

HER2-Based Immunotherapy for Breast Cancer.

Cancer Biother Radiopharm 2018 Jun 6;33(5):169-175. Epub 2018 Jun 6.

3 Breast Medical Oncology, The University of Texas MD Anderson Cancer Center , Houston, Texas.

Resistance to therapies and disease recurrences after surgery or treatment are common challenges in breast cancer management in clinic. Active immunotherapy using human epidermal growth factor receptor 2 (HER2)-targeted vaccines represents an attractive option in combating breast cancer. Different HER2-derived vaccines have been developed over the years. Many clinical trials have been carried out in evaluating HER2-based vaccines. The authors reviewed current literature on HER2-based vaccines in clinical trials. The trials covered in this mini-review represent some of the major trials published in the past 20 years regarding the clinical use and test of HER2 vaccines. Their focus is on trials using HER2 peptide vaccines as the majority of clinical trials initiated or published used HER2 peptide-based vaccines. Findings from combination therapy trials of HER2 peptide vaccines with other treatment modalities are also presented.
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http://dx.doi.org/10.1089/cbr.2017.2327DOI Listing
June 2018

Phytochrome A Negatively Regulates the Shade Avoidance Response by Increasing Auxin/Indole Acidic Acid Protein Stability.

Dev Cell 2018 01 21;44(1):29-41.e4. Epub 2017 Dec 21.

State Key Laboratory of Genetic Engineering and Institute of Plant Biology, School of Life Sciences, Fudan University, Shanghai 200438, People's Republic of China. Electronic address:

The reduction in the red to far-red light ratio (R/FR) and photosynthetically active radiation caused by dense planting initiates shade avoidance responses (SARs) to help plants compete against their neighbors. However, deep shade attenuates shade-induced stem elongation to suppress excessive reversion toward skotomorphogenic development, in which photoreceptor phytochrome A (PHYA) has been known to play the major role. However, the molecular mechanism underlying PHYA function in deep shade is poorly understood. Here, we report that shade-accumulated PHYA can release auxin/indole-3-acetic acid (AUX/IAA), suppressors in the auxin signaling pathway, from SCF, an auxin receptor, to weaken auxin signaling and negatively regulate shade response. Corroborating this, phyA mutants display an enhanced auxin response to deep shade and auxin treatment. Specifically, PHYA competes with TIR1 by directly binding and stabilizing AUX/IAA. Our findings illustrate a mechanistic model of how plants sense different shade levels to fine-tune auxin signaling and generate appropriate SAR.
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http://dx.doi.org/10.1016/j.devcel.2017.11.017DOI Listing
January 2018

EZH2-, CHD4-, and IDH-linked epigenetic perturbation and its association with survival in glioma patients.

J Mol Cell Biol 2017 12;9(6):477-488

Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Glioma is a complex disease with limited treatment options. Recent advances have identified isocitrate dehydrogenase (IDH) mutations in up to 80% lower grade gliomas (LGG) and in 76% secondary glioblastomas (GBM). IDH mutations are also seen in 10%-20% of acute myeloid leukemia (AML). In AML, it was determined that mutations of IDH and other genes involving epigenetic regulations are early events, emerging in the pre-leukemic stem cells (pre-LSCs) stage, whereas mutations in genes propagating oncogenic signal are late events in leukemia. IDH mutations are also early events in glioma, occurring before TP53 mutation, 1p/19q deletion, etc. Despite these advances in glioma research, studies into other molecular alterations have lagged considerably. In this study, we analyzed currently available databases. We identified EZH2, KMT2C, and CHD4 as important genes in glioma in addition to the known gene IDH1/2. We also showed that genomic alterations of PIK3CA, CDKN2A, CDK4, FIP1L1, or FUBP1 collaborate with IDH mutations to negatively affect patients' survival in LGG. In LGG patients with TP53 mutations or IDH1/2 mutations, additional genomic alterations of EZH2, KMC2C, and CHD4 individually or in combination were associated with a markedly decreased disease-free survival than patients without such alterations. Alterations of EZH2, KMT2C, and CHD4 at genetic level or protein level could perturb epigenetic program, leading to malignant transformation in glioma. By reviewing current literature on both AML and glioma and performing bioinformatics analysis on available datasets, we developed a hypothetical model on the tumorigenesis from premalignant stem cells to glioma.
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http://dx.doi.org/10.1093/jmcb/mjx056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907834PMC
December 2017

Hormonal Regulation in Shade Avoidance.

Front Plant Sci 2017 4;8:1527. Epub 2017 Sep 4.

State Key Laboratory of Genetic Engineering, Institute of Plant Biology, School of Life Sciences, Fudan UniversityShanghai, China.

At high vegetation density, shade-intolerant plants sense a reduction in the red (660 nm) to far-red (730 nm) light ratio (R/FR) in addition to a general reduction in light intensity. These light signals trigger a spectrum of morphological changes manifested by growth of stem-like tissue (hypocotyl, petiole, etc.) instead of harvestable organs (leaves, fruits, seeds, etc.)-namely, shade avoidance syndrome (SAS). Common phenotypical changes related to SAS are changes in leaf hyponasty, an increase in hypocotyl and internode elongation and extended petioles. Prolonged shade exposure leads to early flowering, less branching, increased susceptibility to insect herbivory, and decreased seed yield. Thus, shade avoidance significantly impacts on agronomic traits. Many genetic and molecular studies have revealed that phytochromes, cryptochromes and UVR8 (UV-B photoreceptor protein) monitor the changes in light intensity under shade and regulate the stability or activity of phytochrome-interacting factors (PIFs). PIF-governed modulation of the expression of auxin biosynthesis, transporter and signaling genes is the major driver for shade-induced hypocotyl elongation. Besides auxin, gibberellins, brassinosteroids, and ethylene are also required for shade-induced hypocotyl or petiole elongation growth. In leaves, accumulated auxin stimulates cytokinin oxidase expression to break down cytokinins and inhibit leaf growth. In the young buds, shade light promotes the accumulation of abscisic acid to repress branching. Shade light also represses jasmonate- and salicylic acid-induced defense responses to balance resource allocation between growth and defense. Here we will summarize recent findings relating to such hormonal regulation in SAS in , , and certain crops.
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http://dx.doi.org/10.3389/fpls.2017.01527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591575PMC
September 2017

Transcriptional and Genomic Control of Stem Cells in Development and Cancer.

Stem Cells Int 2017 18;2017:2513598. Epub 2017 Jun 18.

MD Anderson Cancer Center, Houston, TX 77030, USA.

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http://dx.doi.org/10.1155/2017/2513598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495003PMC
June 2017

Cadherins Associate with Distinct Stem Cell-Related Transcription Factors to Coordinate the Maintenance of Stemness in Triple-Negative Breast Cancer.

Stem Cells Int 2017 14;2017:5091541. Epub 2017 Mar 14.

College of Pharmacy, Taishan Medical University, Tai'an, Shandong, China; The Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with poor prognosis and is enriched in cancer stem cells (CSCs). However, it is not completely understood how the CSCs were maintained in TNBC. In this study, by analyzing The Cancer Genome Atlas (TCGA) provisional datasets and several small-size breast datasets, we found that cadherins (CDHs) 2, 4, 6, and 17 were frequently amplified/overexpressed in 47% of TNBC while E-cadherin (CDH1) was downregulated/mutated at 10%. The alterations of CDH2/4/6/17 were strongly associated with the elevated levels of several stem cell-related transcription factors (SC-TFs) including FOXM1, MCM2, WWTR1, SNAI1, and SOX9. CDH2/4/6/17-enriched genes including FOXM1 and MCM2 were also clustered and regulated by NFY (nuclear transcription factor Y) and/or EVI1/MECOM. Meanwhile, these SC-TFs including NFYA were upregulated in TNBC cells, but they were downregulated in luminal type of cells. Furthermore, small compounds might be predicted via the Connectivity Map analysis to target TNBC with the alterations of CDH2/4/6/17 and SC-TFs. Together with the important role of these SC-TFs in the stem cell regulation, our data provide novel insights into the maintenance of CSCs in TNBC and the discovery of these SC-TFs associated with the alterations of CDH2/4/6/17 has an implication in targeted therapy of TNBC.
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http://dx.doi.org/10.1155/2017/5091541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5368378PMC
March 2017

Progressive visual disturbance and enlarging prolactinoma caused by melanoma metastasis: A case report and literature review.

Medicine (Baltimore) 2017 Apr;96(14):e6483

Department of Neurosurgery of the Second Affiliated Hospital Institute of Cancer Stem Cell Department of Endocrinology of Affiliated Dalian Municipal Central Hospital, Dalian Medical University, Dalian, Liaoning Province Department of Neurosurgery of Yantaishan Hospital, Yantai, Shandong Province, PR China.

Rationale: Melanoma metastases to the pituitary adenoma (MMPA) are extremely rare, with only 1 reported case. To date, the melanoma metastasis to the existing prolactinoma has not been reported in literatures.

Patient Concerns: We report a case of 62-year-old woman presented with progressive visual disturbance and hyperprolactinemia. Magnetic resonance imaging demonstrated the presence of a round sellar mass.

Diagnoses: Melanoma metastasis to the pituitary adenoma.

Interventions: Surgery was performed and intraoperative frozensection examination found melanin granules and histopathological examination confirmed melanoma metastasis to the pituitary adenoma.

Outcomes: After surgery, the patient developed widespread melanoma metastasis to lower limbs. Twenty-two months later, the patient was alive with worse symptoms.

Lessons: We reviewed and analyzed the clinical data, imaging features, and treatment methods of other reported cases of metastases to pituitary adenoma (MPA). This study provides clinical information for the diagnosis and management of MMPA.
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http://dx.doi.org/10.1097/MD.0000000000006483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411197PMC
April 2017

Exploring the key genes and signaling transduction pathways related to the survival time of glioblastoma multiforme patients by a novel survival analysis model.

BMC Genomics 2017 01 25;18(Suppl 1):950. Epub 2017 Jan 25.

College of Computer and Information Science, Southwest University, Chongqing, 400715, People's Republic of China.

Background: This study is to explore the key genes and signaling transduction pathways related to the survival time of glioblastoma multiforme (GBM) patients.

Results: Our results not only showed that mutually explored GBM survival time related genes and signaling transduction pathways are closely related to the GBM, but also demonstrated that our innovated constrained optimization algorithm (CoxSisLasso strategy) are better than the classical methods (CoxLasso and CoxSis strategy).

Conclusion: We analyzed why the CoxSisLasso strategy can outperform the existing classical methods and discuss how to extend this research in the distant future.
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http://dx.doi.org/10.1186/s12864-016-3256-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310279PMC
January 2017

Molecular Mutations and Their Cooccurrences in Cytogenetically Normal Acute Myeloid Leukemia.

Stem Cells Int 2017 19;2017:6962379. Epub 2017 Jan 19.

Hematologic Malignancies and Stem Cell Transplant, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08903, USA.

Adult acute myeloid leukemia (AML) clinically is a disparate disease that requires intensive treatments ranging from chemotherapy alone to allogeneic hematopoietic cell transplantation (allo-HCT). Historically, cytogenetic analysis has been a useful prognostic tool to classify patients into favorable, intermediate, and unfavorable prognostic risk groups. However, the intermediate-risk group, consisting predominantly of cytogenetically normal AML (CN-AML), itself exhibits diverse clinical outcomes and requires further characterization to allow for more optimal treatment decision-making. The recent advances in clinical genomics have led to the recategorization of CN-AML into favorable or unfavorable subgroups. The relapsing nature of AML is thought to be due to clonal heterogeneity that includes founder or driver mutations present in the leukemic stem cell population. In this article, we summarize the clinical outcomes of relevant molecular mutations and their cooccurrences in CN-AML, including , , , , , , , , , , , , , and , with an emphasis on their relevance to the leukemic stem cell compartment. We have reviewed the available literature and TCGA AML databases (2013) to highlight the potential role of stem cell regulating factor mutations on outcome within newly defined AML molecular subgroups.
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http://dx.doi.org/10.1155/2017/6962379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288537PMC
January 2017

Shade-induced stem elongation in rice seedlings: Implication of tissue-specific phytohormone regulation.

J Integr Plant Biol 2016 Jul 7;58(7):614-7. Epub 2016 Apr 7.

State Key Laboratory of Genetic Engineering, Institute of Plant Biology, School of Life Sciences, Fudan University, Shanghai 200433, China.

A better understanding of shade avoidance syndrome (SAS) is an urgent need because of its effect on energy reallocation. Leverage-related mechanism in crops is of potential economic interest for agricultural applications. Here we report the SAS phenotype at tissue level rice seedlings. Tissue-specific RNA-sequencing indicates auxin plays different roles between coleoptile and the first leaf. Phenotypes of wild type treated by gibberellin and brassinosteroid biosynthesis inhibitors and of related mutants suggest these two hormones positively regulate SAS. Our work reveals the diversity of hormone responses in different organs and different species in shade conditions.
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http://dx.doi.org/10.1111/jipb.12468DOI Listing
July 2016

Oculomotor Paralysis, Postorbital Pain, and Hypopituitarism as First Presentations of Metastatic Gastric Cancer in the Pituitary Flourished by Internal Carotid Aneurysm: A Case Report.

Medicine (Baltimore) 2015 Dec;94(50):e2317

From the Department of Neurosurgery of the Second Affiliated Hospital of Dalian Medical University (CY, HZ, SZ, BM, JL, XS, BZ); and Institute of Cancer Stem Cell (LL), Dalian Medical University, Dalian, PR China.

Metastatic gastric cancer in the pituitary (MGCP) is rare. Few are known on the clinical and radiological characteristics of MGCP. To date, the coexistence of metastatic pituitary tumors and intracranial aneurysms has not been reported in literatures. We present a case of MGCP with internal carotid aneurysm in a 57-year-old woman, who presented with oculomotor paralysis, postorbital pain, and hypopituitarism as onset symptoms. The patient had a history of the surgical removal of gastric cancer. Magnetic resonance imaging and single-photon emission computed tomography revealed a recurrent sellar mass with intracranial and multiple bone metastases. The patient underwent subtotal removal of the tumor, followed by conformal radiotherapy and chemotherapy. Ten months after surgery, the patient died due to deterioration of her overall condition. We also reviewed and analyzed the clinical data, imaging features, and treatment methods of additional 4 cases with MGCP, which were reported in literatures. This study provides important clinical information for the diagnosis and treatment of MGCP.
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http://dx.doi.org/10.1097/MD.0000000000002317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058944PMC
December 2015

Homeostasis of redox status derived from glucose metabolic pathway could be the key to understanding the Warburg effect.

Am J Cancer Res 2015 15;5(4):1265-80. Epub 2015 Mar 15.

Department of Systems Biology, The University of Texas MD Anderson Cancer Center Houston, TX, 77030, USA.

Glucose metabolism in mitochondria through oxidative phosphorylation (OXPHOS) for generation of adenosine triphosphate (ATP) is vital for cell function. However, reactive oxygen species (ROS), a by-product from OXPHOS, is a major source of endogenously produced toxic stressors on the genome. In fact, ATP could be efficiently produced in a high throughput manner without ROS generation in cytosol through glycolysis, which could be a unique and critical metabolic pathway to prevent spontaneous mutation during DNA replication. Therefore glycolysis is dominant in robust proliferating cells. Indeed, aerobic glycolysis, or the Warburg effect, in normal proliferating cells is an example of homeostasis of redox status by transiently shifting metabolic flux from OXPHOS to glycolysis to avoid ROS generation during DNA synthesis and protect genome integrity. The process of maintaining redox homeostasis is driven by genome wide transcriptional clustering with mitochondrial retrograde signaling and coupled with the glucose metabolic pathway and cell division cycle. On the contrary, the Warburg effect in cancer cells is the results of the alteration of redox status from a reprogramed glucose metabolic pathway caused by the dysfunctional OXPHOS. Mutations in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) disrupt mitochondrial structural integrity, leading to reduced OXPHOS capacity, sustained glycolysis and excessive ROS leak, all of which are responsible for tumor initiation, progression and metastasis. A "plumbing model" is used to illustrate how redox status could be regulated through glucose metabolic pathway and provide a new insight into the understanding of the Warburg effect in both normal and cancer cells.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4473309PMC
June 2015

Homeostasis of redox status derived from glucose metabolic pathway could be the key to understanding the Warburg effect.

Am J Cancer Res 2015 15;5(3):928-44. Epub 2015 Feb 15.

Department of Systems Biology, The University of Texas MD Anderson Cancer Center Houston, TX, 77030, USA.

Glucose metabolism in mitochondria through oxidative phosphorylation (OXPHOS) for generation of adenosine triphosphate (ATP) is vital for cell function. However, reactive oxygen species (ROS), a by-product from OXPHOS, is a major source of endogenously produced toxic stressors on the genome. In fact, ATP could be efficiently produced in a high throughput manner without ROS generation in cytosol through glycolysis, which could be a unique and critical metabolic pathway to prevent spontaneous mutation during DNA replication. Therefore glycolysis is dominant in robust proliferating cells. Indeed, aerobic glycolysis, or the Warburg effect, in normal proliferating cells is an example of homeostasis of redox status by transiently shifting metabolic flux from OXPHOS to glycolysis to avoid ROS generation during DNA synthesis and protect genome integrity. The process of maintaining redox homeostasis is driven by genome wide transcriptional clustering with mitochondrial retrograde signaling and coupled with the glucose metabolic pathway and cell division cycle. On the contrary, the Warburg effect in cancer cells is the results of the alteration of redox status from a reprogramed glucose metabolic pathway caused by the dysfunctional OXPHOS. Mutations in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) disrupt mitochondrial structural integrity, leading to reduced OXPHOS capacity, sustained glycolysis and excessive ROS leak, all of which are responsible for tumor initiation, progression and metastasis. A "plumbing model" is used to illustrate how redox status could be regulated through glucose metabolic pathway and provide a new insight into the understanding of the Warburg effect in both normal and cancer cells.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449427PMC
June 2015

A BRCA1 deficient-like signature is enriched in breast cancer brain metastases and predicts DNA damage-induced poly (ADP-ribose) polymerase inhibitor sensitivity.

Breast Cancer Res 2014 Mar 14;16(2):R25. Epub 2014 Mar 14.

Introduction: There is an unmet clinical need for biomarkers to identify breast cancer patients at an increased risk of developing brain metastases. The objective is to identify gene signatures and biological pathways associated with human epidermal growth factor receptor 2-positive (HER2+) brain metastasis.

Methods: We combined laser capture microdissection and gene expression microarrays to analyze malignant epithelium from HER2+ breast cancer brain metastases with that from HER2+ nonmetastatic primary tumors. Differential gene expression was performed including gene set enrichment analysis (GSEA) using publicly available breast cancer gene expression data sets.

Results: In a cohort of HER2+ breast cancer brain metastases, we identified a gene expression signature that anti-correlates with overexpression of BRCA1. Sequence analysis of the HER2+ brain metastases revealed no pathogenic mutations of BRCA1, and therefore the aforementioned signature was designated BRCA1 Deficient-Like (BD-L). Evaluation of an independent cohort of breast cancer metastases demonstrated that BD-L values are significantly higher in brain metastases as compared to other metastatic sites. Although the BD-L signature is present in all subtypes of breast cancer, it is significantly higher in BRCA1 mutant primary tumors as compared with sporadic breast tumors. Additionally, BD-L signature values are significantly higher in HER2-/ER- primary tumors as compared with HER2+/ER + and HER2-/ER + tumors. The BD-L signature correlates with breast cancer cell line pharmacologic response to a combination of poly (ADP-ribose) polymerase (PARP) inhibitor and temozolomide, and the signature outperformed four published gene signatures of BRCA1/2 deficiency.

Conclusions: A BD-L signature is enriched in HER2+ breast cancer brain metastases without pathogenic BRCA1 mutations. Unexpectedly, elevated BD-L values are found in a subset of primary tumors across all breast cancer subtypes. Evaluation of pharmacological sensitivity in breast cancer cell lines representing all breast cancer subtypes suggests the BD-L signature may serve as a biomarker to identify sporadic breast cancer patients who might benefit from a therapeutic combination of PARP inhibitor and temozolomide and may be indicative of a dysfunctional BRCA1-associated pathway.
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http://dx.doi.org/10.1186/bcr3625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053087PMC
March 2014

Embryology of Early Jurassic dinosaur from China with evidence of preserved organic remains.

Nature 2013 Apr;496(7444):210-4

Department of Biology, University of Toronto Mississauga, Mississauga, Ontario L5L 1C6, Canada.

Fossil dinosaur embryos are surprisingly rare, being almost entirely restricted to Upper Cretaceous strata that record the late stages of non-avian dinosaur evolution. Notable exceptions are the oldest known embryos from the Early Jurassic South African sauropodomorph Massospondylus and Late Jurassic embryos of a theropod from Portugal. The fact that dinosaur embryos are rare and typically enclosed in eggshells limits their availability for tissue and cellular level investigations of development. Consequently, little is known about growth patterns in dinosaur embryos, even though post-hatching ontogeny has been studied in several taxa. Here we report the discovery of an embryonic dinosaur bone bed from the Lower Jurassic of China, the oldest such occurrence in the fossil record. The embryos are similar in geological age to those of Massospondylus and are also assignable to a sauropodomorph dinosaur, probably Lufengosaurus. The preservation of numerous disarticulated skeletal elements and eggshells in this monotaxic bone bed, representing different stages of incubation and therefore derived from different nests, provides opportunities for new investigations of dinosaur embryology in a clade noted for gigantism. For example, comparisons among embryonic femora of different sizes and developmental stages reveal a consistently rapid rate of growth throughout development, possibly indicating that short incubation times were characteristic of sauropodomorphs. In addition, asymmetric radial growth of the femoral shaft and rapid expansion of the fourth trochanter suggest that embryonic muscle activation played an important role in the pre-hatching ontogeny of these dinosaurs. This discovery also provides the oldest evidence of in situ preservation of complex organic remains in a terrestrial vertebrate.
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http://dx.doi.org/10.1038/nature11978DOI Listing
April 2013
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