Long noncoding RNAs (lncRNA) play important roles in the tumorigenesis and progression of cancers. However, the clinical significance of lncRNAs and their regulatory mechanisms in nasopharyngeal ...carcinogenesis (NPC) are largely unknown. Here, based on a microarray analysis, we identified 384 dysregulated lncRNAs, of which,
was one of the most upregulated lncRNAs in NPC.
significantly associated with poor survival in NPC. N(6)-Methyladenosine (m6A) was highly enriched within
and enhanced its RNA stability.
functioned as an oncogenic lncRNA that promoted NPC cell proliferation, migration, invasion, tumor growth, and metastasis. Mechanistically,
functioned as a competing endogenous RNA (ceRNA) for sponging miR-590-3p and miR-1275, leading to the upregulation of their target
(
), and the activation of FAK/PI3K/Akt signaling to promote NPC cell proliferation and invasion. In summary, our study reveals a potential ceRNA regulatory pathway in which
modulates
expression by binding to miR-590-3p and miR-1275, ultimately promoting tumorigenesis and metastasis in NPC. SIGNIFICANCE: These findings demonstrate the clinical significance of the lncRNA
in nasopharyngeal carcinoma (NPC) and the regulatory mechanism involved in NPC development and progression, providing a novel prognostic indicator and promising therapeutic target.
Summary The prognostic and predictive implications of programmed death-ligand 1 (PD-L1) is unknown in sarcoma. We sought to examine the immune milieu in sarcoma specimens. We evaluated PD-L1 ...expression by immunohistochemistry in sarcoma specimens and quantified tumor-infiltrating lymphocytes (TIL). We correlated expression with clinical parameters and outcomes. Fifty sarcoma patients treated at Memorial Sloan Kettering Cancer Center were selected. Using the DAKO PD-L1 immunohistochemistry assay and archival formalin-fixed paraffin-embedded tissue specimens; PD-L1 expression was examined. Macrophage and lymphocyte PD-L1 status was determined qualitatively. TIL was quantified. Associations between PD-L1 expression in tumor, macrophages and lymphocytes, TIL and clinical-pathological characteristics were performed. The median age was 46 years (range, 22-76), and 66% of patients were men. Tumor, lymphocyte and macrophage PD-L1 expression was noted in 12%, 30% and 58%, respectively, with the highest prevalence in gastrointestinal stromal tumors (29%). Lymphocyte and macrophage infiltration was present in 98% and 90%, respectively. There was no association between clinical features, overall survival and PD-L1 expression in tumor or immune infiltrates. Lymphocyte and macrophage infiltration is common in sarcoma, but PD-L1 tumor expression is uncommon in sarcoma with the highest frequency observed in gastrointestinal stromal tumors. There was no association between PD-L1 expression, TIL and clinicopathological features and overall survival; however, this is limited by the heterogenous patient sample and minimal death events in the studied cohort.
OBJECTIVE:To determine the prognostic significance of histologic type/subtype in a large series of patients with primary resected retroperitoneal sarcoma.
BACKGROUND:The histologic diversity and ...rarity of retroperitoneal sarcoma has hampered the ability to predict patient outcome.
METHODS:From a single-institution, prospective database, 675 patients treated surgically for primary, nonmetastatic retroperitoneal sarcoma during 1982 to 2010 were identified and histologic type/subtype was reviewed. Clinicopathologic variables were analyzed for association with disease-specific death (DSD), local recurrence (LR), and distant recurrence (DR).
RESULTS:Median follow-up for survivors was 7.5 years. The predominant histologies were well-differentiated liposarcoma, dedifferentiated liposarcoma, and leiomyosarcoma. Five-year cumulative incidence of DSD was 31%, and factors independently associated with DSD were R2 resection, resection of 3 or more contiguous organs, and histologic type. Five-year cumulative incidence for LR was 39% and for DR was 24%. R1 resection, age, tumor size, and histologic type were independently associated with LR; size, resection of 3 or more organs, and histologic type were independently associated with DR. Liposarcoma and leiomyosarcoma were associated with late recurrence and DSD (as long as 15 years from diagnosis). For solitary fibrous tumor, LR was uncommon (<10%), but early distant recurrence was common (36% at 5 years). Nomograms were developed to predict DSD, LR, and DR.
CONCLUSIONS:Histologic type/subtype is the most important independent predictor of DSD, LR, and DR in primary retroperitoneal sarcoma. Histology predicts the pattern and incidence of LR and DR and will aid in more accurate patient counseling and selection of patients for adjuvant therapy trials.
Malignant peripheral nerve sheath tumors (MPNSTs) represent a group of highly aggressive soft-tissue sarcomas that may occur sporadically, in association with neurofibromatosis type I (NF1 ...associated) or after radiotherapy. Using comprehensive genomic approaches, we identified loss-of-function somatic alterations of the Polycomb repressive complex 2 (PRC2) components (EED or SUZ12) in 92% of sporadic, 70% of NF1-associated and 90% of radiotherapy-associated MPNSTs. MPNSTs with PRC2 loss showed complete loss of trimethylation at lysine 27 of histone H3 (H3K27me3) and aberrant transcriptional activation of multiple PRC2-repressed homeobox master regulators and their regulated developmental pathways. Introduction of the lost PRC2 component in a PRC2-deficient MPNST cell line restored H3K27me3 levels and decreased cell growth. Additionally, we identified frequent somatic alterations of CDKN2A (81% of all MPNSTs) and NF1 (72% of non-NF1-associated MPNSTs), both of which significantly co-occur with PRC2 alterations. The highly recurrent and specific inactivation of PRC2 components, NF1 and CDKN2A highlights their critical and potentially cooperative roles in MPNST pathogenesis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
MicroRNA arrays possess a number of unique data features that challenge the assumption key to many normalization methods. We assessed the performance of existing normalization methods using two ...microRNA array datasets derived from the same set of tumor samples: one dataset was generated using a blocked randomization design when assigning arrays to samples and hence was free of confounding array effects; the second dataset was generated without blocking or randomization and exhibited array effects. The randomized dataset was assessed for differential expression between two tumor groups and treated as the benchmark. The non-randomized dataset was assessed for differential expression after normalization and compared against the benchmark. Normalization improved the true positive rate significantly in the non-randomized data but still possessed a false discovery rate as high as 50%. Adding a batch adjustment step before normalization further reduced the number of false positive markers while maintaining a similar number of true positive markers, which resulted in a false discovery rate of 32% to 48%, depending on the specific normalization method. We concluded the paper with some insights on possible causes of false discoveries to shed light on how to improve normalization for microRNA arrays.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
CDK4 is amplified in > 90% of well-differentiated (WDLS) and dedifferentiated liposarcomas (DDLS). The selective cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor PD0332991 inhibits growth and induces ...senescence in cell lines and xenografts. In a phase I trial of PD0332991, several patients with WDLS or DDLS experienced prolonged stable disease. We performed an open-label phase II study to determine the safety and efficacy of PD0332991 in patients with advanced WDLS/DDLS.
Patients age ≥ 18 years experiencing disease progression while receiving systemic therapy before enrollment received PD0332991 200 mg orally once per day for 14 consecutive days in 21-day cycles. All were required to have CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein (RB) expression by immunohistochemistry (≥ 1+). The primary end point was progression-free survival (PFS) at 12 weeks, with 12-week PFS of ≥ 40% considered promising and ≤ 20% not promising. If ≥ nine of 28 patients were progression free at 12 weeks, PD0332991 would be considered active.
We screened 48 patients (44 of 48 had CDK4 amplification; 41 of 44 were RB positive). Of those, 30 were enrolled, and 29 were evaluable for the primary end point. Grade 3 to 4 events included anemia (17%), thrombocytopenia (30%), neutropenia (50%), and febrile neutropenia (3%). At 12 weeks, PFS was 66% (90% CI, 51% to 100%), significantly exceeding the primary end point. The median PFS was 18 weeks. There was one partial response.
Treatment with the CDK4 inhibitor PD0332991 was associated with a favorable progression-free rate in patients with CDK4-amplified and RB-expressing WDLS/DDLS who had progressive disease despite systemic therapy.
One pivotal feature of transcriptomics data is the unwanted variations caused by disparate experimental handling, known as handling effects. Various data normalization methods were developed to ...alleviate the adverse impact of handling effects in the setting of differential expression analysis. However, little research has been done to evaluate their performance in the setting of survival outcome prediction, an important analysis goal for transcriptomics data in biomedical research. Leveraging a unique pair of datasets for the same set of tumor samples-one with handling effects and the other without, we developed a benchmarking tool for conducting such an evaluation in microRNA microarrays. We applied this tool to evaluate the performance of three popular normalization methods-quantile normalization, median normalization and variance stabilizing normalization-in survival prediction using various approaches for model building and designs for sample assignment. We showed that handling effects can have a strong impact on survival prediction and that quantile normalization, a most popular method in current practice, tends to underperform median normalization and variance stabilizing normalization. We demonstrated with a small example the reason for quantile normalization's poor performance in this setting. Our finding highlights the importance of putting normalization evaluation in the context of the downstream analysis setting and the potential of improving the development of survival predictors by applying median normalization. We make available our benchmarking tool for performing such evaluation on additional normalization methods in connection with prediction modeling approaches.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We design and integrate four optical phased arrays (OPAs) in a single chip. Each OPA possesses different output grating period. Furthermore, we use optical switches to select one or more OPAs for ...beam scanning. We demonstrate the longitudinal scanning by tuning the laser wavelength. The experimental results show that the scanning range of the four-lines chip reaches 28.54° when the wavelength ranges from 1520 nm to 1570 nm, and the eight-lines one reaches 19.04° with wavelength range of 1520 nm-1540 nm. We greatly improve the wavelength tuning efficiency for longitudinal scanning.
CDK4/6 inhibitors are being used to treat a variety of human malignancies. In well-differentiated and dedifferentiated liposarcoma their clinical promise is associated with their ability to ...downregulate the MDM2 protein. The downregulation of MDM2 following treatment with CDK4/6 inhibitors also induces many cultured tumor cell lines derived from different types of malignancies to progress from quiescence into senescence. Here we used cultured human cell lines and defined a role for PDLIM7 and CDH18, regulating MDM2 protein in CDK4/6 inhibitor-treated cells. Materials from our previous phase II trials with palbociclib were then used to demonstrate that expression of CDH18 protein was associated with response, measured as both progression-free survival and overall survival. This supports the hypothesis that the biologic transition from quiescence to senescence has clinical relevance for this class of drugs.
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