- Extent of Lymphadenectomy and Postoperative Major Complications Among Women with Endometrial Cancer Treated with Minimally Invasive Surgery. [Journal Article]
- AJAm J Obstet Gynecol 2018 Dec 03
- CONCLUSIONS: Sentinel lymphadenectomy among patients undergoing total laparoscopic hysterectomy for endometrial cancer was associated with a decreased incidence of major postoperative complication and need for readmission when compared with traditional lymphadenectomy.
- Exfoliative cytology for diagnosing basal cell carcinoma and other skin cancers in adults. [Review]
- CDCochrane Database Syst Rev 2018 Dec 03; 12:CD013187
- CONCLUSIONS: The utility of exfoliative cytology for the primary diagnosis of skin cancer is unknown, as all included studies focused on the use of this technique for confirming strongly suspected clinical diagnoses. For the confirmation of BCC in lesions with a high clinical suspicion, there is evidence of high sensitivity and specificity. Since decisions to treat low-risk BCCs are unlikely in practice to require diagnostic confirmation given that clinical suspicion is already high, exfoliative cytology might be most useful for cases of BCC where the treatments being contemplated require a tissue diagnosis (e.g. radiotherapy). The small number of included studies, poor reporting and varying methodological quality prevent us from drawing strong conclusions to guide clinical practice. Despite insufficient data on the use of cytology for cSCC or melanoma, it is unlikely that cytology would be useful in these scenarios since preservation of the architecture of the whole lesion that would be available from a biopsy provides crucial diagnostic information. Given the paucity of good quality data, appropriately designed prospective comparative studies may be required to evaluate both the diagnostic value of exfoliative cytology by comparison to dermoscopy, and its confirmatory value in adequately reported populations with a high probability of BCC scheduled for further treatment requiring a tissue diagnosis.
- Cryopreservation of primary B cells minimally influences their signaling responses. [Journal Article]
- SRSci Rep 2018 Dec 05; 8(1):17651
- Phospho flow is a powerful approach to detect cell signaling aberrations, identify biomarkers and assess pharmacodynamics, and can be performed using cryopreserved samples. The effects of cryopreserv...
Phospho flow is a powerful approach to detect cell signaling aberrations, identify biomarkers and assess pharmacodynamics, and can be performed using cryopreserved samples. The effects of cryopreservation on signaling responses and the reproducibility of phospho flow measurements are however unknown in many cell systems. Here, B lymphocytes were isolated from healthy donors and patients with the B cell malignancy chronic lymphocytic leukemia and analyzed by phospho flow using phospho-specific antibodies targeting 20 different protein epitopes. Cells were analyzed both at basal conditions and after activation of cluster of differentiation 40 (CD40) or the B cell receptor. Pharmacodynamics of the novel pathway inhibitor ibrutinib was also assessed. At all conditions, fresh cells were compared to cryopreserved cells. Minimal variation between fresh and frozen samples was detected. Reproducibility was tested by running samples from the same donors in different experiments. The results demonstrate reproducibility across different phospho flow runs and support the use of cryopreserved samples in future phospho flow studies of B lymphocytes.
- Asymmetric dimethylation at histone H3 arginine 2 by PRMT6 in gastric cancer progression. [Journal Article]
- CCarcinogenesis 2018 Dec 03
- Histone modification plays important molecular roles in development and progression of cancers. Dysregulation of histone H3 arginine (R) methylation is still unknown in primary cancer, including gast...
Histone modification plays important molecular roles in development and progression of cancers. Dysregulation of histone H3 arginine (R) methylation is still unknown in primary cancer, including gastric cancer (GC). Although PRMT6 contributes to asymmetric dimethylation at H3R2 (H3R2me2as) in cancer cells, its molecular functions are poorly understood in GC. In this study, we assessed H3R2me2as and PRMT6 expression levels in 133 primary GC tissues by immunohistochemistry. Increased H3R2me2as was found in 68 GC (51.1%) cases and independently related to poor prognosis. PRMT6 was overexpressed in 70 GC (52.6%) and strongly correlated with the global H3R2me2as levels (P < 0.001). By analyzing biological functions of PRMT6 in GC cell lines by lentivirus-based systems, PRMT6 overexpression enhanced global H3R2me2as and invasiveness in vitro, while PRMT6 knockout (PRMT6-KO) suppressed these effects and tumorigenicity in vivo. ChIP and microarray assays demonstrated that PRMT6-KO GC cells decreased the enrichments of H3R2me2as at the promoter regions of PCDH7, SCD and IGFBP5, resulting in upregulation of their gene expression. PRMT6 was recruited to the promoter regions of PCDH7 and SCD in the PRMT6-overexpressed cells. Knockdown of tumor suppressor PCDH7 in the PRMT6-KO GC cells elevated cell migration and invasion. PRMT6 expression inversely correlated with PCDH7 expression in primary GC (P = 0.021). Collectively, our findings strongly indicate that H3R2me2as is a strong prognostic indicator of GC patients, and PRMT6-overexpressing GC cells may acquire invasiveness through direct transcriptional inhibition of PCDH7 by increasing H3R2me2as level. Thus, inhibition of the PRMT6-H3R2me2as pathway could be a promising new therapeutic strategy in GC.
- BST-2 promotes survival in circulation and pulmonary metastatic seeding of breast cancer cells. [Journal Article]
- SRSci Rep 2018 Dec 04; 8(1):17608
- Bone marrow stromal antigen 2 (BST-2) mediates various facets of cancer progression and metastasis. Here, we show that BST-2 is linked to poor survival in invasive breast cancer patients as its expre...
Bone marrow stromal antigen 2 (BST-2) mediates various facets of cancer progression and metastasis. Here, we show that BST-2 is linked to poor survival in invasive breast cancer patients as its expression positively correlates with disease severity. However, the mechanisms that drive the pro-metastatic functions of BST-2 are not fully understood. Correlation of BST-2 expression and tumor aggressiveness was analyzed in human tissue samples. Migration, invasion, and competitive experimental metastasis assays were used to measure the cellular responses after silencing BST-2 expression. Using a mouse model of breast cancer, we show that BST-2 promotes metastasis independent of the primary tumor. Additional experiments show that suppression of BST-2 renders non-adherent cancer cells non-viable by sensitizing cells to anoikis. Embedment of cancer cells in basement membrane matrix reveals that silencing BTS-2 expression inhibits invadopodia formation, extracellular matrix degradation, and subsequent cell invasion. Competitive experimental pulmonary metastasis shows that silencing BST-2 reduces the numbers of viable circulating tumor cells (CTCs) and decreases the efficiency of lung colonization. Our data define a previously unknown function for BST-2 in the i) formation of invadopodia, ii) degradation of extracellular matrix, and iii) protection of CTCs from hemodynamic stress. We believe that physical (tractional forces) and biochemical (ECM type/composition) cues may control BST-2's role in cell survival and invadopodia formation. Collectively, our findings highlight BST-2 as a key factor that allows cancer cells to invade, survive in circulation, and at the metastatic site.
- CML hematopoietic stem cells expressing IL-1RAP can be targeted by chimeric antigen receptor (CAR)-engineered T cells. [Journal Article]
- CRCancer Res 2018 Dec 04
- Chronic myeloid leukemia (CML) is a chronic disease resulting in myeloid cell expansion through expression of the BCR-ABL1 fusion transcript. Tyrosine kinase inhibitors (TKI) have significantly incre...
Chronic myeloid leukemia (CML) is a chronic disease resulting in myeloid cell expansion through expression of the BCR-ABL1 fusion transcript. Tyrosine kinase inhibitors (TKI) have significantly increased survival of CML patients, and deep responders may consider stopping the treatment. However, more than 50% of patients relapse and restart TKI, subsequently suffering unknown toxicity. Because CML is a model immune system-sensitive disease, we hypothesize that chimeric antigen receptor (CAR) T cells targeting interleukin-1 receptor-associated protein (IL-1RAP) in quiescent CML stem cells may offer an opportunity for a permanent cure. In this study, we produced and molecularly characterized a specific monoclonal anti-IL-1RAP antibody from which fragment antigen-binding nucleotide coding sequences were cloned as a single chain into a lentiviral backbone and secured with the suicide gene iCASP9/rimiducid system. Our CAR T cell therapy exhibited cytotoxicity against both leukemic stem cells and, to a lesser extent, monocytes expressing IL-1RAP, with no apparent effect on the hematopoietic system, including CD34+ stem cells. This suggests IL-1RAP as a tumor-associated antigen for immunotherapy cell targeting. IL-1RAP CAR T cells were activated in the presence of IL-1RAP+ cell lines or primary CML cells, resulting in secretion of pro-inflammatory cytokines and specifically killing in vitro and in a xenograft murine model. Overall, we demonstrate the proof of concept of a CAR T-cell immunotherapy approach in the context of CML that is applicable for young patients and primary TKI-resistant, intolerant, or allograft candidate patients.
- Ultraviolet radiation-induced DNA damage is prognostic for outcome in melanoma. [Journal Article]
- NMedNat Med 2018 Dec 03
- The melanoma genome is dominated by ultraviolet radiation (UVR)-induced mutations. Their relevance in disease progression is unknown. Here we classify melanomas by mutation signatures and identify te...
The melanoma genome is dominated by ultraviolet radiation (UVR)-induced mutations. Their relevance in disease progression is unknown. Here we classify melanomas by mutation signatures and identify ten recurrently mutated UVR signature genes that predict patient survival. We validate these findings in primary human melanomas; in mice we show that this signature is imprinted by short-wavelength UVR and that four exposures to UVR are sufficient to accelerate melanomagenesis.
- FBXW7 mutations reduce binding of NOTCH1, leading to cleaved NOTCH1 accumulation and target gene activation in CLL. [Journal Article]
- BloodBlood 2018 Dec 03
- In chronic lymphocytic leukemia (CLL), NOTCH1 is mutated in 10% of CLL patients and is associated with poor outcome. However, NOTCH1 activation is identified in approximately half of CLL cases even i...
In chronic lymphocytic leukemia (CLL), NOTCH1 is mutated in 10% of CLL patients and is associated with poor outcome. However, NOTCH1 activation is identified in approximately half of CLL cases even in the absence of NOTCH1 mutations, hence there appears to be additional factors responsible for the impairment of NOTCH1 degradation. The E3 ubiquitin ligase FBXW7 is a negative regulator of NOTCH1 and is mutated in 2-6% of CLL patients. So far the functional consequences of these mutations are unknown. We found FBXW7 mutations in 36/905 (4%) of untreated CLL patients, of which all mutations were heterozygous. The majority were missense mutations (78%) that mostly affected the WD40 substrate binding domain, whilst 10% of mutations occurred in the first exon of the α-isoform. In aim to identify target proteins of FBXW7 in CLL, we truncated the WD40 domain in the CLL cell line HG-3 via CRISPR/Cas9. Homozygous truncation of FBXW7 resulted in increase of activated NOTCH1-NICD and c-MYC protein levels as well as elevated HIF1-α activity. In silico modeling predicted that novel mutations G423V and W425C in the FBXW7-WD40 domain change the binding of protein substrates while the mutation A503V was predicted not to be impaired. This differential binding was confirmed via co-immunoprecipitation of overexpressed FBXW7 and NOTCH1. In primary cells from CLL patients harboring FBXW7 mutations, activated NOTCH1-NICD levels were increased and remained stable upon inhibition of translation. Furthermore, FBXW7 mutations coincided with an increase in NOTCH1 target gene expression. Hence, FBXW7 mutations in CLL cells explain a proportion of patients characterized by dysregulated NOTCH1 signaling.
- Use of letrozole after aromatase inhibitor-based therapy (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled phase 3 trial. [Journal Article]
- LOLancet Oncol 2018 Nov 30
- CONCLUSIONS: After 5 years of aromatase inhibitor-based therapy, 5 years of letrozole therapy did not significantly prolong disease-free survival compared with placebo. Careful assessment of potential risks and benefits is required before recommending extended letrozole therapy to patients with early-stage breast cancer.
New Search Next
- De novo annotation of the transcriptome of the Northern Wheatear (Oenanthe oenanthe). [Journal Article]
- PPeerJ 2018; 6:e5860
- We have sequenced a partial transcriptome of the Northern Wheatear (Oenanthe oenanthe), a species with one of the longest migrations on Earth. The transcriptome was constructed de novo using RNA-Seq ...
We have sequenced a partial transcriptome of the Northern Wheatear (Oenanthe oenanthe), a species with one of the longest migrations on Earth. The transcriptome was constructed de novo using RNA-Seq sequence data from the pooled mRNA of six different tissues: brain, muscle, intestine, liver, adipose tissue and skin. The samples came from nine captive-bred wheatears collected at three different stages of the endogenous autumn migratory period: (1) lean birds prior the onset of migration, (2) during the fattening stage and (3) individuals at their migratory body mass plateau, when they have almost doubled their lean body mass. The sample structure used to build up the transcriptome of the Northern Wheatears concerning tissue composition and time guarantees the future survey of the regulatory genes involved in the development of the migratory phenotype. Through the pre-migratory period, birds accomplish outstanding physical and behavioural changes that involve all organ systems. Nevertheless, the molecular mechanisms through which birds synchronize and control hyperphagia, fattening, restlessness increase, immunity boosting and tuning the muscles for such endurance flight are still largely unknown. The use of RNA-Seq has emerged as a powerful tool to analyse complex traits on a broad scale, and we believe it can help to characterize the migratory phenotype of wheatears at an unprecedented level. The primary challenge to conduct quantitative transcriptomic studies in non-model species is the availability of a reference transcriptome, which we have constructed and described in this paper. The cDNA was sequenced by pyrosequencing using the Genome Sequencer Roche GS FLX System; with single paired-end reads of about 400 bp. We estimate the total number of genes at 15,640, of which 67% could be annotated using Turkey and Zebra Finch genomes, or protein sequence information from SwissProt and NCBI databases. With our study, we have made a first step towards understanding the migratory phenotype regarding gene expression of a species that has become a model to study birds long-distance migrations.