Oncoscience最新文献

{"title":"Breast-conserving therapy versus mastectomy","authors":"M. V. van Maaren, P. Poortmans, S. Siesling","doi":"10.18632/oncoscience.331","DOIUrl":"https://doi.org/10.18632/oncoscience.331","url":null,"abstract":"There is an ongoing debate regarding the use of randomised controlled trials (RCTs) versus observational studies when investigating treatment effects in clinical practice [1]. This holds especially true for the comparison of breast-conserving therapy (BCT) and mastectomy (MAST), which gained much attention since the publication of our observational study in Lancet Oncology [2]. RCTs are highly appreciated as they are close to generate perfectly unbiased treatment comparison estimates. Treatment groups in a RCT are expected to be exchangeable; even when switching the treatment between the compared groups, results will be similar and are solely the effect of the treatment under study. Clinical decisions are largely based on this type of evidence. But is this always the best evidence? Is it always feasible or ethical? In the current era of personalised medicine and 'big data', clinical interpretation of an abundance of data (clinical reasoning) is becoming more and more crucial. It integrates all available and relevant information that may contribute to the best clinical decision-making for individual patients. This generally starts with existing guidelines, completed by evidence extracted from observational studies and clinicians' experiences [3]. Importantly, the patient's preference plays an important role in (shared) decision-making. In general, it is difficult to translate the overall results of a RCT in the response of an individual patient to the investigated treatment. Even for patients with identical characteristics to those in the trial population, the overall treatment effect observed in RCTs would only apply if the probability of treatment benefit and detriment was equally distributed in every individual participant [3]. Often, evidence forming the basis of treatment guidelines are based on RCTs conducted a long time ago, while observational studies include a more recently diagnosed population. For BCT and MAST, the trials were all conducted in the eighties. Another important discrepancy between the RCT populations and the real-world population is the increasing share of elderly breast cancer patients in the latter. This is not only due to the ageing population, but also to early detection of breast cancer in the national screening program (which upper age limit is 75 years in the Netherlands), leading to a higher incidence in the elderly. Furthermore, diagnostic and surgical procedures as well as local and systemic therapies improved considerably. Moreover, increasing knowledge about the biological features of breast tumours led to the introduction of more advanced tumour-directed therapies. The combination of these improvements are very likely to …","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"58 1","pages":"304 - 305"},"PeriodicalIF":0.0,"publicationDate":"2016-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80225806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting BIP to induce Endoplasmic Reticulum stress and cancer cell death","authors":"Michaël Cerezo, R. Benhida, S. Rocchi","doi":"10.18632/oncoscience.330","DOIUrl":"https://doi.org/10.18632/oncoscience.330","url":null,"abstract":"Melanoma is the most aggressive form of skin cancer. Recently, significant progress has emerged with the development of new strategies in melanoma treatment. We currently have specific BRAF and MAP3K/MEK inhibitors. However, after a short period of remission, melanomas acquire drug resistance and recurrence of metastases is observed in almost all cases [1]. Second, immunotherapies targeted against CTLA4 and PD1, developed to reactivate the antitumor immune response of the patient, result in an objective and long-lasting response in only approximately 30% of patients [2]. Nevertheless, more than 50% of patients are currently in treatment failure. Therefore, identification of new potential targets is an urgent need to improved melanoma treatment. One promising strategy is the targeting of the Unfolded Protein Response pathway which appears as an emerging pathway to selectively target cancer cells. Indeed, neoplasic growth requires synthesis of lot of different proteins and Unfolded Protein Response is activated to deal with the high flux of proteins processed through the Endoplasmic Reticulum to maintained homeostasis [3]. Recently, we have identified a new molecules family, Thiazole Benzensulfonamides (TZB), whose HA15 (1a) molecule appears as the lead compound, that induce an elevated and maintained Endoplasmic Reticulum stress specifically in cancer cells without any adverse events in normal cells [4] (Figure 1). Briefly, HA15 induces death of all melanoma cells independently of their mutational status and melanoma cells freshly isolated from patients both sensitive or resistant to BRAF inhibitors. HA15 exhibited also a strong efficacy in xenograft mouse models performed with melanoma cells sensitive and resistant to BRAF inhibitors without any sign of toxicity. We next performed pan-genomic, proteomic and biochemical studies to decipher the signaling pathway, the mechanism of action and the target of the best candidate. We identified BIP, an endoplasmic reticulum protein, as the specific target of our compound. We demonstrated clearly that the interaction between our compound and BIP increases Endoplasmic Reticulum Stress and leads to melanoma cell death by concomitant induction of autophagy and apoptosis mechanisms. Overexpression of target BIP in various cancers is described, it is thus not surprising that this molecule was also found to be active against other liquid and solid tumors. Taken together, our data suggest HA15 has an important impact on inhibition of melanoma growth by targeting ER stress, and may therefore be developed for treatment of melanoma and other cancers. Based on these strong data, we developed a lead optimization program in which two series of HA15 derivatives were synthesized that provided clear structure activity relationships. We then selected compound 1b as a new optimized analogue of HA15 [5]. This compound was found to be ten-fold more active then the parent compound on various cancer cell lines including melanom","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"69 6 1","pages":"306 - 307"},"PeriodicalIF":0.0,"publicationDate":"2016-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89125811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Eradication of CML stem cells","authors":"B. Carter, M. Andreeff","doi":"10.18632/oncoscience.327","DOIUrl":"https://doi.org/10.18632/oncoscience.327","url":null,"abstract":"Bcr-Abl tyrosine kinase inhibitors (TKIs) have become the standard of care for patients with chronic myeloid leukemia (CML). Indeed, patients experience high response rates and long-term survival with continuous TKI treatment. However, TKIs rarely cure CML due to their inability to target CML stem cells. Consequently, CML will soon become the most prevalent leukemia with 100,000 patients in the U.S. alone. Long-term treatment with TKIs is extremely expensive, associated with side effects, and development of resistance in some patients. Resistance can fuel the progression to blast crisis (BC), which is associated with almost complete chemo-resistance and extremely poor treatment outcome. During the last decade, significant insights into CML stem cell biology and mechanisms of TKI resistance were gained leading to the development of combinatorial strategies to target CML stem/progenitor cells and to overcome TKI resistance [1,2]. We and others have established Bcl-2 family proteins as key apoptosis regulators and specifically anti-apoptotic Bcl-2 proteins as crucial survival factors for myeloid leukemia cells and stem/progenitor cells. Inhibition of anti-apoptotic Bcl-2 proteins with dual Bcl-2/Bcl-xL or pan-Bcl-2 inhibitors was shown to target CML stem/progenitor cells and enhance the therapeutic efficacy of TKIs [3,4]. The tumor suppressor p53 regulates apoptosis primarily by transcriptional activation of pro-apoptotic Bcl-2 family proteins. Although frequently mutated in solid tumors, p53 mutations are rare in CML. We demonstrated that the activation of p53 via inhibition of its negative regulator, MDM2, in combination with TKIs synergistically targeted quiescent CD34 + BC CML cells [5], and Holyoake recently reported that dual targeting of p53 and c-MYC selectively eliminated CML stem cells [6]. To improve specificity and efficacy, and minimize toxicity, it is important to recognize which Bcl-2 proteins are indispensable for CML stem cell survival. Until recently, most Bcl-2 inhibitors were relatively non-specific and targeted several Bcl-2 proteins. Furthermore, our knowledge of the expression of Bcl-2 family members in hematopoietic and CML stem/progenitor cells is essentially limited to RNA, not protein levels, primarily because stem/progenitor cells account for only a very small portion of total bone marrow (BM) cells. CyTOF (\" cytometry by time-of-flight \") combines mass spectrometry and flow cytometry and constitutes a novel single cell proteomics system that can determine the expression of currently over 40 (potentially 120) cell surface and intracellular proteins simultaneously without the spectral overlap, and therefore able to determine the expression of multiple proteins/phosphoproteins in a phenotypically well-defined cell population. Using CyTOF, and an inducible …","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"97 1","pages":"313 - 315"},"PeriodicalIF":0.0,"publicationDate":"2016-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79208122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BET bromodomain inhibitor (JQ1) and tumor angiogenesis","authors":"H. Bid, S. Kerk","doi":"10.18632/oncoscience.326","DOIUrl":"https://doi.org/10.18632/oncoscience.326","url":null,"abstract":"Angiogenesis is one of the most critical multi-step biological essentials affecting the development and progression of cancer. It has been explored for decades as a potential target for therapy after endless preclinical and clinical studies. Currently, conceptually promising FDA-approved agents, such as bevacizumab (Avastin, Genentech/Roche), sorafenib (Nexavar, Bayer), and sunitinib (Sutent, Pfizer), have twisted only modest effects in the clinic and do not result in lasting responses of cancer treatment [1]. Tumors have proven to be either intrinsic resistant or acquired resistance through evasion via mutation or recruitment of surplus pro-angiogenic factors [1]. Molecular targeted therapies comprising anti-antiangiogenic potential are becoming more widely accepted in drug discovery era as compared to established anticancer treatment approaches and have more promising results in numerous types of cancers. JQ1, a bromodomain inhibitor produced by James Bradner, (Tensha Therapeutics acquired by Roche) has direct antitumor and antiangiogenic properties. This small molecule inhibitor targets BRD4, a member of the bromodomain and extra-terminal (BET) family of transcription factors. BRD4 binds to acetylated lysine residues within chromatin, and recruits positive transcription elongation factor (P-TEFb) and other super enhancers involved in transcription. JQ-1 prevents the BRD4-acetylated lysine interaction by competitively binding to BRD4 and inhibiting transcription. In multiple myeloma (MM), a disease frequently associated with dysregulated BET activity, a direct interaction between BRD4 and IgH enhancers located within the MYC locus was observed. JQ1 prohibited this interaction, suppressed MYC transcription, and reduced the levels of downstream effectors. JQ1 treatment induced cell senescence and apoptosis in multiple MM cell lines, and slowed tumor growth and in orthotopic MM mouse models leading to increased survival [2]. The ability of JQ-1 to inhibit MYC transcription has important implications in angiogenesis via blocking VEGF, notch pathway, etc (Figure 1). One study observed that c-Myc knockout mice displayed dysfunctional endothelial cell activity and impaired vascular development in embryonic yolk sacs. Furthermore, the loss of c-Myc reduced the tumorogenicity and differentiation ability of embryonic stem (ES) cells. Reintroducing VEGF reversed the effects of c-Myc knockout. C-Myc also increased the expression of other pro-angiogenic factors such as angiopoietin-2 (ANG-2) and down-regulated anti-angiogenic factors like ANG-1 and thrombospondin-1 (TSP-1) [3]. Indeed, in a study with a transgenic mouse model of Myc oncogenesis, overexpressing Myc in pancreatic β cells quickly increased the expression of the inflammatory cytokine IL-1β, activating matrix metalloproteases (MMP) that in turn released VEGF-A sequestered in the extracellular matrix (ECM). VEGF-A localized to its …","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"3 1","pages":"316 - 317"},"PeriodicalIF":0.0,"publicationDate":"2016-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87776969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutation hotspots in cis-regulatory regions in cancer","authors":"R. C. Poulos, J. W. Wong","doi":"10.18632/oncoscience.325","DOIUrl":"https://doi.org/10.18632/oncoscience.325","url":null,"abstract":"In recent years, somatic mutations in cis-regulatory elements of cancer genomes have become a focus of much research. A landmark discovery occurred in 2013, in which recurrent somatic mutations were identified in the promoter of the key cancer-associated gene, TERT (reviewed in [1]). In the search for other highly recurrent cis-regulatory mutations which may serve as novel driver events, two papers, published in 2014 [2, 3], revealed somewhat surprising results. These studies investigated large cohorts of cancer genomes and found that, despite identifying many recurrent promoter mutations, few could be associated with gene expression changes. Of those that did alter gene expression, many of their target genes did not have strong links to cancer development. We also published similar unexpected findings in a genomewide survey of promoter mutations in the melanoma cellline, COLO829 [4]. The study showed that while some regulatory mutations can alter promoter activity (~17% of mutant promoter regions surveyed), one such mutation that was recurrent (~4.4%) in other melanomas was not associated with altered gene expression in actual cancer samples [4]. Remarkably, we additionally observed that of the 14 remaining promoter mutations surveyed to not alter promoter activity, five mutations were also recurrent in melanoma samples. Together these articles raised the question of why there are such high rates of recurrence among promoter mutations if many do not appear to arise due to their oncogenic ability to alter gene expression.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"4 1","pages":"318 - 319"},"PeriodicalIF":0.0,"publicationDate":"2016-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83056216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic biomarkers for PD-1/PD-L1 blockade therapy","authors":"K. Kataoka, S. Ogawa","doi":"10.18632/oncoscience.328","DOIUrl":"https://doi.org/10.18632/oncoscience.328","url":null,"abstract":"Immune checkpoint blockade therapy using antibodies against programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) is revolutionizing cancer treatment (1-3). These antibodies provide long-term durable responses for patients with various types of advanced cancers, such as melanoma, non–small-cell lung cancer, kidney cancer, and Hodgkin lymphoma (1-3). Accumulating evidence suggests that these agents convey their therapeutic effects through targeting the PD-1/PD-L1 immune checkpoint to unleash anti-tumor immune responses. In turn, it is supposed that cancer cells depend critically on evading immune surveillance for their malignant growth. As immune checkpoint blockade therapy has benefited only a subset of patients, defining biomarkers that can predict therapeutic efficacy and adverse effects is of urgent importance, which is substantiated by recent approvals for PD-L1 diagnostic tests (2). Here we provide a brief overview of the recent development of genetic biomarkers for PD-1/PD-L1 blockade therapies, with special focus on PD-L1 genetic abnormalities, including its 3′-UTR disruption. Early studies demonstrated the potential value of immunological biomarkers, such as intratumoral lymphoid infiltrates and PD-L1 expression on tumor or infiltrating immune cells, for predicting response to PD-1/PD-L1 blockade (1, 2). However, subsequent studies have revealed a lower but significant response rate in patients with PD-L1-tumors, raising questions about the utility of these immunological markers as an ideal selection criterion for PD-1/PD-L1 blockade therapy (2). Indeed, estimated from the results across 15 studies including various solid cancer types, the overall response rate to PD-1/PD-L1 blockade was 48% in patients with PD-L1 + tumors, in contrast to 15% in those with PD-L1-tumors. In addition, especially in clinical setting, accurate measurement and scoring of PD-L1 protein expression are hampered by a variety of technical and biological pitfalls (2). Genomics-based approaches have the potential to complement immunological biomarkers. In particular, Rizvi et al. demonstrated that a higher load of nonsynonymous mutations and neoantigens detected by whole-exome sequencing positively correlated with clinical response to an anti-PD-1 antibody (pembrolizumab) in non-small cell lung cancer (NSCLC) patients. Moreover, candidate neoantigens were experimentally validated using a high-throughput multimer screening to identify neoantigen-specific T cells. In one responder, neoantigen-specific T-cell reactivity paralleled tumor regression (4). In addition to neoantigen load, the extent of neoantigen intratumoral heterogeneity (ITH) within single tumors affects the sensitivity to immune modulation. An integrated analysis of ITH and neoantigen burden showed that the response to PD-1 blockade in patients with NSCLC was enhanced in tumors enriched for clonal neoantigens, i.e., those shared …","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"1987 1","pages":"311 - 312"},"PeriodicalIF":0.0,"publicationDate":"2016-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82275313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of the SWI/SNF ATPase subunits BRM and BRG1 drives lung cancer development","authors":"Stefanie B. Marquez-Vilendrer, S. Rai, Sarah J B Gramling, Li Lu, D. Reisman","doi":"10.18632/oncoscience.323","DOIUrl":"https://doi.org/10.18632/oncoscience.323","url":null,"abstract":"Inactivation of Brg1 and Brm accelerated lung tumor development, shortened tumor latency, and caused a loss of differentiation. Tumors with Brg1 and/or Brm loss recapitulated the evolution of human lung cancer as observed by the development of local tumor invasion as well as distal tumor metastasis, thereby making this model useful in lung cancer studies. Brg1 loss contributed to metastasis in part by driving E-cadherin loss and Vimentin up-regulation. By changing more than 6% of the murine genome with the down-regulation of tumor suppressors, DNA repair, differentiation and cell adhesion genes, and the concomitant up-regulation of oncogenes, angiogenesis, metastasis and antiapoptosis genes, caused by the dual loss of Brg1/Brm further accelerated tumor development. Additionally, this Brg1/Brm-driven change in gene expression resulted in a nearly two-fold increase in tumorigenicity in Brg1/Brm knockout mice compared with wild type mice. Most importantly, Brg1/Brm-driven lung cancer development histologically and clinically reflects human lung cancer development thereby making this GEMM model potentially useful.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"52 1","pages":"322 - 336"},"PeriodicalIF":0.0,"publicationDate":"2016-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75892238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bevacizumab in HER2-negative inflammatory breast cancer","authors":"F. Bertucci, A. Gonçalves, P. Viens","doi":"10.18632/oncoscience.324","DOIUrl":"https://doi.org/10.18632/oncoscience.324","url":null,"abstract":"Inflammatory breast cancer (IBC) is a rare (~5%) but aggressive form of breast cancer with high metastatic potential [1]. Despite the successful introduction of neoadjuvant anthracycline/taxane-based chemotherapy, combined with neoadjuvant/adjuvant trastuzumab in case of HER2-positivity and adjuvant hormone therapy in case of hormone receptor (HR)-positivity, the 5-year survival ranges from 50 to 60% as compared to more than 85% in non-IBC. Besides its aggressiveness and frequent resistance to treatment, IBC displays other characteristics that make progresses difficult. The disease is rare and the diagnosis challenging, based on clinical signs including rapid (no more than 6 months) onset of breast erythema and oedema, with or without underlying palpable mass. Such features exclude IBC from mass screening, lead to frequent misdiagnosis and delayed diagnosis, and complicate the setup of IBC-specific clinical trials. However, IBC is biologically different from non-IBC [2]. Notably, IBCs are more angiogenic tumours than non-IBC, displaying higher microvessel density, and showing presence of dermal lymphovascular tumour emboli. Combined with the negative prognostic value of VEGF expression, these observations made IBC attractive for testing anti-angiogenic drugs. Based on these observations, and with the intent to continue to study IBC as a separate entity as we did previously [3, 4], we launched in 2008 the BEVERLY-1 trial, a French, multicentric, single arm, prospective phase 2 trial assessing the benefit of neoadjuvant/ adjuvant bevacizumab in patients with HER2-negative (BEVERLY-1) non-metastatic IBC. Bevacizumab is a monoclonal antibody that inhibits tumour angiogenesis by targeting VEGF, approved in 2008 by the US Food and Drug Administration under an accelerated plan in combination with chemotherapy in metastatic breast cancer. During the neo-adjuvant phase, the patients received four cycles of FEC100 plus bevacizumab every three weeks, followed by four cycles of docetaxel plus bevacizumab every three weeks. Then, the surgery included total mastectomy and axillary lymph node dissection, and was followed by adjuvant radiation therapy plus 10 cycles of bevacizumab (every 3 weeks), and hormone therapy if the tumour was HR-positive. Each patient theoretically received 8 cycles of neo-adjuvant chemotherapy and 18 cycles of neo-adjuvant/adjuvant bevacizumab. The primary endpoint was the pathological complete response (pCR) rate in breast and axillary lymph nodes after neo-adjuvant treatment, centrally assessed using the Sataloff classification: the regimen was regarded as efficacious if 30% or more patients had a pCR. Secondary endpoints included disease-free survival (DFS), overall survival (OS), safety, and analysis of circulating tumour cells and endothelial cells. BEVERLY-1 was the …","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"19 1","pages":"297 - 298"},"PeriodicalIF":0.0,"publicationDate":"2016-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91553967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oncogenic mechanisms of HOXB13 missense mutations in prostate carcinogenesis","authors":"Marta Cardoso, S. Maia, P. Paulo, M. Teixeira","doi":"10.18632/oncoscience.322","DOIUrl":"https://doi.org/10.18632/oncoscience.322","url":null,"abstract":"The recurrent germline mutation HOXB13 p.(Gly84Glu) (G84E) has recently been identified as a risk factor for prostate cancer. In a recent study, we have performed full sequencing of the HOXB13 gene in 462 Portuguese prostate cancer patients with early-onset and/or familial/hereditary disease, and identified two novel missense mutations, p.(Ala128Asp) (A128D) and p.(Phe240Leu) (F240L), that were predicted to be damaging to protein function. In the present work we aimed to investigate the potential oncogenic role of these mutations, comparing to that of the recurrent G84E mutation and wild-type HOXB13. We induced site-directed mutagenesis in a HOXB13 expression vector and established in vitro cell models of prostate carcinogenesis with stable overexpression of either the wild-type or the mutated HOXB13 variants. By performing in vitro assays we observed that, while the wild-type promotes proliferation, also observed with the F240L variant along with a decrease in apoptosis, the A128D mutation decreases apoptosis and promotes anchorage independent growth. No phenotypic impact was observed for the G84E mutation in the cell line model used. Our data show that specific HOXB13 mutations are involved in the acquisition of different cancer-associated capabilities and further support an oncogenic role for HOXB13 in prostate carcinogenesis.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"1 1","pages":"288 - 296"},"PeriodicalIF":0.0,"publicationDate":"2016-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88635477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-frequency ultrasound detection of cell death: Spectral differentiation of different forms of cell death in vitro","authors":"Maurice Pasternak, A. Sadeghi-Naini, Shawn Ranieri, A. Giles, M. Oelze, Michael C. Kolios, G. Czarnota","doi":"10.18632/oncoscience.319","DOIUrl":"https://doi.org/10.18632/oncoscience.319","url":null,"abstract":"High frequency quantitative ultrasound techniques were investigated to characterize different forms of cell death in vitro. Suspension-grown acute myeloid leukemia cells were treated to cause apoptosis, oncosis, mitotic arrest, and heat-induced death. Samples were scanned with 20 and 40 MHz ultrasound and assessed histologically in terms of cellular structure. Frequency-domain analysis of 20 MHz ultrasound data demonstrated midband fit changes of 6.0 ± 0.7 dBr, 6.2 ± 1.8 dBr, 4.0 ± 1.0 dBr and −4.6 ± 1.7 dBr after 48-hour cisplatinum-induced apoptosis, 48-hour oncotic decay, 36-hour colchicine-induced mitotic arrest, and heat treatment compared to control, respectively. Trends from 40 MHz ultrasound were similar. Spectral slope changes obtained from 40 MHz ultrasound data were reflective of alterations in cell and nucleus size. Chromatin pyknosis or lysis trends suggested that the density of nuclear material may be responsible for observed changes in ultrasound backscatter. Flow cytometry analysis confirmed the modes of cell death and supported midband fit trends in ultrasound data. Scatterer-size and concentration estimates obtained from a fluid-filled sphere form factor model further corresponded with spectral analysis and histology. Results indicate quantitative ultrasound spectral analysis may be used for probing anti-cancer response and distinguishing various modes of cell death in vitro.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"234 1","pages":"275 - 287"},"PeriodicalIF":0.0,"publicationDate":"2016-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74509184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}