Cancers, Vol. 10, Pages 165: CRISPR-Mediated Reactivation of DKK3 Expression Attenuates TGF-β Signaling in Prostate Cancer

Cancers, Vol. 10, Pages 165: CRISPR-Mediated Reactivation of DKK3 Expression Attenuates TGF-β Signaling in Prostate Cancer

Cancers doi: 10.3390/cancers10060165

Authors: Hoda Kardooni Estela Gonzalez-Gualda Emmanouil Stylianakis Sina Saffaran Jonathan Waxman Robert M. Kypta

The DKK3 gene encodes a secreted protein, Dkk-3, that inhibits prostate tumor growth and metastasis. DKK3 is downregulated by promoter methylation in many types of cancer, including prostate cancer. Gene silencing studies have shown that Dkk-3 maintains normal prostate epithelial cell homeostasis by limiting TGF-β/Smad signaling. While ectopic expression of Dkk-3 leads to prostate cancer cell apoptosis, it is unclear if Dkk-3 has a physiological role in cancer cells. Here, we show that treatment of PC3 prostate cancer cells with the DNA methyltransferase (DNMT) inhibitor decitabine demethylates the DKK3 promoter, induces DKK3 expression, and inhibits TGF-β/Smad-dependent transcriptional activity. Direct induction of DKK3 expression using CRISPR-dCas9-VPR also inhibited TGF-β/Smad-dependent transcription and attenuated PC3 cell migration and proliferation. These effects were not observed in C4-2B cells, which do not respond to TGF-β. TGF-β signals can regulate gene expression directly via SMAD proteins and indirectly by increasing DNMT expression, leading to promoter methylation. Analysis of genes downregulated by promoter methylation and predicted to be regulated by TGF-β found that DKK3 induction increased expression of PTGS2, which encodes cyclooxygenase-2. Together, these observations provide support for using CRISPR-mediated induction of DKK3 as a potential therapeutic approach for prostate cancer and highlight complexities in Dkk-3 regulation of TGF-β signaling.

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Evaluation of external reference levels for central venous pressure measurements of severely obese patients in the supine position

Abstract

Purpose

A proper reference level is important for measuring intracardiac pressures, especially for parameters with small normal values such as central venous pressure (CVP). Although several external zero reference levels (eZRLs) have been proposed for non-obese patients, none has been reported for severely obese patients. The aim of this study was to investigate an appropriate eZRL for CVP measurements of severely obese patients.

Methods

Chest computed tomography images of 65 patients with body mass index (BMI) ≥ 35 kg/m² were retrospectively reviewed. The anteroposterior thoracic diameter and height of the mid-right atrium (RA) were measured. Four reported eZRLs for CVP measurements (midthoracic level, two-thirds and four-fifths of the thoracic diameter above table level, and 5 cm below the anterior thorax) were examined for error when predicting the midpoint of the RA.

Results

The median BMI was 36.9 kg/m² [interquartile range (IQR), 36.0–39.2]. There was a significant difference in the calculated errors for the midpoint of the RA among the four eZRLs (Kruskal–Wallis test, P < 0.001). Two-thirds of the thoracic diameter above table level was the most accurate reference level for CVP measurement (Steel–Dwass post hoc analysis, P < 0.001). The Bland–Altman plot showed acceptable agreement for clinical use (mean difference, − 7 mm; 95% limit of agreement, − 23 to 9 mm).

Conclusion

The most accurate eZRL for CVP measurements of severely obese patients in the supine position was two-thirds of the thoracic diameter above table level. This result is consistent with that of a previous report of non-obese patients.

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Cancers, Vol. 10, Pages 164: Development of an Experimental Model for Analyzing Drug Resistance in Colorectal Cancer

Cancers, Vol. 10, Pages 164: Development of an Experimental Model for Analyzing Drug Resistance in Colorectal Cancer

Cancers doi: 10.3390/cancers10060164

Authors: Mohamed Elbadawy Tatsuya Usui Hideyuki Yamawaki Kazuaki Sasaki

Colorectal cancer (CRC) is one of the most common cancers, for which combination treatment of chemotherapy is employed. However, most patients develop drug resistance during the course of treatment. To clarify the mechanisms of drug resistance, various research models have been developed. Recently, we established a human CRC patients-derived three-dimensional (3D) culture system using an air-liquid interface organoid method. It contained numerous cancer stem cells and showed resistance to 5-fluorouracil and Irinotecan. In this review, we introduce conventional and our established models for studying drug resistance in CRC.

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Editorial Board

Publication date: June 2018
Source:Cancer Treatment Reviews, Volume 67





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Gastrointestinal stromal tumours: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up†

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Soft tissue and visceral sarcomas: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up†

Soft tissue sarcomas (STSs) gather over 80 histological entities, with even more molecular subsets, characterised by a low to very low incidence in all populations. The majority of sarcomas arise from the soft tissue (close to 75%), with ∼15% gastrointestinal stromal tumours (GISTs) and 10% bone sarcomas. These ESMO–EURACAN (European Society for Medical Oncology–European Reference Network for rare adult solid cancers) Clinical Practice Guidelines cover STSs, while GISTs are covered by dedicated ESMO–EURACAN Clinical Practice Guidelines [1]. Kaposi's sarcoma is not considered in the present document. Extraskeletal Ewing and Ewing-like sarcoma is covered by ESMO Clinical Practice Guidelines on bone sarcomas [2]. In general, the same principles for these tumours in children apply to adults. This is also the case for embryonal and alveolar rhabdomyosarcomas, which are exceedingly rare in adults. On the other hand, pleomorphic rhabdomyosarcoma is viewed as a high-grade, adult-type STS. Extraskeletal osteosarcoma is also a high-grade STS, whose clinical resemblance with osteosarcoma of bone is doubtful (prospective collection of data is encouraged to generate evidence on the therapeutic implications of such a diagnosis). Adult STS pathological subtypes occurring in adolescents should be managed the same way as in adult patients, though the same histotype might display clinical peculiarities when occurring at different ages.

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Anterior disc derangement with reduction of the temporomandibular joint: a case report

Temporomandibular dysfunction involving anterior disc derangement with or without reduction, secondary to posterior ligament insufficiency is typically managed conservatively with success in a majority of pati...

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