Cancer by Sfakianakis Alexandros: 04/17/17

Δευτέρα 17 Απριλίου 2017

Radiation therapy for oropharyngeal squamous cell carcinoma: Executive summary of an ASTRO Evidence-Based Clinical Practice Guideline

Publication date: Available online 17 April 2017
Source:Practical Radiation Oncology
Author(s): David J. Sher, David J. Adelstein, Gopal K. Bajaj, David M. Brizel, Ezra E.W. Cohen, Aditya Halthore, Louis B. Harrison, Charles Lu, Benjamin J. Moeller, Harry Quon, James W. Rocco, Erich M. Sturgis, Roy B. Tishler, Andy Trotti, John Waldron, Avraham Eisbruch
PurposeTo present evidence-based guidelines for the treatment of oropharyngeal squamous cell carcinoma (OPSCC) with definitive or adjuvant radiation therapy (RT).Methods and materialsThe American Society for Radiation Oncology convened the OPSCC Guideline Panel to perform a systematic literature review investigating the following key questions: (1) When is it appropriate to add systemic therapy to definitive RT in the treatment of OPSCC? (2) When is it appropriate to deliver postoperative RT with and without systemic therapy following primary surgery for OPSCC? (3) When is it appropriate to use induction chemotherapy in the treatment of OPSCC? (4) What are the appropriate dose, fractionation, and volume regimens with and without systemic therapy in the treatment of OPSCC?ResultsPatients with stage IV and stage T3 N0-1 OPSCC treated with definitive RT should receive concurrent high-dose intermittent cisplatin. Patients receiving adjuvant RT following surgical resection for positive surgical margins or extracapsular extension should be treated with concurrent high-dose intermittent cisplatin, and individuals with these risk factors who are intolerant of cisplatin should not routinely receive adjuvant concurrent systemic therapy. Induction chemotherapy should not be routinely delivered to patients with OPSCC. For patients with stage IV and stage T3 N0-1 OPSCC ineligible for concurrent chemoradiation therapy, altered fractionation RT should be used.ConclusionThe successful management of OPSCC requires the collaboration of radiation, medical, and surgical oncologists. When high-level data are absent for clinical decision-making, treatment recommendations should incorporate patient values and preferences to arrive at the optimal therapeutic approach.

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Radiation therapy for oropharyngeal squamous cell carcinoma: Executive summary of an ASTRO Evidence-Based Clinical Practice Guideline

RhoGDIα is a potential prognostic biomarker and controls telomere regulation in colorectal cancer

Abstract

RhoGDIα is an essential regulator for Rho GTPases. Although RhoGDIα may serve as an oncogene in colorectal cancer (CRC), the underlying mechanism is still unclear. Here,we investigate the function, mechanism, and clinical significance of RhoGDIα in CRC progression. We founded that downregulation of RhoGDIα repressed CRC cell proliferation, motility and invasion. Overexpression of RhoGDIα increased DNA damage response signals at telomeres, and led to telomere shortening in CRC cells, also being validated in 26 pairs of CRC tissues. Mechanistic studies revealed that RhoGDIα can promote TRF1 expression through PI3K-Akt signal pathway. Moreover, RhoGDIα protein levels were strongly correlated with TRF1 in CRC tissues. A cohort of 297 CRC samples validated the positive relationship between RhoGDIα and TRF1, and revealed that RhoGDIα and TRF1 levels were negatively associated with CRC patients' survival. Taken together, our results suggest that RhoGDIα regulate TRF1 and telomere length and may be novel prognostic biomarkers in colorectal cancer.

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RhoGDIα is a potential prognostic biomarker and controls telomere regulation in colorectal cancer

Abstract

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Nasal ala reconstruction: Tunnelled island pedicle melolabial flap; jigsaw puzzle advancement flap; spiral flap; dog-ear island pedicle flap and banner melolabial transposition flap.

http://sfaki.blogspot.gr/2017/04/nasal-ala-reconstruction-surgical.html

Skin tumours of the nasal ala are common and surgery is the treatment
of choice. Nasal ala reconstruction is challenging due to the reduced
mobility and unique features of its thick and sebaceous skin. The
natural arc of the ala and its boundary with the cheek are difficult
features to reproduce. One should bear in mind the functional and
cosmetic risks of nasal ala reconstruction. A distorted nasal contour
may impair the nasal valve; the alar rim may notch or elevate; facial
symmetry may be disrupted by blunting of the alar crease, trapdooring,
bridging of the nasofacial sulcus and poor colour and texture match.

Our aim is to review and compare the functional and cosmetic results
of different local flaps used to correct intermediate-thickness
defects on the nasal ala after surgical excision of cutaneous tumours.
We present representative patients who were treated at our
Dermatological Surgery Unit from June 2015 to September 2016.

The choice of the flap was adapted to the patients' physiognomy and
the defects' size: tunnelled island pedicle melolabial flap [Figure
1]; jigsaw puzzle advancement flap [Figure 2]; spiral flap [Figure 3];
dog-ear island pedicle flap [Figure 4] and banner melolabial
transposition flap [Figure 5]. Surgery was performed under
loco-regional anaesthesia, in an outpatient basis, followed by
prophylactic antibiotic therapy. There were neither immediate
complications nor subsequent flap necrosis. The tumours were
completely excised.
Figure 1: Female, 86-year-old, nodular ulcerated basal cell carcinoma
in the nasal ala: tunnelled island pedicle melolabial flap. (a)
Surgical plan, (b) primary defect, (c) secondary defect after
tunnelling of the flap, (d) immediate post-operative, (e and f) result
after healing (10 months after surgery).

Click here to view
Figure 2: Male, 76-year-old, nodular basal cell carcinoma on the nasal
ala: jigsaw puzzle advancement flap. (a) surgical plan, (b) primary
and secondary defects, (c) anchoring sutures secure the flap in place;
(d) immediate post-operative, (e) result after healing (3 months after
surgery).

Click here to view
Figure 3: Female, 76-year-old, nodular basal cell carcinoma on the
nasal ala: spiral flap, a combination of advancement and rotation. (a)
Surgical plan, (b) immediate post-operative, (c) result after healing
(2 months after surgery).

Click here to view
Figure 4: Female, 76-year-old, basal cell carcinoma on the nasal ala:
dog-ear island flap, combining two flaps: cheek advancement and
rotated island pedicle. (a) Surgical plan, (b) primary defect, (c)
immediate post-operative, (d) day 7 post-operative, (e) result after
healing (1 month after surgery).

Click here to view
Figure 5: Male, 83-year-old, two nodular basal cell carcinomas on the
nasal ala and dorsum: Banner's melolabial transposition flap. (a)
Surgical plan, (b) primary defect, (c) immediate post-operative, (d)
result after healing (7 months after surgery)

Click here to view

Facial symmetry was well preserved by the spiral and jigsaw puzzle
flaps [Figure 2] and [Figure 3]. The nasal sulcus was left intact by
the spiral flap as well as the tunnelled melolabial island flap
[Figure 1] and [Figure 3]. The melolabial flaps and the dog-ear island
flap allowed for the correction of larger defects on the nasal ala
[Figure 1], [Figure 4] and [Figure 5]. The dog-ear island flap [Figure
4] obtained a good result despite the large size of the primary
defect. Banner's melolabial transposition flap [Figure 5] was used to
correct a complex defect involving not only the nasal ala but also the
nasal dorsum and resulted in facial asymmetry due to trapdooring.

The small size of the defects that can be addressed by the spiral and
puzzle flaps may explain their superior cosmetic results.[1],[2] The
tunnelled melolabial island flap, although technically demanding, may
produce excellent results; compared to the cheek-to-nose interpolation
flap, the tunnelling technique offers the advantage of being one-stage
procedure. The dog-ear island flap is an adaptation of the cheek
advancement flap; despite its apparent complexity, it offers a viable
alternative to the melolabial flaps,[3] with a lower risk of trapdoor
effect and with proper preservation of the alar contour. The discussed
flaps are useful alternatives to the bilobed transposition flap and
the skin graft for the surgical reconstruction of the nasal ala.

When planning the surgery, it is important to assess the primary
defect on the nasal ala: size and location (medial or lateral), depth,
involvement of other cosmetic units/subunits and extension to the alar
rim, nasal tip or adjacent cheek. Several techniques have been
developed that are useful for the reconstruction of defects of the
nasal ala. Based on our experience and a review of the literature, we
present an algorithm [Table 1] to optimise the choices in the
reconstruction of intermediate-thickness defects in nasal ala. In
[Table 2], we review the main advantages and caveats of some of the
most useful surgical techniques for nasal ala
reconstruction.[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14]
Table 1: Nasal ala reconstruction: What is the optimal approach
according to the defects' size and location?

Click here to view
Table 2: Nasal ala reconstruction: major advantages and potential
caveats of different surgical techniques

Click here to view

In the nasal ala, given the paucity of surrounding skin and the
importance of minimising nasal ala distortion, flaps that recruit skin
from a distant site should be considered. Mastering different
techniques is essential for a surgeon to optimise treatment for each
patient. At the end of the day, the best choice depends on many
factors and should be adapted on a case-by-case basis and to the
surgeon's expertise.

--
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
alsfakia@gmail.com

Paediatric traumatic pneumomediastinum: the spinnaker sail sign

Description

A 20-month-old female infant was admitted to the emergency room after being run over by a car. She presented with pallor and signs of impaired peripheral perfusion, despite being conscious and alert. Signs of respiratory distress were recognised. There was a bilateral decrease of respiratory murmurs at pulmonary auscultation and her heart sounds were also diminished. Her peripheral oxygen saturation was 94% and her respiratory rate was 54 breaths per minute. A cervical and thoracic crepitus were present. There were no alterations at abdominal examination. Her blood pressure was 142/58 mmHg.

She presented with a Glasgow Coma Scale score of 15 and had normal reactive pupils. Facial oedema was observed and an epicranial haematoma was also detected. Haematological workup revealed a haemoglobin value of 12.9 g/dL.

A supine chest radiograph showed left hydropneumothorax, right pneumothorax and pulmonary contusion. This exam also showed significant pneumomediastinum revealing the spinnaker sail sign,...

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Hormonal and reproductive risk factors of papillary thyroid cancer: A population-based case-control study in France

Publication date: June 2017
Source:Cancer Epidemiology, Volume 48
Author(s): Emilie Cordina-Duverger, Christophe Leux, Monica Neri, Catherine Tcheandjieu, Anne-Valérie Guizard, Claire Schvartz, Thérèse Truong, Pascal Guénel
The three times higher incidence of thyroid cancer in women compared to men points to a role of female sex hormones in its etiology. However the effects of these factors are poorly understood. We analyzed the association between thyroid cancer and hormonal and reproductive factors among women enrolled in CATHY, a population-based case-control study conducted in France. The study included 430 cases of papillary thyroid cancer and 505 controls frequency-matched on age and area of residence. The odds ratios for thyroid cancer increased with age at menarche (p trend 0.05). Postmenopausal women were at increased risk, as compared to premenopausal women, particularly if menopause followed an ovariectomy, and for women with age at menopause <55years. In addition, use of oral contraceptives and menopausal hormone therapy reduced the association with thyroid cancer by about one third, and breastfeeding by 27%. Overall, these findings provide evidence that the risk of thyroid cancer increases with later age at menarche and after menopause, and decreases with use of oral contraceptives and menopausal hormone therapy. These findings confirm an implication of hormonal factors in papillary thyroid cancer risk, whose mechanisms need to be elucidated.

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Overall survival in elderly patients with colorectal cancer: A population-based study in the Caribbean

Publication date: June 2017
Source:Cancer Epidemiology, Volume 48
Author(s): Clarisse Joachim, Lidvine Godaert, Moustapha Dramé, Jacqueline Véronique-Baudin, Jonathan Macni, Juliette Smith-Ravin, Jean-Luc Novella, Rachid Mahmoudi
BackgroundPopulation-based Cancer registries (PBCR) play an important role in cancer surveillance and research. The aim of this study was to examine overall survival in elderly patients with colorectal cancer (CRC) by analysing data from the Martinique PBCR between 1993 and 2012.MethodsThe log-rank test was used to assess the statistical differences of the survival curves by each categorical variable: age at diagnosis, sex, histology, zone of residence, subsite, stage at diagnosis, and chemotherapy. A multivariable Cox model was performed to identify independent prognostic factors for overall survival in elderly patients with colorectal cancer.ResultsAmong 2230 patients included in the study, 60.8% were aged≥65years; mean age at diagnosis of these patients was 75.7±7.2years. For the period 2008–2012, 532 elderly patients were analysed; mean age of those receiving chemotherapy was 73.0±0.4 versus 77.9±0.4years for those not receiving chemotherapy (p<0.0001). Stage at diagnosis was evaluated in 87.8% (467/532) of patients; 63.0% (294/467) had stage III–IV and 49.3% of these patients (145/294) received chemotherapy. Chemotherapy was less frequently prescribed in patients aged 75–84 and ≥85 years as compared to those aged 65–74 years (41.1% and 15.0% versus 64.6% respectively; p<0.0001). Stage III–IV at diagnosis (HR=5.25; 3.70–7.45; p<0.0001), and not receiving chemotherapy (HR=3.05; 2.23–4.16; p<0.0001), were independent prognostic factors for overall survival.ConclusionOur study highlights the role of PBCR in evaluating cancer survival and patterns of care in elderly people of the French West- Indies. Chemotherapy was less frequently prescribed among the elderly

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Hormonal and reproductive risk factors of papillary thyroid cancer: A population-based case-control study in France

Overall survival in elderly patients with colorectal cancer: A population-based study in the Caribbean

Preclinical characterization of BET family bromodomain inhibitor ABBV-075 suggests combination therapeutic strategies

ABBV-075 is a potent and selective BET family bromodomain inhibitor that recently entered Phase I clinical trials. Comprehensive preclinical characterization of ABBV-075 demonstrated broad activity across cell lines and tumor models representing a variety of hematological malignancies and solid tumor indications. In most cancer cell lines derived from solid tumors, ABBV-075 triggers prominent G1 cell cycle arrest without extensive apoptosis. In this study, we show that ABBV-075 efficiently triggers apoptosis in acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM) cells. Apoptosis induced by ABBV-075 was mediated in part by modulation of the intrinsic apoptotic pathway, exhibiting synergy with the BCL-2 inhibitor venetoclax in preclinical models of AML. In germinal center diffuse large B cell lymphoma, BCL-2 levels or venetoclax sensitivity predicted the apoptotic response to ABBV-075 treatment. In vivo combination studies uncovered surprising benefits of low doses of ABBV-075 coupled with bortezomib and azacitidine treatment, despite the lack of in vitro synergy between ABBV-075 and these agents. The in vitro/in vivo activities of ABBV-075 described here may serve as a useful reference to guide the development of ABBV-075 and other BET family inhibitors for cancer therapy.

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Locoregional effects of microbiota in a preclinical model of colon carcinogenesis

Inflammation and microbiota are critical components of intestinal tumorigenesis. To dissect how the microbiota contributes to tumor distribution, we generated germ-free (GF) ApcMin/+ and ApcMin/+;Il10-/- mice and exposed them to specific-pathogen-free (SPF) or colorectal cancer-associated bacteria. We found colon tumorigenesis significantly correlated with inflammation in SPF housed ApcMin/+;Il10-/-, but not ApcMin/+ mice. In contrast, small intestinal neoplasia development significantly correlated with age in both ApcMin/+;Il10-/- and ApcMin/+ mice. GF ApcMin/+;Il10-/- mice conventionalized by an SPF microbiota had significantly more colon tumors compared to GF mice. Gnotobiotic studies revealed that while Fusobacterium nucleatum clinical isolates with FadA and Fap2 adhesins failed to induce inflammation and tumorigenesis, pks+ Escherichia coli promoted tumorigenesis in the ApcMin/+;Il10-/- model in a colibactin-dependent manner, suggesting colibactin is a driver of carcinogenesis. Our results suggest a distinct etiology of cancers in different locations of the gut, where colon cancer is primarily driven by inflammation and the microbiome, while age is a driving force for small intestine cancer.

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NRF2 induction supporting breast cancer cell survival is enabled by oxidative stress-induced DPP3-KEAP1 interaction

NRF2 is a transcription factor serving as a master regulator of the expression of many genes involved in cellular responses to oxidative and other stresses. In the absence of stress, NRF2 is constantly synthesized but maintained at low levels as it is targeted by KEAP1 for ubiquitination and proteasome-mediated degradation. NRF2 binds KEAP1 mainly through a conserved "ETGE" motif that has also been found in several other proteins, such as DPP3, which has been shown to bind KEAP1 and enhance NRF2 function upon overexpression. Here we demonstrate the interaction between endogenous DPP3 and endogenous KEAP1. We further show that the DPP3-KEAP1 interaction is strongly induced by hydrogen peroxide and that DPP3 is required for timely NRF2 induction and nuclear accumulation in the estrogen receptor (ER)-positive MCF7 breast cancer cells. Moreover, we present evidence that the binding of DPP3 to KEAP1 stabilizes the latter. Finally, we show that DPP3 is overexpressed in breast cancer and that elevated levels of DPP3 mRNA correlate with increased NRF2 downstream gene expression and poor prognosis, particularly for ER-positive breast cancer. Our studies reveal novel insights into the regulation of NRF2 and identify DPP3 and an NRF2 transcriptional signature as potential biomarkers for breast cancer prognosis and treatment.

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Activation of NOTCH signaling by tenascin-C promotes growth of human brain tumor-initiating cells

Elevated NOTCH signaling is implicated in tumorigenesis. The brain tumor- initiating cells (BTICs) present in malignant glioma exhibit elevated NOTCH activity but the mechanism of this activation is unknown. Here, we provide evidence that tenascin-C (TNC), an extracellular matrix protein prominent in malignant glioma, increases NOTCH activity in BTICs to promote their growth. We demonstrate the proximal localization of TNC and BTICs in human glioblastoma specimens, and in the brains of mice implanted with human BTIC intracranial xenografts. In culture, TNC was superior amongst several extracellular matrix proteins in enhancing the sphere-forming capacity of glioma patient-derived BTICs. Exogenously applied or autocrine TNC increased BTIC growth through an α2β1 integrin-mediated mechanism that elevated the NOTCH ligand, Jagged1 (JAG1). Microarray analyses and confirmatory PCR and Western blots in BTICs found that components of the NOTCH signaling pathway, including JAG1, ADAMTS15 and NICD1/2 were elevated in BITCs after TNC exposure. Inhibition of gamma secretase and metalloproteinase proteolysis in the NOTCH pathway, or knockdown of α2β1 integrin or JAG1, reduced the proliferative effect of TNC on BTIC. Collectively, our study has several novelties: the identification of TNC as a key initiator of the elevated NOTCH signaling in BTICs; the discovery that a prominent ECM component in malignant gliomas, TNC, is a promoter of BTIC growth; and the establishment of the TNC- α2β1 integrin - JAG1-NOTCH axis as a candidate for therapeutic interventions to improve the prognosis of patients with malignant glioma.

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Metabolic Markers and Statistical Prediction of Serous Ovarian Cancer Aggressiveness by Ambient Ionization Mass Spectrometry Imaging

Ovarian high-grade serous carcinoma (HGSC) results in the highest mortality among gynecological cancers, developing rapidly and aggressively. Dissimilarly, serous borderline ovarian tumors (BOT) can progress into low-grade serous carcinomas and have relatively indolent clinical behavior. The underlying biological differences between HGSC and BOT call for accurate diagnostic methodologies and tailored treatment options, and identification of molecular markers of aggressiveness could provide valuable biochemical insights and improve disease management. Here we used desorption electrospray ionization (DESI) mass spectrometry (MS) to image and chemically characterize the metabolic profiles of HGSC, BOT, and normal ovarian tissue samples. DESI-MS imaging enabled clear visualization of fine papillary branches in serous BOT and allowed for characterization of spatial features of tumor heterogeneity such as adjacent necrosis and stroma in HGSC. Predictive markers of cancer aggressiveness were identified, including various free fatty acids, metabolites, and complex lipids such as ceramides, glycerophosphoglycerols, cardiolipins, and glycerophosphocholines. Classification models built from a total of 89,826 individual pixels, acquired in positive and negative ion modes from 78 different tissue samples, enabled diagnosis and prediction of HGSC and all tumor samples in comparison to normal tissues, with overall agreements of 96.4% and 96.2%, respectively. HGSC and BOT discrimination was achieved with an overall accuracy of 93.0%. Interestingly, our classification model allowed identification of three BOT samples presenting unusual histologic features that could be associated with the development of low-grade carcinomas. Our results suggest DESI-MS as a powerful approach for rapid serous ovarian cancer diagnosis based on altered metabolic signatures.

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Targeting autocrine CCL5-CCR5 axis reprograms immunosuppressive myeloid cells and reinvigorates antitumor immunity

The tumor-promoting potential of CCL5 has been proposed but remains poorly understood. We demonstrate here that an autocrine CCL5-CCR5 axis is a major regulator of immunosuppressive myeloid cells (IMC) of both monocytic and granulocytic lineages. The absence of the autocrine CCL5 abrogated the generation of granulocytic myeloid-derived suppressor cells and tumor-associated macrophages. In parallel, enhanced maturation of intratumoral neutrophils and macrophages occurred in spite of tumor-derived CCL5. The refractory nature of ccl5-null myeloid precursors to tumor-derived CCL5 was attributable to their persistent lack of membrane-bound CCR5. The changes in the ccl5-null myeloid compartment subsequently resulted in increased tumor-infiltrating cytotoxic CD8+ T cells and decreased regulatory T cells in tumor-draining lymph nodes. An analysis of human triple-negative breast cancer specimens demonstrated an inverse correlation between "immune CCR5" levels and the maturation status of tumor-infiltrating neutrophils as well as 5-year-survival rates. Targeting the host CCL5 in bone marrow via nanoparticle-delivered expression silencing, in combination with the CCR5 inhibitor Maraviroc, resulted in strong reductions of IMC and robust anti-tumor immunities. Our study suggests that the myeloid CCL5-CCR5 axis is an excellent target for cancer immunotherapy.

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A squalene-based nanomedicine for oral treatment of colon cancer

Nanotechnology offers many possibilities to improve drug treatments, including with regard to drug pharmacology. The current study reports a simple approach to improve cisplatin efficacy in the treatment of colon cancer through the creation of orally administered squalenoylated nanoparticles loaded with cisplatin (SQ-CDDP NP). Cytotoxic effects of SQ-CDDP NP were assessed in human colonic cells and in mouse models of intestinal cancer. In cell culture, SQ-CDDP NP exhibited at least 10-fold greater cytotoxic potency compared to uncomplexed cisplatin, reflecting an enhancement in intracellular accumulation and DNA platination. Mechanistic investigations showed that SQ-CDDP NP stimulated ROS production, expression of heavy metals-inducible and stress-inducible genes, stress kinase cascades and apoptosis. In ApcMin/+ mice, a model of intestinal tumorigenesis, oral administration of SQ-CDDP NP curtailed spontaneous tumor formation and azoxymethane-induced colon carcinogenesis with no apparent evidence of tissue toxicity. Our results offer preclinical validation of a nanocarrier formulation that can safely improve chemotherapeutic efficacy, address risks of drug resistance, and improve patient compliance by enabling oral administration.

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SSRP1 cooperates with PARP and XRCC1 to facilitate single strand DNA break repair by chromatin priming

DNA single strand breaks (SSB) are the most common form of DNA damage, requiring repair processes that to initiate must overcome chromatin barriers. The FACT complex comprised of the SSRP1 and SPT16 proteins are important for maintaining chromatin integrity, with SSRP1 acting as an histone H2A/H2B chaperone in chromatin disassembly during DNA transcription, replication and repair. In this study, we show that SSRP1 but not SPT16 is critical for cell survival after ionizing radiation or methyl methanesulfonate-induced single-strand DNA damage. SSRP1 is recruited to SSB in PARP-dependent manner and retained at DNA damage sites by N-terminal interactions with the DNA repair protein XRCC1. Mutational analyses showed how SSRP1 function is essential for chromatin decondensation and histone H2B exchange at sites of DNA strand breaks, which are both critical to prime chromatin for efficient SSB repair and cell survival. By establishing how SSRP1 facilitates SSB repair, our findings provide a mechanistic rationale to target SSRP1 as a general approach to selectively attack cancer cells.

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Western diet deregulates bile acid homeostasis, cell proliferation and tumorigenesis in colon

Western-style diets (WD) high in fat and scarce in fiber and vitamin D increase risks of colorectal cancer (CRC). Here we performed a long-term diet study in mice to follow tumorigenesis and characterize structural and metabolic changes in colon mucosa associated with WD and predisposition to CRC. WD increased colon tumor numbers and mucosa proteomic analysis indicated severe deregulation of intracellular bile acid (BA) homeostasis and activation of cell proliferation. WD also increased crypt depth and colon cell proliferation. Despite increased luminal BA, colonocytes from WD-fed mice exhibited decreased expression of the BA transporters FABP6, OSTβ and ASBT and decreased concentrations of secondary BA deoxycholic acid and lithocholic acid, indicating reduced activity of the nuclear BA receptor FXR. Overall, our results suggest that WD increases cancer risk by FXR inactivation leading to BA deregulation and increased colon cell proliferation.

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SFK/FAK signaling attenuates osimertinib efficacy in both drug-sensitive and drug-resistant models of EGFR-mutant lung cancer

Mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as osimertinib, are active agents for the treatment of EGFR-mutant lung cancer. Specifically, these agents can overcome the effects of the T790M mutation, which mediates resistance to first and second-generation EGFR TKI, and recent clinical trials have documented their efficacy in patients with EGFR-mutant lung cancer. Despite promising results, therapeutic efficacy is limited by development of acquired resistance. Here we report that Src family kinases (SFK) and focal adhesion kinase (FAK) sustain AKT and mitogen-activated protein kinase (MAPK) pathway signaling under continuous EGFR inhibition in osimertinib sensitive cells. Inhibiting either the MAPK pathway or the AKT pathway enhanced the effects of osimertinib. Combined SFK/FAK inhibition exhibited the most potent effects on growth inhibition, induction of apoptosis, and delay of acquired resistance. SFK family member YES1 was amplified in osimertinib- resistant EGFR-mutant tumor cells, the effects of which were overcome by combined treatment with osimertinib and SFK inhibitors. In conclusion, our data suggest that concomitant inhibition of both SFK/FAK and EGFR may be a promising therapeutic strategy for EGFR-mutant lung cancer.

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NOTCH1 Signaling Regulates Self-renewal and Platinum Chemoresistance of Cancer Stem-like Cells in Human Non-small Cell Lung Cancer

Cancer stem-like cells (CSC) are thought to drive tumor initiation, metastasis, relapse and therapeutic resistance, but their specific pathogenic characters in many cancers including non-small cell lung cancer (NSCLC) have yet to be well defined. Here we develop findings that the growth factor HGF promotes CSC sphere formation in NSCLC cell populations. In patient-derived sphere-forming assays (PD-SFA) with HGF, CD49f and CD104 were defined as novel markers of lung CSC (LCSC). In particular, we isolated a subpopulation of CD166+CD49fhiCD104-Lin- LCSC present in all human specimens of NSCLC examined, regardless of their histological subtypes or genetic driver mutations. This specific cell population was tumorigenic and capable of self-renewal, giving rise to tumor spheres in vitro and orthotopic lung tumors in immune-compromised mice. Mechanistic investigations established that NOTCH1 was preferentially expressed in this cell subpopulation and required for self-renewal via the transcription factor HES1. Through a distinct HES1-independent pathway, NOTCH1 also protected LCSCs from cisplatin-induced cell death. Notably, treatment with a γ-secretase inhibitor that blunts NOTCH1 function ablated self-renewing LCSC activity and restored platinum sensitivity in vitro and in vivo. Overall, our results define the pathogenic characters of a cancer stem-like subpopulation in lung cancer, the targeting of which may relieve platinum resistance in this disease.

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Preclinical characterization of BET family bromodomain inhibitor ABBV-075 suggests combination therapeutic strategies

Locoregional effects of microbiota in a preclinical model of colon carcinogenesis

NRF2 induction supporting breast cancer cell survival is enabled by oxidative stress-induced DPP3-KEAP1 interaction

Activation of NOTCH signaling by tenascin-C promotes growth of human brain tumor-initiating cells

Metabolic Markers and Statistical Prediction of Serous Ovarian Cancer Aggressiveness by Ambient Ionization Mass Spectrometry Imaging

Targeting autocrine CCL5-CCR5 axis reprograms immunosuppressive myeloid cells and reinvigorates antitumor immunity

A squalene-based nanomedicine for oral treatment of colon cancer

SSRP1 cooperates with PARP and XRCC1 to facilitate single strand DNA break repair by chromatin priming

Western diet deregulates bile acid homeostasis, cell proliferation and tumorigenesis in colon

SFK/FAK signaling attenuates osimertinib efficacy in both drug-sensitive and drug-resistant models of EGFR-mutant lung cancer

NOTCH1 Signaling Regulates Self-renewal and Platinum Chemoresistance of Cancer Stem-like Cells in Human Non-small Cell Lung Cancer

Oncogenic Characterization and Pharmacologic Sensitivity of Activating Fibroblast Growth Factor Receptor (FGFR) Genetic Alterations to the Selective FGFR Inhibitor Erdafitinib

Fibroblast growth factor receptor (FGFR) genetic alterations are frequently observed in cancer, suggesting that FGFR inhibition may be a promising therapy in patients harboring these lesions. Identification of predictive and pharmacodynamic biomarkers to select and monitor patients most likely to respond to FGFR inhibition will be the key to clinical development of this class of agents. Sensitivity to FGFR inhibition and correlation with FGFR pathway activation status were determined in molecularly annotated panels of cancer cell lines and xenograft models. Pathway inhibition in response to FGFR inhibitor treatment was assessed in cell lines (both in-vitro and in-vivo) and in samples from patients treated with the FGFR inhibitor JNJ-42756493 (erdafitinib). Frequency of FGFR aberrations was assessed in a panel of NSCLC, breast, prostate, ovarian, colorectal, and melanoma human tumor tissue samples. FGFR translocations and gene amplifications present in clinical specimens were shown to display potent transforming activity associated with constitutive pathway activation. Tumor cells expressing these FGFR activating mutants displayed sensitivity to the selective FGFR inhibitor erdafitinib and resulted in suppression of FGFR phosphorylation and downstream signal transduction. Clinically, patients receiving erdafitinib showed decreased Erk phosphorylation in tumor biopsies and elevation of serum phosphate. In a phase I study, a heavily pre-treated bladder cancer patient with an FGFR3-TACC3 translocation experienced a partial response when treated with erdafitinib. This preclinical study confirmed pharmacodynamics and identified new predictive biomarkers to FGFR inhibition with erdafitinib and supports further clinical evaluation of this compound in patients with FGFR genetic alterations.

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TRA2A promoted paclitaxel resistance and tumor progression in triple negative breast cancers via regulating alternative splicing

Treatment of triple-negative breast cancer (TNBC) has been challenging and paclitaxel (PTX) resistance is one of the major obstacles to the better prognosis. Deregulation of alternative splicing (AS) may contribute to tumor progression and chemotherapy resistance. Human AS factor TRA2 has two separate gene paralogs encoding TRA2A and TRA2B proteins. TRA2B is associated with cancer cell survival and therapeutic sensitivity. However the individual role of TRA2A in cancer progression has not been reported. Here we report that TRA2A facilitates proliferation and survival, migration and invasion of TNBC cells. In addition, TRA2A promotes PTX resistance of TNBC by specifically controlling cancer-related splicing, which is independent of other splicing factors. TRA2A overexpression could promote AS of CALU, RSRC2 and PALM during PTX treatment of TNBC cells. The isoform shift of RSRC2 from RSRC2s to RSRC2l leads to a decreased RSRC2 protein expression, which could contribute to TNBC PTX resistance. TRA2A can regulate RSRC2 AS by specifically binding upstream intronic sequence of exon4. Strikingly, TRA2A expression is increased dramatically in TNBC patients, and has close relationship with decreased RSRC2 expression; both of them are associated with poor survival of TNBC. Collectively, our findings suggest that PTX targets the TRA2A-RSRC2 splicing pathway and deregulated TRA2A and RSRC2 expression may confer PTX resistance. In addition to providing a novel molecular mechanism of cancer-related splicing dysregulation, our study demonstrates that expression of TRA2A in conjunction with RSRC2 may provide valuable molecular biomarker evidence for TNBC clinical treatment decisions and patient outcome.

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Photodynamic Therapy Using Photosensitizer-encapsulated Polymeric Nanoparticle to Overcome ATP-Binding Cassette Transporter Subfamily G2 Function in Pancreatic Cancer

Chlorin-based photosensitizers are commonly used in photodynamic therapy (PDT). These drugs are effluxed by cell-membrane transporters, such as the ATP-binding cassette subfamily G member 2 (ABCG2). PDT efficacy is limited in tumor cells expressing high levels of these proteins. Pancreatic cancer cell lines AsPC-1 and MIA PaCa-2, which have high and low ABCG2 expression, respectively, were used and ABCG2-overexpressing MIA PaCa-2 cells were generated. We compared PDT efficacy between Chlorin e6 (Ce6) and cationic photosensitizer-encapsulated polymeric nanoparticle (PS-pNP) which is comprised with Ce6, polyethylene glycol and polyethylenimine. The intracellular concentration of Ce6 was significantly higher in MIA PaCa-2 cells than in AsPC-1 or ABCG2-overexpressing MIA PaCa-2 cells. PS-pNP increased intracellular levels of the photosensitizer in all cell lines. The cell viability experiments indicated increased Ce6 resistance in ABCG2-overexpressing cells. In contrast, PS-pNP produced similar levels of cytotoxicity in each of the cancer cell lines tested. Singlet oxygen production was higher in cells treated with PS- pNP than in those treated with Ce6. Furthermore, in heterotopic and orthotopic AsPC-1-xenograft mouse models, PDT using PS-pNP significantly reduced tumor volume in comparison to that of Ce6 treatment. PS-pNP could increase intracellular Ce6 concentration, which were related with reduced ABCG2-mediated efflux of Ce6, thereby enhancing the effects of PDT in pancreatic cancer cells.

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Oncogenic Characterization and Pharmacologic Sensitivity of Activating Fibroblast Growth Factor Receptor (FGFR) Genetic Alterations to the Selective FGFR Inhibitor Erdafitinib

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TRA2A promoted paclitaxel resistance and tumor progression in triple negative breast cancers via regulating alternative splicing

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Photodynamic Therapy Using Photosensitizer-encapsulated Polymeric Nanoparticle to Overcome ATP-Binding Cassette Transporter Subfamily G2 Function in Pancreatic Cancer

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LALF 32-51 -E7 therapeutic vaccine induces antitumor immunity against human papillomavirus type 16 E7-expressing murine tumor metastases in the lungs

Abstract

One important goal of cancer immunotherapy is to prevent and treat tumor metastasis. We have previously reported the significant antitumor effect induced by the immunization with our human papillomavirus therapeutic protein-based vaccine (LALF_32-51-E7) without adjuvant and admixed with clinically relevant adjuvants in the subcutaneous TC-1 tumor challenge model. In the present study, we evaluated the efficacy of the above mentioned vaccine formulations in controlling the hematogenous spread of TC-1 tumor cells using a more tumourigenic clone named TC-1* and other intravenous injection site less stressful than the tail vein. We generated a lung metastasis model by injecting TC-1* cells into the retro-orbital venous sinus and this is the first study describing it. Also, this is the first study that demonstrates the efficacy of the immunization with LALF_32-51-E7 without adjuvant and admixed with VSSP or Al(OH)₃ in controlling metastatic tumors increasing the survival of the mice. Our TC-1 lung metastasis model can be used to test the efficacy of other immunotherapeutic strategies based on E6/E7 antigens.

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LALF 32-51 -E7 therapeutic vaccine induces antitumor immunity against human papillomavirus type 16 E7-expressing murine tumor metastases in the lungs

Abstract

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Long Noncoding RNA MNX1-AS1 Knockdown Inhibits Cell Proliferation and Migration in Ovarian Cancer

Cancer Biotherapy & Radiopharmaceuticals Apr 2017, Vol. 32, No. 3: 91-99.

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Expression of Long Noncoding RNA Urothelial Cancer Associated 1 Promotes Cisplatin Resistance in Cervical Cancer

Cancer Biotherapy & Radiopharmaceuticals Apr 2017, Vol. 32, No. 3: 101-110.

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Long Noncoding RNA MNX1-AS1 Knockdown Inhibits Cell Proliferation and Migration in Ovarian Cancer

Cancer Biotherapy & Radiopharmaceuticals Apr 2017, Vol. 32, No. 3: 91-99.

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Expression of Long Noncoding RNA Urothelial Cancer Associated 1 Promotes Cisplatin Resistance in Cervical Cancer

Cancer Biotherapy & Radiopharmaceuticals Apr 2017, Vol. 32, No. 3: 101-110.

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Impact of BCL2 polymorphisms on survival in transitional cell carcinoma of the bladder

Abstract

Purpose

To evaluate the impact of three BCL2 single-nucleotide polymorphisms, i.e., c.−938C>A (rs2279115), c.21G>A (rs1801018), and c.*2203A>G (rs4987853) on survival in patients with transitional cell carcinoma of the bladder.

Methods

We analyzed 179 patients who underwent surgical treatment for bladder cancer at the Clinic of Urology, University Hospital Essen, Germany. Genomic DNA was extracted and genotyped for the polymorphisms. For all polymorphisms, linkage analysis was performed. Kaplan–Meier and Cox regression analyses were used to determine the putative impact of the three polymorphisms on outcome.

Results

c.−938C>A and c.21G>A, but not c.*2203A>G, are in strong linkage disequilibrium (D′ 0.96). We found a significant association between c.−938C>A and relapse-free survival (p = 0.024) with an allele dose effect. In the same way, c.21G>A had a significant impact on both relapse-free survival (p = 0.009) and progression-free survival (p = 0.012), as well as a pronounced allele dose effect. Regression analysis proved c.21G>A and c.−938C>A, to be an independent risk factor in univariate and multivariable analyses.

Conclusions

In our cohort, both c.−938C>A and c.21G>A showed a significant impact on outcome with TCC of the bladder. Due to the linkage disequilibrium of both SNPs, maybe, only one of them could mediate this effect. In multivariable analysis, however, both proved to be independently associated with overall survival. Contrary to other findings which found the c.−938C>A mainly influencing outcome, our data may suggest that the main effect on TCC could be due to the c.21G>A polymorphism.

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RRx-001 protects against cisplatin-induced toxicities

Abstract

Purpose

RRx-001, a minimally toxic tumor-associated macrophage and neutrophil-repolarizing agent, is under investigation in Phase II clinical trials as a sensitizer/resensitizer to cisplatin and carboplatin. On the basis of anecdotal clinical observations of improved platinum tolerability following a priming period with RRx-001 as well as preclinical studies that have previously demonstrated radioprotection of intestinal stem cells and cardioprotection from doxorubicin, the in vivo cytoprotective potential of RRx-001 pretreatment against cisplatin-induced bone marrow suppression and renal toxicity was investigated.

Methods

BALB/c mice were divided into three groups: (1) no treatment, (2) vehicle and cisplatin only, and (3) RRx-001 and cisplatin. RRx-001 treatment (5 mg/kg every other day for 3 days) was initiated 3 days prior to cisplatin administration. Blood was collected from the femoral vein at different intervals to measure total hemoglobin and leukocyte counts as well as renal functional markers (serum urea, creatinine and creatinine clearance). Metaphase spreads were prepared from whole bone marrow cells as markers of clastogenicity.

Results

RRx-001 pretreatment significantly decreased (P < 0.05) the blood urea nitrogen and creatinine levels. A statistically significant (P < 0.05) reduction in the mean total chromosome aberration frequency per metaphase in the RRx-001 and cisplatin group compared to the cisplatin-only group was observed.

Conclusions

This study is the first to demonstrate that RRx-001 has nephro-, geno- and myeloprotective effects in vivo. Importantly, RRx-001 did not protect sarcoma-180 solid tumor xenografts against cisplatin-induced cytotoxicity. These results potentially support the use of RRx-001 as a chemoprotector against cisplatin-induced toxicities.

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Impact of BCL2 polymorphisms on survival in transitional cell carcinoma of the bladder

Abstract

Purpose

Methods

Results

Conclusions

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RRx-001 protects against cisplatin-induced toxicities

Abstract

Purpose

Methods

Results

Conclusions

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The protective effects of dexmedetomidine on ischemic brain injury: A meta-analysis

Intracranial lesions, trauma or surgery-related damage activate immune inflammation and neuroendocrine responses, causing ischemic brain injury. Studies have shown that inflammatory cascade mediated by neuroendocrine hormones and proinflammatory mediators is implicated in the pathophysiology of ischemic brain injury. Alpha2-adrenoceptor agonists, dexmedetomidine, is widely used as neuroprotectants in anesthesia practice. However, it is still lack of a comprehensive meta-analysis to evaluate the neuroprotection of dexmedetomidine against ischemic brain injury via suppressing these two physiological responses.

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Human tissue Kallikreins: Blood levels and response to radiotherapy in intermediate risk prostate cancer

Kallikreins are serine proteases over expressed in many malignancies. In this study, we measure changes in serum kallikrein (KLKs) levels during intensity-modulated radiotherapy (IMRT) in prostate cancer patients, and find potential correlations between serum kallikrein level and normal tissues toxicity during radiation.

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Involved-field irradiation concurrently combined with nedaplatin/5-fluorouracil for inoperable esophageal cancer on basis of 18FDG-PET scans: A long follow-up results of phase II study

Previously we reported our prospective phase II study in this journal [1]. The follow up time increased 26months at this time from the previous analysis. The median follow-up time was 64months (range; 50–85months) for surviving patients. The recurrence of the esophageal cancer increased by three patients to the total of 31 patients, who had a first recurrence in liver at 25months, primary tumor at 37months, and right recurrent laryngeal nerve lymph node within radiation field at 39months after the onset of treatment, respectively.

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MiR-186 inhibited aerobic glycolysis in gastric cancer via HIF-1α regulation

MiR-186 inhibited aerobic glycolysis in gastric cancer via HIF-1α regulation

Oncogenesis 6, e318 (April 2017). doi:10.1038/oncsis.2017.20

Authors: L Liu, Y Wang, R Bai, K Yang & Z Tian

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Inhibition of DNA2 nuclease as a therapeutic strategy targeting replication stress in cancer cells

Inhibition of DNA2 nuclease as a therapeutic strategy targeting replication stress in cancer cells

Oncogenesis 6, e319 (April 2017). doi:10.1038/oncsis.2017.15

Authors: S Kumar, X Peng, J Daley, L Yang, J Shen, N Nguyen, G Bae, H Niu, Y Peng, H-J Hsieh, L Wang, C Rao, C C Stephan, P Sung, G Ira & G Peng

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Initial sites of hepadnavirus integration into host genome in human hepatocytes and in the woodchuck model of hepatitis B-associated hepatocellular carcinoma

Initial sites of hepadnavirus integration into host genome in human hepatocytes and in the woodchuck model of hepatitis B-associated hepatocellular carcinoma

Oncogenesis 6, e317 (April 2017). doi:10.1038/oncsis.2017.22

Authors: R Chauhan, N D Churchill, P M Mulrooney-Cousins & T I Michalak

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p16 controls epithelial cell growth and suppresses carcinogenesis through mechanisms that do not require RB1 function

p16 controls epithelial cell growth and suppresses carcinogenesis through mechanisms that do not require RB1 function

Oncogenesis 6, e320 (April 2017). doi:10.1038/oncsis.2017.5

Authors: M Sen, N Akeno, A Reece, A L Miller, D S Simpson & K A Wikenheiser-Brokamp

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MiR-186 inhibited aerobic glycolysis in gastric cancer via HIF-1α regulation

MiR-186 inhibited aerobic glycolysis in gastric cancer via HIF-1α regulation

Oncogenesis 6, e318 (April 2017). doi:10.1038/oncsis.2017.20

Authors: L Liu, Y Wang, R Bai, K Yang & Z Tian

http://ift.tt/2pKWI55

Inhibition of DNA2 nuclease as a therapeutic strategy targeting replication stress in cancer cells

Inhibition of DNA2 nuclease as a therapeutic strategy targeting replication stress in cancer cells

Oncogenesis 6, e319 (April 2017). doi:10.1038/oncsis.2017.15

Authors: S Kumar, X Peng, J Daley, L Yang, J Shen, N Nguyen, G Bae, H Niu, Y Peng, H-J Hsieh, L Wang, C Rao, C C Stephan, P Sung, G Ira & G Peng

http://ift.tt/2pKTqPg

Initial sites of hepadnavirus integration into host genome in human hepatocytes and in the woodchuck model of hepatitis B-associated hepatocellular carcinoma

Initial sites of hepadnavirus integration into host genome in human hepatocytes and in the woodchuck model of hepatitis B-associated hepatocellular carcinoma

Oncogenesis 6, e317 (April 2017). doi:10.1038/oncsis.2017.22

Authors: R Chauhan, N D Churchill, P M Mulrooney-Cousins & T I Michalak

http://ift.tt/2pKZ3g7

p16 controls epithelial cell growth and suppresses carcinogenesis through mechanisms that do not require RB1 function

p16 controls epithelial cell growth and suppresses carcinogenesis through mechanisms that do not require RB1 function

Oncogenesis 6, e320 (April 2017). doi:10.1038/oncsis.2017.5

Authors: M Sen, N Akeno, A Reece, A L Miller, D S Simpson & K A Wikenheiser-Brokamp

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FDA Approves Pembrolizumab for Hodgkin Lymphoma

The FDA approved pembrolizumab for the treatment of some adult and pediatric patients with classical Hodgkin lymphoma.

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Maternal height and breast cancer risk: results from a study nested within the EPIC-Greece cohort

Abstract

The positive association of adult height with breast cancer (BC) risk has been hypothesized to be partly accounted for by an association of this risk with maternal height (operating in utero to modify hormone effects). In a case–control study (271 BC patients and 791 controls) nested within the EPIC-Greece cohort, we applied mediation analysis to calculate the direct and indirect (through the woman's own height) effect of maternal height on BC risk. Per 5 cm increase in maternal height and depending on its reference value: the indirect effect odds ratio ranges from 1.02 to 1.07; the direct effect odds ratio from 1.06 to 1.11; and the total (direct and indirect effects) from 1.08 to 1.19. The effect sizes consistently increased for higher reference categories of maternal height, but did not generally reach statistical significance, possibly due to the limited sample size.

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FDA Approves Pembrolizumab for Hodgkin Lymphoma

The FDA approved pembrolizumab for the treatment of some adult and pediatric patients with classical Hodgkin lymphoma.

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Maternal height and breast cancer risk: results from a study nested within the EPIC-Greece cohort

Abstract

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A phase I dose-escalation study of the safety and pharmacokinetics of a tablet formulation of voxtalisib, a phosphoinositide 3-kinase inhibitor, in patients with solid tumors

Summary

Background Voxtalisib, a PI3K/mTOR inhibitor, has shown antitumor activity in capsule formulation in patients with solid tumors. This Phase I study assessed safety and pharmacokinetics of voxtalisib administered as immediate-release tablets in patients with solid tumors (NCT01596270). Methods A "3 + 3" dose escalation design was used. Adverse events (AEs), pharmacokinetics (PK), food effect and tumor response were evaluated. Results Thirty-two patients received voxtalisib doses ranging from 50 mg to 70 mg once daily (QD) and 17 patients received voxtalisib doses ranging from 30 mg to 50 mg twice daily (BID), for two 28-day cycles. Dose-limiting toxicities (DLTs) were Grade 3 fatigue (two patients at 70 mg QD, one patient at 40 mg BID) and Grade 3 rash (two patients at 50 mg BID). The maximum tolerated dose (MTD) was 60 mg for QD and 40 mg for BID regimens. Common treatment-emergent AEs were diarrhea (41%), nausea (37%) and fatigue (33%). Voxtalisib appeared to follow linear PK, with a general increase in plasma exposure with dose and no significant accumulation. Administration with food caused a slight decrease in exposure; however, given the high variability observed in the exposure parameters, this should be interpreted with caution. Best response was stable disease in 29% and 50% of patients (QD and BID regimens, respectively). Conclusions The safety profile of voxtalisib tablets at the MTD in patients with solid tumors was consistent with that observed with voxtalisib capsules. Given the limited activity observed across multiple clinical trials, no further trials of voxtalisib are planned.

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Bis-anthracycline WP760 abrogates melanoma cell growth by transcription inhibition, p53 activation and IGF1R downregulation

Summary

Anthracycline chemotherapeutics, e.g. doxorubicin and daunorubicin, are active against a broad spectrum of cancers. Their cytotoxicity is mainly attributed to DNA intercalation, interference with topoisomerase activity, and induction of double-stranded DNA breaks. Since modification of anthracyclines can profoundly affect their pharmacological properties we attempted to elucidate the mechanism of action, and identify possible molecular targets, of bis-anthracycline WP760 which previously demonstrated anti-melanoma activity at low nanomolar concentrations. We studied the effect of WP760 on several human melanoma cell lines derived from tumors in various development stages and having different genetic backgrounds. WP760 inhibited cell proliferation (IC₅₀ = 1–99 nM), impaired clonogenic cell survival (100 nM), and inhibited spheroid growth (≥300 nM). WP760 did not induce double-stranded DNA breaks but strongly inhibited global transcription. Moreover, WP760 caused nucleolar stress and led to activation of the p53 pathway. PCR array analysis showed that WP760 suppressed transcription of ten genes (ABCC1, MTOR, IGF1R, EGFR, GRB2, PRKCA, PRKCE, HDAC4, TXNRD1, AKT1) associated with, inter alia, cytoprotective mechanisms initiated in cancer cells during chemotherapy. Furthermore, WP760 downregulated IGF1R and upregulated PLK2 expression in most of the tested melanoma cell lines. These results suggest that WP760 exerts anti-melanoma activity by targeting global transcription and activation of the p53 pathway and could become suitable as an effective therapeutic agent.

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A phase I dose-escalation study of the safety and pharmacokinetics of a tablet formulation of voxtalisib, a phosphoinositide 3-kinase inhibitor, in patients with solid tumors

Summary

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Bis-anthracycline WP760 abrogates melanoma cell growth by transcription inhibition, p53 activation and IGF1R downregulation

Summary

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Negative prognostic effect of low nuclear GLI1 expression in glioblastomas

Abstract

The hedgehog signaling plays supportive roles in various aspects of tumorigenesis. Increased expression of the key component, GLI1, has been shown to correlate with poor prognosis in many types of cancers. We aimed to investigate the effect of GLI1 expression in glioblastoma focusing on the nuclear localization. Immunohistochemistry for GLI1, GLI2, PTCH1, SMO, and SHH were done in 140 glioblastoma tissues, and the staining was graded. For GLI1, nuclear and cytoplasmic expression was separately assessed. No significant correlation was found between clinicopathologic parameters and expression grades of the five proteins. Low nuclear GLI1 expression was associated with a worse progression-free survival while overall survival was not significantly affected. In contrast, cytoplasmic GLI1 expression did not have a prognostic effect. PTCH1 expression correlated with nuclear GLI1 expression without exerting a significant prognostic effect. Analysis of the TCGA–glioblastoma dataset revealed that low GLI1 mRNA level also correlated with a poor prognosis for both overall and progression-free survival. The adverse effect of low nuclear GLI1 expression in glioblastomas is in contrast with the negative prognostic effect of high GLI1 expression reported in non-cranial malignancies. The relative impact of hedgehog signaling among other oncogenic pathways in the brain may be responsible for the difference. The different implication of GLI1 expression in glioblastomas needs to be considered in studies of hedgehog signaling-targeted therapy.

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Negative prognostic effect of low nuclear GLI1 expression in glioblastomas

Abstract

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Long non-coding RNA NKILA inhibits migration and invasion of non-small cell lung cancer via NF-κB/Snail pathway

Abstract

Background

Numerous studies have shown that long non-coding RNAs (lncRNAs) play key roles during multiple cancer processes, such as cell proliferation, apoptosis, migration and invasion. The previous studies found that NKILA interacted with and suppressed the nuclear translocation of NF-KappaB, which influenced metastasis and prognosis in breast cancer. However the clinical significance and biological role of NKILA in non-small cell lung cancer (NSCLC) remains unknown.

Methods

We examined expression levels of NKILA in 106 pairs of NSCLC tissues and cell lines. The expression level of NKILA after TGF-β1 stimulation also was examined by qRT-PCR and validated by Chromatin immunoprecipitation (ChIP). Gain-of-function and loss-of-function assays were performed to examine the effect of NKILA on proliferation, migration and invasion of NSCLC cells. RNA immunoprecipitation (RIP), western blot and rescue experiments were carried out to reveal the interrelation between NKILA, NF-κB and EMT signal pathway.

Results

The expression of NKILA was down-regulated in NSCLC cancer tissues compared with matched adjacent noncancerous tissues, and lower NKILA expression in tumor tissues were significantly correlated with lymph node metastasis and advanced TNM stage. We found that the expression of NKILA was mainly regulated by classical TGF-β signal pathway in NSCLC cells rather than NF-κB pathway reported in breast cancer. Gain and loss of function assays found that NKILA inhibited migration, invasion and viability of NSCLC cells. Mechanistic study showed that NKILA attenuated Snail expression via inhibiting the phosphorylation of IκBα and NF-κB activation, subsequently suppressed the expression of markers of epithelial-mesenchymal transition process.

Conclusions

The present study found that the expression of NKILA was downregulated in tumor tissues of NSCLC, which improved the metastasis of NSCLC patients. In vitro studies further clarified that the expression of NKILA was regulated through classical TGF-β signal pathway, which subsequently inhibited migration and invasion of NSCLC cells through interfering NF-κB/Snail signal pathway in NSCLC cells.

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Long non-coding RNA NKILA inhibits migration and invasion of non-small cell lung cancer via NF-κB/Snail pathway

Abstract

Background

Methods

Results

Conclusions

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Table of Content Volume 56, Number 6, June 2017

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Table of Content Volume 56, Number 6, June 2017

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Relationships between dispositional mindfulness, self-acceptance, perceived stress and psychological symptoms in advanced gastrointestinal cancer patients

Abstract

Objective

Previous studies have shown that dispositional mindfulness is associated with less psychological symptoms in cancer patients. The present study investigated how dispositional mindfulness is related to psychological symptoms in advanced gastrointestinal cancer patients by considering the roles of self-acceptance and perceived stress.

Methods

A total of 176 patients with advanced gastrointestinal cancer were recruited to complete a series of questionnaires including Mindfulness Attention Awareness Scale (MAAS), Self-acceptance Questionnaire (SAQ), Chinese Perceived Stress Scale (CPSS) and General Health Questionnaire (GHQ).

Results

Results showed that the proposed model fitted the data very well (χ² = 7.564, df = 7, p = 0.364, χ²/df = 1.094, GFI = 0.986, CFI = 0.998, TLI = 0.995, RMSEA = 0.023). Further analyses revealed that, self-acceptance and perceived stress mediated the relation between dispositional mindfulness and psychological symptoms (indirect effect = -0.052, 95% CI = -0.087 ~ -0.024), while self-acceptance also mediated the relation between dispositional mindfulness and perceived stress (indirect effect = -0.154, 95% CI = -0.261 ~ -0.079).

Conclusions

Self-acceptance and perceived stress played critical roles in the relation between dispositional mindfulness and psychological symptoms. Limitations, clinical implications, and directions for future research were discussed.

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