The dataset of duplex ultrasound assessment of the internal mammary artery in women with unilateral mastectomy followed by radiotherapy for breast cancer.

Adjuvant radiotherapy for breast cancer may involve some incidental exposure of the ipsilateral internal mammary artery to ionizing radiation. However, the relevant evidence is limited and inconsistent. The dataset presented in this article contains the information used to assess the effects of accidental radiation exposure on the internal mammary artery in patients with unilateral total mastectomy followed radiotherapy for breast cancer. The study population consists of two groups: the irradiated group and the control group. The left and right internal mammary arteries were assessed through the second intercostal spaces using a computed sonography system (Vivid S6; GE, Tirat Carmel, Israel) equipped with a 5.5 - 11 MHz transducer. The recorded parameters were the diameter, time-averaged maximum velocity, and blood flow of the internal mammary artery. The dataset contains two files of data: a raw and an analyzed data. The raw data file contains the individual information of each participant, including demographic characteristics and the parameters of the internal mammary artery duplex ultrasound imaging. The analyzed data file was made up of R Markdown, a markup language of R. The results of data analysis were presented in the related research article which has been accepted for publication in the Annals of Vascular Surgery. The dataset presented in this article may be reused for further studies in which the internal mammary artery is considered as potential donor or recipient vessels for a vascular bypass or free flap anastomosis.

Duplex Imaging Assessment of the Internal Mammary Arteries in Women after Unilateral Mastectomy and Radiotherapy for Breast Cancer.

BACKGROUND: The effects of incidental radiation exposure on internal mammary arteries remain unclear. The present study was designed to test the hypothesis by comparing diameter and blood flow of the irradiated and nonirradiated internal mammary arteries, using Duplex ultrasound imaging. METHODS: The study was designed as a single-center, transversal, comparative study. The main outcomes were diameter and volumetric blood flow of the internal mammary arteries. The Wilcoxon rank-sum test was used to assess the differences between the irradiated and nonirradiated internal mammary arteries with regard to the diameter and volumetric blood flow. RESULTS: The diameter (median [interquartile range]) of the irradiated internal mammary arteries (0.170 mm [0.160, 0.180]) was smaller than that of the contralateral nonirradiated ones (0.180 mm [0.170, 0.200], P < 0.0001) and that of the internal mammary arteries in the control group (0.180 mm [0.170, 0.190], P < 0.0001). Similarly, blood flow (median [interquartile range]) of the irradiated internal mammary arteries (52.4 ml/min [37.78, 65.57]) was smaller than that of the contralateral nonirradiated ones (62.7 ml/min [46.87, 84.17], P < 0.0001), as well as of the left (56.7 ml/min [46.88, 72.58], P = 0.02) and the right internal mammary arteries in the control group (61.0 ml/min [47.47, 74.52], P = 0 0.0009). CONCLUSIONS: The data indicate that the irradiated internal mammary arteries in patients with a history of total mastectomy followed by radiotherapy for breast cancer had significantly smaller diameter and blood flow compared to the nonirradiated internal mammary arteries.

[Study of immunophenotypic characteristics, clinicopathological parameters and prognosis in gastric cancer microenvironment].

Objective: To explore the immunophenotypic characteristics of gastric cancer microenvironment and analyze its correlation with clinicopathological parameters and prognosis of patients. Methods: The expression levels of leukocyte differentiation antigen (CD) 8, CD4, T lymphocyte immunoglobulin mucoprotein 3 (TIM3), human forkhead box protein P3 (Foxp3) and co-localized tumor infiltrating lymphocytes (TILs) were detected in 92 cases of gastric cancer tissue [58 males and 34 females; aged M(Q1, Q3), 70(59, 77) years ] and 84 cases of paracancer tissue [57 males and 27 females, aged 70(59, 77) years] purchased from Shanghai Xinchao Biotechnology Co., Ltd., and the samples were from 28 hospitals in the sample bank. Gastric cancer and adjacent tissues were divided into high expression group and low expression group according to the optimal cut-off value of positive lymphocytepercentage. The expression of immunophenotypes in gastric cancer and adjacent tissues was analyzed. Kaplan-Meier method was used for survival analysis. Cox proportional hazard model was used to explore the prognostic factors of gastric cancer patients. Results: The optimal cut-off values of CD8, CD4, TIM3 and Foxp3 positive cells in gastric cancer were 12.73%, 1.39%, 10.77% and 2.44%, respectively. The expression of Foxp3 in gastric cancer tissues was higher than that in paracancer tissues [M (Q1, Q3), 0.93 (0.45, 2.16) vs 0.31 (0.09, 0.86), P<0.001], and the expression of CD8 [4.92 (2.34, 8.80) vs 8.81 (6.61, 12.17), P<0.001], CD4 [4.79 (1.77, 11.36) vs 8.40 (4.84, 12.77), P=0.022] and TIM3 [5.68 (2.05, 11.58) vs 7.07 (3.13, 11.43), P=0.338] were lower than that in paracancer tissues. There were significant differences in TIM3 expression in gastric cancer patients with different lymph node metastasis and clinical stage (all P<0.05). The 5-year survival rate of patients with high CD4 expression, low TIM3 expression and low Foxp3 expression in gastric cancer tissues was poor, among which the high CD4 expression and low CD4 expression groups were 29.3% and 64.7%, respectively; The high and low TIM3 expression groups were 60.9% and 30.4%, respectively; The high and low Foxp3 expression groups were 64.3% and 33.3%, respectively (all P<0.05). The optimal cut-off values of CD8+TIM3+TILs, CD4+TIM3+TILs, CD8+Foxp3+TILs and CD4+Foxp3+TILs were 3.86%, 0.23%, 0.08% and 0.76%, respectively. Colocalization analysis showed that the expression of CD8+Foxp3+TILs in gastric cancer tissues was higher than that in adjacent tissues(all P<0.05). Multivariate Cox regression analysis showed that high expression of CD4 (HR=3.079, 95%CI: 1.350-7.024,P=0.008), low expression of TIM3 (HR=0.428, 95%CI: 0.208-0.879, P=0.021) and low expression of Foxp3 (HR=0.288, 95%CI: 0.121-0.687, P=0.005) were the influencing factor for the 5-year survival rate of patients with gastric cancer after operation. Conclusions: Gastric cancer tissues have complex immune microenvironment characteristics. The expression of CD4, TIM3 and Foxp3 is closely related to the prognosis of patients.

Validation of a three-dimensionally printed simulator for training in endoscopic sinonasal surgery.

BACKGROUND: The ability to incorporate different materials in the construction of 3-D printed models has resulted in the ability to mimic a variety of anatomical structures such as cartilage, mucosa and bone. The aim of this study was to evaluate the face and content validities of a model as a training tool for endoscopic sinus surgery. METHODS: Twenty-six delegates and ten teaching faculty members were invited to complete a post-hoc questionnaire survey. The survey consisted of a 22-question 5-point Likert scale to assess the model's realism (face validity) and its effectiveness as a training tool (content validity). RESULTS: Over 80% of the delegates agreed or strongly agreed that the appearance of anatomical structures within the model was realistic and mimicked actual sinus anatomy. In addition, a similar proportion agreed or strongly agreed that the application of instruments on the composite materials of the model realistically mimicked bone. All faculty agreed that the model was useful to develop hand-eye coordination and was a useful training tool for endoscopic sinus surgery. Overall, the sinus model received high scores regarding its use for training surgeons, especially to develop camera and instrument handling skills. CONCLUSION: The results of this study suggest that otolaryngology doctors in their early or intermediate stage of training would benefit most from a clinical-based modular programme. The model requires further development in areas such as the realism of mucosa, incorporation of sinonasal pathology and having more complex anatomy to be useful for the training of more advanced surgeons.

The role of pleural fluid lactate dehydrogenase-to-adenosine deaminase ratio in differentiating the etiology of pleural effusions.

Exudative pleural effusion includes tuberculous pleural effusion (TPE), parapneumonic pleural effusion (PPE), and malignant pleural effusion (MPE). An elevated pleural fluid adenosine deaminase (ADA) typically implies TPE, but the rule may not apply to every individual case. Recent studies proposed that the pleural fluid lactate dehydrogenase (LDH)-to-ADA ratio showed a higher diagnostic power than pleural fluid ADA alone in differentiating the etiology of pleural effusion. Hence, we aimed to investigate the performance of pleural fluid LDH-to-ADA ratio as a biomarker in assistance with the diagnosis of TPE, PPE, and MPE. All patients who underwent thoracentesis for the first time with a pleural fluid ADA >40 U/L were included in this retrospective study. The clinical data including pleural fluid ADA and LDH-to-ADA ratio were analyzed. A total of 311 patients were enrolled during the study interval. The pleural fluid LDH-to-ADA ratio <14.2 (sensitivity: 74.2%; specificity: 90.4%) favored TPE, while the pleural fluid LDH-to-ADA ratio >14.5 (sensitivity: 79.9%; specificity: 78.5%) favored PPE. Besides, the pleural fluid LDH-to-ADA ratio >46.7 (sensitivity: 56.3%; specificity: 78.3%) favored MPE owing to primary lung cancers. In conclusion, the pleural fluid LDH-to-ADA ratio was an effective indicator in differentiating the etiology of pleural effusions in the cases of high ADA level in the pleural fluid.

Outage Analysis of the Power Splitting Based Underlay Cooperative Cognitive Radio Networks.

In the present paper, we investigate the performance of the simultaneous wireless information and power transfer (SWIPT) based cooperative cognitive radio networks (CCRNs). In particular, the outage probability is derived in the closed-form expressions under the opportunistic partial relay selection. Different from the conventional CRNs in which the transmit power of the secondary transmitters count merely on the aggregate interference measured on the primary networks, the transmit power of the SWIPT-enabled transmitters is also constrained by the harvested energy. As a result, the mathematical framework involves more correlated random variables and, thus, is of higher complexity. Monte Carlo simulations are given to corroborate the accuracy of the mathematical analysis and to shed light on the behavior of the OP with respect to several important parameters, e.g., the transmit power and the number of relays. Our findings illustrate that increasing the transmit power and/or the number of relays is beneficial for the outage probability.

Diversity of cultivable endophytic fungi in two Rubia plants and their potential for production of anti-tumour Rubiaceae-type cyclopeptides.

Rubia plants are one of the most important plant resources possessing significant commercial and medicinal values. Plant endophytes could benefit their host plants in different ways. Rubiaceae-type cyclopeptides (RAs), mainly isolated from Rubia plants, have attracted considerable attentions for their distinctive bicyclic structures and significant antitumor activities, but their contents in plants are low. The aim of this study is to investigate the diversity of endophytic fungi in Rubia plants and their potential for production of RAs. In this work, 143 endophytic fungi isolates were obtained from two Rubia plants. Phylogenetic analysis was performed based on the ITS rDNA sequences, and the isolates were classified into 29 genera. Among them, four endophytic fungal strains were found to produce anti-tumour RAs by LC-MS/MS analysis. This work successfully provides valuable knowledges of endophytic fungi microbiome in Rubia plants for agricultural and industrial applications, and exploits a new environmental-friendly resource of RAs.

HIV-associated neurocognitive impairment in stable people living with HIV on ART in rural Tanzania.

OBJECTIVES: Few studies have assessed cognitive impairment among healthy people living with HIV (PLWH) who are stable on antiretroviral treatment (ART) in sub-Saharan Africa. METHODS: We conducted a cross-sectional study among a random sample of stable adult PLWH from rural Tanzania on ART for more than 1 year and without immunological failure or pre-existing neurological disease. We evaluated the prevalence and risk factors for neurocognitive impairment (NCI), assessed through neuropsychological tests, functional and depression questionnaires and defined as a mean Z-score ≤ -1 in two or more cognitive domains. RESULTS: Among 243 participants [median age = 44.3 years (interquartile range: 36-52] and 71% female] we found a rate of NCI of 19.3% (95% confidence interval: 14.8-24.8%). Memory and psychomotor domains demonstrated the highest impairment. Independent predictors of NCI were age and self-reported alcohol use. Other classical risk factors were not associated with HIV-associated NCI. CONCLUSION: Despite effective ART roll-out, NCI remained a prevalent condition in this healthy rural Tanzanian population of PLWH on ART. Age and alcohol use were key risk factors.

Circular RNA circ_0000034 upregulates STX17 level to promote human retinoblastoma development via inhibiting miR-361-3p.

OBJECTIVE: Retinoblastoma (RB) is a common intraocular tumor of infancy and childhood. Circular RNAs (circRNAs) are related to the development of RB. The purpose of this research was to reveal the functional mechanism of circRNA circ_0000034 in RB. MATERIALS AND METHODS: Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Western blot were applied to determine the levels of genes. MTT assay and flow cytometry were employed to assess cell proliferation and apoptosis rate, respectively. Furthermore, cell migratory and invasive abilities were measured using the transwell assay. Mouse xenograft was conducted to analyze the effect of circ_0000034 on tumor growth in vivo. Besides, the interaction between miR-361-3p and circ_0000034 or syntaxin 17 (STX17) was predicted by starBase, and then, confirmed by the Dual-Luciferase reporter assay and RNA immunoprecipitation (RIP) assay. RESULTS: The levels of circ_0000034 and STX17 were increased and miR-361-3p level was decreased in RB tissues and cells. Circ_0000034 knockdown suppressed cell proliferation, migration, invasion, autophagy, and tumor growth, and induced apoptosis in RB. Circ_0000034 targeted miR-361-3p and miR-361-3p bound to STX17. Circ_0000034 overexpression and miR-361-3p knockdown reversed the effect of miR-361-3p upregulation and STX17 depletion on the growth of RB cells, respectively. Besides, circ_0000034 elevated STX17 level by repressing miR-361-3p expression. CONCLUSIONS: We demonstrated that circ_0000034 knockdown suppressed the development of RB by the modulation of miR-361-3p/STX17 axis. Our findings provided a theoretical basis for the treatment of RB.

Extended endoscopic approaches to the maxillary sinus.

OBJECTIVES: Treatment of inflammatory and neoplastic disease in the maxillary sinus, pterygopalatine and infratemporal fossae requires appropriate surgical exposure. As modern rhinology evolves, so do the techniques available. This paper reviews extended endoscopic approaches to the maxillary sinus and the evidence supporting each technique. METHODS: A literature search of the Ovid Medline and PubMed databases was performed using appropriate key words relating to endoscopic approaches to the maxillary sinus. RESULTS: Mega-antrostomy and medial maxillectomy have a role in the surgical treatment of refractory inflammatory disease and sinonasal neoplasms. The pre-lacrimal fossa approach provides excellent access but can be limited because of anatomical variations. Both the transseptal and endoscopic Denker's approaches were reviewed; these appear to be associated with morbidity, without any significant increase in exposure over the afore-described approaches. CONCLUSION: A range of extended endoscopic approaches to the maxillary sinus exist, each with its own anatomical limitations and potential complications.

Cloning, overexpression, purification, and modeling of a lectin (Rhinocelectin) with antiproliferative activity from Tiger Milk Mushroom, Lignosus rhinocerus.

A lectin gene from the Tiger Milk Mushroom Lignosus rhinocerus TM02® was successfully cloned and expressed via vector pET28a in Escherichia coli BL21(DE3). The recombinant lectin, Rhinocelectin, with a predicted molecular mass of 22.8 kDa, was overexpressed in water-soluble form without signal peptide and purified via native affinity chromatography Ni-NTA agarose. Blast protein analysis indicated the lectin to be homologous to jacalin-related plant lectin. In its native form, Rhinocelectin exists as a homo-tetramer predicted with four chains of identical proteins consisting of 11 beta-sheet structures with only one alpha-helix structure. The antiproliferative activity of the Rhinocelectin against human cancer cell lines was concentration dependent and selective. The IC50 values against triple negative breast cancer cell lines MDA-MB-231 and breast cancer MCF-7 are 36.52 ± 13.55 µg mL-1 and 53.11 ± 22.30 µg mL-1 , respectively. Rhinocelectin is only mildly cytotoxic against the corresponding human nontumorigenic breast cell line 184B5 with IC50 value at 142.19 ± 36.34 µg mL-1 . The IC50 against human lung cancer cell line A549 cells is 46.14 ± 7.42 µg mL-1 while against nontumorigenic lung cell line NL20 is 41.33 ± 7.43 µg mL-1 . The standard anticancer drug, Doxorubicin exhibited IC50 values mostly below 1 µg mL-1 for the cell lines tested. Flow cytometry analysis showed the treated breast cancer cells were arrested at G0/G1 phase and apoptosis induced. Rhinocelectin agglutinated rat and rabbit erythrocytes at a minimal concentration of 3.125 µg mL-1 and 6.250 µg mL-1 , respectively.

Sleep disordered breathing and dysphonia in a pediatric patient - Laryngeal amyloidosis as an unusual diagnosis.

Primary laryngeal amyloidosis is an uncommon condition, and cases in the pediatric population are even rarer. We present a case of a nine year old female patient who presented with sleep disordered breathing and dysphonia to our outpatient clinic. The patient underwent Microlaryngoscopy and Bronchoscopy for diagnosis which identified a large soft tissue mass in the supraglottis. After Histological diagnosis was made, she had subtotal debridement of the mass and has maintained a good exercise tolerance with no airway compromise.

A rapidly fatal intracranial anaplastic hemangiopericytoma with de-novo dedifferentiation: emphasis on diagnostic recognition, molecular confirmation and discussion on treatment dilemma.

Solitary fibrous tumors/ hemangiopericytomas (SFT/HPC) are mesenchymal tumors that share a common genetic aberration and very rarely undergo dedifferentiation. We report a unique case of an intracranial anaplastic SFT/HPC with de-novo dedifferentiation, which pursued a rapidly fatal clinical course in a 41-year-old lady. The dedifferentiated component comprised a focal area of glandular formation with epithelial immunophenotype acquisition. The distinct biphasic pattern of the tumor imparted great diagnostic challenges to the pathologists. An increased awareness of SFT/HPCs with a diverse morphologic spectrum or even a biphasic histologic pattern is essential in working up such cases. We first attempted gamma knife radiosurgery in treating a recurrent dedifferentiated SFT/HPC; unfortunately it was to no avail. Although it is now known that SFT/HPC is characterized by NAB2-STAT6 gene fusion, the unavailability of targeted therapy against this molecular signature still results in a treatment dilemma.

Giant cell arteritis in patients of Indian Subcontinental descent in the UK.

BACKGROUND: GCA in the Indian Subcontinent (ISC) is rare. Our centre in London, UK, serves an ethnically diverse population, including a significant population of patients of ISC descent. We hypothesise that patients of ISC descent are no less likely than others to present with symptoms suggestive of GCA and therefore to undergo temporal artery biopsy (TAB). METHOD: A retrospective audit of all TABs performed at our institution over an 8 year period, to identify ethnicity (white, black, ISC, other, unknown) and biopsy result. We compared the proportion of all patients of ISC descent attending the ED to the proportion of ISC patients undergoing TAB. We compared the proportion of positive TABs among ISC patients with positive TABs among white patients. We also compared the proportion of TAB in ISC patients with all non-ISC ethnicities combined. RESULTS: The proportion of patients undergoing TAB who were of ISC descent (16.3% of 92) was comparable to the proportion of A&E attendances made up by ISC patients [p = 0.1339]. 3.8% (1/26) of positive biopsies were among patients of ISC descent. White patients were significantly more likely to have a positive biopsy than patients of ISC ethnicity (33% of 61 white patients vs. 7% of 15 ISC [p = 0.0456]), as were patients of non-ISC ethnicity (32.5% of 77 non-ISC patients vs. 7% of 15 ISC patients [p = 0.0464]). DISCUSSION: At our centre, biopsy proven GCA occurs in patients of ISC descent, but rarely. Full investigation for GCA continues to be appropriate where it is suspected, regardless of ethnicity.

Secrecy Performance Enhancement for Underlay Cognitive Radio Networks Employing Cooperative Multi-Hop Transmission with and without Presence of Hardware Impairments.

In this paper, we consider a cooperative multi-hop secured transmission protocol to underlay cognitive radio networks. In the proposed protocol, a secondary source attempts to transmit its data to a secondary destination with the assistance of multiple secondary relays. In addition, there exists a secondary eavesdropper who tries to overhear the source data. Under a maximum interference level required by a primary user, the secondary source and relay nodes must adjust their transmit power. We first formulate effective signal-to-interference-plus-noise ratio (SINR) as well as secrecy capacity under the constraints of the maximum transmit power, the interference threshold and the hardware impairment level. Furthermore, when the hardware impairment level is relaxed, we derive exact and asymptotic expressions of end-to-end secrecy outage probability over Rayleigh fading channels by using the recursive method. The derived expressions were verified by simulations, in which the proposed scheme outperformed the conventional multi-hop direct transmission protocol.

Predicting the Outcomes of New Short-Course Regimens for Multidrug-Resistant Tuberculosis Using Intrahost and Pharmacokinetic-Pharmacodynamic Modeling.

Short-course regimens for multidrug-resistant tuberculosis (MDR-TB) are urgently needed. Limited data suggest that the new drug bedaquiline (BDQ) may have the potential to shorten MDR-TB treatment to less than 6 months when used in conjunction with standard anti-TB drugs. However, the feasibility of BDQ in shortening MDR-TB treatment duration remains to be established. Mathematical modeling provides a platform to investigate different treatment regimens and predict their efficacy. We developed a mathematical model to capture the immune response to TB inside a human host environment. This model was then combined with a pharmacokinetic-pharmacodynamic model to simulate various short-course BDQ-containing regimens. Our modeling suggests that BDQ could reduce MDR-TB treatment duration to just 18 weeks (4 months) while still maintaining a very high treatment success rate (100% for daily BDQ for 2 weeks, or 95% for daily BDQ for 1 week during the intensive phase). The estimated time to bacterial clearance of these regimens ranges from 27 to 33 days. Our findings provide the justification for empirical evaluation of short-course BDQ-containing regimens. If short-course BDQ-containing regimens are found to improve outcomes, then we anticipate clear cost savings and a subsequent improvement in the efficiency of national TB programs.

Targeting nuclear receptors in cancer-associated fibroblasts as concurrent therapy to inhibit development of chemoresistant tumors.

Most anticancer therapies to date focus on druggable features of tumor epithelia. Despite the increasing repertoire of treatment options, patient responses remain varied. Moreover, tumor resistance and relapse remain persistent clinical challenges. These observations imply an incomplete understanding of tumor heterogeneity. The tumor microenvironment is a major determinant of disease progression and therapy outcome. Cancer-associated fibroblasts (CAFs) are the dominant cell type within the reactive stroma of tumors. They orchestrate paracrine pro-tumorigenic signaling with adjacent tumor cells, thus exacerbating the hallmarks of cancer and accelerating tumor malignancy. Although CAF-derived soluble factors have been investigated for tumor stroma-directed therapy, the underlying transcriptional programs that enable the oncogenic functions of CAFs remain poorly understood. Nuclear receptors (NRs), a large family of ligand-responsive transcription factors, are pharmacologically viable targets for the suppression of CAF-facilitated oncogenesis. In this study, we defined the expression profiles of NRs in CAFs from clinical cutaneous squamous cell carcinoma (SCC) biopsies. We further identified a cluster of driver NRs in CAFs as important modifiers of CAF function with profound influence on cancer cell invasiveness, proliferation, drug resistance, energy metabolism and oxidative stress status. Importantly, guided by the NR profile of CAFs, retinoic acid receptor ß and androgen receptor antagonists were identified for concurrent therapy with cisplatin, resulting in the inhibition of chemoresistance in recurred SCC:CAF xenografts. Our work demonstrates that treatments targeting both the tumor epithelia and the surrounding CAFs can extend the efficacy of conventional chemotherapy.

Recellularization of decellularized adipose tissue-derived stem cells: role of the cell-secreted extracellular matrix in cellular differentiation.

Adipose-derived stem cells (ASCs) are found in a location within the adipose tissue known as the stem cell niche. The ASCs in the niche are maintained in the quiescent state, and upon exposure to various microenvironmental triggers are prompted to undergo proliferation or differentiation. These microenvironmental triggers also modulate the extracellular matrix (ECM), which interacts with the cells through the cytoskeleton and induces downstream events inside the cells that bring about a change in cell behaviour. In response to these changes, the cells remodel the ECM, which will differ according to the type of tissue being formed by the cells. As the ECM itself plays an important role in the regulation of cellular differentiation, this study aims to explore the role of the cell-secreted ECM at various stages of differentiation of stem cells in triggering the differentiation of ASCs. To this end, the ASCs cultured in proliferation, osteogenic and adipogenic media were decellularized and the secreted ECM was characterized. Overall, it was found that osteo-differentiated ASCs produced higher amounts of collagen and glycosaminoglycans (GAG) compared to the undifferentiated and adipo-differentiated ASCs. The two types of differentiated ECMs were subsequently shown to trigger initial but not terminal differentiation of ASCs into osteo- and adipo-lineages respectively, as indicated by the upregulation of lineage specific markers. In addition, integrin subunits alpha (α) 6 and integrin beta (ß) 1 were found to be produced by ASCs cultured on cell-secreted ECM-coated substrates, suggesting that the integrins α6 and ß1 play an instrumental role in cell-ECM interactions. Taken together, this study demonstrates the importance of the ECM in cellular fate decisions and how ECM-coated substrates can potentially be used for various tissue engineering applications.

Elevation of adenylate energy charge by angiopoietin-like 4 enhances epithelial-mesenchymal transition by inducing 14-3-3γ expression.

Metastatic cancer cells acquire energy-intensive processes including increased invasiveness and chemoresistance. However, how the energy demand is met and the molecular drivers that coordinate an increase in cellular metabolic activity to drive epithelial-mesenchymal transition (EMT), the first step of metastasis, remain unclear. Using different in vitro and in vivo EMT models with clinical patient's samples, we showed that EMT is an energy-demanding process fueled by glucose metabolism-derived adenosine triphosphate (ATP). We identified angiopoietin-like 4 (ANGPTL4) as a key player that coordinates an increase in cellular energy flux crucial for EMT via an ANGPTL4/14-3-3γ signaling axis. This augmented cellular metabolic activity enhanced metastasis. ANGPTL4 knockdown suppresses an adenylate energy charge elevation, delaying EMT. Using an in vivo dual-inducible EMT model, we found that ANGPTL4 deficiency reduces cancer metastasis to the lung and liver. Unbiased kinase inhibitor screens and Ingenuity Pathway Analysis revealed that ANGPTL4 regulates the expression of 14-3-3γ adaptor protein via the phosphatidylinositol-3-kinase/AKT and mitogen-activated protein kinase signaling pathways that culminate to activation of transcription factors, CREB, cFOS and STAT3. Using a different mode of action, as compared with protein kinases, the ANGPTL4/14-3-3γ signaling axis consolidated cellular bioenergetics and stabilized critical EMT proteins to coordinate energy demand and enhanced EMT competency and metastasis, through interaction with specific phosphorylation signals on target proteins.