The regulation network consisting of microRNAs (miRNAs) and their target genes remains largely elusive in hepatocellular carcinoma (HCC), especially the reciprocal loop between specific miRNAs and the miRNA processing machinery. In this study, we found that miR-99a was remarkably decreased in 111 of 152 (73.03%) primary HCC tissues and low-level expression of miR-99a was correlated with low tumor differentiation (P=0.001), liver cirrhosis (P=0.015), poor tumor-free survival (P=0.004) and overall survival (P=0.006) for HCC patients. By restoration of miR-99a, the HCC growth could be considerably inhibited both in vitro and in vivo. Subsequently, Argonaute-2 (Ago2), a central component of RNA-induced silencing complex, was found to be directly regulated by miR-99a via translational repression. Overexpression of Ago2 could partly impair the inhibitory effect of miR-99a on HCC cells in vitro. Then, we demonstrated that Ago2 was upregulated in HCC tissues at both RNA and protein levels and the expression of AGO2 protein and miR-99a was negatively correlated within detected HCC tissues (r=−0.727, P=0.004). Interestingly, the tumorigenicity of Ago2-knockdown HCC cells was severely impaired (4/10 vs 10/10, P<0.05), and this was in contrast to the miR-99a-overexpressing HCC cells. Functionally, the increased AGO2 protein could specifically facilitate oncogenic miR-21 to repress its targeted gene phosphatase and tensin homolog (Pten) in HCC, whereas leave the regulatory capacity of let-7a on its targeted oncogenes almost unaltered. In summary, our study has revealed a novel pathway for the tumor suppressor miR-99a to control tumor growth in HCC, via its downstream signaling of AGO2/miR-21/PTEN. In addition, this study provides potential strategies for HCC therapy by reintroduction of miRNA suppressors.
Hepatocellular carcinoma; miR-99a; AGO2; PTEN
Laparoscopic radical cystectomy (LRC) is increasingly being used for muscle-invasive bladder cancer. However, high levels of clinical evidence comparing laparoscopic vs open radical cystectomy (ORC) are lacking.
A prospective randomised controlled clinical trial comparing LRC vs ORC in patients undergoing radical cystectomy for bladder cancer. Thirty-five patients were eligible for final analysis in each group.
The median follow-up was 26 months (range, 4–59 months) for laparoscopic vs 32 months (range, 6–60 months) for ORC. Significant differences were noted in operative time, estimated blood loss (EBL), blood transfusion rate, analgesic requirement, and time to resumption of oral intake. No significant differences were noted in the length of hospital stay, complication rate, lymph node yield (14.1±6.3 for LRC and 15.2±5.9 for ORC), positive surgical margin rate, postoperative pathology, or recurrence rate (7 for LRC and 8 for ORC). The 5-year recurrence-free survival with laparoscopic vs ORC was 78.5% vs 70.9%, respectively (P=0.773). The overall survival with laparoscopic vs ORC was 73.8% vs 67.4%, respectively (P=0.511).
Our study demonstrated that LRC is superior to ORC in perioperative outcomes, including EBL, blood transfusion rate, and analgesic requirement. We found no major difference in oncologic outcomes. The number of patients is too small to allow for a final conclusion.
bladder cancer; laparoscopic radical cystectomy; open radical cystectomy; orthotopic ileal neobladder; randomised controlled study
Cancer stem cells (CSCs) are responsible for tumor initiation and progression. Toll-like receptors (TLRs) are highly expressed in cancer cells and associated with poor prognosis. However, a linkage between CSCs and TLRs is unclear, and potential intervention strategies to prevent TLR stimulation-induced CSC formation and underlying mechanisms are lacking. Here, we demonstrate that stimulation of toll-like receptor 3 (TLR3) promotes breast cancer cells toward a CSC phenotype in vitro and in vivo. Importantly, conventional NF-κB signaling pathway is not exclusively responsible for TLR3 activation-enriched CSCs. Intriguingly, simultaneous activation of both β-catenin and NF-κB signaling pathways, but neither alone, is required for the enhanced CSC phenotypes. We have further identified a small molecule cardamonin that can concurrently inhibit β-catenin and NF-κB signals. Cardamonin is capable of effectively abolishing TLR3 activation-enhanced CSC phenotypes in vitro and successfully controlling TLR3 stimulation-induced tumor growth in human breast cancer xenografts. These findings may provide a foundation for developing new strategies to prevent the induction of CSCs during cancer therapies.
Many advanced applications of X-ray free-electron lasers require pulse durations and time resolutions of only a few femtoseconds. To generate these pulses and to apply them in time-resolved experiments, synchronization techniques that can simultaneously lock all independent components, including all accelerator modules and all external optical lasers, to better than the delivered free-electron laser pulse duration, are needed. Here we achieve all-optical synchronization at the soft X-ray free-electron laser FLASH and demonstrate facility-wide timing to better than 30 fs r.m.s. for 90 fs X-ray photon pulses. Crucially, our analysis indicates that the performance of this optical synchronization is limited primarily by the free-electron laser pulse duration, and should naturally scale to the sub-10 femtosecond level with shorter X-ray pulses.
Few-femtosecond synchronization at free-electron lasers is key for nearly all experimental applications, stable operation and future light source development. Here, Schulz et al. demonstrate all-optical synchronization of the soft X-ray FEL FLASH to better than 30 fs and illustrate a pathway to sub-10 fs.
Patients with relapsed/refractory leukemias or advanced myelodysplastic syndrome (MDS) fare poorly following allogeneic hematopoietic cell transplant (HCT). We report prospective phase II study results of 29 patients given clofarabine 30 mg/m2/day i.v. × 5 days followed immediately by HCT conditioning while at the cytopenic nadir. A total of 15/29 patients (52%) were cytoreduced according to pre-defined criteria (cellularity < 20% and blasts < 10%). Marrow cellularity (P < 0.0001) and blast% (P = 0.03) were reduced. Toxicities were acceptable, with transient hyperbilirubinemia (48%) and gr3–4 infections (10%). In all, 28/29 proceeded to transplant; 27 received ATG or alemtuzumab. Post HCT, 180 day non-relapse mortality (NRM) was 7% (95% confidence interval (CI): 1–21), relapse was 29% (95% CI: 13–46) and OS was 71% (95% CI: 51–85), comparing favorably to published data for high-risk patients. Two-year graft vs host disease incidence was 40% (95% CI: 21–58) and 2 year OS was 31% (95% CI: 14–48). Disease at the nadir correlated with inferior OS after HCT (HR = 1.22 for each 10% marrow blasts, 95% CI: 1.02–1.46). For AML/MDS patients, there was a suggestion that successful cytoreduction increased PFS (330 vs 171 days, P = 0.3) and OS (375 vs 195 days, P = 0.31). Clofarabine used as a bridge to HCT reduces disease burden, is well tolerated, and permits high-risk patients to undergo HCT with acceptable NRM. Late relapses are common; thus, additional strategies should be pursued. NCT-00724009.
allo-SCT; relapsed leukemia; AML; bridge therapy; myelodysplastic syndrome
Interferon-γ (IFN-γ), a pleiotropic lymphokine, has important regulatory effects on many cell types. Although IFN-γ is essential for the initiation of uterine vascular modifications and maintenance of decidual integrity, IFN-γ administration can also cause pregnancy failure in many species. However, little is known about the effector mechanisms involved. In this study, using an IFN-γ-induced abortion mouse model, we reported that no Dolichos biflorus agglutinin lectin-positive uterine natural killer (uNK) cells were observed in the uteri from IFN-γ-induced abortion mice. By contrast, the percentage of CD3−CD49b+ NK cells in the uterus and blood from a foetal resorption group was significantly higher than that of the control group. Similarly, significantly upregulated expression of CD49b (a pan-NK cell marker), CX3CL1 and CX3CR1 (CX3CL1 receptor) was detected in the uteri of IFN-γ-induced abortion mice. Using isolated uterine stromal cells, we showed that upregulated expression of CX3CL1 by IFN-γ was dependent on a Janus family kinase 2-signal transducers and activators of transcription 1 (JAK2-STAT1) pathway. We further demonstrated the chemotactic activity of CX3CL1 in uterine stromal cell conditioned medium on primary splenic NK cells. Finally, we observed increased recruitment of CD49b+ NK cells into the endometrium after exogenous CX3CL1 administration. Collectively, our findings indicate that IFN-γ can significantly increase uterine CX3CL1 expression via activation of the JAK2-STAT1 pathway, thus inducing CD49b+ NK cell uterine homing, and eventually provoke foetal loss. Thus, we provide a new line of evidence correlating the deleterious effects of IFN-γ on pregnancy with the aberrant regulation of CX3CL1 and CD49b+ NK cells.
p73, a member of the p53 tumor suppressor family, is involved in neurogenesis, sensory pathways, immunity, inflammation, and tumorigenesis. How p73 is able to participate in such a broad spectrum of different biological processes is still largely unknown. Here, we report a novel role of p73 in regulating lipid metabolism by direct transactivation of the promoter of autophagy-related protein 5 (ATG5), a gene whose product is required for autophagosome formation. Following nutrient deprivation, the livers of p73-deficient mice demonstrate a massive accumulation of lipid droplets, together with a low level of autophagy, suggesting that triglyceride hydrolysis into fatty acids is blocked owing to deficient autophagy (macrolipophagy). Compared with wild-type mice, mice functionally deficient in all the p73 isoforms exhibit decreased ATG5 expression and lower levels of autophagy in multiple organs. We further show that the TAp73α is the critical p73 isoform responsible for inducing ATG5 expression in a p53-independent manner and demonstrate that ATG5 gene transfer can correct autophagy and macrolipophagy defects in p73-deficient hepatocytes. These data strongly suggest that the p73–ATG5 axis represents a novel, key pathway for regulating lipid metabolism through autophagy. The identification of p73 as a major regulator of autophagy suggests that it may have an important role in preventing or delaying disease and aging by maintaining a homeostatic control.
ATG5; autophagy; lipid droplets; lipophagy; liver; metabolism; p73; starvation; transcription
The adult fungiform taste papilla is a complex of specialized cell types residing in the stratified squamous tongue epithelium. This unique sensory organ includes taste buds, papilla epithelium and lateral walls that extend into underlying connective tissue to surround a core of lamina propria cells. Fungiform papillae must contain long-lived, sustaining or stem cells and short-lived, maintaining or transit amplifying cells that support the papilla and specialized taste buds. Shh signaling has established roles in supporting fungiform induction, development and patterning. However, for a full understanding of how Shh transduced signals act in tongue, papilla and taste bud formation and maintenance, it is necessary to know where and when the Shh ligand and pathway components are positioned. We used immunostaining, in situ hybridization and mouse reporter strains for Shh, Ptch1, Gli1 and Gli2-expression and proliferation markers to identify cells that participate in hedgehog signaling. Whereas there is a progressive restriction in location of Shh ligand-expressing cells, from placode and apical papilla cells to taste bud cells only, a surrounding population of Ptch1 and Gli1 responding cells is maintained in signaling centers throughout papilla and taste bud development and differentiation. The Shh signaling targets are in regions of active cell proliferation. Using genetic-inducible lineage tracing for Gli1-expression, we found that Shh-responding cells contribute not only to maintenance of filiform and fungiform papillae, but also to taste buds. A requirement for normal Shh signaling in fungiform papilla, taste bud and filiform papilla maintenance was shown by Gli2 constitutive activation. We identified proliferation niches where Shh signaling is active and suggest that epithelial and mesenchymal compartments harbor potential stem and/or progenitor cell zones. In all, we report a set of hedgehog signaling centers that regulate development and maintenance of taste organs, the fungiform papilla and taste bud, and surrounding lingual cells. Shh signaling has roles in forming and maintaining fungiform papillae and taste buds, most likely via stage-specific autocrine and/or paracrine mechanisms, and by engaging epithelial/mesenchymal interactions.
fungiform papilla; papilla placode; paracrine signaling; stem cells; taste cell progenitors; Ptch; Gli1; Gli2
In mammalian ovaries, follicular atresia occurs periodically and destroys almost all the follicles in the ovary. Follicle-stimulating hormone (FSH) acts as the primary survival factor during follicular atresia by preventing apoptosis in granulosa cells. FoxO1 is a critical factor in promoting follicular atresia and granulosa cell apoptosis. FSH inhibits the induction of FoxO1. In this report, we investigated the role of FSH-FoxO1 pathway in mouse follicular atresia. FSH dampened stress-induced apoptosis and the expression of FoxO1 and pro-apoptosis genes in mouse granulosa cells (MGCs). In contrast, overexpression of FoxO1 inhibited the viability of MGCs and induced the expression of endogenous FoxO1. The signaling cascades involved in regulating FoxO1 activity upon FSH treatment were identified using FSH signaling antagonists. Blocking protein kinase A (PKA), phosphatidylinositol-3 kinase (PI3K) or protein kinase B (AKT) restored the upregulation of FoxO1 and apoptotic signals, which was suppressed by FSH. Moreover, inhibition of PKA or PI3K impaired FSH-induced AKT activity, but inactivation of PI3K or AKT had little effect on PKA activity in the presence of FSH. Correspondingly, constitutive activation of FoxO1 (all three AKT sites were replaced by alanines) also promoted MGC apoptosis despite FSH administration. Furthermore, both luciferase reporter assays and chromatin immunoprecipitation assays showed that FoxO1 directly bound to a FoxO-recognized element site within the FoxO1 promoter and contributed to the regulation of FoxO1 expression in response to FSH. Taken together, we propose a novel model in which FSH downregulates FoxO1-dependent apoptosis in MGCs by coordinating the PKA–PI3K–AKT–FoxO1 axis and FoxO1–FoxO1 positive feedback.
In this work, the electronic properties of phosphorene nanoribbons with different width and edge configurations are studied by using density functional theory. It is found that the armchair phosphorene nanoribbons are semiconducting while the zigzag nanoribbons are metallic. The band gaps of armchair nanoribbons decrease monotonically with increasing ribbon width. By passivating the edge phosphorus atoms with hydrogen, the zigzag series also become semiconducting, while the armchair series exhibit a larger band gap than their pristine counterpart. The electronic transport properties of these phosphorene nanoribbons are then investigated using Boltzmann theory and relaxation time approximation. We find that all the semiconducting nanoribbons exhibit very large values of Seebeck coefficient and can be further enhanced by hydrogen passivation at the edge. Taking pristine armchair nanoribbons and hydrogen-passivated zigzag naoribbons with width N = 7, 8, 9 as examples, we calculate the lattice thermal conductivity with the help of phonon Boltzmann transport equation and evaluate the width-dependent thermoelectric performance. Due to significantly enhanced Seebeck coefficient and decreased thermal conductivity, we find that at least one type of phosphorene nanoribbons can be optimized to exhibit very high figure of merit (ZT values) at room temperature, which suggests their appealing thermoelectric applications.
Background. Cisplatin and carboplatin cause nephrotoxicity by forming platinum-DNA adducts and lead to cell death. Methods. One-hundred and sixteen Taiwanese lung cancer patients who received cisplatin or carboplatin more than twice were recruited, and their genotypes were determined. The risk of renal dysfunction, injury to the kidney, failure of kidney function, loss of kidney function, and end-stage kidney disease (RIFLE) criteria were used to evaluate the occurrence of nephrotoxicity. A logistic regression, multiple regression with a classification and regression tree (CART), and the Framingham study risk score were used to analyze interactions between genetic and nongenetic factors in producing platinum-induced nephrotoxicity. Results. ERCC1 118C and TP53 72Arg polymorphisms were associated with increased risks of platinum-induced nephrotoxicity. Other risk factors found included the platinum type, baseline serum creatinine (Scr), coadministration of vinorelbine, and the number of chemotherapy cycles. The overall prediction rate of the CART was 82.7%, with a sensitivity of 0.630 and specificity of 0.896. The Framingham study risk prediction model contained 7 factors. Its prediction rate was 84.5%, with a sensitivity of 0.643 and specificity of 0.909. Conclusions. Genetic polymorphisms of ERCC1 and TP53 are risk factors for nephrotoxicity. The CART analysis may provide a clinically applicable model to predict the risk of cisplatin- and carboplatin-induced nephrotoxicity.
We investigated the value of lung perfusion imaging in predicting the risk of developing pulmonary complications after chemoradiation (CRT) or RT for lung cancer.
Fifty patients who underwent lung perfusion imaging prior to RT for lung cancer were included. Planar and SPECT/CT images of the lungs were obtained. Lung perfusion score (LPS) was developed to visually grade localized perfusion defect per lung on a scale of 0-4 and perfusion pattern in the remaining lungs on a scale of 1-4. The LPS is the sum of the score for the localized perfusion defect in each lung plus the score for the remaining lungs perfusion. LPSs were correlated with pulmonary function tests (PFT) and the patients were followed for 8 months after therapy to determine the incidence of grade 2 to 5 symptomatic therapy related pulmonary complications according to the common terminology criteria for adverse events (CTCAE 3.0).
Thirty four patients underwent CRT and 16 underwent RT. The mean total radiation dose delivered was 56.1 ± 10.4 Gy. Eighteen patients (36%) suffered from pulmonary complications at a mean interval of 3.4 months after therapy. Nine patients had grade 2, 7 had grade 3, 1 had grade 4 and 1 had grade 5 pulmonary complications. The mean LPS was 4.9 in patients who developed pulmonary complications versus 3.5 in patients who did not (p=0.01). There were no significant difference between PFTs in the patients with pulmonary complications and the patient without. Additionally, there were no significant differences between the mean lung radiation dose, the volume of lung irradiated or the percentage of lung receiving greater than 20 Gy between the two groups.
LPS using lung perfusion imaging is useful for predicting possible pulmonary complications after CRT or RT in lung cancer patients.
Lung Perfusion Imaging; SPECT-CT; Lung Cancer; Pulmonary Complications
While it is well established that the principal ascending pathways for pain originate in the dorsal horn of the spinal cord and in the medulla, the control and sensitivity to pain may reside in additional neurological loci, especially in the mesolimbic system of the brain (i.e., a reward center), and a number of genes and associated polymorphisms may indeed impact pain tolerance and or sensitivity. It is hypothesized that these polymorphisms associate with a predisposition to intolerance or tolerance to pain. It is further hypothesized that identification of certain gene polymorphisms provides a unique therapeutic target to assist in the treatment of pain. It is hereby proposed that pharmacogenetic testing of certain candidate genes (i.e., mu receptors, PENK etc.) will result in pharmacogenomic solutions personalized to the individual patient, with potential improvement in clinical outcomes.
Recently, the role of miR-29b in colorectal carcinoma (CRC) development appears to be controversial. Until now, the expression and function of miR-29b in CRC have not been clarified clearly. We showed that decreased expression of miR-29b usually occurred in CRC cell lines and tissue samples. Loss- and gain-of-function assays in vitro revealed suppressive effects of miR-29b on cell proliferation and migration. Endogenous overexpression of miR-29b was sufficient to suppress aggressive behavioral phenotypes in mice. Proteomic analysis showed that miR-29b involved in integrate several key biological processes. In addition, miR-29b mediated the inhibition of epithelial–mesenchymal transition (EMT) and the inactivation of mitogen-activated protein kinase and phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT signal transduction pathway. Further studies found that T lymphoma invasion and metastasis 1 (Tiam1) was identified as a direct target of miR-29b. In contrast to the phenotypes induced by miR-29b restoration, Tiam1-induced cell proliferation and migration partly rescued miR-29b-mediated biological behaviors. Our results illustrated that miR-29b as a suppressor has a critical role in CRC progression, which suggests its potential role in the molecular therapy of patients with advanced CRC.
Patients suffering from cancer can shed tumor cells into the bloodstream, leading to one of the most important mechanisms of metastasis. As such, the capture of these cells is of great interest. Circulating tumor cells are typically extracted from circulation through positive selection with the epithelial cell-adhesion molecule (EpCAM), leading to currently unknown biases when cells are undergoing epithelial-to-mesenchymal transition. For prostate cancer, prostate-specific membrane antigen (PSMA) presents a compelling target for immunocapture, as PSMA levels increase in higher-grade cancers and metastatic disease and are specific to the prostate epithelium. This study uses monoclonal antibodies J591 and J415—antibodies that are highly specific for intact extracellular domains of PSMA on live cells— in microfluidic devices for the capture of LNCaPs, a PSMA-expressing immortalized prostate cancer cell line, over a range of concentrations and shear stresses relevant to immunocapture. Our results show that J591 outperforms J415 and a mix of the two for prostate cancer capture, and that capture performance saturates following incubation with antibody concentrations of 10 micrograms per milliliter.
CTC; microfluidic; PSMA; J591; circulating tumor cell; prostate cancer
Capecitabine and paclitaxel are established effective treatments, alone and combined with other cytotoxic and targeted agents, for metastatic breast cancer (MBC). Paclitaxel polyglumex (a macromolecular conjugate of paclitaxel bound to poly-L-glutamic acid) has potential advantages over conventional paclitaxel, including little alopecia, short infusion time with no premedication, enhanced tumor permeability/retention effect, and improved tolerability. We therefore examined tolerability & efficacy of paclitaxel polyglumex with capecitabine in patients with MBC.
Patients and Methods
This was a single stage phase 2 study, with interim analysis conducted with endpoints of tumor response, adverse events (toxicities), time to progression & overall survival. The main eligibility criteria were: age >18, no prior MBC chemotherapy, ECOG performance score <2, disease measurable by RECIST criteria, no HER2 overexpression or amplification, no brain metastases or peripheral sensory neuropathy. Treatment consisted of paclitaxel polyglumex 135 mg/m2 by intravenous infusion on day 1 + capecitabine 825 mg/m2 orally twice daily days 1 - 14, repeated on a 3-week cycle. Forty one (41) evaluable patients were required to test null hypothesis that complete and partial tumor response rate (CR + PR) was at most 40% against the alternative of at least 60%. Paclitaxel polyglumex + capecitabine would be considered promising in this population if ≥21 responses were observed among first 41 evaluable patients.
48 patients were enrolled between April 2006 - April 2007; all patients were evaluable. The median cycles administered was 6. Eighteen (18) patients (38%; 95% CI: 24-53%) had a confirmed tumor response (2 CR, 16 PR) by RECIST criteria. Fifteen (15; 38%, 95% CI: 23%-53%) responses occurred in first 41 patients, falling short of prespecified goal of 21 responses. Median duration of tumor response was 13.2 months. Three of the responders were progression free at last follow-up with a median follow-up of 43 months. Median progression-free survival was 5.1 months (95% CI: 4.0-7.6 months). Six-month progression free survival was 42% (95% CI: 30-58%). Median dose level administered = 135 mg/m2 paclitaxel polyglumex, 825 mg/m2 capecitabine for cycles 1-7. Most common severe (grade 3/4) toxicities (at least possibly related to study drug) were: leukopenia 9 (19%), neutropenia 8 (17%), neuro-sensory 4 (8%), skin reaction-hand/foot 4 (8%), dyspnea 2 (4%). Forrty-six% (22/47) of patients experienced a grade ≥3 toxicity and 8% (4/48) experienced a grade ≥4 toxicity. No alopecia was reported.
Although the trial failed to reach goal of 21 confirmed tumor responses among the first 41 evaluable patients, paclitaxel polyglumex and capecitabine is well tolerated and effective in MBC.
Reduced expression of the pro-apoptotic protein SMAC (second
mitochondria-derived activator of caspase) has been reported to correlate with
cancer progression, while its significance and underlying mechanisms are poorly
understood. In this study, we investigated the role of SMAC in intestinal
tumorigenesis using both human samples and animal models. Decreased SMAC
expression was found to correlate with increased cIAP2 expression and higher
grades of human colon cancer. In mice, SMAC deficiency
significantly increased the incidence and size of colon tumors induced by
azoxymethane (AOM)/dextran sulfate sodium salt (DSS), and highly enriched
β-catenin hot spot mutations. SMAC
deficiency also significantly increased the incidence of spontaneous intestinal
polyps in APCMin/+ mice. Loss of
SMAC in mice led to elevated levels of cIAP1 and cIAP2,
increased proliferation and activation of the NF-κB p65 subunit in
normal and tumor tissues. Unexpectedly, SMAC deficiency had
little effect on the incidence of precursor lesions, or apoptosis induced by AOM
or DSS, or in established tumors in mice. Furthermore, SMAC
knockout enhanced TNFα-mediated NF-κB activation via cIAP2 in
HCT 116 colon cancer cells. These results demonstrate an essential and
apoptosis-independent function of SMAC in tumor suppression and provide new
insights into the biology and targeting of colon cancer.
SMAC; cIAP; NF-κB; proliferation; colon cancer
To describe the radiological and clinical features of adult non-puerperal mastitis and to determine the most accurate method of preventing unnecessary surgical procedures.
Clinical and imaging findings were retrospectively reviewed in 51 females with non-puerperal mastitis, which was confirmed by biopsy/surgical pathology. All 51 patients had pre-operative MRI; 45 patients also had sonograms and 25 also had mammograms, pre-operatively.
Of the 51 cases with non-puerperal mastitis, 94.1% (48/51) were confirmed as having acute or chronic inflammation, and the other 3 had plasma cell mastitis; areola papillaris inflammation was found in 39.2% (20/51) of the cases. Overall, 6 of the 25 cases that were examined with mammography and 2 of the 45 cases that were examined with sonography appeared normal, but all 51 lesions were positively identified on MRI. Asymmetrical density (12/25) on mammograms and solitary or separated/contiguous, clustered, hypoechoic mass-like lesions (31/45) on ultrasound were the most common signs of non-puerperal mastitis. On enhanced MRI, 90.2% (46/51) of patients showed non-mass-like enhanced lesions. Multiple regional enhancements in the pattern of distribution (32/46) and separated or contiguous, clustered, rim-like enhancements in the pattern of internal enhancement (29/46) were the most common manifestations in non-mass-like enhanced lesions. Of the 51 patients, mastitis Type 1 and Type 2 in the time–signal intensity curve were detected in 47.1% and 51.0% of the patients, respectively. The breast imaging reporting and data system categories with the highest number of patients were Category 0 (9/25) on mammography, Category 4a on sonography (18/45) and Category 4a on MRI (29/51).
The findings from mammography and ultrasound are non-specific; therefore, using MR can be helpful in the diagnosis, especially in the presence of non-mass-like enhancements that are multiple, regional, separated, or contiguous, clustered and rim-like.
Advances in knowledge:
Mastitis is often neglected because of the lack of typical clinical signs and symptoms. This study has assessed and described the clinical features and imaging findings of adult non-puerperal mastitis on mammograms, sonograms and MRI and found that MRI is more specific in the diagnosis of disease.
Upper digestive endoscopy with biopsy and histopathological evaluation of the biopsy material is the standard method for diagnosing gastric cancer (GC). However, this procedure may not be widely available for screening in the developing world, whereas in developed countries endoscopy is frequently used without major clinical gain. There is a high demand for a simple and non-invasive test for selecting the individuals at increased risk that should undergo the endoscopic examination. Here, we studied the feasibility of a nanomaterial-based breath test for identifying GC among patients with gastric complaints.
Alveolar exhaled breath samples from 130 patients with gastric complaints (37 GC/32 ulcers / 61 less severe conditions) that underwent endoscopy/biopsy were analyzed using nanomaterial-based sensors. Predictive models were built employing discriminant factor analysis (DFA) pattern recognition, and their stability against possible confounding factors (alcohol/tobacco consumption; Helicobacter pylori) was tested. Classification success was determined (i) using leave-one-out cross-validation and (ii) by randomly blinding 25% of the samples as a validation set. Complementary chemical analysis of the breath samples was performed using gas chromatography coupled with mass spectrometry.
Three DFA models were developed that achieved excellent discrimination between the subpopulations: (i) GC vs benign gastric conditions, among all the patients (89% sensitivity; 90% specificity); (ii) early stage GC (I and II) vs late stage (III and IV), among GC patients (89% sensitivity; 94% specificity); and (iii) ulcer vs less severe, among benign conditions (84% sensitivity; 87% specificity). The models were insensitive against the tested confounding factors. Chemical analysis found that five volatile organic compounds (2-propenenitrile, 2-butoxy-ethanol, furfural, 6-methyl-5-hepten-2-one and isoprene) were significantly elevated in patients with GC and/or peptic ulcer, as compared with less severe gastric conditions. The concentrations both in the room air and in the breath samples were in the single p.p.b.v range, except in the case of isoprene.
The preliminary results of this pilot study could open a new and promising avenue to diagnose GC and distinguish it from other gastric diseases. It should be noted that the applied methods are complementary and the potential marker compounds identified by gas-chromatography/mass spectrometry are not necessarily responsible for the differences in the sensor responses. Although this pilot study does not allow drawing far-reaching conclusions, the encouraging preliminary results presented here have initiated a large multicentre clinical trial to confirm the observed patterns for GC and benign gastric conditions.
gastric cancer; breath analysis; diagnosis; volatile organic compound; sensor
Studies have indicated that early-life or early-onset depression is associated with a 2- to 4-fold increased risk of developing Alzheimers disease (AD). In AD, aggregation of an abnormally phosphorylated form of the tau protein may be a key pathological event. Tau is known to play a major role in promoting microtubule assembly and stabilization, and in maintaining the normal morphology of neurons. Several studies have reported that stress may induce tau phosphorylation. The main aim of the present study was to investigate possible alterations in the tau protein in the hippocampus and frontal cortex of 32 male Sprague-Dawley rats exposed to chronic unpredictable mild stress (CUMS) and then re-exposed to CUMS to mimic depression and the recurrence of depression, respectively, in humans. We evaluated the effects of CUMS, fluoxetine, and CUMS re-exposure on tau and phospho-tau. Our results showed that a single exposure to CUMS caused a significant reduction in sucrose preference, indicating a state of anhedonia. The change in behavior was accompanied by specific alterations in phospho-tau protein levels, but fluoxetine treatment reversed the CUMS-induced impairments. Moreover, changes in sucrose preference and phospho-tau were more pronounced in rats re-exposed to CUMS than in those subjected to a single exposure. Our results suggest that changes in tau phosphorylation may contribute to the link between depression and AD.
Alzheimers disease; Depression; Tau; Chronic unpredictable mild stress (CUMS); Re-exposure to CUMS; Fluoxetine
We compared the outcomes of endovascular coiling with microsurgical clipping of aneurysms in a Taiwanese population.
In an ambi-directional cohort design, patient baseline characteristics and clinical course after treatment for ruptured subarachnoid aneurysm were abstracted from medical records from three hospitals to examine and compare differences in post-operative outcomes between those treated with endovascular coiling and those treated with microsurgical clipping. Outcomes were measured, using the modified Rankin scale, two months, one year and two years postoperatively.
Of the 642 patients enrolled in the study, 281 underwent endovascular treatment and 361 underwent neurosurgery. The demographics and baseline characteristics of two groups were comparable except for a larger maximum target aneurysm lumen size (p=0.02) in the endovascular group. Patients who underwent the endovascular procedure tended to have a better quality of life than those who had neurosurgery (p<0.01). When the severity of symptom data was pooled into two groups (Rankin values 0-2 and 3-6) a statistically significant relationship was found between the severity of symptoms and age, Hunt and Hess grade, number of target aneurysms detected, and log of maximum target aneurysm lumen size (all p≤0.01). After controlling for potential confounding factors and using the lumped Rankin outcome data, no significant difference in outcome was found between the two procedures at either time point.
Our study indicated that endovascular coiling achieves results comparable to surgical clipping for patients with ruptured subarachnoid aneurysms in a Taiwanese population.
aneurysm, hemorrhage, microsurgery, endovascular coiling, size, outcome, quality of life
BACKGROUND AND PURPOSE
Determination of hemispheric language dominance is critical for planning epilepsy surgery. We assess the usefulness of spatiotemporal source analysis of magnetoencephalography for determining language laterality.
MATERIALS AND METHODS
Thirty-five patients with epilepsy were studied. The patients performed a semantic word-processing task during MEG recording. Epochs containing language-related neuromagnetic activity were averaged after preprocessing. The averaged data between 250 and 550 ms after stimulus were analyzed by using dynamic statistical parametric mapping. ROIs were obtained in the opercular and triangular parts of the inferior frontal gyrus, superior temporal gyrus, and supramarginal gyrus in both hemispheres. We calculated laterality indices according to 1) dSPM-amplitude method, based on the amplitude of activation in the ROIs, and 2) dSPM-counting method, based on the number of unit dipoles with activation over a threshold in the ROIs. The threshold was determined as half of the maximum value in all ROIs for each patient. A LI ≥0.10 or ≤−0.10 was considered left- or right-hemisphere dominance, respectively; a LI between −0.10 and 0.10 was considered bilateral. All patients underwent an intracarotid amobarbital procedure as part of presurgical evaluation.
The dSPM-counting method demonstrated laterality consistent with the IAP in 32 of 35 patients (91.4%), the remaining 3 (8.6%) demonstrated bilateral language representation, whereas the dSPM-amplitude method showed 18 (51.4%) concordant and 17 (48.6%) bilateral. No laterality opposite to the IAP was found.
Spatiotemporal mapping of language lateralization with the dSPM-counting method may reduce the necessity for an IAP in as many as 90% of patients.
Mucosal apoptosis has been demonstrated to be an essential pathological feature in portal hypertensive gastropathy (PHG). p53-upregulated modulator of apoptosis (PUMA) was identified as a BH3-only Bcl-2 family protein that has an essential role in apoptosis induced by a variety of stimuli, including endoplasmic reticulum (ER) stress. However, whether PUMA is involved in mucosal apoptosis in PHG remains unclear, and whether PUMA induces PHG by mediating ER stress remains unknown. The aim of the study is to investigate whether PUMA is involved in PHG by mediating ER stress apoptotic signaling. To identify whether PUMA is involved in PHG by mediating ER stress, gastric mucosal injury and apoptosis were studied in both PHG patients and PHG animal models using PUMA knockout (PUMA-KO) and PUMA wild-type (PUMA-WT) mice. The induction of PUMA expression and ER stress signaling were investigated, and the mechanisms of PUMA-mediated apoptosis were analyzed. GES-1 and SGC7901 cell lines were used to further identify whether PUMA-mediated apoptosis was induced by ER stress in vitro. Epithelial apoptosis and PUMA were markedly induced in the gastric mucosa of PHG patients and mouse PHG models. ER stress had a potent role in the induction of PUMA and apoptosis in PHG models, and the apoptosis was obviously attenuated in PUMA-KO mice. Although the targeted deletion of PUMA did not affect ER stress, mitochondrial apoptotic signaling was downregulated in mice. Meanwhile, PUMA knockdown significantly ameliorated ER stress-induced mitochondria-dependent apoptosis in vitro. These results indicate that PUMA mediates ER stress-induced mucosal epithelial apoptosis through the mitochondrial apoptotic pathway in PHG, and that PUMA is a potentially therapeutic target for PHG.
PHG; PUMA; ER stress; mitochondria; apoptosis
Regulator of Cullins-1 (ROC1) or RING box protein-1 (RBX1) is an essential RING component of Cullin-RING ligase (CRL). Our previous studies showed that ROC1 is required for the growth of several cancer cell lines while ROC1 siRNA silencing inactivates CRL, leading to cell cycle arrest, cell senescence and/or apoptosis. However, it is completely unknown whether ROC1 knockdown triggers autophagic response by inactivating CRL. Moreover, the role of ROC1 in liver cancer remains elusive. In this study, we reported that ROC1 knockdown significantly inhibited the growth of liver cancer cells by sequentially and independently inducing autophagy and p21-dependent cell senescence. Mechanism analysis revealed that ROC1 silencing triggered autophagy by inhibition of mammalian target of rapamycin (mTOR) activity due to accumulation of mTOR-inhibitory protein Deptor, a substrate of CRL. Consistently, Deptor knockdown significantly blocked autophagy response upon ROC1 silencing. Biologically, autophagy response upon ROC1 silencing was a survival signal, and blockage of autophagy pathway sensitized cancer cells to apoptosis. Finally, we demonstrated that ROC1 was overexpressed in hepatocellular carcinomas, which is associated with poor prognosis of liver cancer patients. These findings suggest that ROC1 is an appealing drug target for liver cancer and provide a proof-of-concept evidence for a novel drug combination of ROC1 inhibitor and an autophagy inhibitor for effective treatment of liver cancer by enhancing apoptosis.
ROC1; Cullin-RING ligase; autophagy; senescence; Deptor
Sorafenib is the only drug approved for the treatment of hepatocellular carcinoma (HCC). The bioenergetic propensity of cancer cells has been correlated to anticancer drug resistance, but such correlation is unclear in sorafenib resistance of HCC.
Six sorafenib-naive HCC cell lines and one sorafenib-resistant HCC cell line (Huh-7R; derived from sorafenib-sensitive Huh-7) were used. The bioenergetic propensity was calculated by measurement of lactate in the presence or absence of oligomycin. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, and siRNA of hexokinase 2 (HK2) were used to target relevant pathways of cancer metabolism. Cell viability, mitochondrial membrane potential, and sub-G1 fraction were measured for in vitro efficacy. Reactive oxygen species (ROS), adenosine triphosphate (ATP) and glucose uptake were also measured. A subcutaneous xenograft mouse model was used for in vivo efficacy.
The bioenergetic propensity for using glycolysis correlated with decreased sorafenib sensitivity (R2=0.9067, among sorafenib-naive cell lines; P=0.003, compared between Huh-7 and Huh-7 R). DCA reduced lactate production and increased ROS and ATP, indicating activation of oxidative phosphorylation (OXPHOS). DCA markedly sensitised sorafenib-resistant HCC cells to sorafenib-induced apoptosis (sub-G1 (combination vs sorafenib): Hep3B, 65.4±8.4% vs 13±2.9% Huh-7 R, 25.3± 5.7% vs 4.3±1.5% each P<0.0001), whereas siRNA of HK2 did not. Sorafenib (10 mg kg−1 per day) plus DCA (100 mg kg−1 per day) also resulted in superior tumour regression than sorafenib alone in mice (tumour size: −87% vs −36%, P<0.001).
The bioenergetic propensity is a potentially useful predictive biomarker of sorafenib sensitivity, and activation of OXPHOS by PDK inhibitors may overcome sorafenib resistance of HCC.
glycolysis; oxidative phosphorylation; sorafenib; dichloroacetate; hepatocellular carcinoma