We investigated the mutational landscape of mammalian target of rapamycin (mTOR) signalling cascade in hepatocellular carcinomas (HCCs) with chronic HBV background, aiming to evaluate and delineate ...mutation-dependent mechanism of mTOR hyperactivation in hepatocarcinogenesis.
We performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence. Protein expressions of tuberous sclerosis complex (TSC)1, TSC2 and pRPS6 were assessed by immunohistochemistry in human HCC samples. Rapamycin sensitivity was estimated by colony-formation assay in HCC cell lines and the treatment was further tested using our patient-derived tumour xenograft (PDTX) models.
We identified and confirmed multiple mTOR components as recurrently mutated in HBV-associated HCCs. Of significance, we detected frequent (16.2%, n=18/111) mutations of
and
genes in the HCC samples. The spectrum of
mutations likely disrupts the endogenous gene functions in suppressing the downstream mTOR activity through different mechanisms and leads to more aggressive tumour behaviour. Mutational disruption of
and
was also observed in HCC cell lines and our PDTX models.
-mutant cells exhibited reduced colony-forming ability on rapamycin treatment. With the use of biologically relevant
-mutant PDTXs, we demonstrated the therapeutic benefits of the hypersensitivity towards rapamycin treatment.
Taken together, our findings suggest the significance of previously undocumented mutation-dependent mTOR hyperactivation and frequent
mutations in HBV-associated HCCs. They define a molecular subset of HCC having genetic aberrations in mTOR signalling, with potential significance of effective specific drug therapy.
Signal transducer and activator of transcription 3 (STAT3) triggered production of Th‐17 cytokines mediates protective immunity against fungi. Mutations affecting the STAT3/interleukin 17 (IL‐17) ...pathway cause selective susceptibility to fungal (Candida) infections, a hallmark of chronic mucocutaneous candidiasis (CMC). In patients with autosomal dominant CMC, we and others previously reported defective Th17 responses and underlying gain‐of‐function (GOF) STAT1 mutations, but how this affects STAT3 function leading to decreased IL‐17 is unclear. We also assessed how GOF‐STAT1 mutations affect STAT3 activation, DNA binding, gene expression, cytokine production, and epigenetic modifications. We excluded impaired STAT3 phosphorylation, nuclear translocation, and sequestration of STAT3 into STAT1/STAT3 heterodimers and confirm significantly reduced transcription of STAT3‐inducible genes (RORC/IL‐17/IL‐22/IL‐10/c‐Fos/SOCS3/c‐Myc) as likely underlying mechanism. STAT binding to the high affinity sis‐inducible element was intact but binding to an endogenous STAT3 DNA target was impaired. Reduced STAT3‐dependent gene transcription was reversed by inhibiting STAT1 activation with fludarabine or enhancing histone, but not STAT1 or STAT3 acetylation with histone deacetylase (HDAC) inhibitors trichostatin A or ITF2357. Silencing HDAC1, HDAC2, and HDAC3 indicated a role for HDAC1 and 2. Reduced STAT3‐dependent gene transcription underlies low Th‐17 responses in GOF‐STAT1 CMC, which can be reversed by inhibiting acetylation, offering novel targets for future therapies.
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There are established differences in breast cancer epidemiology between Asian and white individuals, but little is known about hereditary breast cancer in Asian populations. Although increasing ...numbers of Asian individuals are clinically tested for BRCA1/2 mutations, it is not known whether computer models that predict mutations work accurately in Asian individuals. We compared the performance in Asian and white individuals of two widely used BRCA1/2 mutation prediction models, BRCAPRO and Myriad II.
We evaluated BRCAPRO and Myriad II in 200 Asian individuals and a matched control group of 200 white individuals who were tested for BRCA1/2 mutations at four cancer genetics clinics, by comparing numbers of observed versus predicted mutation carriers and by evaluating area under the receiver operating characteristic curve (AUC) for each model.
BRCAPRO and Myriad II accurately predicted the number of white BRCA1/2 mutation carriers (25 observed v 24 predicted by BRCAPRO; 25 predicted by Myriad II, P > or = .69), but underpredicted Asian carriers by two-fold (49 observed v 25 predicted by BRCAPRO; 26 predicted by Myriad II; P < or = 3 x 10(-7)). For BRCAPRO, this racial difference reflects substantial underprediction of Asian BRCA2 mutation carriers (26 observed v 4 predicted; P = 1 x 10(-30)); for Myriad II, separate mutation predictions were not available. For both models, AUCs were nonsignificantly lower in Asian than white individuals, suggesting less accurate discrimination between Asian carriers and noncarriers.
Both BRCAPRO and Myriad II underestimated the proportion of BRCA1/2 mutation carriers, and discriminated carriers from noncarriers less well, in Asian compared with white individuals.
Background Acute respiratory distress syndrome (ARDS) is a life-threatening medical condition. Extracorporeal membrane oxygenation (ECMO) is a salvage therapy for patients with ARDS and refractory ...hypoxia. This study compared the characteristics and outcomes of ARDS patients who did or did not receive ECMO matched with Acute Physiology and Chronic Health Evaluation II (APACHE II) score and age. Methods This retrospective, case-control study enrolled patients with ARDS admitted to the intensive care unit of a tertiary referral hospital between January 2007 and December 2012. Overall, 216 patients with ARDS—81 receiving ECMO (ECMO group) and 135 not receiving ECMO (non-ECMO group)—were enrolled in this study. Patients were paired when the difference in their APACHE II scores was within 3 points and their age difference was 3 years. In total, 126 patients could not be matched and were thus excluded. Eventually, of the 90 patients with ARDS enrolled in this study, 45 ECMO group patients were matched with 45 non-ECMO group patients. The demographic data, reasons for intensive care unit admission, and laboratory variables were evaluated. Results The primary etiology of ARDS was infection (72.2%). The APACHE II score and age-matched group receiving ECMO therapy had higher inhospital survival rates. Moreover, the patients receiving ECMO therapy had significantly lower 6-month mortality rates than did the non-ECMO group. Conclusions Patients with ARDS who received ECMO treatment had higher inhospital survival rates than did those with a similar disease severity and at a similar age who did not receive ECMO.
Photoreceptor-specific nuclear receptor (PNR/NR2E3) and Tailless homolog (TLX/NR2E1) are human orthologs of the NR2E group, a subgroup of phylogenetically related members of the nuclear receptor (NR) ...superfamily of transcription factors. We assessed the ability of these NRs to form heterodimers with other members of the human NRs representing all major subgroups. The TLX ligand-binding domain (LBD) did not appear to form homodimers or interact directly with any other NR tested. The PNR LBD was able to form homodimers, but also exhibited robust interactions with the LBDs of peroxisome proliferator-activated receptor-γ (PPARγ)/NR1C3 and thyroid hormone receptor b (TRb) TRβ/NR1A2. The binding of PNR to PPARγ was specific for this paralog, as no interaction was observed with the LBDs of PPARα/NR1C1 or PPARδ/NR1C2. In support of these findings, PPARγ and PNR were found to be co-expressed in human retinal tissue extracts and could be co-immunoprecipitated as a native complex. Selected sequence variants in the PNR LBD associated with human retinopathies, or a mutation in the dimerization region of PPARγ LBD associated with familial partial lipodystrophy type 3, were found to disrupt PNR/PPARγ complex formation. Wild-type PNR, but not a PNR309G mutant, was able to repress PPARγ-mediated transcription in reporter assays. In summary, our results reveal novel heterodimer interactions in the NR superfamily, suggesting previously unknown functional interactions of PNR with PPARγ and TRβ that have potential importance in retinal development and disease.
Background Multiinstitutional analysis of single-port video-assisted thoracic surgery (VATS) for anatomic pulmonary resection is rare. This study aimed to address the technical feasibility and ...applicability of single-port video-assisted anatomical resection for primary lung cancer. Methods A total of 121 patients with primary lung cancer undergoing single-port video-assisted anatomical resection between 2011 and 2014 in 4 hospitals were included. The clinicopathologic variables and perioperative outcomes were collected and analyzed retrospectively. Results Single-port VATS segmentectomies and lobectomies were performed in 24 (19.8%) and 97 (80.2%) patients, respectively. One hundred seven of 121 (88.4%) patients had adenocarcinoma and 93 of 121 (76.9%) had pathologic stage I lung cancer. The average operative time and estimated blood loss was 198.8 ± 65.4 minutes and 99.1 ± 147.6 mL, respectively. The conversion and complication rates were 2.5% (3 of 121 cases) and 14.0% (17 of 121 cases), respectively. There was no surgical mortality, and the average length of hospital stay was 6.6 ± 2.6 days. The mean resected lymph node was 22.6 ± 12.0. We also identified patient age of 60 years or more, male sex, and tumor size greater than 3 cm as unfavorable perioperative outcome predictors after single-port video-assisted anatomical pulmonary resection. Conclusions This first multiinstitutional single-port VATS study demonstrated that anatomical resection for primary lung cancer can be safely and effectively completed through a single-port VATS approach in hospitals experienced in VATS techniques.
In this communication, novel moisture-sensitive shape memory polyurethane (SMPU) was synthesized from 1,6-hexamethylene diisocyanate (HDI) and N,N-bis(2-hydroxylethyl) isonicotinamide (BINA) and ...1,4-butanediol (BDO). Results show that the BINA based SMPUs have excellent moisture absorption properties which are not only influenced by the temperature, but also by the relative humidity (RH). As a result, high strain recovery with fast recovery speed is obtained after immersion in the moisture condition for a short time. FT-IR spectra provide a proof to the mechanism of moisture-sensitive SME which is based on the dissociation or disrupt of hydrogen bonding in the pyridine ring induced by moisture absorption. Thus, the strain recovery is achieved in the moisture-sensitive SMPUs by decreasing the glass transition temperature (Tg) below ambient temperature without external heating.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Aim
Although much attention has been on integrating the palliative care approach into services of long‐term care homes for older people living with frailty and progressive diseases, little is known ...about the staff preparedness for these new initiatives. The present study aimed to develop and test the psychometric properties of an instrument for measuring care home staff preparedness in providing palliative and end‐of‐life care.
Methods
A 16‐item instrument, covering perceived knowledge, skill and psychological readiness, was developed. A total of 247 staff members of different ranks from four care homes participated in the study. Exploratory factor analysis using the principal component analysis extraction method with varimax rotation was carried out for initial validation. Known group comparison was carried out to examine its discriminant validity. Reliability of the instrument was assessed based on test–retest reliability of a subsample of 20 participants and the Cronbach's alpha of the items.
Results
Exploratory factor analysis showed that the instrument yielded a three‐factor solution, which cumulatively accounted for 68.5% of the total variance. Three subscales, namely, willingness, capability and resilience, showed high internal consistency and test–retest reliability. It also showed good discriminant validity between staff members of professional and non‐professional groups.
Conclusions
This is a brief, valid and reliable scale for measuring care home staff preparedness for providing palliative and end‐of‐life care. It can be used to identify their concerns and training needs in providing palliative and end‐of‐life care, and as an outcome measure to evaluate the effects of interventional studies for capacity building in this regard. Geriatr Gerontol Int 2018; 18: 745–749
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract Background Whether dabigatran is associated with a lower risk of acute kidney injury (AKI) in patients with nonvalvular atrial fibrillation (NVAF) remains unknown. Objectives The authors ...compared the risk of AKI in Asians with NVAF who were prescribed dabigatran versus warfarin. Methods The authors analyzed patients enrolled in the Taiwan nationwide retrospective cohort study from June 1, 2012, to December 31, 2013. Dabigatran and warfarin were taken by 7,702 and 7,885 NVAF patients without a history of chronic kidney disease (CKD) and 2,256 and 2,089 NVAF patients with a history of CKD, respectively. A propensity-score weighted method was used to balance covariates across study groups. Results A total of 6,762 (88%) and 940 (12%) CKD-free patients and 2,025 (90%) and 231 (10%) CKD patients took dabigatran 110 mg and 150 mg twice daily, respectively. Dabigatran was associated with a lower risk of AKI than warfarin for either the CKD-free (hazard ratio HR: 0.62; 95% confidence interval CI: 0.49 to 0.77; p < 0.001) or CKD (HR: 0.56; 95% CI: 0.46 to 0.69; p < 0.001) cohort. As the increment in CHA2 DS2 -VASc score (a risk score based on congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, previous stroke/transient ischemic attack, vascular disease, aged 65 to 74 years, and female sex) increased from 0/1 to 6+ points, the incidence of AKI for the dabigatran group was relatively stable (1.87% to 2.91% per year for the CKD-free cohort; 7.31% to 13.15% per year for the CKD cohort) but increased obviously for patients taking warfarin for either CKD-free (2.00% to 6.16% per year) or CKD cohorts (6.82 to 26.03% per year). The warfarin group had a significantly higher annual risk of AKI than the dabigatran group for those with a high CHA2 DS2 -VASc score (≥4 for the CKD-free cohort and ≥3 for the CKD cohort). Subgroup analysis revealed that among dabigatran users, those taking either low-dose or standard-dose dabigatran, those with a warfarin-naïve or warfarin-experienced history, those with or without diabetes, and those with CHA2 DS2 -VASc ≥4 or HAS-BLED ≥3 (risk score based on hypertension, abnormal renal and liver function, stroke, prior major bleeding, labile international normalized ratios, age 65 years or older, drugs or alcohol usage history) all had a lower risk of AKI than those taking warfarin. Conclusions Among Asians with NVAF, dabigatran is associated with a lower risk of AKI than warfarin.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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