Here we report a facile, prompt protocol based on deep-learning techniques to sort out intricate phase identification and quantification problems in complex multiphase inorganic compounds. We ...simulate plausible powder X-ray powder diffraction (XRD) patterns for 170 inorganic compounds in the Sr-Li-Al-O quaternary compositional pool, wherein promising LED phosphors have been recently discovered. Finally, 1,785,405 synthetic XRD patterns are prepared by combinatorically mixing the simulated powder XRD patterns of 170 inorganic compounds. Convolutional neural network (CNN) models are built and eventually trained using this large prepared dataset. The fully trained CNN model promptly and accurately identifies the constituent phases in complex multiphase inorganic compounds. Although the CNN is trained using the simulated XRD data, a test with real experimental XRD data returns an accuracy of nearly 100% for phase identification and 86% for three-step-phase-fraction quantification.
Immunotherapy has emerged as a promising anti-cancer treatment, however, little is known about the genetic characteristics that dictate response to immunotherapy. We develop a transcriptional ...predictor of immunotherapy response and assess its prediction in genomic data from ~10,000 human tissues across 30 different cancer types to estimate the potential response to immunotherapy. The integrative analysis reveals two distinct tumor types: the mutator type is positively associated with potential response to immunotherapy, whereas the chromosome-instable type is negatively associated with it. We identify somatic mutations and copy number alterations significantly associated with potential response to immunotherapy, in particular treatment with anti-CTLA-4 antibody. Our findings suggest that tumors may evolve through two different paths that would lead to marked differences in immunotherapy response as well as different strategies for evading immune surveillance. Our analysis provides resources to facilitate the discovery of predictive biomarkers for immunotherapy that could be tested in clinical trials.
Public-private mix (PPM) programs on tuberculosis (TB) have a critical role in engaging and integrating the private sector into the national TB control efforts in order to meet the End TB Strategy ...targets. South Korea's PPM program can provide important insights on the long-term impact and policy gaps in the development and expansion of PPM as a nationwide program. Healthcare is privatized in South Korea, and a majority (80.3% in 2009) of TB patients sought care in the private sector. Since 2009, South Korea has rapidly expanded its PPM program coverage under the National Health Insurance (NHI) scheme as a formal national program with dedicated PPM nurses managing TB patients in both the private and public sectors. Using the difference in differences (DID) analytic framework, we compared relative changes in TB treatment outcomes-treatment success (TS) and loss to follow-up (LTFU)-in the private and public sector between the 2009 and 2014 TB patient cohorts. Propensity score matching (PSM) using the kernel method was done to adjust for imbalances in the covariates between the 2 population cohorts. The 2009 cohort included 6,195 (63.0% male, 37.0% female; mean age: 42.1) and 27,396 (56.1% male, 43.9% female; mean age: 45.7) TB patients in the public and private sectors, respectively. The 2014 cohort included 2,803 (63.2% male, 36.8% female; mean age: 50.1) and 29,988 (56.5% male, 43.5% female; mean age: 54.7) patients. In both the private and public sectors, the proportion of patients with transfer history decreased (public: 23.8% to 21.7% and private: 20.8% to 17.6%), and bacteriological confirmed disease increased (public: 48.9% to 62.3% and private: 48.8% to 58.1%) in 2014 compared to 2009. After expanding nationwide PPM, absolute TS rates improved by 9.10% (87.5% to 93.4%) and by 13.6% (from 70.3% to 83.9%) in the public and private sectors. Relative to the public, the private saw 4.1% (95% confidence interval CI 2.9% to 5.3%, p-value < 0.001) and -8.7% (95% CI -9.7% to -7.7%, p-value <0.001) higher rates of improvement in TS and reduction in LTFU. Treatment outcomes did not improve in patients who experienced at least 1 transfer during their TB treatment. Study limitations include non-longitudinal nature of our original dataset, inability to assess the regional disparities, and verify PPM program's impact on TB mortality. We found that the nationwide scale-up of the PPM program was associated with improvements in TB treatment outcomes in the private sector in South Korea. Centralized financial governance and regulatory mechanisms were integral in facilitating the integration of highly diverse South Korean private sector into the national TB control program and scaling up of the PPM intervention nationwide. However, TB care gaps continued to exist for patients who transferred at least once during their treatment. These programmatic gaps may be improved through reducing administrative hurdles and making programmatic amendments that can help facilitate management TB patients between institutions and healthcare sectors, as well as across administrative regions.
Achieving a deep molecular response (DMR) to tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia (CML) remains challenging and at present, there is no biomarker to predict DMR in ...this setting. Herein, we report that an HMGCLL1 genetic variant located in 6p12.1 can be used as a predictive genetic biomarker for intrinsic sensitivity to imatinib (IM) therapy. We measured DMR rate according to HMGCLL1 variant in a discovery set of CML patients (n = 201) and successfully replicated it in a validation set (n = 270). We also investigated the functional relevance of HMGCLL1 blockade with respect to response to TKI therapy and showed that small interfering RNA mediated blockade of HMGCLL1 isoform 3 results in significant decrease in viability of BCR-ABL1-positive cells including K562, CML-T1 or BaF3 cell lines with or without ABL1 kinase domain mutations such as T315I mutation. Decreased cell viability was also demonstrated in murine CML stem cells and human hematopoietic progenitor cells. RNA sequencing showed that blockade of HMGCLL1 was associated with G0/G1 arrest and the cell cycle. In summary, the HMGCLL1 gene polymorphism is a novel genetic biomarker for intrinsic sensitivity to IM therapy in CML patients that predicts DMR in this setting.
The phase 2 LEO study showed that everolimus (EVE) plus letrozole (LET) with ovarian suppression increased progression‐free survival (PFS) in tamoxifen‐exposed premenopausal women with hormone ...receptor‐positive, HER2‐negative metastatic breast cancer with visceral metastases. Here we report final survival outcomes from the LEO study, and the results of exploratory analyses of bone turnover marker changes and bone‐specific progressive disease. Patients who were exposed to or progressed on tamoxifen as adjuvant/palliative treatments were randomly assigned (2:1) to the EVE (leuprorelin + LET + EVE, n = 92) or LET (leuprorelin + LET, n = 45) arm. In a median 51‐months of follow‐up, the median PFS was 17.5 and 13.8 months in the EVE and LET arms, respectively (P = .245). Patients in the EVE arm with baseline visceral (median PFS 16.4 vs 9.5 months, P = .040) and bone (median PFS 17.1 vs 10.9, P = .003) metastases had greater PFS compared to the LET arm. No differences in overall survival (OS) were observed (median OS, 48.3 vs 50.8 months, P = .948). The 1‐year cumulative incidences of bone‐specific disease progression were 6.0% and 23.4% in the EVE and LET arms, respectively (hazard ratio 0.26, P < .001). Bone turnover markers at 6 and 12 weeks after treatment decreased in the EVE arm but were increased or stationary in the LET arm. Skeletal‐related events occurred in 6.5% and 11.1% of patients in the EVE and LET arms, respectively. EVE + LET with ovarian suppression prolonged PFS in patients with baseline visceral or bone metastases and offered bone‐protective effects in the overall study population. However, these clinical benefits did not translate into an OS benefit.
What's new?
In the phase 2 LEO study, women with hormone receptor‐positive, human epidermal growth factor receptor 2‐negative metastatic breast cancer with visceral metastases who were previously treated with tamoxifen, experienced significant improvements in progression‐free survival following combination therapy with the protein kinase inhibitor everolimus and the aromatase inhibitor letrozole. This report describes final survival outcomes from the LEO study. Patients with visceral or bone metastases treated with combined leuprorelin, letrozole, and everolimus survived longer with progression‐free disease compared to women who received leuprorelin and letrozole. Regimens employing everolimus were associated with reductions in bone turnover, bone‐specific disease progression, and skeletal‐related events, suggesting a role for everolimus in bone protection.
Metabolic activation is a common feature of many cancer cells and is frequently associated with the clinical outcomes of various cancers, including hepatocellular carcinoma. Thus, aberrantly ...activated metabolic pathways in cancer cells are attractive targets for cancer therapy. Yes‐associated protein 1 (YAP1) and transcriptional coactivator with PDZ‐binding motif (TAZ) are oncogenic downstream effectors of the Hippo tumor suppressor pathway, which is frequently inactivated in many cancers. Our study revealed that YAP1/TAZ regulates amino acid metabolism by up‐regulating expression of the amino acid transporters solute carrier family 38 member 1 (SLC38A1) and solute carrier family 7 member 5 (SLC7A5). Subsequently, increased uptake of amino acids by the transporters (SLC38A1 and SLC7A5) activates mammalian target of rapamycin complex 1 (mTORC1), a master regulator of cell growth, and stimulates cell proliferation. We also show that high expression of SLC38A1 and SLC7A5 is significantly associated with shorter survival in hepatocellular carcinoma patients. Furthermore, inhibition of the transporters and mTORC1 significantly blocks YAP1/TAZ‐mediated tumorigenesis in the liver. These findings elucidate regulatory networks connecting the Hippo pathway to mTORC1 through amino acid metabolism and the mechanism's potential clinical implications for treating hepatocellular carcinoma. Conclusion: YAP1 and TAZ regulate cancer metabolism and mTORC1 through regulation of amino acid transportation, and two amino acid transporters, SLC38A1 and SLC7A5, might be important therapeutic targets. (Hepatology 2016;63:159–172)
Although the introduction of human epidermal growth factor receptor (HER)2‐directed therapy including trastuzumab, pertuzumab, lapatinib and trastuzumab emtansine (T‐DM1) in the treatment of ...HER2‐positive metastatic breast cancers (mBCs) favorably changed the natural history of this disease, most cases of HER2‐positive mBC will eventually progress. Poziotinib is an oral pan‐HER kinase inhibitor showing potent activity through irreversible inhibition of these kinases. This open‐label, multicenter phase II study was designed to evaluate the efficacy and safety of poziotinib monotherapy in patients with HER2‐positive mBC who had progressed from more than two HER2‐directed therapies. Patients received 12 mg poziotinib once daily on a 14‐day on/7‐day off schedule. Progression‐free survival (PFS) as the primary endpoint, the objective response rate (ORR), overall survival (OS) and safety were evaluated. From April 2015 to February 2016, 106 patients were enrolled in the trial from seven institutes in South Korea. They had a median age of 51 years (range 30–76) and had received a median of four prior therapies including two HER2‐directed therapies for advanced or metastatic cancers. The median follow‐up duration was 12 months. The median PFS was 4.04 months (95% confidence interval CI, 2.94–4.40 months), and median overall survival has not been reached. The most common treatment‐related adverse events were (total/grade ≥3) diarrhea (96.23%/14.15%), stomatitis (92.45%/12.26%) and rashes (63.21%/3.77%). Poziotinib showed meaningful activity in these heavily treated HER2‐positive mBCs. Diarrhea and stomatitis were the major toxicities. Biomarker studies analyzed are warranted to support further evaluation of this treatment in such cases.
What's new?
Targeting human epidermal growth factor receptor 2 (HER2) has revolutionized treatment of HER2‐positive cancers but rapid resistance development causes significant clinical problems. In this phase II study, the authors tested poziotinib, a new oral pan‐HER inhibitor, in patients with metastatic breast cancer after two prior HER2‐directed therapies. Treatment with poziotinib achieved on average a progression‐free survival of ~4 months with relatively mild side effects (skin rash and diarrhoea), an encouraging result for patients with repeated treatment failure.
Gastric adenocarcinoma (GAC) is a lethal disease characterized by genomic and clinical heterogeneity. By integrating 8 previously established genomic signatures for GAC subtypes, we identified 6 ...clinically and molecularly distinct genomic consensus subtypes (CGSs). CGS1 have the poorest prognosis, very high stem cell characteristics, and high IGF1 expression, but low genomic alterations. CGS2 is enriched with canonical epithelial gene expression. CGS3 and CGS4 have high copy number alterations and low immune reactivity. However, CGS3 and CGS4 differ in that CGS3 has high HER2 activation, while CGS4 has high SALL4 and KRAS activation. CGS5 has the high mutation burden and moderately high immune reactivity that are characteristic of microsatellite instable tumors. Most CGS6 tumors are positive for Epstein Barr virus and show extremely high levels of methylation and high immune reactivity. In a systematic analysis of genomic and proteomic data, we estimated the potential response rate of each consensus subtype to standard and experimental treatments such as radiation therapy, targeted therapy, and immunotherapy. Interestingly, CGS3 was significantly associated with a benefit from chemoradiation therapy owing to its high basal level of ferroptosis. In addition, we also identified potential therapeutic targets for each consensus subtype. Thus, the consensus subtypes produced a robust classification and provide for additional characterizations for subtype-based customized interventions.
The purpose of this study was to investigate the morphological and histological change of vocal folds (VFs) after steroid injection in a rabbit model.
Prospective animal study.
Tertiary academic ...medical center.
Twenty-four New Zealand white rabbits were used in this study. We randomly classified rabbits into the 3 groups and triamcinolone acetonide suspension was injected to the right VF with different concentrations. Left VF was injected with the same volume of phosphate-buffered saline as control. Endoscopic evaluation was performed to measure morphological changes. The larynges were collected for histological analysis, and the VFs were stained with hematoxylin-eosin for assessing inflammatory response, glandular atrophy, and muscular atrophy and with Masson's trichrome for assessing collagen deposition.
In morphological assessment, there were no differences in VF mass reduction, mucosal atrophy, and granulation formation between both VFs. Histological assessments showed no significant difference in inflammatory response, glandular atrophy, and collagen deposition between both VFs. However, there was a difference in muscular atrophy and epithelial layer thinning in steroid injected right VFs. Muscular atrophy had been completely recovered over time, but mild epithelial thinning was continued until 12 weeks. The longer exposure time and larger dose did not increase the intensity of muscular atrophy or epithelial thinning.
We demonstrated that the VF steroid injection resulted in no significant changes in morphology and histology of rabbit VF. However, steroid injection may induce several VF histological changes and these results are needed to be considered when treating humans.
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