Predicting the Mortality of ICU Patients by Topic Model with Machine-Learning Techniques.

Predicting clinical patients' vital signs is a leading critical issue in intensive care units (ICUs) related studies. Early prediction of the mortality of ICU patients can reduce the overall mortality and cost of complication treatment. Some studies have predicted mortality based on electronic health record (EHR) data by using machine learning models. However, the semi-structured data (i.e., patients' diagnosis data and inspection reports) is rarely used in these models. This study utilized data from the Medical Information Mart for Intensive Care III. We used a Latent Dirichlet Allocation (LDA) model to classify text in the semi-structured data of some particular topics and established and compared the classification and regression trees (CART), logistic regression (LR), multivariate adaptive regression splines (MARS), random forest (RF), and gradient boosting (GB). A total of 46,520 ICU Patients were included, with 11.5% mortality in the Medical Information Mart for Intensive Care III group. Our results revealed that the semi-structured data (diagnosis data and inspection reports) of ICU patients contain useful information that can assist clinical doctors in making critical clinical decisions. In addition, in our comparison of five machine learning models (CART, LR, MARS, RF, and GB), the GB model showed the best performance with the highest area under the receiver operating characteristic curve (AUROC) (0.9280), specificity (93.16%), and sensitivity (83.25%). The RF, LR, and MARS models showed better performance (AUROC are 0.9096, 0.8987, and 0.8935, respectively) than the CART (0.8511). The GB model showed better performance than other machine learning models (CART, LR, MARS, and RF) in predicting the mortality of patients in the intensive care unit. The analysis results could be used to develop a clinically useful decision support system.

Combination Vaccination With Tetanus Toxoid and Enhanced Tumor-Cell Based Vaccine Against Cervical Cancer in a Mouse Model.

Cervical cancer is the fourth most common cancer in women with an estimated 570,000 new cases in 2018 which constitute about 6. 6% of all cancers in women according to WHO report 2018. Approximately 90% of the 270,000 deaths from cervical cancer in 2015 occurred in low- and middle-income countries. In cervical cancers, which is caused by human papillomavirus (HPV) infection, the expression of HPV 16 E6 and E7 proteins are essential for tumor cell transformation and maintenance of malignancy. Prophylactic vaccines against cervical cancer caused by human papillomavirus have not proven successful. Although virus-like particle-based (VLPs) vaccines have been developed with prophylactic activities to prevent most HPV infections, the therapeutic effect of VLP vaccines has yet to be demonstrated for those who were already infected. A recent study showed that pre-conditioning mice with a potent antigen such as tetanus toxoid significantly improves lymph node homing and efficacy of dendritic cells. Tetanus toxoid has also been used in combination with DNA vaccines designed from tumor based antigens. In the present study, we pre-conditioned mice with tetanus toxoid followed by vaccination with a Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) overexpressing tumor-cell based vaccine (GVAX). We observed that pre-conditioning with tetanus toxoid followed by vaccination with GVAX regressed tumor growth and enhanced the overall survival of the mice. Pre-conditioning with tetanus toxoid enhanced the immune response which was observed by enlarged spleen size, higher proliferation rate of lymphocytes, a higher level of IFN-γ, TNF-α, and IL-4 antigen-specific secretions by the splenocytes. Pre-conditioning with tetanus toxoid increased memory T cell migration into the tumor site and spleen. The antigen-specific cytotoxic T cell lysis percentage was also found to be higher in the group of mice vaccinated with the combination of tetanus toxoid and GVAX. Hence, pre-conditioning with tetanus toxoid prior to vaccination with a tumor-cell based vaccine overexpressing GM-CSF might be an effective strategy for targeting E7-specific HPV-associated cervical malignancy.

Sarcosine Prostate Cancer Biomarker Detection by Controlling Oxygen in NiOx Membrane on Vertical Silicon Nanowires in Electrolyte-Insulator-Nanowire Structure.

Sarcosine prostate cancer biomarker with the low concentration of 1 pM has been detected by controlling oxygen from 1 to 15 sccm in a NiOx membrane on chemically etched vertical Si nanowires (SiNWs) in an electrolyte-insulator-nanowire (EIN) structure. The vertical Si nanowires with approximately 17 µm length and polycrystalline NiOx membrane are observed by both field-emission scanning electron microscope (FE-SEM) and high-resolution transmission electron microscope (HRTEM) images, respectively. The optimized NiOx membrane with oxygen content of 4 sccm on planar SiOx/Si substrate shows good pH sensitivity of approximately 50 mV/pH, low hysteresis of 3.4 mV, and low drift rate of 2.4 mV/h as compared to other oxygen content membranes of 1, 10, and 15 sccm. Further, uric acid with the concentration of 0.1 µM is detected directly by using the optimized NiOx membrane. In addition, repeatable H2O2 sensing with the low concentration of 10 pM as well as prostate cancer biomarker is detected, which is owing to the reduction-oxidation phenomena of the NiOx membranes. The sensing mechanism is owing to the Ni2+/Ni3+ oxidation states of the NiOx membrane, which is confirmed by X-ray photoelectron spectroscopy. The optimized NiOx membrane on vertical Si nanowire in the EIN structure shows a good drift rate of 3.84 mV/h and sarcosine detection with improvement of approximately 1000 times as compared to the planar Si in an electrolyte-insulator-semiconductor (EIS) structure. This sensor paves a way to detect early-stage diagnosis of prostate cancer rapidly in the near future.

Controlling Cu Migration on Resistive Switching, Artificial Synapse, and Glucose/Saliva Detection by Using an Optimized AlO x Interfacial Layer in a-CO x -Based Conductive Bridge Random Access Memory.

The Cu migration is controlled by using an optimized AlO x interfacial layer, and effects on resistive switching performance, artificial synapse, and human saliva detection in an amorphous-oxygenated-carbon (a-CO x )-based CBRAM platform have been investigated for the first time. The 4 nm-thick AlO x layer in the Cu/AlO x /a-CO x /TiN x O y /TiN structure shows consecutive >2000 DC switching, tight distribution of SET/RESET voltages, a long program/erase (P/E) endurance of >109 cycles at a low operation current of 300 µA, and artificial synaptic characteristics under a small pulse width of 100 ns. After a P/E endurance of >108 cycles, the Cu migration is observed by both ex situ high-resolution transmission electron microscopy and energy-dispersive X-ray spectroscopy mapping images. Furthermore, the optimized Cu/AlO x /a-CO x /TiN x O y /TiN CBRAM detects glucose with a low concentration of 1 pM, and real-time measurement of human saliva with a small sample volume of 1 µL is also detected repeatedly in vitro. This is owing to oxidation-reduction of Cu electrode, and the switching mechanism is explored. Therefore, this CBRAM device is beneficial for future artificial intelligence application.

Highly efficient and tumor-selective nanoparticles for dual-targeted immunogene therapy against cancer.

While immunotherapy holds great promise for combating cancer, the limited efficacy due to an immunosuppressive tumor microenvironment and systemic toxicity hinder the broader application of cancer immunotherapy. Here, we report a combinatorial immunotherapy approach that uses a highly efficient and tumor-selective gene carrier to improve anticancer efficacy and circumvent the systemic toxicity. In this study, we engineered tumor-targeted lipid-dendrimer-calcium-phosphate (TT-LDCP) nanoparticles (NPs) with thymine-functionalized dendrimers that exhibit not only enhanced gene delivery capacity but also immune adjuvant properties by activating the stimulator of interferon genes (STING)-cGAS pathway. TT-LDCP NPs delivered siRNA against immune checkpoint ligand PD-L1 and immunostimulatory IL-2-encoding plasmid DNA to hepatocellular carcinoma (HCC), increased tumoral infiltration and activation of CD8+ T cells, augmented the efficacy of cancer vaccine immunotherapy, and suppressed HCC progression. Our work presents nanotechnology-enabled dual delivery of siRNA and plasmid DNA that selectively targets and reprograms the immunosuppressive tumor microenvironment to improve cancer immunotherapy.

Delivery of nitric oxide with a nanocarrier promotes tumour vessel normalization and potentiates anti-cancer therapies.

Abnormal tumour vasculature has a significant impact on tumour progression and response to therapy. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis and, thus, can be delivered to normalize tumour vasculature. However, a NO-delivery system with a prolonged half-life and a sustained release mechanism is currently lacking. Here we report the development of NanoNO, a nanoscale carrier that enables sustained NO release to efficiently deliver NO into hepatocellular carcinoma. Low-dose NanoNO normalizes tumour vessels and improves the delivery and effectiveness of chemotherapeutics and tumour necrosis factor-related, apoptosis-inducing, ligand-based therapy in both primary tumours and metastases. Furthermore, low-dose NanoNO reprogrammes the immunosuppressive tumour microenvironment toward an immunostimulatory phenotype, thereby improving the efficacy of cancer vaccine immunotherapy. Our findings demonstrate the ability of nanoscale NO delivery to efficiently reprogramme tumour vasculature and immune microenvironments to overcome resistance to cancer therapy, resulting in a therapeutic benefit.

Effect of Multiple Vaccinations with Tumor Cell-Based Vaccine with Codon-Modified GM-CSF on Tumor Growth in a Mouse Model.

Ectopic expression of codon-modified granulocyte-macrophage colony-stimulating factor (cGM-CSF) in TC-1 cells (TC-1/cGM-CSF), a model cell line for human papillomavirus (HPV)-infected cervical cancer cells, increased the expression level of GM-CSF and improved the efficacy of tumor cell-based vaccines in a cervical cancer mouse model. The number of vaccine doses required to induce a long-term immune response in a cervical cancer mouse model is poorly understood. Here, we investigated one, three, and five doses of the irradiated TC-1/cGM-CSF vaccine to determine which dose was effective in inducing a greater immune response and the suppression of tumors. Our findings showed that three doses of irradiated TC-1/cGM-CSF vaccine elicited slower tumor growth rates and enhanced survival rates compared with one dose or five doses of irradiated TC-1/cGM-CSF vaccine. Consistently, mice vaccinated with three doses of irradiated TC-1/cGM-CSF vaccine exhibited stronger interferon gamma (IFN-γ) production in HPV E7-specific CD8⁺ T cells and CD4⁺ T cells. A higher percentage of natural killer cells and interferon-producing killer dendritic cells (IKDCs) appeared in the splenocytes of the mice vaccinated with three doses of irradiated TC-1/cGM-CSF vaccine compared with those of the mice vaccinated with one dose or five doses of irradiated TC-1/cGM-CSF vaccine. Our findings demonstrate that single or multiple vaccinations, such as five doses, with irradiated TC-1/cGM-CSF vaccine suppressed the immune response, whereas three doses of irradiated TC-1/cGM-CSF vaccine elicited a greater immune response and subsequent tumor suppression.

Controlling Resistive Switching by Using an Optimized MoS2 Interfacial Layer and the Role of Top Electrodes on Ascorbic Acid Sensing in TaO x-Based RRAM.

Controlled resistive switching by using an optimized 2 nm thick MoS2 interfacial layer and the role of top electrodes (TEs) on ascorbic acid (AA) sensing in a TaO x-based resistive random access memory (RRAM) platform have been investigated for the first time. Both the high-resolution transmission electron microscopy (HRTEM) image and depth profile from energy dispersive X-ray spectroscopy confirm the presence of each layer in IrO x/Al2O3/TaO x/MoS2/TiN structure. The pristine device including the IrO x TE with the 2 nm thick interfacial layer shows the highest uniform rectifying direct current endurance >1000 cycles and a large rectifying ratio >3.2 × 104, and a high nonlinearity factor >700 is obtained, greater than that of Pt and Ru TEs. After formation, this IrO x device produces bipolar resistive switching characteristics and a long program/erase (P/E) endurance >107 cycles at a low operation current of <50 µA with small pulse width of 100 ns. The stressed device shows a reduced Al2O3/TaO x interface from the HRTEM image, which is owing to O2- ions' migration toward TiN electrode. By adjusting the RESET voltage and current level, consecutive >100 complementary resistive switching as well as long P/E endurance of >106 cycles are obtained. Schottky barrier height modulation at a low field is observed owing to reduction-oxidation of the TE, which is evidenced through reversible AA detection. At a higher field, Fowler-Nordheim tunneling and hopping conduction are observed. Ascorbic acid detection with a low concentration of 1 pM by using a porous IrO x/Al2O3/TaO x/MoS2/TiN RRAM device directly is an additional novelty of this work, which will be useful in future for early diagnosis of scurvy.

Biodegradable andrographolide-eluting nanofibrous membranes for the treatment of cervical cancer.

BACKGROUND: In this study, we developed biodegradable andrographolide (AG)-eluting nanofibrous mats and evaluated their efficacy in treating cervical cancer. MATERIALS AND METHODS: Membranes of two different poly[(d,l)-lactide-co-glycolide] (PLGA)-to-AG ratios (6:1 and 3:1) were prepared via electrospinning technology. The liberation behavior of AG was evaluated. A cervical cancer model with C57BL/6J mice was created and employed for an in vivo efficacy assessment of the drug-eluting nanofibers. Twelve mice with cervical cancer were stochastically divided into three different groups (four animals per group): group A received no treatment as the control, group B was treated with pure PLGA mats, and group C was treated with AG-loaded nanofibrous membranes. The changes in tumor sizes were recorded. RESULTS: All membranes eluted high concentrations of AG at the target area for three weeks, while the systemic drug concentration in the blood remained low. Histological analysis showed no obvious tissue inflammation. Compared with the mice in groups A and B, the tumor size of the mice in group C decreased with time until day 25, when the daily drug concentration reduced to 3 µg/mL. CONCLUSION: Biodegradable nanofibers with a sustainable release of AG exhibit adequate efficacy and durability for the treatment of mice with cervical cancer.

Cellular energy metabolism maintains young status in old queen honey bees (Apis mellifera).

Trophocytes and oenocytes of queen honey bees are used in studies of cellular longevity, but their cellular energy metabolism with age is poorly understood. In this study, the molecules involved in cellular energy metabolism were evaluated in the trophocytes and oenocytes of young and old queen bees. The findings indicated that there were no significant differences between young and old queen bees in ß-oxidation, glycolysis, and protein synthesis. These results indicate that the cellular energy metabolism of trophocytes and oenocytes in old queen bees is similar to young queen bees and suggests that maintaining cellular energy metabolism in a young status may be associated with the longevity of queen bees. Fat and glycogen accumulation increased with age indicating that old queen bees are older than young queen bees.

A multifunctional nanocarrier for efficient TRAIL-based gene therapy against hepatocellular carcinoma with desmoplasia in mice.

The anticancer efficacy of TNF-related apoptosis-inducing ligand (TRAIL)-based therapy is limited because of systemic toxicity, poor bioavailability, and development of TRAIL resistance. We developed a tumor-targeted LCPP (lipid/calcium/phosphate/protamine) nanoparticle (NP) to deliver TRAIL plasmid DNA (pDNA) into hepatocellular carcinoma (HCC) cells in a mouse model of HCC. TRAIL pDNA was encapsulated in a pH stimuli-responsive calcium phosphate (CaP) core, and protamine was added to facilitate nuclear delivery of pDNA. In addition, intracellular release of Ca2+ from the CaP core overcame TRAIL resistance by calcium influx-dependent DR5 up-regulation. TRAIL expression also attenuated fibrosis in liver tissues surrounding HCCs by reverting activated hepatic stellate cells (HSCs) to a quiescent state or by directly inducing apoptosis in activated HSCs. CONCLUSION: TRAIL pDNA delivered by HCC-targeted LCPP NPs in combination with conventional sorafenib treatment attenuated HCC progression as well as liver fibrosis. Overall, our study presents an effective TRAIL-based cancer therapy that could be developed for clinical applications. (Hepatology 2018;67:899-913).

Outcomes and prognoses of patients with ovarian cancer using bevacizumab: 6-year experience in a tertiary care hospital of northern Taiwan.

PURPOSE: Bevacizumab (BEV) has been used for ovarian cancer (OC) for years in Taiwan, but the associated data related to outcome is scant. This retrospective study reviewed patients with OC treated with BEV and analyzed their results. PATIENTS AND METHODS: All patients with OC treated with BEV from 2009 to 2015 in the Linkou branch of Chang Gung Memorial Hospital in Northern Taiwan were included. According to the means of administration, the patients were classified into 6 groups as follows: A-BEV plus chemotherapy (C/T) for initial platinum-resistant (PR) recurrent OC, B-BEV plus C/T for initial platinum-sensitive (PS) recurrent OC, C-BEV alone for recurrent OC, D-BEV plus 1st adjuvant C/T, E-BEV plus neoadjuvant C/T, and F-intraperitoneal (IP) BEV. Progression-free survival (PFS), overall survival (OS), hazard ratios (HRs), overall response rate (ORR), and mean number of BEV cycles were analyzed for groups A to E. Clinical improvement of ascites was assessed for group F. RESULTS: A comparison of early use (only one round of prior C/T) versus late use (multiple rounds of prior C/T) in patients of groups A and B showed a superior PFS (8.27 vs. 3.67, p = 0.037) in the early use group. No significant differences were found between groups A and B (PFS: 4.24 vs. 4.17 months, p = 0.690; OS: 10.06 vs. 9.93 months, p = 0.819; mean BEV cycles: 4.63 vs. 5.0 p = 0.992; ORR: 48.1% vs. 53.5%, p = 0.425). Comparing the response and non-response subgroups of patients in groups A and B, a better outcome was associated with endometrioid type cell (HR = 0.28, p = 0.008), good ECOG performance status (HR = 0.51, p = 0.005), and lack of ascites (HR = 0.67, p = 0.004). Comparing group C with groups A plus B, the BEV alone group had a poorer PFS (1.02 VS. 4.19, p = 0.04) and OS (1.42 VS. 9.99 p = 0.001) than the BEV plus C/T group. In group F, a good clinical benefit rate (85.6%) of ascites improvement was noted. Two patients had grade 5 gastrointestinal bleeding and venous/arterial thromboembolic events after administration of BEV. Grade 3 neutropenia and thrombocytopenia occurred more frequently in our study. CONCLUSION: Early use of BEV combined with chemotherapy had a significant benefit in PFS for patients with recurrent OC. BEV plus chemotherapy was better than BEV alone for recurrent OC. In addition, IP BEV was helpful for improving clinical ascites.

Novel GM-CSF-based vaccines: One small step in GM-CSF gene optimization, one giant leap for human vaccines.

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a potent immunomodulatory cytokine that is known to facilitate vaccine efficacy by promoting the development and prolongation of both humoral and cellular immunity. In the past years we have generated a novel codon-optimized GM-CSF gene as an adjuvant. The codon-optimized GM-CSF gene significantly increased protein expression levels in all cells tested and helped in generating a strong immune responses against HIV-1 Gag and HPV-associated cancer. Here, we review the literature dealing with the adjuvant activity of GM-CSF both in animal models and clinical trials. We anticipate that the codon-optimized GM-CSF gene offers a practical molecular strategy for potentiating immune responses to tumor cell-based vaccinations as well as other immunotherapeutic strategies.

Cellular degradation activity is maintained during aging in long-living queen bees.

Queen honeybees (Apis mellifera) have a much longer lifespan than worker bees. Whether cellular degradation activity is involved in the longevity of queen bees is unknown. In the present study, cellular degradation activity was evaluated in the trophocytes and oenocytes of young and old queen bees. The results indicated that (i) 20S proteasome activity and the size of autophagic vacuoles decreased with aging, and (ii) there were no significant differences between young and old queen bees with regard to 20S proteasome expression or efficiency, polyubiquitin aggregate expression, microtubule-associated protein 1 light chain 3-II (LC3-II) expression, 70 kDa heat shock cognate protein (Hsc70) expression, the density of autophagic vacuoles, p62/SQSTM1 expression, the activity or density of lysosomes, or molecular target of rapamycin expression. These results indicate that cellular degradation activity maintains a youthful status in the trophocytes and oenocytes of queen bees during aging and that cellular degradation activity is involved in maintaining the longevity of queen bees.

The efficacy of a novel vaccine approach using tumor cells that ectopically express a codon-optimized murine GM-CSF in a murine tumor model.

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a potent immunomodulatory cytokine that is known to facilitate vaccine efficacy by promoting the development and prolongation of both humoral and cellular immunity. Here, we investigated a novel vaccine approach using a human papillomavirus (HPV)-16 E6/E7-transformed cell line, TC-1, that ectopically expresses a codon-optimized 26-11-2015 murine GM-CSF (cGM-CSF). Ectopically expressing cGM-CSF in TC-1 (TC-1/cGM) cells significantly increased expression of a GM-CSF that was functionally identical to wt GM-CSF by 9-fold compared with ectopically expressed wild type GM-CSF in TC-1 cells (TC-1/wt). Mice vaccinated with irradiated TC-1/cGM cells exhibited enhanced survival compared with mice vaccinated with TC-1/wt cells when both groups were subsequently injected with live TC-1. Consistently, mice vaccinated with irradiated TC-1/cGM cells exhibited stronger IFN-γ production in HPV E7-specific CD8(+) T cells. More dendritic cells were recruited to the draining lymph nodes (dLNs) of mice vaccinated with TC-1/cGM cells than C-1/wt cells. Regarding dLN cell recall responses, both proliferation and IFN-γ production in the HPV E7-specific CD8(+) T cells were enhanced in mice that were vaccinated with TC-1/cGM cells. Our results demonstrate that a novel practical molecular strategy utilizing a codon-optimized GM-CSF gene overcomes the limitation and improves the efficacy of tumor cell-based vaccines.

High-resolution melting molecular signatures for rapid identification of human papillomavirus genotypes.

BACKGROUND: Genotyping of human papillomarvirus (HPV) is crucial for patient management in a clinical setting. This study accesses the combined use of broad-range real-time PCR and high-resolution melting (HRM) analysis for rapid identification of HPV genotypes. METHODS: Genomic DNA sequences of 8 high-risk genotypes (HPV16/18/39/45/52/56/58/68) were subject to bioinformatic analysis to select for appropriate PCR amplicon. Asymmetric broad-range real-time PCR in the presence of HRM dye and two unlabeled probes specific to HPV16 and 18 was employed to generate HRM molecular signatures for HPV genotyping. The method was validated via assessment of 119 clinical HPV isolates. RESULTS: A DNA fragment within the L1 region was selected as the PCR amplicon ranging from 215-221 bp for different HPV genotypes. Each genotype displayed a distinct HRM molecular signature with minimal inter-assay variability. According to the HRM molecular signatures, HPV genotypes can be determined with one PCR within 3 h from the time of viral DNA isolation. In the validation assay, a 91% accuracy rate was achieved when the genotypes were in the database. Concomitantly, the HRM molecular signatures for additional 6 low-risk genotypes were established. CONCLUSIONS: This assay provides a novel approach for HPV genotyping in a rapid and cost-effective manner.