Gut microbiota and clinical response to immune checkpoint inhibitor therapy in patients with advanced cancer.

BACKGROUND: There is currently no well-accepted consensus on the association between gut microbiota and the response to treatment of immune checkpoint inhibitors (ICIs) in patients with advanced cancer. METHODS: Fecal samples were collected before ICI treatment. Gut microbiota was analyzed using 16 S ribosomal RNA sequencing. We investigated the relationship between the α-diversity of fecal microbiota and patients' clinical outcomes. Microbiota profiles from patients and healthy controls were determined. Pre-treatment serum was examined by cytokine array. RESULTS: We analyzed 74 patients, including 42 with melanoma, 8 with kidney cancer, 13 with lung cancer, and 11 with other cancers. Combination therapy of anti-PD1 and anti-CTLA-4 was used in 14 patients, and monotherapy in the rest. Clinical benefit was observed in 35 (47.3 %) cases, including 2 complete responses, 16 partial responses, and 17 stable diseases according to RECIST criteria. No significant difference in α-diversity was found between the benefiter and non-benefiter groups. However, patients with α-diversity within the range of our healthy control had a significantly longer median overall survival (18.9 months), compared to the abnormal group (8.2 months) (p = 0.041, hazard ratio = 0.546) for all patients. The microbiota composition of the benefiters was similar to that of healthy individuals. Furthermore, specific bacteria, such as Prevotella copri and Faecalibacterium prausnitzii, were associated with a favorable outcome. We also observed that serum IL-18 before treatment was significantly lower in the benefiters, compared to non-benefiters. CONCLUSIONS: The α-diversity of gut microbiota is positively correlated with more prolonged overall survival in cancer patients following ICI therapy.

Ampelopsis grossedentata Represents a New Host of the 16SrI Group of Phytoplasma Associated with Yellow Leaf Symptoms in China.

Ampelopsis grossedentata, commonly known as "Vine Tea" and well-recognized for its rich flavonoid content, is mainly distributed in the southern regions of the Yangtze River basin in China. These regions include Hunan, Hubei, Jiangxi, and Guizhou provinces. Vine Tea is mainly consumed as an herbal tea and has garnered attention for its reported health benefits, including antioxidant, anti-inflammatory, anti-tumor, anti-diabetic, and neuroprotective properties. It has been used to alleviate coughs and sore throats (Zhang et al., 2021; Wang et al., 2017; Gao et al., 2009). In the Zhangjiajie region of Hunan province alone, the Vine Tea planting area reached 7,670.5 hectares and produced commercial goods worth 1.417 billion RMB in 2022. In May 2021, leaf margins and veins fading to yellowing mottling, and crumpling of leaf blades in the shape of a boat symptoms were found in ~16% of Vine Tea plants in the Sanjiakuan Township, Yongding District, Zhangjiajie region (29°15'E, 110°30' N) (Figure 1a, b, c). (Figure 1a, b, c). Phytoplasma-like microbial cells (small oval shaped bacterial cells, around 1000 nm in size) were observed in sieve tube cells in the phloem of diseased leaves using transmission electron microscopy. No such cell was observed in the phloem of healthy leaves (Figure 2a, b). To investigate the potential association between phytoplasma and the observed symptoms of the diseased plants, total DNA was isolated from ten diseasedeaves and compared with ten healthy leaves from the same field using SteadyPure Plant Genomic DNA Extraction Kit. The isolated DNAs were analyzed first in a direct PCR using universal phytoplasma primer pair R16mF2/R16mR1 targeting the 16S rRNA gene (Gundersen and Lee 1996) and specific pair rpF1/rpR1 (Lee et al. 1998) targeting the DNA fragment encoding partial ribosomal proteins (rp) L22 (complete) and S3 and S19 (partial). The initial amplified products were used as templates and further amplified by nested PCR respectively with primer pair R16F2n/R16R2 for the 16S rRNA gene (Lee et al. 1998) and the rpF2/rpR2 primer pair for the rp gene (Martini et al. 2007). No amplification was obtained with DNA from healthy leaf samples using any of the four primer pairs. The amplified fragments from diseased leaves by nested PCR were cloned and sequenced (Qingke Biotech, China). The obtained sequences have been deposited in GenBank with accession numbers OR282806 for the 16S rRNA gene and GenBank OR353012 for the rp gene. BLASTn analysis revealed that the partial 16S rRNA gene sequence in our sample shared 99.4% nucleotide sequence identity with 'Candidatus Phytoplasma sp.' (MW364378) and 'Peony yellows phytoplasma' (KY814723) of the 16SrI group. Similarly, our rp gene sequence shared 99.6% nucleotide identity with the rpI group of phytoplasma such as the 'Balsamine virescence phytoplasma' (JN572890) and 'Paulownia witches'-broom phytoplasma' (HM146079). Phylogenetic analysis of the 16S rRNA and rp sequences using MEGA version 7.0 revealed that the phytoplasma strain associated with A. grossedentata yellow leaf syndrome in our study site belonged to the 16SrI (Candidatus Phytoplasma asteris) group of phytoplasma (Figure 3a, b). Using the interactive online phytoplasma classification tool iPhyClassifier (Zhao et al., 2009), virtual restriction fragment length polymorphism (RFLP) analysis of the 16S rRNA gene sequences showed our strain having a distinct RFLP map but was closest to that of the onion yellow phytoplasma 16SrI-B subgroup (GenBank accession number: AP006628), with a similarity coefficient of 0.94 (Figure 4a, b). To confirm phytoplasma transmission, healthy plants were inoculated with three scions of infected plants of A. grossedentata. After 16 days, the new leaves of the inoculated A. grossedentata showed yellow leaf symptoms (Figure 5a, b, c), akin to the symptoms originally observed in the field, and the outer contour of the leaf margin appeared chlorotic. After 26 days, primer pairs R16mF2/R16R1 and R16F2n/R16R2 were used for nested PCR detection of phytoplasma in symptomatic A. grossedentata leaves. Phytoplasma was detected in the first and second leaves of symptomatic branches and leaves while negative control showed no amplification. Sequencing of the amplified fragments showed 100% nucleotide identity to the strain from the grafting source. Our results indicated that the pathogen and the disease can be transmitted by tissue grafting, consistent with the biological characteristics of phytoplasma, and further confirmed that the phytoplasma was the pathogen of yellow leaf syndrome of A. grossedentata. Toour knowledge, this is the first report of phytoplasma of group 16SrI affecting A. grossedentata.

NIR-activated quercetin-based nanogels embedded with CuS nanoclusters for the treatment of drug-resistant biofilms and accelerated chronic wound healing.

We have developed multifunctional nanogels with antimicrobial, antioxidant, and anti-inflammatory properties, facilitating rapid wound healing. To prepare the multifunctional nanogels, we utilized quercetin (Qu) and a mild carbonization process to form carbonized nanogels (CNGs). These CNGs possess excellent antioxidative and bacterial targeting properties. Subsequently, we utilized the Qu-CNGs as templates to prepare nanogels incorporating copper sulfide (CuS) nanoclusters, further enhancing their functionality. Notably, the CuS/Qu-CNGs nanocomposites demonstrated an exceptional minimum inhibitory concentration against tested bacteria, approximately 125-fold lower than monomeric Qu or Qu-CNGs. This enhanced antimicrobial effect was achieved by leveraging near-infrared II (NIR-II) light irradiation. Additionally, the CuS/Qu-CNGs exhibited efficient penetration into the extracellular biofilm matrix, eradicating methicillin-resistant Staphylococcus aureus-associated biofilms in diabetic mice wounds. Furthermore, the nanocomposites were found to suppress proinflammatory cytokines, such as IL-1ß, at the wound sites while regulating the expression of anti-inflammatory factors, including IL-10 and TGF-ß1, throughout the recovery process. The presence of CuS/Qu-CNGs promoted angiogenesis, epithelialization, and collagen synthesis, thereby accelerating wound healing. Our developed CuS/Qu-CNGs nanocomposites have great potential in addressing the challenges associated with delayed wound healing caused by microbial pathogenesis.

Combining virtual screening with cis-/trans-cleavage enzymatic assays effectively reveals broad-spectrum inhibitors that target the main proteases of SARS-CoV-2 and MERS-CoV.

The main protease (Mpro) of SARS-CoV-2 is essential for viral replication, which suggests that the Mpro is a critical target in the development of small molecules to treat COVID-19. This study used an in-silico prediction approach to investigate the complex structure of SARS-CoV-2 Mpro in compounds from the United States National Cancer Institute (NCI) database, then validate potential inhibitory compounds against the SARS-CoV-2 Mpro in cis- and trans-cleavage proteolytic assays. Virtual screening of ∼280,000 compounds from the NCI database identified 10 compounds with highest site-moiety map scores. Compound NSC89640 (coded C1) showed marked inhibitory activity against the SARS-CoV-2 Mpro in cis-/trans-cleavage assays. C1 strongly inhibited SARS-CoV-2 Mpro enzymatic activity, with a half maximal inhibitory concentration (IC50) of 2.69 µM and a selectivity index (SI) of >74.35. The C1 structure served as a template to identify structural analogs based on AtomPair fingerprints to refine and verify structure-function associations. Mpro-mediated cis-/trans-cleavage assays conducted with the structural analogs revealed that compound NSC89641 (coded D2) exhibited the highest inhibitory potency against SARS-CoV-2 Mpro enzymatic activity, with an IC50 of 3.05 µM and a SI of >65.57. Compounds C1 and D2 also displayed inhibitory activity against MERS-CoV-2 with an IC50 of <3.5 µM. Thus, C1 shows potential as an effective Mpro inhibitor of SARS-CoV-2 and MERS-CoV. Our rigorous study framework efficiently identified lead compounds targeting the SARS-CoV-2 Mpro and MERS-CoV Mpro.

In Vitro Assessment of the Antioxidant and Anticancer Properties of Flammulina velutipes Stipe Extracts.

BACKGROUND/AIM: Flammulina velutipes (FV), also known as the golden needle mushroom, is an edible and medicinal fungus that contains bioactive substances regulating various physiological functions. While the fruiting bodies of FV are commonly consumed, their stipes are often discarded despite containing polysaccharides. In this study, the biological functions of FV stipes (FV-S) were investigated to reduce waste and pollution while increasing their value. MATERIALS AND METHODS: The antioxidant activity of FV was evaluated using three methods: the DPPH radical-scavenging capacity assay, ferrous ion chelating assay, and reducing power analysis. The anti-cancer potential was assessed through MTT viability and immunoblotting analyses. RESULTS: Results showed that FV-S had higher polysaccharide and total phenolic contents and greater antioxidant abilities, particularly in ethanolic extracts. FV-S also exhibited significant anticancer properties, specifically in hot water extracts with high polysaccharide contents, and suppressed prostate cancer cell viability by inhibiting androgen receptor and PCa-specific antigen mRNA expression while inducing caspase-3/7 activation. CONCLUSION: FV-S is rich in bioactive components, possesses higher antioxidant and anticancer abilities, and has potential as an anticancer agent, which could enhance the value of FV.

The Application of Wireless Underground Sensor Networks to Monitor Seepage inside an Earth Dam.

Earth dams or embankments are susceptible to instability due to internal seepage, piping, and erosion, which can lead to catastrophic failure. Therefore, monitoring the seepage water level before the dam collapses is an important task for early warning of dam failure. Currently, there are hardly any monitoring methods that use wireless underground transmission to monitor the water content inside earth dams. Real-time monitoring of changes in the soil moisture content can more directly determine the water level of seepage. Wireless transmission of sensors buried underground requires signal transmission through the soil medium, which is more complex than traditional air transmission. Henceforth, this study establishes a wireless underground transmission sensor that overcomes the distance limitation of underground transmission through a hop network. A series of feasibility tests were conducted on the wireless underground transmission sensor, including peer-to-peer transmission tests, multi-hop underground transmission tests, power management tests, and soil moisture measurement tests. Finally, field seepage tests were conducted to apply wireless underground transmission sensors to monitor the internal seepage water level before an earth dam failure. The findings show that wireless underground transmission sensors can achieve the monitoring of seepage water levels inside earth dams. In addition, the results supersede those of a conventional water level gauge. This could be crucial in early warning systems during the era of climate change, which has caused unprecedented flooding events.

Coupling a Borehole Thermal Model and MT3DMS to Simulate Dynamic Ground Source Heat Pump Efficiency.

We present a novel integrated two-region model that couples simulation of local heat transfer processes in borehole heat exchangers (BHEs) with field-scale heat transport simulation using MT3DMS to fulfill the dynamic simulation of the borehole geothermal systems. This includes the prediction of subsurface thermal perturbation induced by BHEs, derivation of the U-pipe circulating fluid temperature profile within boreholes, and the evaluation of the ground source heat pump efficiency based on available time series of building heat load. In our approach, MT3DMS is the simulator for the two-dimensional field-scale heat transport, while new Python modules are developed to analytically solve the thermal transfer process within boreholes and interface iteratively with MT3DMS. A Python package for scripting MODFLOW-based code named Flopy is used to establish the MT3DMS numerical model. The proposed model is validated against analytical solutions and we demonstrate the application to more complex test problems with field-scale heterogeneity and pumping. Instructions are provided to access the source code and example problems which are available online.

Distributed Thermal Response Multi-Source Modeling to Evaluate Heterogeneous Subsurface Properties.

A thorough assessment of thermal properties in heterogeneous subsurface is necessary in design of low-temperature borehole heat exchangers (BHEs). A distributed thermal response test (DTRT), which combines distributed temperature sensing (DTS) with a conventional thermal response test (TRT), was conducted in a U-bend geothermal loop installed in an open borehole at the University of Illinois at Urbana-Champaign to estimate thermal properties by analyzing the thermal response of different geologic materials while applying a constant heat input rate. Fiber-optic cables in the DTRT were deployed both inside the U-bend geothermal loop and in the center of the borehole to improve the accuracy of calculated heat-loss rates and borehole temperature profile measurements. To assess the subsurface thermal conductivity during the heating phase of the DTRT, a single-source model and a multi-source model, both based on the infinite line source method, were developed using the borehole temperature data and temperatures inside and along the outside of the loop, separately. The two models returned similar thermal conductivity values. The multi-source modeling has the advantage of predicting the thermal conductivity of heterogeneous geologic materials from borehole temperature profiles during the DTRT heating phase. In addition, based on the distributed thermal conductivity measured in the borehole, estimates were made for both radial thermal impacts and the rate of heat loss in the BHE.

Interleukin-11/gp130 upregulates MMP-13 expression and cell migration in OSCC by activating PI3K/Akt and AP-1 signaling.

Oral squamous cell carcinoma (OSCC) is an extremely common head and neck cancer with a poor 5-year survival rate, especially in cases of metastatic disease. Interleukin (IL)-11 reportedly promotes cell growth and the epithelial-mesenchymal transition process in metastasis. However, the molecular mechanisms of IL-11 in OSCC metastasis are unclear. This study found that IL-11 upregulates matrix metalloproteinase 13 (MMP-13) expression in OSCC via the IL-11 receptor alpha subunit/glycoprotein 130 receptors that activate phosphatidyl-inositol 3-kinase, Ak strain transforming, and activator protein 1 signaling, which subsequently enhance MMP-13-induced tumor metastasis. TIMER2.0 analysis revealed a positive correlation between MMP-13 and IL-11 levels (r = 0.454). Moreover, a strong positive association was observed between higher levels of IL-11 expression in OSCC tissue (p < 0.01), lymph node metastasis (p = 0.0154), and clinical disease stage (p = 0.0337). IL-11 knockdown suppressed the migration of OSCC cells (p < 0.05). The evidence indicates that IL-11 can serve as a new molecular therapeutic target in OSCC metastasis.

Photoswitchable carbon-dot liposomes mediate catalytic cascade reactions for amplified dynamic treatment of tumor cells.

Most biochemical reactions that occur in living organisms are catalyzed by a series of enzymes and proceed in a tightly controlled manner. The development of artificial enzyme cascades that resemble multienzyme complexes in nature is of current interest due to their potential in various applications. In this study, a nanozyme based on photoswitchable carbon-dot liposomes (CDsomes) was developed for use in programmable catalytic cascade reactions. These CDsomes prepared from triolein are amphiphilic and self-assemble into liposome-like structures in an aqueous environment. CDsomes feature excitation-dependent photoluminescence and, notably, can undergo reversible switching between a fluorescent on-state and nonfluorescent off-state under different wavelengths of light irradiation. This switching ability enables the CDsomes to exert photocatalytic oxidase- and peroxidase-like activities in their on- (bright) and off- (dark) states, respectively, resulting in the conversion of oxygen molecules into hydrogen peroxide (H2O2), followed by the generation of active hydroxyl radicals (OH). The two steps of oxygen activation can be precisely controlled in a sequential manner by photoirradiation at different wavelengths. Catalytic reversibility also enables the CDsomes to produce sufficient reactive oxygen species (ROS) to effectively kill tumor cells. Our results reveal that CDsomes is a promising photo-cycling nanozyme for precise tumor phototherapy through regulated programmable cascade reactions.

MIB2: metal ion-binding site prediction and modeling server.

MOTIVATION: MIB2 (metal ion-binding) attempts to overcome the limitation of structure-based prediction approaches, with many proteins lacking a solved structure. MIB2 also offers more accurate prediction performance and more metal ion types. RESULTS: MIB2 utilizes both the (PS)2 method and the AlphaFold Protein Structure Database to acquire predicted structures to perform metal ion docking and predict binding residues. MIB2 offers marked improvements over MIB by collecting more MIB residue templates and using the metal ion type-specific scoring function. It offers a total of 18 types of metal ions for binding site predictions. AVAILABILITY AND IMPLEMENTATION: Freely available on the web at http://bioinfo.cmu.edu.tw/MIB2/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Successful treatment of severe pityriasis rubra pilaris with secukinumab in a 3-year-old boy.

Pityriasis rubra pilaris (PRP) is a rare, scaly, keratotic inflammatory skin disease characterized by red scaly patches, keratosis papules, palmoplantar keratoderma and scaling of the scalp. In severe cases, ectropion of the eyelid may occur, and erythroderma may further develop. Recently, it has been reported that secukinumab, a monoclonal anti-interleukin-17A antibody, has certain efficacy in the treatment of PRP. Herein, we report a 3-year-old Chinese boy with severe Type III (classic juvenile) PRP who was successfully treated with secukinumab alone.

Self-redox reaction driven in situ formation of Cu2O/Ti3C2Tx nanosheets boost the photocatalytic eradication of multi-drug resistant bacteria from infected wound.

BACKGROUND: MXenes with interesting optical and electrical properties have been attractive in biomedical applications such as antibacterial and anticancer agents, but their low photogeneration efficiency of reactive oxygen species (ROS) and poor stability are major concerns against microbial resistance. METHODS: Water-dispersible single layer Ti3C2Tx-based MXene through etching tightly stacked MAX phase precursor using a minimally intensive layer delamination method. After addition of Cu(II) ions, the adsorbed Cu(II) ions underwent self-redox reactions with the surface oxygenated moieties of MXene, leading to in situ formation of Cu2O species to yield Cu2O/Ti3C2Tx nanosheets (heterostructures). RESULTS: Under NIR irradiation, the Cu2O enhanced generation of electron-hole pairs, which boosted the photocatalytic production of superoxide and subsequent transformation into hydrogen peroxide. Broad-spectrum antimicrobial performance of Cu2O/Ti3C2Tx nanosheets with sharp edges is attributed to the direct contact-induced membrane disruption, localized photothermal therapy, and in situ generated cytotoxic free radicals. The minimum inhibitory concentration of Cu2O/Ti3C2Tx nanosheets reduced at least tenfold upon NIR laser irradiation compared to pristine Cu2O/Ti3C2Tx nanosheets. The Cu2O/Ti3C2Tx nanosheets were topically administrated on the methicillin-resistant Staphylococcus aureus (MRSA) infected wounds on diabetic mice. CONCLUSION: Upon NIR illumination, Cu2O/Ti3C2Tx nanosheets eradicated MRSA and their associated biofilm to promote wound healing. The Cu2O/Ti3C2Tx nanosheets with superior catalytic and photothermal properties have a great scope as an effective antimicrobial modality for the treatment of infected wounds.

Evaluation of chemotherapeutic response in living cells using subcellular Organelle‒Selective amphipathic carbon dots.

Monitoring of structural changes in subcellular organelles is critical to evaluate the chemotherapeutic response of cells. However, commercial organelle selective fluorophores are easily photobleached, and thus are unsuitable for real-time and long-term observation. We have developed photostable carbon-dot liposomes (CDsomes)-based fluorophores for organellar and suborganellar imaging to circumvent these issues. The CDs synthesized through a mild pyrolysis/hydrolysis process exhibit amphipathic nature and underwent self-assembly to form liposome-like structures (CDsomes). The controlled hydrophilicity or hydrophobicity-guided preparation of CDsomes are used to selectively and rapidly (<1 min) stain nucleolus, cytoplasm, and membrane. In addition, the CDsomes offer universal high-contrast staining not only in fixed cells but also in living cells, allowing real-time observation and morphological identification in the specimen. The as-prepared CDsomes exhibit excitation-dependent fluorescence, and are much more stable under photoirradiation (e.g., ultraviolet light) than traditional subcellular dyes. Interestingly, the CDsomes can be transferred to daughter cells by diluting the particles, enabling multigenerational tracking of suborganelle for up to six generations, without interrupting the staining pattern. Therefore, we believe that the ultra-photostable CDsomes with high biocompatibility, and long-term suborganellar imaging capabilities, hold a great potential for screening and evaluating therapeutic performance of various chemotherapeutic drugs.

Angiotensin II Receptor Blocker Associated With Less Outcome Risk in Patients With Acute Kidney Disease.

Objective: The aim of this study was to explore the respective use of angiotensin-converting-enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) on the outcomes of patients who could be weaned from dialysis-requiring acute kidney injury (AKI-D). Methods: This case-control study enrolled 41,731 patients who were weaned from AKI-D for at least 7 days from Taiwan's National Health Insurance Administration. We further grouped AKI-D patients according to ACEi and ARB use to evaluate subsequent risks of all-cause mortality and re-dialysis. The outcomes included the all-cause mortality and new-onset of end-stage kidney disease (ESKD; re-dialysis) following withdraw from AKI-D. Results: A total of 17,141 (41.1%) patients surviving AKI-D could be weaned from dialysis for at least 7 days. The overall events of mortality were 366 (48.9%) in ACEi users, 659 (52.1%) in ARB users, and 6,261 (41.3%) in ACEi/ARB nonusers, during a mean follow-up period of 1.01 years after weaning from AKI-D. In regard to all-cause of mortality, pre-dialysis ARB users had lower incidence than ACEi users [hazard ratio (HR 0.82), p = 0.017]. Compared with ACEi/ARB nonusers, continuing ARB users had a significantly low risk of long-term all-cause mortality (adjusted hazard ratio 0.51, p = 0.013) after propensity score matching. However, new users of ACEi at the acute kidney disease (AKD) period had a higher risk of re-dialysis after weaning than ACEi/ARB nonusers (aHR 1.82, p < 0.001), whereas neither ACEi nor ARB users confronted significantly increased risks of hyperkalemia after weaning. Conclusions: Compared with patients without ACEi/ARB, those continuing to use ARB before the event and after weaning had low all-cause mortality, while new users of ACEi at AKD had increased risk of re-dialysis. AKI-D patients continuing to use ACEi or ARB did not have higher risk of hyperkalemia. Future prospective randomized trials are expected to confirm these findings.

Divergent Characteristics of T-Cell Receptor Repertoire Between Essential Hypertension and Aldosterone-Producing Adenoma.

Aldosterone-producing adenoma (APA) is a benign adrenal tumor that results in persistent hyperaldosteronism. As one major subtype of primary aldosteronism, APA leads to secondary hypertension that is associated with immune dysregulation. However, how the adaptive immune system, particularly the T-cell population, is altered in APA patients remains largely unknown. Here, we performed TCR sequencing to characterize the TCR repertoire between two age-matched groups of patients: one with APA and the other one with essential hypertension (EH). Strikingly, we found a significant reduction of TCR repertoire diversity in the APA group. Analyses on TCR clustering and antigen annotation further showed that the APA group possessed lower diversity in TCR clonotypes with non-common antigen-specific features, compared with the EH group. In addition, our results indicated that the strength of correlation between generation probabilities and frequencies of TCR clonotypes was significantly higher in the APA group than that in the EH group. Finally, we observed that clinical features, including plasma aldosterone level, aldosterone-renin ratio, and blood sodium level, were positively associated with the strength of correlation between generation and abundance of TCR clonotypes in the APA group. Our findings unveiled the correlation between T-cell immune repertoire and APA, suggesting a critical role of such adrenal adenoma in the T-cell immunity of patients with hypertension.

Recognition of a Novel Gene Signature for Human Glioblastoma.

Glioblastoma (GBM) is one of the most common malignant and incurable brain tumors. The identification of a gene signature for GBM may be helpful for its diagnosis, treatment, prediction of prognosis and even the development of treatments. In this study, we used the GSE108474 database to perform GSEA and machine learning analysis, and identified a 33-gene signature of GBM by examining astrocytoma or non-GBM glioma differential gene expression. The 33 identified signature genes included the overexpressed genes COL6A2, ABCC3, COL8A1, FAM20A, ADM, CTHRC1, PDPN, IBSP, MIR210HG, GPX8, MYL9 and PDLIM4, as well as the underexpressed genes CHST9, CSDC2, ENHO, FERMT1, IGFN1, LINC00836, MGAT4C, SHANK2 and VIPR2. Protein functional analysis by CELLO2GO implied that these signature genes might be involved in regulating various aspects of biological function, including anatomical structure development, cell proliferation and adhesion, signaling transduction and many of the genes were annotated in response to stress. Of these 33 signature genes, 23 have previously been reported to be functionally correlated with GBM; the roles of the remaining 10 genes in glioma development remain unknown. Our results were the first to reveal that GBM exhibited the overexpressed GPX8 gene and underexpressed signature genes including CHST9, CSDC2, ENHO, FERMT1, IGFN1, LINC00836, MGAT4C and SHANK2, which might play crucial roles in the tumorigenesis of different gliomas.

Predicting Anticancer Drug Resistance Mediated by Mutations.

Cancer drug resistance presents a challenge for precision medicine. Drug-resistant mutations are always emerging. In this study, we explored the relationship between drug-resistant mutations and drug resistance from the perspective of protein structure. By combining data from previously identified drug-resistant mutations and information of protein structure and function, we used machine learning-based methods to build models to predict cancer drug resistance mutations. The performance of our combined model achieved an accuracy of 86%, a Matthews correlation coefficient score of 0.57, and an F1 score of 0.66. We have constructed a fast, reliable method that predicts and investigates cancer drug resistance in a protein structure. Nonetheless, more information is needed concerning drug resistance and, in particular, clarification is needed about the relationships between the drug and the drug resistance mutations in proteins. Highly accurate predictions regarding drug resistance mutations can be helpful for developing new strategies with personalized cancer treatments. Our novel concept, which combines protein structure information, has the potential to elucidate physiological mechanisms of cancer drug resistance.

Integrated approach for multimorbid patients in a hospitalist setting: Survival analysis of a two-year prospective study.

BACKGROUND/PURPOSE: Multimorbidity is a worldwide issue when aging is rapidly. The aim of this study was to evaluate the impact of demography, morbidity, disability and depression on short-term and long-term mortality for multimorbid inpatients. METHODS: The participants' information were assessed upon recruitment. Multimorbidity and disability were measured by modified Charlson comorbidities Index (CCI) and Barthel Index for Activity of Daily Living (ADL), respectively. Depression was screened over one-item self-reported perceptions of depressed mood rated as yes or no. The factors of in-hospital mortality and periodic mortality after discharge were examined by Cox proportional hazard regression and Kaplan-Meier survival analyses. RESULTS: A total of 201 inpatients from a hospitalist's ward were recruited. The in-hospital mortality was 14.4%, while 24-month mortality was 57.8%. After adjustment, severe ADL dependence (<35) was the only contributing factor for in-hospital mortality (Hazard Ratio [HR] = 12.94, p = 0.018). The hazard ratios of 3-6-12-24-months of high CCI (≥6) and severe ADL dependence were 8.12-13.57 (p < 0.001) and 2.91-5.39 (p < 0.001) respectively; both trends of impacts were decreasing overtime. Gender rather than age effect was evident. Besides, self-reported depression was associated with 12-month (HR = 1.72, p = 0.04) and 24-month (HR = 1.65, p = 0.038) mortality. Moreover, severe ADL dependence (p = 0.001) and depression (p = 0.01) contributed to higher mortality in non-cancer patients. CONCLUSION: Our findings suggested that gender, multimorbidity, and disability influenced the two-year survival, while depression was the strongest factor related to long-term mortality. Clinicians should notice the importance of integrated approach and mental health care for those with severe disabilities and morbidity.