Nitrogen Configuration Effects on Charge Carrier Dynamics in CsPbBr3/Carbon Dots S-Scheme Heterojunction for Photocatalytic CO2 Reduction.

Nitrogen-doped carbon dots (NCDs) featuring primary pyrrolic N and pyridinic N dominated configurations were prepared using hydrothermal (H-NCDs) and microwave (M-NCDs) methods, respectively. These H-NCDs and M-NCDs were subsequently applied to decorate CsPbBr3 nanocrystals (CPB NCs) individually, using a ligand-assisted reprecipitation process. Both CPB/M-NCDs and CPB/H-NCDs nanoheterostructures (NHSs) exhibited S-scheme charge transfer behavior, which enhanced their performance in photocatalytic CO2 reduction and selectivity of CO2-to-CH4 conversion, compared to pristine CPB NCs. The presence of pyrrolic N configuration at the heterojunction of CPB/H-NCDs facilitated efficient S-scheme charge transfer, leading to a remarkable 43-fold increase in photoactivity. In contrast, CPB/M-NCDs showed only a modest 3-fold enhancement in photoactivity, which was attributed to electron trapping by pyridinic N at the heterojunction. The study offers crucial insights into charge carrier dynamics within perovskite/carbon NHSs at the molecular level to advance the understanding of solar fuel generation.

Efficacy of local infiltration of tranexamic acid in subcutaneous surgery: A protocol from a single medical center.

BACKGROUND: The purpose of this study was to explore efficacy of locally injected tranexamic acid (TXA) at a concentration of 1 mg/mL for reduction perioperative bleeding and postoperative complications in subcutaneous tumor excisions. We present the protocol and also compare results between the group of use antithrombotic group and not used. METHODS: This is a retrospective study. Fifty-three patients were divided into 3 groups. Group 1 (n = 14): using antithrombotic drugs (antiplatelet or anticoagulants) with locally injected TXA. Group 2 (n = 17): using antithrombotic drugs without locally injected TXA. Group 3 (n = 22): not using antithrombotic drugs but with locally injected TXA. TXA was diluted to 1 mg/mL for use based on our experience. All patients were operated by 1 surgeon in 1 single medical center in Taipei from March 1st, 2020, to March 31st 2022. Outcomes such as the quality of perioperative surgical field and postoperative surgical complications were evaluated and compared. The quality of field was intraoperatively recorded by an assessment and photos from the surgeon. The statistical relationships between the complication rates were analyzed using χ2 test and a 1-way ANOVA by SPSS 25. RESULTS: From Groups 1 and 3, a total of 36 patients, 29 patients had a clear surgical field during procedure. When comparing Groups 1 and 2, use of locally injected TXA had greater positive advantage in terms of a clearer vision whilst surgery (P = .031). Group 2 had more minor complications such as hematoma, severe ecchymosis, wound dehiscence, wound infection. By postoperatively reducing hematomas for 24 hours, it significantly reduce the incidence of abovementioned minor complications (P = .036). With the help of locally injected TXA, shorter time was required to remove drain, hence reducing duration of in-hospital stay. CONCLUSION: The use of locally injected TXA whilst performing subcutaneous surgery on patients taking antithrombotic drugs is cost-effective. It could reduce bleeding and provide a more effective surgical field. In our study, favorable results were obtained from the use of diluted tranexamic acid (1 mg/mL) mixed with lidocaine, namely in clearing the surgical field as well as reducing postoperative surgical complications.

Flexor pollicis longus tendon rupture: a case series on palmaris longus tendon graft reconstruction after volar plate fixation.

Flexor pollicis longus (FPL) tendon rupture is a debilitating condition that can impair hand function. This case series study aimed to evaluate the outcomes of FPL tendon rupture and subsequent palmaris longus (PL) tendon graft reconstruction. Three cases of FPL tendon rupture in patients who had previously undergone open reduction and internal fixation with a volar plate were included. The surgical intervention involved volar plate removal, tenolysis and PL tendon graft reconstruction. Follow-up assessments showed gradual improvement in wrist function, with no post-operative complications or infections observed. These findings suggest that PL tendon grafting can be an effective surgical technique for FPL tendon rupture. Further research is needed to determine optimal surgical approaches and post-operative rehabilitation protocols for this condition.

Acetylation-Mimic Mutation of TRIM28-Lys304 to Gln Attenuates the Interaction with KRAB-Zinc-Finger Proteins and Affects Gene Expression in Leukemic K562 Cells.

TRIM28/KAP1/TIF1ß is a crucial epigenetic modifier. Genetic ablation of trim28 is embryonic lethal, although RNAi-mediated knockdown in somatic cells yields viable cells. Reduction in TRIM28 abundance at the cellular or organismal level results in polyphenism. Posttranslational modifications such as phosphorylation and sumoylation have been shown to regulate TRIM28 activity. Moreover, several lysine residues of TRIM28 are subject to acetylation, but how acetylation of TRIM28 affects its functions remains poorly understood. Here, we report that, compared with wild-type TRIM28, the acetylation-mimic mutant TRIM28-K304Q has an altered interaction with Krüppel-associated box zinc-finger proteins (KRAB-ZNFs). The TRIM28-K304Q knock-in cells were created in K562 erythroleukemia cells by CRISPR-Cas9 (Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein nuclease 9) gene editing method. Transcriptome analysis revealed that TRIM28-K304Q and TRIM28 knockout K562 cells had similar global gene expression profiles, yet the profiles differed considerably from wild-type K562 cells. The expression levels of embryonic-related globin gene and a platelet cell marker integrin-beta 3 were increased in TRIM28-K304Q mutant cells, indicating the induction of differentiation. In addition to the differentiation-related genes, many zinc-finger-proteins genes and imprinting genes were activated in TRIM28-K304Q cells; they were inhibited by wild-type TRIM28 via binding with KRAB-ZNFs. These results suggest that acetylation/deacetylation of K304 in TRIM28 constitutes a switch for regulating its interaction with KRAB-ZNFs and alters the gene regulation as demonstrated by the acetylation mimic TRIM28-K304Q.

Charge Carrier Dynamics of CsPbBr3/g-C3N4 Nanoheterostructures in Visible-Light-Driven CO2-to-CO Conversion.

The photon energy-dependent selectivity of photocatalytic CO2-to-CO conversion by CsPbBr3 nanocrystals (NCs) and CsPbBr3/g-C3N4 nanoheterostructures (NHSs) was demonstrated for the first time. The surficial capping ligands of CsPbBr3 NCs would adsorb CO2, resulting in the carboxyl intermediate to process the CO2-to-CO conversion via carbene pathways. The type-II energy band structure at the heterojunction of CsPbBr3/g-C3N4 NHSs would separate the charge carriers, promoting the efficiency in photocatalytic CO2-to-CO conversion. The electron consumption rate of CO2-to-CO conversion for CsPbBr3/g-C3N4 NHSs was found to intensively depend on the rate constant of interfacial hole transfer from CsPbBr3 to g-C3N4. An in situ transient absorption spectroscopy investigation revealed that the half-life time of photoexcited electrons in optimized CsPbBr3/g-C3N4 NHS was extended two times more than that in the CsPbBr3 NCs, resulting in the higher probability of charge carriers to carry out the CO2-to-CO conversion. The current work presents important and novel insights of semiconductor NHSs for solar energy-driven CO2 conversion.

Breast Cancer with Increased Drug Resistance, Invasion Ability, and Cancer Stem Cell Properties through Metabolism Reprogramming.

Breast cancer is a heterogeneous disease, and the survival rate of patients with breast cancer strongly depends on their stage and clinicopathological features. Chemoradiation therapy is commonly employed to improve the survivability of patients with advanced breast cancer. However, the treatment process is often accompanied by the development of drug resistance, which eventually leads to treatment failure. Metabolism reprogramming has been recognized as a mechanism of breast cancer resistance. In this study, we established a doxorubicin-resistant MCF-7 (MCF-7-D500) cell line through a series of long-term doxorubicin in vitro treatments. Our data revealed that MCF-7-D500 cells exhibited increased multiple-drug resistance, cancer stemness, and invasiveness compared with parental cells. We analyzed the metabolic profiles of MCF-7 and MCF-7-D500 cells through liquid chromatography−mass spectrometry. We observed significant changes in 25 metabolites, of which, 21 exhibited increased levels (>1.5-fold change and p < 0.05) and 4 exhibited decreased levels (<0.75-fold change and p < 0.05) in MCF-7 cells with doxorubicin resistance. These results suggest the involvement of metabolism reprogramming in the development of drug resistance in breast cancer, especially the activation of glycolysis, the tricarboxylic acid (TCA) cycle, and the hexamine biosynthesis pathway (HBP). Furthermore, most of the enzymes involved in glycolysis, the HBP, and the TCA cycle were upregulated in MCF-7-D500 cells and contributed to the poor prognosis of patients with breast cancer. Our findings provide new insights into the regulation of drug resistance in breast cancer, and these drug resistance-related metabolic pathways can serve as targets for the treatment of chemoresistance in breast cancer.

Pharmacological Interventions for Excessive Daytime Sleepiness in Adults with Narcolepsy: A Systematic Review and Network Meta-Analysis.

Narcolepsy is a neurological disease characterized by a core symptom of excessive daytime sleepiness (EDS). Although effective pharmacological interventions for narcolepsy have been developed, a lack of comparative evidence supporting the relative efficacy among these medications leads to clinical treatment challenge. Therefore, we performed a network meta-analysis to overcome this lack of head-to-head comparisons. Databases were searched systematically for randomized controlled trials that compared pharmacological interventions for narcolepsy. The primary outcomes were changes in the Epworth Sleepiness Scale (ESS) and the Maintenance of Wakefulness Test (MWT). A random-effects frequentist network meta-analysis was conducted. A total of 19 RCTs involving 2504 patients were included. Solriamfetol achieved the highest ranking based on the P-scores, and was superior to pitolisant (MD -2.88, 95% CI -4.89--0.88) and sodium oxybate (MD -2.56, 95% CI -4.62--0.51) for ESS change. Consistently, solriamfetol achieved the highest ranking according to MWT change, and was superior to pitolisant (SMD 0.45, 95% CI 0.02-0.88) and modafinil (SMD 0.42, 95% CI 0.05-0.79). Although solriamfetol demonstrated superior efficacy in EDS improvement, evidence from the clustered ranking plot supported that efficacy-safety profiles of pitolisant, sodium oxybate, and modafinil are more balanced than solriamfetol. Therefore, the choice of medication for EDS in narcolepsy should be made on an individual basis.

Generation of TRIM28 Knockout K562 Cells by CRISPR/Cas9 Genome Editing and Characterization of TRIM28-Regulated Gene Expression in Cell Proliferation and Hemoglobin Beta Subunits.

TRIM28 is a scaffold protein that interacts with DNA-binding proteins and recruits corepressor complexes to cause gene silencing. TRIM28 contributes to physiological functions such as cell growth and differentiation. In the chronic myeloid leukemia cell line K562, we edited TRIM28 using CRISPR/Cas9 technology, and the complete and partial knockout (KO) cell clones were obtained and confirmed using quantitative droplet digital PCR (ddPCR) technology. The amplicon sequencing demonstrated no off-target effects in our gene editing experiments. The TRIM28 KO cells grew slowly and appeared red, seeming to have a tendency towards erythroid differentiation. To understand how TRIM28 controls K562 cell proliferation and differentiation, transcriptome profiling analysis was performed in wild-type and KO cells to identify TRIM28-regulated genes. Some of the RNAs that encode the proteins regulating the cell cycle were increased (such as p21) or decreased (such as cyclin D2) in TRIM28 KO cell clones; a tumor marker, the MAGE (melanoma antigen) family, which is involved in cell proliferation was reduced. Moreover, we found that knockout of TRIM28 can induce miR-874 expression to downregulate MAGEC2 mRNA via post-transcriptional regulation. The embryonic epsilon-globin gene was significantly increased in TRIM28 KO cell clones through the downregulation of transcription repressor SOX6. Taken together, we provide evidence to demonstrate the regulatory network of TRIM28-mediated cell growth and erythroid differentiation in K562 leukemia cells.

Did the severity of appendicitis increase during the COVID-19 pandemic?

BACKGROUND: This study aimed to assess the severity of appendicitis during the coronavirus disease 2019 (COVID-19) pandemic, as patients with appendicitis may procrastinate seeking medical attention during the pandemic. METHODS: Information on patients with appendicitis who were treated at the Taipei City Hospital during the COVID-19 pandemic (January 1, 2020 to June 30, 2020) was retrieved. Patients who were diagnosed with appendicitis and treated at the same hospital from January 1, 2019 to July 1, 2019 were designated as the control group. Multivariate logistic regression analysis was conducted to assess changes in the severity of appendicitis (at a 2-week interval) between the two groups. RESULTS: We identified 307 (study group: 149; control group: 158) consecutive patients with appendicitis. The mean age was 46.2 +- 19.8 years. Between the two groups, there were no significant differences in age, sex, comorbidity, surgery type (laparoscopic or open appendectomy) or surgery time. The number of patients in the study group decreased between January 29, 2020 and April 21, 2020, which paralleled the period of spikes in the confirmed COVID-19 cases and restricted daily activities. The percentage of uncomplicated and complicated appendicitis (excluding mild appendicitis or normal appendix) in the study group increased between February 26 and March 10, as well as between April 8 and April 21. In the multivariate regression analysis, the odds of uncomplicated and complicated appendicitis increased in three bi-weeks for the study group but not in the control group. CONCLUSION: The severity of acute appendicitis might increase during the COVID-19 pandemic, because patients with mild appendicitis (or abdominal pain) may hesitate to seek help.

LOC550643, a Long Non-coding RNA, Acts as Novel Oncogene in Regulating Breast Cancer Growth and Metastasis.

Metastatic disease is responsible for over 90% of death in patients with breast cancer. Therefore, identifying the molecular mechanisms that regulate metastasis and developing useful therapies are crucial tasks. Long non-coding RNAs (lncRNAs), which are non-coding transcripts with >200 nucleotides, have recently been identified as critical molecules for monitoring cancer progression. This study examined the novel lncRNAs involved in the regulation of tumor progression in breast cancer. This study identified 73 metastasis-related lncRNA candidates from comparison of paired isogenic high and low human metastatic breast cancer cell lines, and their expression levels were verified in clinical tumor samples by using The Cancer Genome Atlas. Among the cell lines, a novel lncRNA, LOC550643, was highly expressed in breast cancer cells. Furthermore, the high expression of LOC550643 was significantly correlated with the poor prognosis of breast cancer patients, especially those with triple-negative breast cancer. Knockdown of LOC550643 inhibited cell proliferation of breast cancer cells by blocking cell cycle progression at S phase. LOC550643 promoted important in vitro metastatic traits such as cell migration and invasion. Furthermore, LOC550643 could inhibit miR-125b-2-3p expression to promote breast cancer cell growth and invasiveness. In addition, by using a xenograft mouse model, we demonstrated that depletion of LOC550643 suppressed the lung metastatic potential of breast cancer cells. Overall, our study shows that LOC550643 plays an important role in breast cancer cell metastasis and growth, and LOC550643 could be a potential diagnosis biomarker and therapeutic target for breast cancer.

Long-Term Survival of Combined Hepatocellular-Cholangiocarcinoma: A Nationwide Study.

BACKGROUND: Combined hepatocellular-cholangiocarcinoma (HCC-CC) is an aggressive primary liver cancer. However, the clinical features are not clearly understood because of limited literature and the complex nature of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). METHODS: The records of 100,754 patients with newly diagnosed liver cancer between 2004 and 2013 were obtained from the Taiwan Cancer Registry. The primary outcome measures were overall survival and local recurrence-free survival. The median follow-up time was 60 months (29-120 months). RESULTS: HCC-CC tended to share some characteristics with HCC, including increased frequency of stage I cases, high individual tumor rates, and similar patterns of viral hepatitis B and hepatitis C infections. In contrast, HCC-CC showed malignant behavior similar to that of CC, as high-grade tumor cell differentiation and presentation of jaundice were predominant in HCC-CC and CC compared with HCC. Overall survival and local recurrence-free survival rates of HCC-CC were between HCC and CC rates. The mortality rate of HCC-CC was 79.2% (HCC, 77.5%; CC, 93.5%) and the local recurrence rate of HCC-CC was 65.3% (HCC, 74.6%; CC, 88.4%). Surgical treatment was an independent factor for the long-term prognosis of HCC-CC, whereas transarterial chemoembolization (TAcE) promoted survival in both surgical and nonsurgical groups. CONCLUSION: Our data confirmed that, although it reflects the malignant behavior of CC, HCC-CC should mainly be characterized as a subtype of HCC. With careful selection of patients, curative resection and TAcE might benefit the survival of patients with HCC-CC. IMPLICATIONS FOR PRACTICE: Combined hepatocellular-cholangiocarcinoma (HCC-CC) is a rare cancer that shares demographic characteristics, as well as survival probabilities, with both hepatocellular carcinoma and cholangiocarcinoma. It occurs frequently in patients with hepatitis B virus infection, cirrhotic liver background, and early-stage disease. Compared with 20% of initial resection rates of its counterparts, HCC-CC has higher initial resection rate (55%). Although short-term overall survival is inferior to HCC, its long-term overall survival is similar with HCC.

The functional characterization of phosphorylation of tristetraprolin at C-terminal NOT1-binding domain.

BACKGROUND: Tristetraprolin (TTP) family proteins contain conserved tandem CCCH zinc-finger binding to AU-rich elements and C-terminal NOT1-binding domain. TTP is phosphorylated extensively in cells, and its mRNA destabilization activity is regulated by protein phosphorylation. METHODS: We generated an antibody against phospho-Serine316 located at the C-terminal NOT1-binding site and examined TTP phosphorylation in LPS-stimulated RAW264.7 cells. Knockout of TTP was created in RAW264.7 cells using CRISPR/Cas9 gene editing to explore TTP functions. RESULTS: We demonstrated that Ser316 was phosphorylated by p90 ribosomal S6 kinase 1 (RSK1) and p38-activated protein kinase (MK2) and dephosphorylated by Protein Phosphatase 2A (PP2A). A phosphorylation-mimic mutant of S316D resulted in dissociation with the CCR4-NOT deadenylase complex through weakening interaction with CNOT1. Furthermore, Ser316 and serines 52 and 178 were independently contributed to the CCR4-NOT complex recruitment in the immunoprecipitation assay using phosphor-mimic mutants. In RAW264.7 macrophages, TTP was induced, and Ser316 was phosphorylated through RSK1 and MK2 by LPS stimulation. Knockout of TTP resulted in TNFα mRNA increased due to mRNA stabilization. Overexpression of non-phosphorylated S316A TTP mutant can restore TTP activity and lead to TNFα mRNA decreased. GST pull-down and RNA pull-down analyses demonstrated that endogenous TTP with Ser316 phosphorylation decreased the interaction with CNOT1. CONCLUSIONS: Our results suggest that the TTP-mediated mRNA stability is modulated by Ser316 phosphorylation via regulating the TTP interaction with the CCR4-NOT deadenylase complex.

Using a kinect-based game to teach oral hygiene in four elementary students with intellectual disabilities.

BACKGROUND: Individuals with intellectual disabilities (ID) may have difficulties in performing daily living tasks. Among other daily living tasks, independent oral hygiene is an essential life skill for people with ID. MATERIALS AND METHODS: Four children with intellectual disabilities (two males and two females, ages 7-11) participated in the experiment. We employed the KinectTM V2 sensor to gamify oral hygiene skill training. Specifically, a non-concurrent multiple baseline design was adopted to demonstrate the relation between game-based intervention and independent oral hygiene skills. RESULTS: All students learned how to brush their teeth independently and maintained the skill 4 weeks later with the introduction of the game-based training. Social validity results showed the teachers and parents considered the video game was useful. CONCLUSIONS: The proposed Kinect-based video game might be used for effective training of elementary students with ID to improve oral hygiene independently.

Radiofrequency ablation versus surgical resection for the treatment of solitary hepatocellular carcinoma 2 cm or smaller: A cohort study in Taiwan.

BACKGROUND/PURPOSE: Radiofrequency ablation (RFA) is increasingly being used instead of surgical resection for the treatment of hepatocellular carcinoma (HCC) tumor measuring ≦2 cm. However, the long-term outcomes of RFA, especially in comparison to surgical resection, are still debated. We compared the outcomes of surgical resection and RFA in patients with a solitary HCC tumor measuring ≦2 cm from a 10-year cohort study. METHODS: From Jan 2006 to Dec 2016, 156 patients with a resectable HCC measuring ≦2 cm who underwent surgical resection (n = 83) or RFA (n = 73) at the Buddhist Tzu Chi Medical Foundation were enrolled. Patient characteristics, overall survival (OS), and recurrence-free survival (RFS) were retrospectively examined, and comparisons were made between the two groups and through subgroup analyses. RESULTS: The 1-year, 3-year, 5-year, and 7-year OS outcomes were comparable between the surgical resection group and the RFA group (P = 0.193), but the surgical resection group had significantly higher 1-year, 3-year, 5-year, 7-year, and 10-year RFS than the RFA group (P = 0.018). Multivariate analysis revealed that patients with lower age, Child-Turcotte-Pugh score, or albumin-bilirubin score before treatment had better OS, and patients with an HCV infection or receiving RFA treatment had higher HCC recurrence rates. CONCLUSION: The liver reserve determined the long-term OS of patients with an HCC tumor ≦ 2 cm, and surgical resection offered better RFS than RFA (ClinicalTrials.gov number, NCT04525833.).

Survival Predictability Between the American Joint Committee on Cancer 8th Edition Staging System and the Barcelona Clinic Liver Cancer Classification in Patients with Hepatocellular Carcinoma.

This study compared the prognostic significance of staging between the American Joint Committee on Cancer 8th edition Tumor, Node, Metastasis (TNM) staging system and the Barcelona Clinic Liver Cancer (BCLC) classification in patients with hepatocellular carcinoma (HCC). The study population comprised patients with liver cancer registered in the Taiwan Cancer Database from 2007 to 2013 and was followed up until December 31, 2016. The study included patients with HCC, with known staging in both TNM and BCLC systems, and with follow-up >1 month. Primary endpoint was overall survival. Univariate and multivariate Cox proportional hazards model were constructed to investigate the significance of staging by two systems. Goodness-of-fit of model was evaluated via Akaike's information criterion (AIC), the lower the better. Among 73,136 patients with newly diagnosed liver cancer, a total of 37,062 patients with HCC (25.6% underwent surgery) were eligible. The mean age and overall survival of this cohort were 63.9 years and 27.2%, respectively. Overall survivals for stages I, II, III, and IV (the TNM system) were 54.5%, 34.9%, 10.3%, and 6.4%, respectively. Overall survivals for stages A, B, C, and D (the BCLC classification) were 54.5%, 29.2%, 9.8%, and 4.0%, respectively. The median follow-up time was 59.4 months. Multivariate Cox proportional hazards model revealed that both systems predicted overall survival, cancer-specific survival, disease-free survival, and local recurrence-free rate well. Values of ΔAIC of the BCLC classification and the TNM system were lower for the surgery group and nonsurgery group, respectively. The TNM system (8th edition) predicted long-term outcome better than the BCLC classification in patients with HCC. But in patients treated initially with surgery, the BCLC classification outperformed the 8th edition of the TNM system. IMPLICATIONS FOR PRACTICE: This work demonstrates that the Tumor, Node, Metastasis (TNM) system (8th edition) and the Barcelona Clinic Liver Cancer (BCLC) classification both predict long-term outcome significantly in patients with hepatocellular carcinoma but that the TNM system (8th edition) predicts long-term outcome better than the BCLC classification. For patients treated initially with surgery, BCLC classification outperforms in 8th edition TNM system in predicting long-term outcome.

TRIM28 Regulates Dlk1 Expression in Adipogenesis.

The tripartite motif-containing protein 28 (TRIM28) is a transcription corepressor, interacting with histone deacetylase and methyltransferase complexes. TRIM28 is a crucial regulator in development and differentiation. We would like to investigate its function and regulation in adipogenesis. Knockdown of Trim28 by transducing lentivirus-carrying shRNAs impairs the differentiation of 3T3-L1 preadipocytes, demonstrated by morphological observation and gene expression analysis. To understand the molecular mechanism of Trim28-mediated adipogenesis, the RNA-seq was performed to find out the possible Trim28-regulated genes. Dlk1 (delta-like homolog 1) was increased in Trim28 knockdown 3T3-L1 cells both untreated and induced to differentiation. Dlk1 is an imprinted gene and known as an inhibitor of adipogenesis. Further knockdown of Dlk1 in Trim28 knockdown 3T3-L1 would rescue cell differentiation. The epigenetic analysis showed that DNA methylation of Dlk1 promoter and differentially methylated regions (DMRs) was not altered significantly in Trim28 knockdown cells. However, compared to control cells, the histone methylation on the Dlk1 promoter was increased at H3K4 and decreased at H3K27 in Trim28 knockdown cells. Finally, we found Trim28 might be recruited by transcription factor E2f1 to regulate Dlk1 expression. The results imply Trim28-Dlk1 axis is critical for adipogenesis.

Hsc70/Stub1 promotes the removal of individual oxidatively stressed peroxisomes.

Peroxisomes perform beta-oxidation of branched and very-long chain fatty acids, which leads to the formation of reactive oxygen species (ROS) within the peroxisomal lumen. Peroxisomes are therefore prone to ROS-mediated damages. Here, using light to specifically and acutely induce ROS formation within the peroxisomal lumen, we find that cells individually remove ROS-stressed peroxisomes through ubiquitin-dependent pexophagy. Heat shock protein 70 s mediates the translocation of the ubiquitin E3 ligase Stub1 (STIP1 Homology and U-Box Containing Protein 1) onto oxidatively-stressed peroxisomes to promote their selective ubiquitination and autophagic degradation. Artificially targeting Stub1 to healthy peroxisomes is sufficient to trigger pexophagy, suggesting a key role Stub1 plays in regulating peroxisome quality. We further determine that Stub1 mutants found in Ataxia patients are defective in pexophagy induction. Dysfunctional peroxisomal quality control may therefore contribute to the development of Ataxia.

Hierarchical microstructure strengthening in a single crystal high entropy superalloy.

A hierarchical microstructure strengthened high entropy superalloy (HESA) with superior cost specific yield strength from room temperature up to 1,023 K is presented. By phase transformation pathway through metastability, HESA possesses a hierarchical microstructure containing a dispersion of nano size disordered FCC particles inside ordered L12 precipitates that are within the FCC matrix. The average tensile yield strength of HESA from room temperature to 1,023 K could be 120 MPa higher than that of advanced single crystal superalloy, while HESA could still exhibit an elongation greater than 20%. Furthermore, the cost specific yield strength of HESA can be 8 times that of some superalloys. A template for lighter, stronger, cheaper, and more ductile high temperature alloy is proposed.

Enhanced NK-92 Cytotoxicity by CRISPR Genome Engineering Using Cas9 Ribonucleoproteins.

Natural killer (NK) cells are an attractive cell-type for adoptive immunotherapy, but challenges in preparation of therapeutic primary NK cells restrict patient accessibility to NK cell immunotherapy. NK-92 is a well-characterized human NK cell line that has demonstrated promising anti-cancer activities in clinical trials. Unlimited proliferation of NK-92 cells provides a consistent supply of cells for the administration and development of NK cell immunotherapy. However, the clinical efficacy of NK-92 cells has not reached its full potential due to reduced immune functions as compared to primary NK cells. Improvements of NK-92 functions currently rely on conventional transgene delivery by mRNA, plasmid and viral vector with limited efficiencies. To enable precise genetic modifications, we have established a robust CRISPR genome engineering platform for NK-92 based on the nucleofection of Cas9 ribonucleoprotein. To demonstrate the versatility of the platform, we have performed cell-based screening of Cas9 guide RNA, multiplex gene knockout of activating and inhibitory receptors, knock-in of a fluorescent gene, and promoter insertion to reactivate endogenous CD16 and DNAM-1. The CRISPR-engineered NK-92 demonstrated markedly enhanced cytotoxicity and could mediate antibody-dependent cellular cytotoxicity against hard to kill cancer cell lines. Our genome editing platform is straightforward and robust for both functional studies and therapeutic engineering of NK-92 cells.

Population-based matching comparison between radiofrequency ablation and percutaneous ethanol or acetic acid injection for hepatocellular carcinoma.

BACKGROUND: Loco-regional therapies are evolving for hepatocellular carcinoma (HCC) treatment. Radiofrequency ablation (RFA) has changed the landscape in treating HCC; however, percutaneous ethanol or acetic acid injection (PEI/PAI) remains a widely used and easily performed technique by experienced clinicians. Nevertheless, the effectiveness of RFA compared to that of PEI/PAI remains unclear. METHODS: Records of 73,136 patients with newly diagnosed HCC between 2007 and 2013 were drawn from the Taiwan Cancer Registry. The primary outcome measures were the overall survival and local recurrence-free survival. Propensity score matching (PSM) was performed to compare the effectiveness of RFA and PEI. Median follow-up time was 61.6 months (36-120 months). RESULTS: After PSM, 4496 patients diagnosed with stage I-III HCC, who were initially treated with RFA (3372 patients) or PEI/PAI (1124 patients), were assessed. Compared to PEI/PAI, patients treated with RFA had better 5- and 9-year overall survival, cancer-specific survival, disease-free survival, and local recurrence-free survival. Median overall survival and recurrence-free survival of patients treated with RFA vs PEI/PAI were 61.5 vs 41.9 months and 72.1 vs 45.2 months, respectively. Multivariate Cox model analysis revealed that, except for patients with high cell grade or advanced stage, RFA resulted in better overall survival (HR: 0.74, 95% CI 0.68-0.81, P < 0.001) and local recurrence-free survival (HR: 0.69, 95% CI 0.63-0.75, P < 0.001) than PEI/PAI. CONCLUSIONS: RFA provides advantages over conventional PEI/PAI for HCC. Considering technological advances in instruments, loco-regional therapies for HCC can be employed in carefully selected patients.