Combined impact of myosteatosis and liver steatosis on prognosis in stage I-III colorectal cancer patients.

BACKGROUND: Myosteatosis and liver steatosis (LS) have been recognized as patient-derived image biomarkers that correlate with prognosis in colorectal cancer (CRC) patients. However, the significance of considering fat deposition in multiple body areas simultaneously has been underestimated. This study aimed to investigate the combined effect of myosteatosis and LS in stage I-III CRC patients. METHODS: A total of 616 stage I-III CRC patients were included in the study. Myosteatosis was assessed using skeletal muscle radiodensity (SMD), and LS was estimated by calculating the Hounsfield unit of the liver and spleen ratio (LSR). Cox proportional hazard models were utilized to evaluate disease-free survival (DFS). A combination of myosteatosis and LS was proposed, and its discriminatory performance was compared using the C-index. RESULTS: Among the 616 participants, the median (interquartile) age was 64 (55-72) years, and 240 (38.9%) were female. The median and interquartile range of LSR were determined as 1.106 (0.967-1.225). The optimal cutoff value for LSR was identified as 1.181, leading to the classification of patients into low (410, 66.5%) and high LSR (206, 33.4%) groups. Among the patients, 200 were categorized into the low SMD group, while 416 were allocated to the high SMD group. Both myosteatosis and LS were identified as independent prognostic factors in the multivariable analysis. The combination of these two variables resulted in a three-group classification: high SMD with low LSR group, high SMD with high LSR group, and low SMD group. When comparing the C-index values, the three-group classification exhibited superior discriminatory performance compared with considering myosteatosis and LS separately. CONCLUSIONS: Myosteatosis was associated with poorer survival, while the presence of LS was linked to a better prognosis in non-metastatic CRC patients. Simultaneously considering fat infiltration can serve as a more effective prognosticator in non-metastatic CRC patients.

A CRISPR activation screen identifies MUC-21 as critical for resistance to NK and T cell-mediated cytotoxicity.

BACKGROUND: Immunotherapy has significantly advanced cancer treatments, but many patients do not respond to it, partly due to immunosuppressive mechanisms used by tumor cells. These cells employ immunosuppressive ligands to evade detection and elimination by the immune system. Therefore, the discovery and characterization of novel immunosuppressive ligands that facilitate immune evasion are crucial for developing more potent anti-cancer therapies. METHODS: We conducted gain-of-function screens using a CRISPRa (CRISPR activation) library that covered the entire human transmembrane sub-genome to identify surface molecules capable of hindering NK-mediated cytotoxicity. The immunosuppressive role and mechanism of MUC21 were validated using NK and T cell mediated cytotoxicity assays. Bioinformatics tools were employed to assess the clinical implications of mucin-21 (MUC21) in cancer cell immunity. RESULTS: Our genetic screens revealed that MUC21 expression on cancer cell surfaces inhibits both the cytotoxic activity of NK cells and antibody-dependent cellular cytotoxicity, but not affecting complement-dependent cytotoxicity. Additionally, MUC21 expression hinders T cell activation by impeding antigen recognition, thereby diminishing the effectiveness of the immune checkpoint inhibitor, anti-PD-L1. Moreover, MUC21 expression suppress the antitumor function of both CAR-T cells and CAR-NK cells. Mechanistically, MUC21 facilitates immune evasion by creating steric hindrance, preventing interactions between cancer and immune cells. Bioinformatics analysis revealed elevated MUC21 expression in lung cancer, which correlated with reduced infiltration and activation of cytotoxic immune cells. Intriguingly, MUC21 expression was higher in non-small cell lung cancer (NSCLC) tumors that were non-responsive to anti-PD-(L)1 treatment compared to responsive tumors. CONCLUSIONS: These findings indicate that surface MUC21 serves as a potent immunosuppressive ligand, shielding cancer cells from NK and CD8+T cell attacks. This suggests that inhibiting MUC21 could be a promising strategy to improve cancer immunotherapy.

Synergism Between Taurine and Dexamethasone in Anti-inflammatory Response in LPS-Activated Macrophages.

The aim of the present study is to examine the potential effect of dexamethasone (DEX) and taurine (TAU) on endoplasmic reticular stress (ERS) and inflammation. The macrophages were pre-treated with DEX or TAU, and the level of ERS and pro-inflammatory response was evaluated in LPS-activated macrophages. The expression of ERS marker proteins (GRP78 and CHOP) and the pro-inflammatory cytokines (IL-1ß and IL-6) was analyzed by immunoblotting and ELISA of LPS-induced macrophages. At lower concentrations (<50 nM), DEX alone reduced the levels of ERS and pro-inflammatory markers. Similarly, TAU reduced the expression of LPS-induced ERS and pro-inflammatory markers. When treated with a combination of DEX and TAU, however, the macrophages showed even a greater level of reduction in ERS and pro-inflammatory responses. The RT-qPCR data indicate that the reduction of ERS markers is caused by the inhibition of their own transcriptional expression. The significant level of reduction can be interpreted as a strong synergistic effect (p < 0.01). In summary, the results strongly indicate that a single pre-treatment of DEX or TAU may attenuate ERS and inflammation in LPS-induced macrophages at the concentrations tested in this study. Most importantly, concurrent treatment of macrophages by both agents reduced the level of ERS and pro-inflammatory cytokines in a synergistic fashion.

Implementation of Ambipolar Polysilicon Thin-Film Transistors with Nickel Silicide Schottky Junctions by Low-Thermal-Budget Microwave Annealing.

In this study, the efficient fabrication of nickel silicide (NiSix) Schottky barrier thin-film transistors (SB-TFTs) via microwave annealing (MWA) technology is proposed, and complementary metal-oxide-semiconductor (CMOS) inverters are implemented in a simplified process using ambipolar transistor properties. To validate the efficacy of the NiSix formation process by MWA, NiSix is also prepared via the conventional rapid thermal annealing (RTA) process. The Rs of the MWA NiSix decreases with increasing microwave power, and becomes saturated at 600 W, thus showing lower resistance than the 500 °C RTA NiSix. Further, SB-diodes formed on n-type and p-type bulk silicon are found to have optimal rectification characteristics at 600 W microwave power, and exhibit superior characteristics to the RTA SB-diodes. Evaluation of the electrical properties of NiSix SB-TFTs on excimer-laser-annealed (ELA) poly-Si substrates indicates that the MWA NiSix junction exhibits better ambipolar operation and transistor performance, along with improved stability. Furthermore, CMOS inverters, constructed using the ambipolar SB-TFTs, exhibit better voltage transfer characteristics, voltage gains, and dynamic inverting behavior by incorporating the MWA NiSix source-and-drain (S/D) junctions. Therefore, MWA is an effective process for silicide formation, and ambipolar SB-TFTs using MWA NiSix junctions provide a promising future for CMOS technology.

PBK/TOPK Is a Favorable Prognostic Biomarker Correlated with Antitumor Immunity in Colon Cancers.

Immune checkpoint inhibitor therapy has proven efficacy in a subset of colon cancer patients featuring a deficient DNA mismatch repair system or a high microsatellite instability profile. However, there is high demand for more effective biomarkers to expand the colon cancer population responding to ICI therapy. PBK/TOPK, a serine/threonine kinase, plays a role in cell cycle regulation and mitotic progression. Here, we investigated the correlation between PBK/TOPK expression and tumor immunity and its prognostic value in colon cancer. Based on large-scale bioinformatics analysis, we discovered that elevated PBK/TOPK expression predicted a favorable outcome in patients with colon cancer and was positively associated with immune infiltration levels of CD8+ T cells, CD4+ T cells, natural killer cells, and M1 macrophages. In contrast, a negative correlation was found between PBK/TOPK expression and immune suppressor cells, including regulatory T cells and M2 macrophages. Furthermore, the expression of PBK/TOPK was correlated with the expression of T-cell cytotoxicity genes in colon cancer. Additionally, high PBK/TOPK expression was associated with mutations in DNA damage repair genes, and thus with increased tumor mutation and neoantigen burden. These findings suggest that PBK/TOPK may serve as a prognostic and predictive biomarker for immunotherapy in colon cancer.

Therapeutic effect of steroids on vestibular neuritis: Systematic review and meta-analysis.

OBJECTIVES: The present meta-analysis sought to assess further evidence for the efficacy of steroids in vestibular neuritis (VN). METHODS: The PubMed, EMBASE and Cochrane Library databases were searched through 30 August 2019. The main outcome measure was dizziness handicap inventory (DHI) and secondary outcomes included complete caloric recovery and improvement of canal paresis (CP). The follow-up times were divided into short, mid and long-term. RESULTS: Among 276 records identified, 5 studies (n = 253) were included in the analysis. The therapeutic effect of steroid on VN was confirmed (Hedges' g = 0.172, 95% CI 0.05-0.30, p = .006). Although there was no significant difference between steroids and control in the DHI score (Hedges' g = -0.323, 95% CI -0.533 to -0.113, p < .01), significant effect was seen on complete caloric recovery and improvement in CP (Hedges' g = 0.364, 95% CI 0.18-0.55, p < .0001; Hedges' g = 0.592, 95% CI 0.32-0.59, p < .0001). CONCLUSIONS: The results suggest that corticosteroids have an effect on the results of caloric tests for VN recovery, especially in long-term follow-up. However, in terms of dizziness handicap, we did not find any evidence of positive effect on corticosteroid. More data are required before recommendations can be made regarding management in patients on corticosteroids.

Association of Body Mass Index with Survival in Asian Patients with Colorectal Cancer.

PURPOSE: The clinical significance of body mass index (BMI) on long-term outcomes has not been extensively investigated in Asian patients with colorectal cancer (CRC). This study aims to describe the association between BMI and survival, plus providing BMI cut-off value for predicting prognosis in CRC patients. MATERIALS AND METHODS: A total of 1,182 patients who had undergone surgery for stage I-III CRC from June 2004 to February 2014 were included. BMI was categorized into four groups based on the recommendation for Asian ethnicity. The optimal BMI cut-off value was determined to maximize overall survival (OS) difference. RESULTS: In multivariable analysis, underweight BMI was significantly associated with poor OS (hazard ratio [HR], 2.38; 95% confidence interval [CI], 1.55 to 3.71; p < 0.001) and obese BMI was associated with better OS (HR, 0.72; 95% CI, 0.53 to 0.97; p=0.036) compared with the normal BMI. Overweight and obese BMI were associated with better recurrence-free survival (HR, 0.64; 95% CI, 0.42 to 0.99; p=0.046 and HR, 0.58; 95% CI, 0.38 to 0.89; p=0.014, respectively) compared with the normal BMI group. BMI cutoff value was 20.44 kg/m2. Adding the BMI cutoff value to cancer staging could increase discriminatory performance in terms of integrated area under the curve and Harrell's concordance index. CONCLUSION: Compared to normal BMI, underweight BMI was associated with poor survival whereas obese BMI was associated with better survival. BMI cut-off value of 20.44 kg/m2 is a useful discriminator in Asian patients with CRC.

Evaluation of Estrogen Receptor Agonistic Activity of Medicinal Herbs Using Organization for Economic Cooperation and Development Transactivation Assay with Rat Liver S9 Fraction.

A number of studies employing different in vitro assays have demonstrated the estrogen-like activity of natural substances. All assays have their advantages and limitations as a screening tool. No single in vitro assay is considered ideal for predicting estrogenic action in a complex in vivo system. To assess agonistic activities of several medicinal herbs on the estrogen receptor (ER) and their metabolic alteration, the Organization for Economic Cooperation and Development (OECD) Performance-Based Test Guideline No. 455 in vitro assay was performed in this study using recombinant VM7Luc4E2 cells in combination with rat liver S9 fractions. Ethanol extracts of medicinal herbs showed binding affinities for ER-α and ER-ß at different levels. However, luciferase reporter assay using VM7Luc4E2 cells revealed that only two test extracts [Pueraria lobata root extract (PLE); Glycyrrhiza glabra root extract (GGE)] exhibited ER transcriptional activity when their activities were compared with the response by 17ß-estradiol. Importantly, incubation of PLE or GGE with rat liver S9 fractions increased their ER transcriptional activities, in particular when phase I metabolic enzymes were activated. Puerarin and glabridin were the most abundant isoflavones found in PLE and GGE, respectively. The present results demonstrate that PLE and GGE possess potential as ER agonists with their metabolic activation. This study also suggests that the application of OECD in vitro assay with rat liver S9 fraction is an efficient screening tool to evaluate estrogenic activities of natural substances.

Mucin1 and Mucin16: Therapeutic Targets for Cancer Therapy.

The mucin (MUC) family is a group of highly glycosylated macromolecules that are abundantly expressed in mammalian epithelial cells. MUC proteins contribute to the formation of the mucus barrier and thus have protective functions against infection. Interestingly, some MUC proteins are aberrantly expressed in cancer cells and are involved in cancer development and progression, including cell growth, proliferation, the inhibition of apoptosis, chemoresistance, metabolic reprogramming, and immune evasion. With their unique biological and structural features, MUC proteins have been considered promising therapeutic targets and also biomarkers for human cancer. In this review, we discuss the biological roles of the transmembrane mucins MUC1 and MUC16 in the context of hallmarks of cancer and current efforts to develop MUC1- and MUC16-targeted therapies.

Five Surfactin Isomers Produced during Cheonggukjang Fermentation by Bacillus pumilus HY1 and Their Properties.

The cyclic lipopeptide produced from Bacillus pumilus strain HY1 was isolated from Korean soybean sauce cheonggukjang. The chemical structures of the surfactin isomers were analyzed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) and electrospray ionization tandem mass spectrometry (ESI-MS/MS). The five potential surfactin isoforms were detected with protonated masses of m/z 994.7, 1008.7, 1022.7, 1036.7, and 1050.7 and different structures in combination with Na+, K+, and Ca2+ ions. ESI-MS/MS analysis revealed that the isolated surfactin possessed the precise amino acid sequence LLVDLL and hydroxyl fatty acids with 12 to 16 carbons. The surfactin content during cheonggukjang fermentation increased from 0.3 to 51.2 mg/kg over 60 h of fermentation. The mixture of five surfactin isoforms of cheonggukjang inhibited the growth of two cancer cell lines. The growth of both MCF-7 and Caco-2 cells was strongly inhibited with 100 µg/µL of surfactin. This study is the first-time report of five surfactin isomers of Bacillus pumilus strain HY1 during Korean soybean sauce cheonggukjang fermentation, which has cytotoxic properties.

Genome wide CRISPR screening reveals a role for sialylation in the tumorigenesis and chemoresistance of acute myeloid leukemia cells.

Aberrant activation of cytokine and growth factor signal transduction pathways confers enhanced survival and proliferation properties to acute myeloid leukemia (AML) cells. However, the mechanisms underlying the deregulation of signaling pathways in leukemia cells are unclear. To identify genes capable of independently supporting cytokine-independent growth, we employed a genome-wide CRISPR/Cas9-mediated loss-of-function screen in GM-CSF-dependent human AML TF-1 cells. More than 182 genes (p < 0.01) were found to suppress the cytokine-independent growth of TF-1 cells. Among the top hits, genes encoding key factors involved in sialylation biosynthesis were identified; these included CMAS, SLC35A1, NANS, and GNE. Knockout of either CMAS or SLC35A1 enabled cytokine-independent proliferation and survival of AML cells. Furthermore, NSG (NOD/SCID/IL2Rγ-/-) mice injected with CMAS or SLC35A1-knockout TF-1 cells exhibited a shorter survival than mice injected with wild-type cells. Mechanistically, abrogation of sialylation biosynthesis in TF-1 cells induced a strong activation of ERK signaling, which sensitized cells to MEK inhibitors but conferred resistance to JAK inhibitors. Further, the surface level of α2,3-linked sialic acids was negatively correlated with the sensitivity of AML cell lines to MEK/ERK inhibitors. We also found that sialylation modulated the expression and stability of the CSF2 receptor. Together, these results demonstrate a novel role of sialylation in regulating oncogenic transformation and drug resistance development in leukemia. We propose that altered sialylation could serve as a biomarker for targeted anti-leukemic therapy.

TIGIT/CD226 Axis Regulates Anti-Tumor Immunity.

Tumors escape immune surveillance by inducing various immunosuppressive pathways, including the activation of inhibitory receptors on tumor-infiltrating T cells. While monoclonal antibodies (mAbs) blocking programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have been approved for multiple cancer indications, only a subset of patients benefit from immune checkpoint blockade therapies, highlighting the need for additional approaches. Therefore, the identification of new target molecules acting in distinct or complementary pathways in monotherapy or combination therapy with PD-1/PD-L1 blockade is gaining immense interest. T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) has received considerable attention in cancer immunotherapy. Recently, anti-TIGIT mAb (tiragolumab) has demonstrated promising clinical efficacy in non-small cell lung cancer treatment when combined with an anti-PD-L1 drug (Tecentriq), leading to phase III trial initiation. TIGIT is expressed mainly on T and natural killer cells; it functions as an inhibitory checkpoint receptor, thereby limiting adaptive and innate immunity. CD226 competes for binding with the same ligands with TIGIT but delivers a positive stimulatory signal to the immune cells. This review discusses the recent discoveries regarding the roles of TIGIT and CD226 in immune cell function and their potential application in cancer immunotherapy.

Harnessing NK cells for cancer immunotherapy: immune checkpoint receptors and chimeric antigen receptors.

Natural killer (NK) cells, key antitumor effectors of the innate immune system, are endowed with the unique ability to spontaneously eliminate cells undergoing a neoplastic transformation. Given their broad reactivity against diverse types of cancer and close association with cancer prognosis, NK cells have gained considerable attention as a promising therapeutic target for cancer immunotherapy. NK cell-based therapies have demonstrated favorable clinical efficacies in several hematological malignancies but limited success in solid tumors, thus highlighting the need to develop new therapeutic strategies to restore and optimize anti-tumor activity while preventing tumor immune escape. The current therapeutic modalities yielding encouraging results in clinical trials include the blockade of immune checkpoint receptors to overcome the immune-evasion mechanism used by tumors and the incorporation of tumor-directed chimeric antigen receptors to enhance NK cell anti-tumor specificity and activity. These observations, together with recent advances in the understanding of NK cell activation within the tumor microenvironment, will facilitate the optimal design of NK cell-based therapy against a broad range of cancers and, more desirably, refractory cancers. [BMB Reports 2021; 54(1): 44-58].

Hemorrhoids Are Associated with Urinary Incontinence.

Background: Hemorrhoids are a common anal disorder and are more frequent in women than in men. Urinary incontinence (UI) also occurs more frequently in women than in men. Although both diseases share similar risk factors, research on the association between the two diseases is lacking. This study aimed to investigate the relationship between hemorrhoids and UI in adult Korean women. Methods: This study was based on the data of the 2008-2009 Korean National Health and Nutrition Examination Survey. Logistic regression test was performed to determine the relationship between hemorrhoids and UI after adjusting for age, body mass index (BMI), smoking, heavy drinking, physical activity, education level, income, diabetes mellitus, and hypertension. Results: Analysis of the data of 8,139 adult women revealed that the prevalence of hemorrhoids, which were self-reported and diagnosed by a physician, was 17.5% and 7.9%, respectively. Both types of hemorrhoids were more prevalent in older women with spouses, those with a large waist circumference, and those with a high BMI. The prevalence of UI was significantly high in the hemorrhoid group, regardless of whether it was self-reported or diagnosed by a physician. Multiple logistic regression analyses revealed a significant association between the prevalence of UI and hemorrhoids, both of which were found to peak at 19-39 years of age. Conclusions: Our findings demonstrate that hemorrhoids are significantly correlated with UI in adult Korean women. When treating adult women with hemorrhoids, it is, therefore, necessary to consider other pelvic floor diseases such as UI.

CD226hiCD8+ T Cells Are a Prerequisite for Anti-TIGIT Immunotherapy.

Clinical trials are evaluating the efficacy of anti-TIGIT for use as single-agent therapy or in combination with programmed death 1 (PD-1)/programmed death-ligand 1 blockade. How and whether a TIGIT blockade will synergize with immunotherapies is not clear. Here, we show that CD226loCD8+ T cells accumulate at the tumor site and have an exhausted phenotype with impaired functionality. In contrast, CD226hiCD8+ tumor-infiltrating T cells possess greater self-renewal capacity and responsiveness. Anti-TIGIT treatment selectively affects CD226hiCD8+ T cells by promoting CD226 phosphorylation at tyrosine 322. CD226 agonist antibody-mediated activation of CD226 augments the effect of TIGIT blockade on CD8+ T-cell responses. Finally, mFOLFIRINOX treatment, which increases CD226hiCD8+ T cells in patients with pancreatic ductal adenocarcinoma, potentiates the effects of TIGIT or PD-1 blockade. Our results implicate CD226 as a predictive biomarker for cancer immunotherapy and suggest that increasing numbers of CD226hiCD8+ T cells may improve responses to anti-TIGIT therapy.

Preparing the surgical area for non-shaved ear surgery: a clinical assessment.

OBJECTIVE: To review the clinical experience for non-shaved middle ear/mastoid surgery and evaluate the proper method of preparing the postauricular surgical field. METHODS: This retrospective study reviewed medical records of cases where the non-shaved surgical procedure was carried out for middle ear/mastoid diseases. In all cases, middle ear and mastoid surgery was performed by one otologic surgeon without hair shaving to treat chronic perforation of tympanic membrane, as well as chronic suppurative otitis media, with or without mastoiditis during two years. The prevalence of surgical site infection (SSI) and bacterial culture of the surgical field was assessed just before the skin incision. RESULTS: In this review of 106 cases, the SSI rate was 1.6% for the non-shaved ear surgery. Bacterial colonisation was found on the prepared surgical field in 8.5% of cases and these bacteria was different from true pathogens. SSI of the skin incision occurred in two cases, although no bacterial colonisation of the non-shaved surgical field was found. The surgical exposure of postauricular area was enough to do tympanoplasty or tympanomastoidectomy, even though in cases where a hairline was close to postauricular sulcus. CONCLUSION: This study showed that when preparing the non-shaved ear surgery, the surgeons should not have to worry about skin contamination by hair. We suggest that the non-shaved ear surgery would appear to be preferable for the postauricular approach.

A randomized Comparison of laparoscopic LEns defogging using Anti-fog solution, waRm saline, and chlorhexidine solution (CLEAR).

OBJECTIVE: Current literature demonstrates a lack of comparative in vivo studies regarding laparoscopic lens fogging (LLF). This randomized trial aimed to compare 3 popular methods of minimizing or reducing LLF in laparoscopic surgery by heating the lens using warm saline, applying anti-fog solution to the lens, and rubbing the lens with chlorhexidine solution. METHODS: Ninety-six participants underwent randomization to be allocated in control (n = 24), warm saline (n = 24), anti-fog solution (n = 24), and chlorhexidine groups (n = 24). The primary outcome measure was the severity of LLF during the first 3 min after laparoscope insertion into the abdominal cavity. The severity of LLF was rated on a 10-point visual clarity scale ranging from 0 (clearest) to 10 (foggiest). The secondary outcome measures were (1) the severity of LLF during the remaining operative time other than the first 3 min, (2) the number of lens cleansings, and (3) the total time required to clean the lens. RESULTS: Lens fogging during the first 3 min and remaining operative time other than the first 3 min was significantly decreased in the warm saline group compared to that in the other 3 groups (all, P < 0.001). In post hoc analysis, the anti-fog solution group was significantly foggier than the warm saline group, but clearer than the chlorhexidine and control groups. The number of lens cleansings and total time required to clean the lens were significantly lower in the warm saline and anti-fog solution groups than in the chlorhexidine and control groups (all, P < 0.05). CONCLUSION: The use of warm saline leads to significantly fewer fogging events than the use of anti-fog solution or chlorhexidine solution, resulting in an improved continuity of surgery.

Extracellular pH modulating injectable gel for enhancing immune checkpoint inhibitor therapy.

Clinical data from diverse cancer types shows that the increased T cell infiltration in tumors correlates with improved patient prognosis. Acidic extracellular pH is a major attribute of the tumor microenvironment (TME) that promotes immune evasion and tumor progression. Therefore, antagonizing tumor acidity can be a powerful approach in cancer immunotherapy. Here, Pluronic F-127 is used as a NaHCO3 releasing carrier to focally alleviate extracellular tumor acidity. In a mouse tumor model, intratumoral treatment with pH modulating injectable gel (pHe-MIG) generates immune-favorable TME, as evidenced by the decrease of immune-suppressive cells and increase of tumor infiltrating CD8+T cells. The combination of pHe-MIG with immune checkpoint inhibitors, anti-PD-1 and anti-TIGIT antibodies, increases intratumoral T cell function, which leads to tumor clearance. Mechanistically, extracellular acidity was shown to upregulate co-inhibitory immune checkpoint receptors and inhibit mTOR signaling pathways in memory CD8+T cells, which impaired effector functions. Furthermore, an acidic pH environment increased the expression and engagement of TIGIT and its ligand CD155, which suggested that the extracellular pH can regulate the suppressive function of TIGIT pathway. Collectively, these findings suggest that pHe-MIG holds potential as a new TME modulator for effective immune checkpoint inhibitor therapies.

Plastidial and Mitochondrial Malonyl CoA-ACP Malonyltransferase is Essential for Cell Division and Its Overexpression Increases Storage Oil Content.

Malonyl-acyl carrier protein (ACP) is a key building block for the synthesis of fatty acids, which are important components of cell membranes, storage oils and lipid-signaling molecules. Malonyl CoA-ACP malonyltransferase (MCAMT) catalyzes the production of malonyl-ACP and CoA from malonyl-CoA and ACP. Here, we report that MCAMT plays a critical role in cell division and has the potential to increase the storage oil content in Arabidopsis. The quantitative real-time PCR and MCAMT promoter:GUS analyses showed that MCAMT is predominantly expressed in shoot and root apical meristems, leaf hydathodes and developing embryos. The fluorescent signals of MCAMT:eYFP were observed in both chloroplasts and mitochondria of tobacco leaf protoplasts. In particular, the N-terminal region (amino acid residues 1-30) of MCAMT was required for mitochondrial targeting. The Arabidopsis mcamt-1 and -2 mutants exhibited an embryo-lethal phenotype because of the arrest of embryo development at the globular stage. The transgenic Arabidopsis expressing antisense MCAMT RNA showed growth retardation caused by the defects in cell division. The overexpression of MCAMT driven by the promoter of the senescence-associated 1 (SEN1) gene, which is predominantly expressed in developing seeds, increased the seed yield and storage oil content of Arabidopsis. Taken together, the plastidial and mitochondrial MCAMT is essential for Arabidopsis cell division and is a novel genetic resource useful for enhancing storage oil content in oilseed crops.

Changing Disease Trends in the Northern Gyeonggi-do Province of South Korea from 2002 to 2013: A Big Data Study Using National Health Information Database Cohort.

OBJECTIVES: To investigate the chronological patterns of diseases in Northern Gyeonggi-do province, South Korea, and compare these with national data. METHODS: A National Health Insurance cohort based on the National Health Information Database (NHID Cohort 2002-2013) was used to perform a retrospective, population-based study (46,605,433 of the target population, of which 1,025,340 were randomly sampled) to identify disease patterns from 2002 to 2013. Common diseases including malaria, cancer (uterine cervix, urinary bladder, colon), diabetes mellitus, psychiatric disorders, hypertension, intracranial hemorrhage, bronchitis/bronchiolitis, peptic ulcer, and end stage renal disease were evaluated. RESULTS: Uterine cervix cancer, urinary bladder cancer and colon cancer had the greatest rate of increase in Northern Gyeonggi-do province compared with the rest of the country, but by 2013 the incidence of these cancers had dropped dramatically. Acute myocardial infarction and end stage renal disease also increased over the study period. Psychiatric disorders, diabetes mellitus, hypertension and peptic ulcers showed a gradual increase over time. No obvious differences were found for intracranial hemorrhage or bronchitis/bronchiolitis between the Northern Gyeonggi-do province and the remaining South Korean provinces. Malaria showed a unique time trend, only observed in the Northern Gyeonggi province, peaking in 2004, 2007 and 2009 to 2010. CONCLUSION: This study showed that the Northern Gyeonggi-do province population had a different disease profile over time, compared with collated data for the remaining provinces in South Korea. "Big data" studies using the National Health Insurance cohort database can provide insight into the healthcare environment for healthcare providers, stakeholders and policymakers.