Proteomic profiling of tumor microenvironment and prognosis risk prediction in stage I lung adenocarcinoma.

OBJECTIVES: With the increasing popularity of CT screening, more cases of early-stage lung cancer are being diagnosed. However, 24.5% of stage I non-small-cell lung cancer (NSCLC) patients still experience treatment failure post-surgery. Biomarkers to predict lung cancer patients at high risk of recurrence are needed. MATERIALS AND METHODS: We collected protein mass spectrometry data from the Taiwan Lung Cancer Moonshot Project and performed bioinformatics analysis on proteins with differential expressions between tumor and adjacent normal tissues in 74 stage I lung adenocarcinoma (LUAD) cases, aiming to explore the tumor microenvironment related prognostic biomarkers. Findings were further validated in 6 external cohorts. RESULTS: The analysis of differentially expressed proteins revealed that the most enriched categories of diseases and biological functions were cellular movement, immune cell trafficking, and cancer. Utilizing proteomic profiling of the tumor microenvironment, we identified five prognostic biomarkers (ADAM10, MIF, TEK, THBS2, MAOA). We then developed a risk score model, which independently predicted recurrence-free survival and overall survival in stage I LUAD. Patients with high risk scores experienced worse recurrence-free survival (adjusted hazard ratio = 8.28, p < 0.001) and overall survival (adjusted hazard ratio = 6.88, p = 0.013). Findings had been also validated in the external cohorts. CONCLUSION: The risk score model derived from proteomic profiling of tumor microenvironment can be used to predict recurrence risk and prognosis of stage I LUAD.

Ago2/CAV1 interaction potentiates metastasis via controlling Ago2 localization and miRNA action.

Ago2 differentially regulates oncogenic and tumor-suppressive miRNAs in cancer cells. This discrepancy suggests a secondary event regulating Ago2/miRNA action in a context-dependent manner. We show here that a positive charge of Ago2 K212, that is preserved by SIR2-mediated Ago2 deacetylation in cancer cells, is responsible for the direct interaction between Ago2 and Caveolin-1 (CAV1). Through this interaction, CAV1 sequesters Ago2 on the plasma membranes and regulates miRNA-mediated translational repression in a compartment-dependent manner. Ago2/CAV1 interaction plays a role in miRNA-mediated mRNA suppression and in miRNA release via extracellular vesicles (EVs) from tumors into the circulation, which can be used as a biomarker of tumor progression. Increased Ago2/CAV1 interaction with tumor progression promotes aggressive cancer behaviors, including metastasis. Ago2/CAV1 interaction acts as a secondary event in miRNA-mediated suppression and increases the complexity of miRNA actions in cancer.

The frequency of pathogenic variation in the All of Us cohort reveals ancestry-driven disparities.

Disparities in data underlying clinical genomic interpretation is an acknowledged problem, but there is a paucity of data demonstrating it. The All of Us Research Program is collecting data including whole-genome sequences, health records, and surveys for at least a million participants with diverse ancestry and access to healthcare, representing one of the largest biomedical research repositories of its kind. Here, we examine pathogenic and likely pathogenic variants that were identified in the All of Us cohort. The European ancestry subgroup showed the highest overall rate of pathogenic variation, with 2.26% of participants having a pathogenic variant. Other ancestry groups had lower rates of pathogenic variation, including 1.62% for the African ancestry group and 1.32% in the Latino/Admixed American ancestry group. Pathogenic variants were most frequently observed in genes related to Breast/Ovarian Cancer or Hypercholesterolemia. Variant frequencies in many genes were consistent with the data from the public gnomAD database, with some notable exceptions resolved using gnomAD subsets. Differences in pathogenic variant frequency observed between ancestral groups generally indicate biases of ascertainment of knowledge about those variants, but some deviations may be indicative of differences in disease prevalence. This work will allow targeted precision medicine efforts at revealed disparities.

Long-Term Survival and Cancer Risk in the Hepatitis C Virus-Infected Patients After Antiviral Treatment: A Nationwide Cohort Study.

Background: Exposure to the Hepatitis C virus (HCV) has been identified as one of the most critical risk factors for Hepatocellular carcinoma (HCC). Interferons and direct-acting antivirals (DAAs) have been used to treat HCV infection with high rates (95%) of prolonged virological response, a suitable safety profile, and good compliance rates. Methods: We obtained information from Taiwan's Health and Welfare Data Science Center. (HWDSC). In this observational cohort research, patients with HCV who received a diagnosis in Taiwan between 2011 and 2018 were included. Results: 78,300 untreated HCV patients were paired for age, sex, and index date with 39,150 HCV patients who received interferon or DAAs treatment. Compared to the control group, the Interferon or DAAs treatment sample has fewer low-income individuals and more hospitalization requirements. The percentage of kidney illness was reduced in the therapy group compared to the control group, but the treatment group had a greater comorbidity rate of gastric ulcers. Interferon or DAA therapy for HCV-infected patients can substantially lower mortality. All cancer diagnoses after HCV infection with interferon treatment aHR 95% CI = 0.809 (0.774-0.846), Sofosbuvir-based DAA aHR 95% CI = 1.009 (0.737-1.381) and Sofosbuvir free DAA aHR 95% CI = 0.944 (0.584-1.526) showing cancer-protective effects in the INF-treated cohort but not DAA. Conclusion: Following antiviral therapy, women appear to have a more substantial preventive impact than men against pancreatic, colorectal, and lung cancer. Interferon or DAAs treatment effect was more significant in the cirrhotic group.

Low-dose imiquimod induces melanogenesis in melanoma cells through an ROS-mediated pathway.

BACKGROUND: Melanogenesis is the process of melanin maturation which not only protects skin from UV radiation but also plays an important role in antigenicity of melanomas. Imiquimod (IMQ) is a toll-like receptor 7 (TLR7) agonist that exhibits antiviral and anticancer activity. OBJECTIVE: To explore whether IMQ could induce melanogenesis in melanoma cells. METHODS: The mouse melanoma cell line B16F10, the mouse immortalized melanocyte Melan-A, and human melanoma cell lines MNT-1, C32 and A375 were utilized in this study. The pigmented level was observed by the centrifuged cell pellet. The intracellular and extracellular melanin levels were examined in the absorbance in NaOH-extracted cell lysate and cell-cultured medium, respectively. The expression of melanogenesis related proteins was examined by immunoblotting. The intracellular cyclic AMP amount was evaluated by the cAMP Glo assay kit. The activity of phosphodiesterase 4B (PDE4B) was investigated by CREB reporter assay with overexpressed PDE4B or not. RESULTS: We demonstrated that a low dose of IMQ could trigger melanogenesis in B16F10 cells. IMQ induced microphthalmia-associated transcription factor (MITF) nuclear translocation, upregulated the expression of melanogenesis-related proteins, increased tyrosinase (TYR) activity, and led to pigmentation in B16F10 cells. Next, we found that IMQ-induced melanogenesis was activated by excessive intracellular cAMP accumulation, which was regulated through IMQ-mediated PDE4B inhibition. Finally, IMQ-induced ROS production was found to be involved in melanogenesis by its control of PDE4B activity. CONCLUSIONS: Low dose of IMQ could activate melanogenesis through the ROS/PDE4B/PKA pathway in melanoma cells.

The epidemiology of pediatric psoriasis: A nationwide cohort study in Taiwan.

Psoriasis can affect individuals of all age groups. While the epidemiology of psoriasis in adults has been extensively studied, there is limited research specifically investigating pediatric cases. This study aimed to investigate the prevalence and incidence of skin psoriasis (PsO) and psoriatic arthritis (PsA) among pediatric patients in Taiwan. A nationwide cohort of 17 535 patients with psoriatic diseases under the age of 18 was enrolled from the National Health Insurance Research Database for the period 2000-2013, including 16 129 PsO patients and 2022 PsA patients. The age- and sex-standardized prevalence and incidence of pediatric PsO and PsA were calculated. The 2007 yearly reports of age- and sex-specific distribution of the general population was adopted as a standard. The results showed that between 2000 and 2013, the prevalence for pediatric PsO increased from 0.03% to 0.07%, and from 0.003% to 0.014% for pediatric PsA. During the same period, the incidence slightly decreased from 19.81 to 17.55 per 100 000 for pediatric PsO but increased from 1.02 to 5.06 per 100 000 for pediatric PsA. Adolescents (12 to <18 years) had higher prevalence and incidence rates of PsO and PsA than children (aged ≤ 12 years), with no sex difference observed in either age group. PsA preceding PsO was more common among children than adolescents (27.07% vs. 13.46%). This study provides important insights into the prevalence and incidence of psoriatic diseases in the pediatric population. Further research is needed to identify risk factors for pediatric psoriasis and to investigate its long-term health outcomes.

Methotrexate did not add skin cancer risk in patients with psoriasis receiving narrow-band ultraviolet B phototherapy: a nationwide retrospective cohort study.

BACKGROUND: In the era of biologic therapy, phototherapy and methotrexate (MTX) are still commonly employed for patients with moderate-to-severe psoriasis. However, the skin cancer risk following a combination of MTX and narrow-band ultraviolet B (NB-UVB) has rarely been explored. OBJECTIVES: To investigate whether MTX plus NB-UVB increases skin cancer risk in patients with psoriasis. METHODS: We conducted a retrospective cohort study of data in Taiwan National Health Insurance Research Database from 1997 to 2013. We performed cumulative incidences and multivariate analysis using competing risk regression model, comparing skin cancer risk between cohorts of combination therapy and using NB-UVB alone, matched by relative confounders. We further conducted sensitivity analysis for those receiving higher MTX dosage. Standardized incidence ratio (SIR) was calculated for skin cancer risk. RESULTS: We enrolled 3203 subjects in each cohort. No significant differences in skin cancers were noted between the two cohorts in the cumulative incidences (log-rank test, p = 0.282) and hazard ratio (HR) (adjusted HR = 0.50, 95% CI 0.15, 1.63, p= 0.247) on the competing risk regression model. There were also no significant differences between those receiving higher dose MTX and UVB alone in the cumulative incidences of skin cancers (p = 0.227) and HR (adjusted HR = 0.29, 95% CI 0.04, 2.21, p = 0.231) in the multivariate analysis. There was no significant difference of SIR between the two cohorts compared to the general population. CONCLUSIONS: MTX does not increase skin cancer risk in patients with moderate-to-severe psoriasis receiving NB-UVB in the Taiwanese population.

Comparison of Minimally Invasive Surgery with Open Surgery for Type II Endometrial Cancer: An Analysis of the National Cancer Database.

OBJECTIVE: Prior studies comparing minimally invasive surgery with open surgery among patients with endometrial cancer have reported similar survival outcomes and improved perioperative outcomes with minimally invasive surgery (MIS). However, patients with Type II endometrial cancer were underrepresented in these studies. We sought to compare the overall survival and surgical outcomes between open surgery and MIS in a large cohort of women with Type II endometrial cancer. METHODS: Using data from the National Cancer Database, we identified a cohort of women who underwent hysterectomy for type II endometrial cancer (serous, clear cell, and carcinosarcoma) between January 2010 and December 2014. The primary outcome was a comparison of the overall survival for MIS with that for the open approach. The secondary outcomes included a comparison of the length of hospital stay, readmission within 30 days of discharge, and 30- and 90-day mortality. Outcomes were compared between the cohorts using the Mann-Whitney U test, Pearson's chi-square test, or Fisher's exact test. Multivariable logistic regression with inverse propensity weighting was used to determine clinical characteristics that were statistically significant predictors of outcomes. p values < 0.05 were considered significant. RESULTS: We identified 12,905 patients with Type II, Stage I-III endometrial cancer that underwent a hysterectomy. In total, 7123 of these women (55.2%) underwent MIS. The rate of MIS increased from 39% to 64% over four years. Women who underwent MIS were more often White, privately insured, older, and had a higher income. The laparotomy group had a higher rate of carcinosarcoma histology (30.9% vs. 23.6%, p < 0.001), stage III disease (38.4% vs. 27.4%, p < 0.001), and larger primary tumors (59 vs. 45 mm, p < 0.001). Lymph node dissection was more commonly performed in the MIS group (89.6% vs. 85.4%, p < 0.001). With regard to adjuvant therapy, subjection to postoperative radiation was more common in the MIS group (37% vs. 40.1%, p < 0.001), while chemotherapy was more common in the laparotomy group (37.6% vs. 33.9%, p < 0.001). The time interval between surgery and the initiation of chemotherapy was shorter in the MIS group (39 vs. 42 days, p < 0.001). According to the results of propensity-score-weighted analysis, MIS was associated with superior overall survival (101.7 vs. 86.7 months, p = 0.0003 determined using the long-rank test), which corresponded to a 10% decreased risk of all-cause mortality (HR 0.9; CI 0.857-0.954, p = 0.0002). The survival benefit was uniform across all three histology types and stages. MIS was associated with superior perioperative outcomes, including shorter length of stay (1 vs. 4 days, p < 0.001), lower 30-day readmission rates (2.5% vs. 5%), and lower 30- and 90-day postoperative mortality (0.5% vs. 1.3% and 1.5% vs. 3.6%, respectively; p < 0.001 for both). The increased adoption of MIS from 2010 to 2014 corresponds to a decrease in 90-day postoperative mortality (2.8% to 2.2%, r = -0.89; p = 0.04) and overall mortality (51% to 38%, r = -0.95; p = 0.006). CONCLUSIONS: In a large cohort of patients from the National Cancer Database, MIS was associated with improved overall survival and superior perioperative outcomes compared to open surgery among women with Type II endometrial cancer. A decrease in postoperative mortality and a shorter interval between surgery and the initiation of chemotherapy may contribute to the survival benefit of MIS. A racial and economic disparity in the surgical management of Type II endometrial cancer was identified, and further investigation is warranted to narrow this gap and improve patient outcomes.

Deep convolutional neural network with fusion strategy for skin cancer recognition: model development and validation.

We aimed to develop an accurate and efficient skin cancer classification system using deep-learning technology with a relatively small dataset of clinical images. We proposed a novel skin cancer classification method, SkinFLNet, which utilizes model fusion and lifelong learning technologies. The SkinFLNet's deep convolutional neural networks were trained using a dataset of 1215 clinical images of skin tumors diagnosed at Taichung and Taipei Veterans General Hospital between 2015 and 2020. The dataset comprised five categories: benign nevus, seborrheic keratosis, basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. The SkinFLNet's performance was evaluated using 463 clinical images between January and December 2021. SkinFLNet achieved an overall classification accuracy of 85%, precision of 85%, recall of 82%, F-score of 82%, sensitivity of 82%, and specificity of 93%, outperforming other deep convolutional neural network models. We also compared SkinFLNet's performance with that of three board-certified dermatologists, and the average overall performance of SkinFLNet was comparable to, or even better than, the dermatologists. Our study presents an efficient skin cancer classification system utilizing model fusion and lifelong learning technologies that can be trained on a relatively small dataset. This system can potentially improve skin cancer screening accuracy in clinical practice.

Psoriatic arthritis risk in psoriasis patients prescribed acitretin versus disease-modifying antirheumatic drugs: a nationwide cohort study.

OBJECTIVES: To compare the risk of psoriatic arthritis (PsA) in psoriasis (PsO) patients treated with acitretin vs disease-modifying antirheumatic drugs (DMARDs). METHODS: This retrospective study used Taiwan's National Health Insurance Research Database from 1997 to 2013. Adult PsO patients without PsA prescribed acitretin or DMARDs for ≥30 days within a year were assigned to the acitretin cohort or DMARDs cohort, respectively. Patients in the acitretin cohort prescribed DMARDs for >7 days, or in the DMARDs cohort prescribed acitretin for >7 days, were excluded. Cumulative incidence of PsA were determined within both cohorts using the Kaplan-Meier method. The hazard ratio (HR) comparing acitretin to DMARDs was calculated with Cox regression models, adjusting for demographic and clinical covariates including the use of non-steroidal anti-inflammatory drugs (NSAIDs) and comorbidities. RESULTS: The study included 1,948 patients in each cohort. The 5-year cumulative incidence of PsA in the acitretin cohort was lower than that in the reference cohort (7.52% vs 9.93%; P=0.005), with a more pronounced difference in the subpopulation receiving NSAIDs treatment. However, in subpopulations without NSAIDs treatment, the 5-year cumulative incidence of PsA in the acitretin cohort was comparable to the DMARDs cohort (5.26% vs 6.98%; P = 0.106). Acitretin was not associated with PsA development in PsO (HR 0.83, 95% confidence interval 0.65-1.05). This risk remained consistent regardless of adjustments for NSAID treatment and comorbidities. Other independent risk factors for PsA included female and NSAIDs treatment. CONCLUSION: Compared with DMARDs, acitretin was not associated with increased PsA risk in PsO patients.

Blockade of the SRC/STAT3/BCL-2 Signaling Axis Sustains the Cytotoxicity in Human Colorectal Cancer Cell Lines Induced by Dehydroxyhispolon Methyl Ether.

Colorectal cancer (CRC) is the third most prevalent human cancer globally. 5-Fluorouracil (5-FU)-based systemic chemotherapy is the primary strategy for advanced CRC treatment, yet is limited by poor response rate. Deregulated activation of signal transducer and activator of transcription 3 (STAT3) is fundamental to driving CRC malignant transformation and a poor prognostic marker for CRC, underscoring STAT3 as a promising CRC drug target. Dehydroxyhispolon methyl ether (DHME) is an analog of Hispolon, an anticancer polyphenol abundant in the medicinal mushroom Phellinus linteus. Previously, we have established DHME's cytotoxic effect on human CRC cell lines by eliciting apoptosis through the blockade of WNT/ß-catenin signaling, a preeminent CRC oncogenic pathway. Herein, we unraveled that compared with 5-FU, DHME is a more potent killer of CRC cells while being much less toxic to normal colon epithelial cells. DHME suppressed both constitutive and interleukin 6 (IL-6)-induced STAT3 activation represented by tyrosine 705 phosphorylation of STAT3 (p-STAT3 (Y705)); notably, DHME-induced CRC apoptosis and clonogenicity limitation were abrogated by ectopic expression of STAT3-C, a dominant-active STAT3 mutant. Additionally, we proved that BCL-2 downregulation caused by DHME-mediated STAT3 blockage is responsible for DHME-induced CRC cell apoptosis. Lastly, DHME inhibited SRC activation, and v-src overexpression restored p-STAT3 (Y705) levels along with lowering the levels of apoptosis in DHME-treated CRC cells. We conclude DHME provokes CRC cell apoptosis by blocking the SRC/STAT3/BCL-2 axis besides thwarting WNT/ß-catenin signaling. The notion that DHME targets two fundamental CRC signaling pathways underpins the potential of DHME as a CRC chemotherapy agent.

Prognosis of Midkine and AT1R expression in resectable head and neck squamous cell carcinoma.

BACKGROUND: Research studies have demonstrated that Midkine (MDK) can influence the expression and activity of Renin-angiotensin system (RAS) components. Angiotensin II is involved in tumor growth and angiogenesis in different cancers. We previously observed Angiotensin II receptor blockers (ARBs) improve the survival rates of patients with oral cancers. These findings have prompted us to investigate whether MDK can influence the RAS pathway, mainly through its association with angiotensin II type 1 receptor (AT1R), which contributes to the observed poor prognosis in head and neck squamous cell carcinoma (HNSCC) patients. METHODS: MDK and AT1R expressions were examined in 150 HNSCC patients post-operation by immunohistochemical staining between 1 January 2010 and 31 December 2016. We tested the over-expression and silencing of MDK to evaluate the AT1R expression and functional biological assays in HNSCC cell lines HSC-3 and SAS. RESULTS: Positive expression of MDK is correlated with positive AT1R expression. MDK predicted poor NSCC patients' survival. Silencing MDK could suppress AT1R and pAKT expression and reduce the growth, migration, and invasion of HNSCC cells. ARB also inhibits MDK stimulating HNSCC cell proliferation. Overexpression of MDK could upregulate AT1R and pAKT. CONCLUSIONS: MDK is an independent prognostic factor of HNSCC post-operation, and AT1R regulates HNSCC cell growth, invasion, and migration. Positive MDK and AT1R expressions are highly correlated. Mechanistically, the interaction between MDK and AT1R is crucial for MDK-mediated cell viability, and inhibiting AT1R can effectively counteract or abolish these effects. Furthermore, MDK exerts a regulatory role in the expression of AT1R, as well as in the growth and motility of HNSCC cells. These findings highlight the involvement of the interaction between MDK, AT1R, and the pAkt signaling pathways in HNSCC cell viability growth.

Principle active metabolites of Pinus morrisonicola Hayata synergistically inhibit cell proliferation and autophagy to elevate apoptosis in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC), a common primary tumor of liver is a leading cause of cancer-associated deaths. Improving cellular apoptosis and enhancing autophagic clearance is been considered to improve treatment outcomes of HCC. Polyphenols from Pinus morrisonicola (Hayata) have shown various physiological and therapeutic benefits and the flavonoid chrysin is been known for their anticancer effects. However, the main bioactive principle and the mechanism underlying the antitumor activity of pine needle extract are not clear yet. In this study, the effects of ethanol extract from pine needle on HCC cells were determined. The results show that when compared with administration of chrysin alone, a fraction containing pinocembrin, chrysin, and tiliroside significantly reduced autophagy and increased apoptosis. The results also correlated with decrease in cell cycle regulators and the autophagic proteins like LC3-II. Collectively, the results imply the fraction containing pinocembrin, chrysin, and tiliroside as an ideal complementary medicine for an effective antitumor activity.

Daily aspirin associated with a reduced risk of hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: a population-based cohort study.

Background: Emerging laboratory and animal studies suggest that aspirin may prevent non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC), however clinical evidence remains lacking. Methods: Using Taiwan's National Health Insurance Research Database, we screened 145,212 NAFLD patients from 1997 through 2011. After excluding any confounding conditions, 33,484 patients who continuously received a daily dose of aspirin for 90 days or more (treated group), along with 55,543 patients who had not received antiplatelet therapy (untreated group), were respectively recruited. Inverse probability of treatment weighting using the propensity score was applied to balance the baseline characteristics. Cumulative incidence of, and hazard ratio (HR) for HCC occurrence were analyzed after adjusting competing events. The high-risk patients, who were defined as age ≥ 55 years & elevated serum alanine aminotransferase, were further analyzed. Findings: The 10-year cumulative incidence of HCC in the treated group was significantly lower than that in the untreated group (0.25% [95% CI, 0.19-0.32%] vs. 0.67% [95% CI, 0.54-0.81%]; P < 0.001). Aspirin therapy was significantly associated with a reduced HCC risk (adjusted HR [aHR] 0.48 [95% CI, 0.37-0.63]; P < 0.001). In the high-risk patients, the 10-year cumulative incidence of HCC in the treated group was significantly lower than that in the untreated group (3.59% [95% CI, 2.99-4.19%] vs. 6.54% [95% CI, 5.65-7.42%]; P < 0.001). Aspirin therapy remained associated with a reduced HCC risk (aHR 0.63 [95% CI, 0.53-0.76]; P < 0.001). Subgroup sensitivity analyses verified this significant association in nearly all subgroups. In the time-varying model amongst aspirin users, HCC risk was significantly lower through the use of aspirin for ≥ 3 years (aHR 0.64 [95% CI, 0.44-0.91]; P = 0.013), when compared with short-term use (< 1 year). Interpretation: Daily aspirin therapy is significantly associated with a reduced HCC risk in NAFLD patients. Funding: Ministry of Science and Technology, Ministry of Health and Welfare, and Taichung Veterans General Hospital, Taiwan.

Site-Specific and Multiple Fluorogenic Metabolic Glycan Labeling and Glycoproteomic Profiling in Live Cells.

Multicolor labeling for monitoring the intracellular localization of the same target type in the native environment using chemical fluorescent dyes is a challenging task. This approach requires both bioorthogonal and biocompatible ligations with an excellent fluorescence signal-to-noise ratio. Here, we present a metabolic glycan labeling technique that uses homemade fluorogenic dyes to investigate glycosylation patterns in live cells. These dyes allowed us to demonstrate rapid and efficient simultaneous multilabeling of glycoconjugates with minimum fluorescence noise. Our results demonstrate that this approach is capable of not only probing sialylation and GlcNAcylation in cells but also specifically labeling the cell-surface and intracellular sialylated glycoconjugates in live cells. In particular, we performed site-specific dual-channel fluorescence imaging of extra and intracellular sialylated glycans in HeLa and PC9 cancer cells as well as identified fluorescently labeled sialylated glycoproteins and glycans by a direct enrichment approach combined with an MS-based proteomic analysis in the same experiment. In conclusion, this study provides multilabeling tools in cellular systems for simultaneous site-specific glycan imaging and glycoproteomic analysis to study potential cancer- and disease-associated glycoconjugates.

Identification of novel genetic variants, including PIM1 and LINC01491, with ICD-10 based diagnosis of pulmonary arterial hypertension in the UK Biobank cohort.

Pulmonary arterial hypertension (PAH) is characterized by remodeling and narrowing of the pulmonary vasculature which results in elevations of pulmonary arterial pressures. Here, we conducted a genome-wide association study (GWAS) using the UK Biobank, analyzing the genomes of 493 individuals diagnosed with primary pulmonary hypertension, based on ICD-10 coding, compared to 24,650 age, sex, and ancestry-matched controls in a 1:50 case-control design. Genetic variants were analyzed by Plink's firth logistic regression and assessed for association with primary pulmonary hypertension. We identified three linked variants in the PIM1 gene, which encodes a protooncogene that has been garnering interest as a potential therapeutic target for PAH, that were associated with PAH with genome wide significance, one (rs192449585) of which lies in the promoter region of the gene. We also identified 15 linked variants in the LINC01491 gene. These results provide genetic evidence supporting the role of PIM1 inhibitors as a potential therapeutic option for PAH.

CAR-T: What Is Next?

The year 2017 was marked by the Food and Drug Administration (FDA) approval of the first two chimeric antigen receptor-T (CAR-T) therapies. The approved indications were for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and for the treatment of patients up to 25 years of age with acute lymphoblastic leukemia (ALL) that is refractory or in a second or later relapse. Since then, extensive research activities have been ongoing globally on different hematologic and solid tumors to assess the safety and efficacy of CAR-T therapy for these diseases. Limitations to CAR-T therapy became apparent from, e.g., the relapse in up to 60% of patients and certain side effects such as cytokine release syndrome (CRS). This led to extensive clinical activities aimed at overcoming these obstacles, so that the use of CAR-T therapy can be expanded. Attempts to improve on efficacy and safety include changing the CAR-T administration schedule, combining it with chemotherapy, and the development of next-generation CAR-T therapies, e.g., through the use of CAR-natural killer (CAR-NK) and CAR macrophages (CAR-Ms). This review will focus on new CAR-T treatment strategies in hematologic malignancies, clinical trials aimed at improving efficacy and addressing side effects, the challenges that CAR-T therapy faces in solid tumors, and the ongoing research aimed at overcoming these challenges.

Is OLP potentially malignant? A clue from ZNF582 methylation.

OBJECTIVE: Whether oral lichen planus (OLP) was potentially malignant remains controversial. Here, we examined associations of ZNF582 methylation (ZNF582m ) with OLP lesions, dysplastic features and squamous cell carcinoma (OSCC). MATERIALS AND METHODS: This is a case-control study. ZNF582m was evaluated in both lesion and adjacent normal sites of 42 dysplasia, 90 OSCC and 43 OLP patients, whereas ZNF582m was evaluated only in one mucosal site of 45 normal controls. High-risk habits affecting ZNF582m such as betel nut chewing and cigarette smoking were also compared in those groups. RESULTS: OLP lesions showed significantly lower ZNF582m than those of dysplasia and OSCC. At adjacent normal mucosa, ZNF582m increased from patients of OLP, dysplasia, to OSCC. In addition, ZNF582m at adjacent normal sites in OLP patients was comparable to normal mucosa in control group. Dysplasia/OSCC patients with high-risk habits exhibited significantly higher ZNF582m than those without high-risk habits. However, ZNF582m in OLP patients was not affected by those high-risk habits. CONCLUSIONS: OLP is unlikely to be potentially malignant based on ZNF582m levels. ZNF582m may also be a potential biomarker for distinguishing OLP from true dysplastic features and OSCC, and for monitoring the malignant transformation of OLP, potentially malignant disorders with dysplastic features and OSCC.