KLK7, KLK10, and KLK11 in Papillary Thyroid Cancer: Bioinformatic Analysis and Experimental Validation.

Despite many studies on papillary thyroid carcinoma (PTC) in the past few decades, some critical and significant genes remain undiscovered. To explore genes that may play crucial roles in PTC, a detailed analysis of the expression levels, mutations, and clinical significance of Kallikrein-related peptidases (KLKs) family genes in PTC was undertaken to provide new targets for the precise treatment of the disease. A comprehensive analysis of KLK family genes was performed using various online tools, such as GEPIA, Kaplan-Meier Plotter, LinkedOmics, GSCA, TIMER, and Cluego. KLK7, KLK10, and KLK11 were critical factors of KLK family genes. Then, functional assays were carried out on KLK7/10/11 to determine their proliferation, migration, and invasion capabilities in PTC. The mRNA expression levels of KLK7, KLK10, KLK11, and KLK13 were significantly elevated in thyroid carcinoma, while KLK1, KLK2, KLK3 and KLK4 mRNA levels were decreased compared to normal tissues. Correlations between KLK2/7-12/15 expression levels and tumor stage were also observed in thyroid carcinoma. Survival analysis demonstrated that KLK4/5/7/9-12/14 was associated with overall survival in patients with thyroid cancer. Not only were KLK genes strongly associated with cancer-related pathways, but also KLK7/10/11 was associated with immune-cell infiltration. Finally, silencing KLK7/10/11 impaired human papillary thyroid carcinoma cells' growth, migration ability, and invasiveness. The increased expression of KLK7, KLK10, and KLK11 may serve as molecular markers to identify PTC patients. KLK7, KLK10, and KLK11 could be potential prognostic indicators and targets for precision therapy against PTC.

Design and Application of Multi-Center Clinical Research Platform for Phenotyping of Voriconazole Hepatotoxicity.

We introduce a phenotyping pipeline for voriconazole hepatotoxicity based on a multi-center clinical research platform. Using the platform's queue construction, feature generation, and feature screening functions, 52 features were obtained for model training. The prediction model of voriconazole hepatotoxicity was obtained by using the model training and evaluation functions of the platform. Important risk factors and protection factors of the model were listed.

A Post-Marketing Drug Evaluation Framework Based on Real-World Electronic Health Records Data.

Real-world data (RWD) could be a new way to evaluate the safety and efficacy of post-marketing drugs, while there is no common method for how to use RWD for drug evaluation. In this paper, we present a framework for real-world drug evaluation based on electronic medical record (EHR) data. We designed a data model customized for post-marketing drug evaluation and a unified post-marketing drug evaluation pipeline. The proposed framework can be applied to drug evaluations with different study paradigms for different purposes by flexible use of the proposed data model and pipeline. A prototype system has been developed according to the framework. Real-world EHRs in a tertiary hospital in China between 2010 and 2020 were converted to the proposed data model, and as a test case, we conducted a research on the risk of allergic reactions to cefodizime and ceftriaxone using the prototype system.

Association between serum gamma-glutamyltransferase and early-onset coronary artery disease: a retrospective case-control study.

BACKGROUND: Serum gamma-glutamyltransferase (GGT) activity has been proposed as a promising predictor of atherosclerosis-related complications and a prognostic marker for cardiovascular diseases. The objective of this study was to investigate the potential correlation between serum levels of GGT and early-onset coronary artery disease (EOCAD). METHODS: A retrospective, hospital-based case-control study was conducted, which included 860 patients with EOCAD and gender- and age-matched controls. Serum levels of GGT were measured using the reference measurement procedure on an automatic biochemistry analyser. RESULTS: The serum GGT levels of patients with EOCAD (34.90 ± 31.44 U/L) were significantly higher than those of the control group (21.57 ± 16.44 U/L, p < .001). Elevated serum levels of GGT were found to be an independent risk factor for EOCAD, with an odds ratio (OR) of 1.021 (95% confidence interval (CI): 1.014-1.029). Additionally, for every quartile increase in serum GGT levels, the risk of developing EOCAD increased by 1.6-fold. Moreover, serum GGT levels were significantly associated with disease severity, with lower GGT levels observed in patients without significant vascular disease (31.74 ± 24.06 U/L) compared to those with two-vessel disease (33.06 ± 25.00 U/L, p = .002) and three-vessel disease (37.75 ± 36.76 U/L, p = .001). CONCLUSIONS: The results of this study suggest that elevated serum GGT levels are associated with the development of EOCAD, and GGT may be implicated in the pathogenesis of the disease. Further large-scale prospective studies are needed to explore the potential relationship between serum GGT levels and the dynamic development of EOCAD.

Population structure and genetic diversity of Tamarix chinensis as revealed with microsatellite markers in two estuarine flats.

Background: Tamarix chinensis Lour. is a 3-6-meter-tall small tree with high salt- and alkali- tolerance and aggressive invasiveness, mainly distributed in the eastern part of China in warm-temperate and subtropical climate zones, yet there is little information available regarding genetic diversity and population structure. Methods: A total of 204 individuals of nine T. chinensis populations were investigated for genetic diversity and population structure using a set of 12 highly polymorphic microsatellite markers. Results: The total number of alleles detected was 162, the average number of effective allele was 4.607, the average polymorphism information content (PIC) value of the 12 loci was 0.685, and the mean observed heterozygosity (Ho) and the mean expected heterozygosity (He) was 0.653 and 0.711, respectively. Analysis of molecular variance (AMOVA) showed a 5.32% genetic variation among T. chinensis populations. Despite a low population differentiation, Bayesian clustering analysis, discriminant analysis of principal components (DAPC) and the unweighted pair group method with arithmetic mean (UPGMA) clearly identified three genetic clusters correlated to the populations' geographic origin: the northern populations including those from Yellow River Delta, the Fangshan (FS) population from Beijing, the Changyi (CY) population from Bohai Bay, the Huanjiabu (HHJ) population from Hangzhou Bay, and the remaining two populations from Hangzhou Bay. There was a significant relationship between the genetic distance and geographical distance of the paired populations. Gene flow (Nm) was 4.254 estimated from FST. Conclusion: T. chinensis possessed high genetic diversity comparable to tree species, and although the population differentiation is shallow, our results classified the sampled populations according to sampling localities, suggesting the different origins of the study populations.

The Essential Role of H2S-ABA Crosstalk in Maize Thermotolerance through the ROS-Scavenging System.

Hydrogen sulfide (H2S) and abscisic acid (ABA), as a signaling molecule and stress hormone, their crosstalk-induced thermotolerance in maize seedlings and its underlying mechanism were elusive. In this paper, H2S and ABA crosstalk as well as the underlying mechanism of crosstalk-induced thermotolerance in maize seedlings were investigated. The data show that endogenous levels of H2S and ABA in maize seedlings could be mutually induced by regulating their metabolic enzyme activity and gene expression under non-heat stress (non-HS) and HS conditions. Furthermore, H2S and ABA alone or in combination significantly increase thermotolerance in maize seedlings by improving the survival rate (SR) and mitigating biomembrane damage. Similarly, the activity of the reactive oxygen species (ROS)-scavenging system, including enzymatic antioxidants catalase (CAT), ascorbate peroxidase (APX), guaiacol peroxidase (POD), glutathione reductase (GR), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), and superoxide dismutase (SOD), as well as the non-enzymatic antioxidants reduced ascorbic acid (AsA), carotenoids (CAR), flavone (FLA), and total phenols (TP), was enhanced by H2S and ABA alone or in combination in maize seedlings. Conversely, the ROS level (mainly hydrogen peroxide and superoxide radical) was weakened by H2S and ABA alone or in combination in maize seedlings under non-HS and HS conditions. These data imply that the ROS-scavenging system played an essential role in H2S-ABA crosstalk-induced thermotolerance in maize seedlings.

Regulating structural asymmetry via fluorination engineering in hybrid lead bromide perovskites.

Here, we synthesized a pair of chiral two-dimensional lead bromide perovskites R-/S-(C3H7NF3)2PbBr4 (1R/2S) using a H/F substitution strategy, which exhibit circular dichroism (CD) and circularly polarized luminescence (CPL) activity. Compared with one-dimensional non-centrosymmetric (C3H10N)3PbBr5 with local asymmetry obtained by isopropylamine, 1R/2S show a centrosymmetric inorganic layer despite the global chiral space group. Density functional theory calculations show that the formation energy of 1R/2S is lower than that of (C3H10N)3PbBr5, which implies the improved moisture stability in photophysical properties and CPL activity.

Key role of reactive oxygen species-scavenging system in nitric oxide and hydrogen sulfide crosstalk-evoked thermotolerance in maize seedlings.

Nitric oxide (NO) and hydrogen sulfide (H2S) are novel signaling molecules, which participate in plant growth, development, and response to stress. In this study root-irrigation with 0.15 mM sodium nitroprusside (SNP, NO donor) up-regulated gene expression of L-CYSTEINE DESULFHYDRASE1 (LCD1), activities of L-cysteine desulfhydrase (LCD) and D-cysteine desulfhydrase (DCD), as well as an endogenous H2S level, compared to control seedlings. The SNP-up-regulated effects were enhanced by 0.5 mM sodium hydrosulfide (NaHS, H2S donor), but weakened by NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) and H2S scavenger hypotaurine (HT) alone. NaHS had no significant effect on gene expression and activity of nitrate reductase (NR, a NO candidate producing enzyme). These data indicate that NO could trigger the LCD/H2S signaling pathway in maize seedlings. To further investigate the effect of NO and H2S crosstalk on thermotolerance in maize seedlings, thermotolerance parameters and reactive oxygen species (ROS)-scavenging system were estimated. The results show that SNP increased survival rate and tissue viability, decreased malondialdehyde (MDA) accumulation, and electrolyte leakage in maize seedlings under heat stress (HS), implying NO could improve thermotolerance in maize seedlings. The NO-improved thermotolerance was impaired by H2S inhibitor DL-propargylglycine (PAG) and scavenger HT alone. Similarly, SNP up-regulated the gene expression of DEHYDROASCORBATE REDUCTASE (DHAR) and GLUTATHIONE REDUCTASE1 (GR1); activities of ascorbate peroxidase, glutathione reductase, and catalase; as well as levels of ascorbic acid, glutathione, flavonoids, carotenoids, and total phenols. SNP also reduced hydrogen peroxide and superoxide radical accumulation in maize seedlings under HS compared to the control. The effects of SNP on ROS and their scavenger system were weakened by PAG and HT alone. These data hint that NO could evoke thermotolerance in maize seedlings by triggering the LCD/H2S signaling pathway, and the ROS-scavenging system played a key role in the NO and H2S crosstalk-evoked thermotolerance.

The Diverse Analysis Identifies Mutated KRAS Associated With Radioresistance in Non-Small Cell Lung Cancer.

Background: To analyze the relationship between V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) status and radioresistance in non-small cell lung cancer (NSCLC), we identified potential genotypic differences and pathways involved. Methods: We retrospectively analyzed epidermal growth factor receptor (EGFR) and KRAS status in patients undergoing definitive radiotherapy for NSCLC between 2004 and 2018. Cox proportional hazard models were used to evaluate local progression-free survival (LPFS). Using clonogenic survival and measurement of γH2AX foci, we analyzed the difference in radiosensitivity between NSCLC cell lines with different KRAS status. The Cancer Genome Atlas (TCGA) analysis was used to explore the potential pathways involved. Results: The results showed that of the 286 patients identified, 68 (24%) had local tumor progression (mean ± standard deviation (SD), 27 ± 17.4 months); of these patients, KRAS mutations were found in 14 (23%), and KRAS status was associated with LPFS. After adjusting for concurrent chemotherapy, gross tumor volume, and mutation status in multivariate analysis, KRAS mutation was associated with shorter LPFS (hazard ratio: 1.961; 95% confidence interval: 1.03 - 2.17; P = 0.032). KRAS mutation showed higher radioresistance in vitro. TCGA data showed that the ERK1/2 pathway, phosphatidylinositol I3 kinase (PI3K)/mTOR, p38 MAPK pathway, cell cycle checkpoint signaling, DNA damage, repair pathways, and EGFR/PKC/AKT pathway were differentially expressed in patients with KRAS mutations or cell lines compared with their expression in the wild-type group. Conclusions: Diverse analyses identified that KRAS mutation was associated with radioresistance in NSCLC. KRAS mutation status may be helpful as a biomarker of radioresistance and a potential target to increase radiosensitivity.

Hyperprogression, a challenge of PD-1/PD-L1 inhibitors treatments: potential mechanisms and coping strategies.

Immunotherapy is now a mainstay in cancer treatments. Programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) immune checkpoint inhibitor (ICI) therapies have opened up a new venue of advanced cancer immunotherapy. However, hyperprogressive disease (HPD) induced by PD-1/PD-L1 inhibitors caused a significant decrease in the overall survival (OS) of the patients, which compromise the efficacy of PD-1/PD-L1 inhibitors. Therefore, HPD has become an urgent issue to be addressed in the clinical uses of PD-1/PD-L1 inhibitors. The mechanisms of HPD remain unclear, and possible predictive factors of HPD are not well understood. In this review, we summarized the potential mechanisms of HPD and coping strategies that can effectively reduce the occurrence and development of HPD.

APOE Is a Prognostic Biomarker and Correlates with Immune Infiltrates in Papillary Thyroid Carcinoma.

Background: Recent research showed that abnormal lipid metabolism was associated with cancers. As one of the genes that can regulate the level of lipid metabolism, abnormal APOE expression was associated with carcinogenesis. However, the clinical value of APOE in papillary thyroid carcinoma (PTC) remains to be determined. Methods: ONCOMINE, GEPIA, UALCAN, STRING, GeneMANIA, LinkedOmics, GSCALite, TISIDB, EPIC and TIMER were utilized to achieve comprehensively bioinformatics analysis of APOE in this study. And the immunohistochemical staining of APOE was used to verify the predicted results. Results: The mRNA level and protein level of APOE of PTC tissues were significantly elevated in TCGA cohort and Shanghai cohort. PTC patients with low mRNA level of APOE were associated with a bad prognosis. The functions of APOE co-expressed genes were mainly enriched in adaptive immune response, protein-lipid complex subunit organization, actin cytoskeleton reorganization, cell chemotaxis, protein activation cascade and transcriptional misregulation in cancer. APOE level was significantly correlated with tumor-infiltrating cells (B cells, CD8+ T cells, neutrophils, and dendritic) and immune biomarkers in PTC. Conclusions: APOE is a potential independent biomarker for PTC and APOE expression is positively correlated with immune cell infiltration in PTC.

Using air cholangiography to reduce postendoscopic retrograde cholangiopancreatography cholangitis in patients with malignant hilar obstruction.

Background: Cholangitis after endoscopic retrograde cholangiopancreatography (ERCP) is a major problem for patients with hilar biliary obstruction. To date, it remains unclear whether air-contrast cholangiography (ACC) can reduce cholangitis in these patients. For this reason, our study assesses the efficacy of reducing cholangitis through ACC. Methods: This paper presents a retrospective study conducted at a tertiary university hospital. We enrolled patients who were diagnosed with hilar structures and underwent ERCP between January 2012 and December 2018. From 2015 onwards, ACC was performed following the successful selective cannulation into the dilated intrahepatic bile duct of these patients. The primary aim was to assess patients with cholangitis in both an ACC group and iodine contrast cholangiography (ICC) group. Results: This study included 80 patients, 35 of whom received ACC and 45 who received ICC. There were no differences between the 2 groups in terms of the number of patients who underwent endoscopic papillotomy, endoscopic nasobiliary drainage, endoscopic biliary stent placement, or other technical procedures or complications. A total of 19 patients (23.8%) presented with fever (cholangitis) after the ERCP procedure (4 ACC, 15 ICC; 11.4% vs. 33.3%, respectively; P=0.03). One patient in the ICC group who obtained a plastic stent for palliative drainage died 2 weeks post-ERCP. Among the other 18 cholangitis patients, 8 (1 ACC, 7 ICC) were treated with additional ERCP or percutaneous transhepatic biliary drainage (PTBD), while the remaining 10 only received antibiotics. One patient in the ICC group who obtained a plastic stent for palliative drainage died 2 weeks post-ERCP. Conclusions: We found that ACC significantly reduced the incidence of cholangitis in patients with hilar obstruction.

Involvement of osmoregulation, glyoxalase, and non-glyoxalase systems in signaling molecule glutamic acid-boosted thermotolerance in maize seedlings.

Glutamic acid (Glu) is not only an important protein building block, but also a signaling molecule in plants. However, the Glu-boosted thermotolerance and its underlying mechanisms in plants still remain unclear. In this study, the maize seedlings were irrigated with Glu solution prior to exposure to heat stress (HS), the seedlings' thermotolerance as well as osmoregulation, glyoxalase, and non-glyoxalase systems were evaluated. The results manifested that the seedling survival and tissue vitality after HS were boosted by Glu, while membrane damage was reduced in comparison with the control seedlings without Glu treatment, indicating Glu boosted the thermotolerance of maize seedlings. Additionally, root-irrigation with Glu increased its endogenous level, reinforced osmoregulation system (i.e., an increase in the levels of proline, glycine betaine, trehalose, and total soluble sugar, as well as the activities of pyrroline-5-carboxylate synthase, betaine dehydrogenase, and trehalose-5-phosphate phosphatase) in maize seedlings under non-HS and HS conditions compared with the control. Also, Glu treatment heightened endogenous methylglyoxal level and the activities of glyoxalase system (glyoxalase I, glyoxalase II, and glyoxalase III) and non-glyoxalase system (methylglyoxal reductase, lactate dehydrogenase, aldo-ketoreductase, and alkenal/alkenone reductase) in maize seedlings under non-HS and HS conditions as compared to the control. These data hint that osmoregulation, glyoxalase, and non-glyoxalase systems are involved in signaling molecule Glu-boosted thermotolerance of maize seedlings.

Phylogenetic analysis and character evolution of tribe Arethuseae (Orchidaceae) reveal a new genus Mengzia.

Delimitation of the tribe Arethuseae has varied considerably since it was first defined. The relationships within Arethuseae, particularly within the subtribe Arethusinae, remain poorly elucidated. In this study, we reconstructed the phylogeny of Arethuseae, using six plastid markers (matK, ycf1, rbcL rpoc1, rpl32-trnL and trnL-F) from 83 taxa. The ancestral state reconstruction of 11 selected morphological characters was also conducted to identify synapomorphies and assess potential evolutionary transitions. Morphological character comparision between the distinct species Bletilla foliosa and other species are conducted. Our results unequivocally supported the monophyly of Arethuseae, which included highly supported clades and a clear synapomorphy of non-trichome-like lamellae. Furthermore, B. foliosa formed a separate clade in the subtribe Arethusinae, instead of clustering with the other Bletilla species in the subtribe Coelogyninae. The morphological characters comparision further showed that the B. foliosa clade could be distinguished from other genera in Arethuseae by multiple characters, including presence of lateral inflorescence, three lamellae with trichome-like apex and four pollinia. In light of these molecular and morphological evidences, we propose Mengzia as a new genus to accommodate B. foliosa and accordingly provide descriptions of this new genus and combination.

Risk factors for post-endoscopic retrograde cholangiopancreatography (ERCP) abdominal pain in patients without post-ERCP pancreatitis.

BACKGROUND: Abdominal pain is often observed after endoscopic retrograde cholangiopancreatography (ERCP). Few studies have focused on the risk factors of post-ERCP abdominal pain without post-ERCP pancreatitis (PEP). This study aimed to identify risk factors of post-ERCP abdominal pain without PEP and investigate characteristics of the abdominal pain in non-PEP patients. METHODS: Data from patients who underwent ERCP from August 2019 to January 2020 were retrospectively collected. Characteristics of the abdominal pain after ERCP were recorded and compared between PEP and non-PEP patients. Multivariate analysis was conducted to identify risk factors of non-PEP abdominal pain. RESULTS: A total of 1295 ERCP procedures were investigated in this study, among which 100 (7.72%) patients presented post-ERCP abdominal pain without PEP and 63 (4.86%) patients with PEP. Multivariate analysis found 9 risk factors of non-PEP abdominal pain: age ≤ 65 years [odds ratio (OR): 1.971], primary ERCP (OR: 2.442), dilated extrahepatic bile duct (OR: 1.803), no papilla opening (OR: 2.095), pancreatic guidewire passages (OR: 2.258), white blood cells (WBC) ≤ 6.0 × 109/L (OR: 1.689), platelet (PLT) ≤ 250 × 109/L (OR: 2.505), serum γ-glutamyl transferase (γ - GT) ≤ 35 U/L (OR: 2.190), and albumin ≥ 40 g/L (OR: 1.762). The PEP group had later pain onset, higher pain frequency and longer hospital stay than those of the non-PEP pain group (P < 0.05). There were no significant differences in the pain duration, visual analogue scale score and mortality between the PEP group and non-PEP pain group (P > 0.05). CONCLUSIONS: This study indicated that age ≤ 65 years, primary ERCP, dilated extrahepatic bile duct, no papilla opening, pancreatic guidewire passages, lower WBC, lower PLT, normal γ - GT and elevated albumin were independent risk factors for post-ERCP abdominal pain without PEP. The pain occurred earlier in non-PEP patients than in PEP patients.

Impatienschenmoui (Balsaminaceae), a new species from southern Yunnan, China.

Impatienschenmoui (Balsaminaceae), a new species from southern Yunnan, China, was described and illustrated based on morphological and molecular evidence. This new species is morphologically most similar to Impatiensoblongata Ruchis. & Niet, but can be distinguished by 7-9 pairs of leaf veins, glabrous perianth, obovate upper petal, and capsule with trichome.

Erratum: Oncogenic roles of carbonic anhydrase IX in human nasopharyngeal carcinoma.

[This corrects the article on p. 2942 in vol. 7, PMID: 25031713.].

Mangiferin Inhibits Human Lung Adenocarcinoma by Suppressing MiR-27b and MiR-92a.

Lung adenocarcinoma (LUAD) is one of the most prevalent malignancies. However, its mechanism and therapeutic strategy remain to be clarified. Mangiferin is a flavonoid derived from the leaves of mango trees of the lacquer family that has many pharmacological and physiological effects. This research aimed to elucidate the biological effect of mangiferin in LUAD cell lines and clarify the in vitro mechanism of mangiferin. Mangiferin was shown to significantly restrain the proliferation of LUAD cells (A549, H1299, and H2030 cells) in a dose- and time-dependent manner. Furthermore, mangiferin was capable of stimulating apoptosis, and more cells were blocked in G1 and S phase in the mangiferin-treated cells than in those not treated with mangiferin. Microarrays and micro-RNA sequencing data suggested that there is a higher level of miR-27b and miR-92a in LUAD tissues than in non-LUAD tissues. Additional experiments indicated that mangiferin may be related to the downregulated levels of miR-92a and miR-27b. In conclusion, mangiferin likely regulates proliferation and apoptosis in LUAD cells by reducing the expression levels of miR-92a and miR-27b.