A gene-based score for the risk stratification of stage IA lung adenocarcinoma.

OBJECTIVE: We aim to molecularly stratify stage IA lung adenocarcinoma (LUAD) for precision medicine. METHODS: Twelve multi-institution datasets (837 cases of IA) were used to classify the high- and low-risk types (based on survival status within 5 years), and the biological differences were compared. Then, a gene-based classifying score (IA score) was trained, tested and validated by several machine learning methods. Furthermore, we estimated the significance of the IA score in the prognostic assessment, chemotherapy prediction and risk stratification of stage IA LUAD. We also developed an R package for the clinical application. The SEER database (15708 IA samples) and TCGA Pan-Cancer (1881 stage I samples) database were used to verify clinical significance. RESULTS: Compared with the low-risk group, the high-risk group of stage IA LUAD has obvious enrichment of the malignant pathway and more driver mutations and copy number variations. The effect of the IA score on the classification of high- and low-risk stage IA LUAD was much better than that of classical clinicopathological factors (training set: AUC = 0.9, validation set: AUC = 0.7). The IA score can significantly predict the prognosis of stage IA LUAD and has a prognostic effect for stage I pancancer. The IA score can effectively predict chemotherapy sensitivity and occult metastasis or invasion in stage IA LUAD. The R package IAExpSuv has a good risk probability prediction effect for both groups and single stages of IA LUAD. CONCLUSIONS: The IA score can effectively stratify the risk of stage IA LUAD, offering good assistance in precision medicine.

Regiodivergent Hydrosilylation of Polar Enynes to Synthesize Site-Specific Silyl-Substituted Dienes.

Herein, we present catalyst-regulated switchable site-selective hydrosilylation of enynes, which are suitable for a wide range of alkyl and aryl substituted polar enynes and exhibit excellent functional group compatibility. Under the optimized conditions, silyl groups can be precisely installed at various positions of 1,3-dienes. While α- and γ-silylation products were obtained under platinum-catalytic systems, ß-silylation products were delivered with [Cp*RuCl]4 as catalyst. This process lead to the formation of 1,3-dienoates with diverse substitutions, which would pose challenges with other methodologies.

Combined pembrolizumab and bevacizumab therapy effectively inhibits non-small-cell lung cancer growth and prevents postoperative recurrence and metastasis in humanized mouse model.

Antibodies targeting the programmed cell death protein 1/programmed cell death ligand-1 (PD-1/PD-L1) pathway have dramatically changed the treatment landscape of advanced non-small cell lung cancer (NSCLC). However, combination approaches are required to extend this benefit beyond a subset of patients. In addition, it is of equal interest whether these combination therapy can be applied to neoadjuvant therapy of early-stage NSCLC. In this study, we hypothesized that combining immunotherapy with anti-angiogenic therapy may have a synergistic effect in local tumor control and neoadjuvant therapy. To this end, the effect of combination of bevacizumab and pembrolizumab in humanized mouse models was evaluated. Furthermore, we innovatively constructed a neoadjuvant mouse model that can simulate postoperative recurrence and metastasis of NSCLC to perform neoadjuvant study. Tumor growth and changes in the tumor vasculature, along with the frequency and phenotype of tumor-infiltrating lymphocytes, were examined. Additionally, in vivo imaging system (IVIS) was used to observe the effect of neoadjuvant therapy. Results showed that combination therapy could inhibited tumor growth by transforming tumor with low immunoreactivity into inflamed ('hot') tumor, as demonstrated by increased CD8+granzyme B+ cytotoxic T cell infiltration. Subsequent studies revealed that this process is mediated by vascular normalization and endothelial cell activation. IVIS results showed that neoadjuvant therapy can effectively prevent postoperative recurrence and metastasis. Taken together, these preclinical studies demonstrated that the combination of bevacizumab and pembrolizumab had a synergistic effect in both advanced tumor therapy and neoadjuvant setting and therefore provide a theoretical basis for translating this basic research into clinical applications.

Electrochemical Phenyl-Carbonyl Coupling Reaction of Aromatic Aldehydes or Ketones.

An electrochemical phenyl-carbonyl coupling reaction of aromatic aldehydes or ketones to synthesize 4-(hydroxy(phenyl)methyl)benzaldehyde derivatives has been developed. The method shows high chemoselectivity, broad functional group compatibility, atom economy, and environmental benignity and has good potential applicability.

Synthesis of (E)-2-(1-(methoxyimino)ethyl)-2-phenylbenzofuran-3(2H)-ones from (E)-1-(benzofuran-2-yl)ethan-1-one O-methyl oximes and iodobenzenes via a palladium-catalyzed dearomative arylation/oxidation reaction.

A new method has been successfully developed that offers a facile and reliable approach for synthesizing (E)-2-(1-(methoxyimino)ethyl)-2-phenylbenzofuran-3(2H)-one, providing 28 compounds. This optimized process enables efficient preparation of a wide range of compounds using readily available (E)-1-(benzofuran-2-yl)ethan-1-one O-methyl oxime and iodobenzene, and provides alternative ideas for the structural modification of benzofuran ketones.

Simulation study of an x-ray sub-picosecond resolution detection system based on time-domain amplification.

This study proposes what we believe to be a novel x-ray detection system that achieves a temporal resolution of 930 fs with photorefractive and four-wave mixing effects. The system comprises two parts: a signal-conversion system and signal-acquisition system. The signal-conversion system is based on the photorefractive effect, which converts x-ray evolution into the variation of infrared interference intensity. The signal-conversion sensor consists of ultra-fast response LT-GaAs and a high-resolution interference cavity, achieving a resolution of  767 fs. The signal-acquisition system consists of a time-domain amplification system based on four-wave mixing and a high-resolution signal-recording system with a resolution of 21 ps, providing a temporal resolution of 525 fs.

Effects of zero-valent iron (ZVI) on nitrogen conversion, transformation of sulfamethoxazole (SMX) and abundance of antibiotic resistance genes (ARGs) in aerobic granular sludge process.

Even after pre-treatment, livestock and poultry wastewater still contain high concentrations of ammonia and residual antibiotics. These could be removed economically using the aerobic granular sludge (AGS) process with zero-valent iron (ZVI). The interaction of antibiotics and nitrogen in this process needs to be clarified and controlled, however, to achieve good removal performance. Otherwise, antibiotics might generate transformation products (TPs) with higher toxicity and lead to the emergence of antibiotic-resistant bacteria carrying antibiotic resistance genes (ARGs), which could cause persistent toxicity and the risk of disease transmission to the ecological environment. This study investigated the impact of ZVI on AGS for nitrogen and sulfamethoxazole (SMX) removal. The results show that AGS could maintain good ammonia removal performance and that the existence of SMX had a negative impact on ammonia oxidation activities. ZVI contributed to an increase in the abundance of nitrite oxidation bacteria, denitrifying bacteria and the functional genes of nitrogen removal. This led to better total nitrogen removal and a decrease in N2O emission. Accompanied by biological nitrogen transformation, SMX could be transformed into 14 TPs through five pathways. ZVI has the potential to enhance transformation pathways with TPs of lower ecotoxicity, thereby reducing the acute and chronic toxicity of the effluent. Unfortunately, ZVI might enhance the abundance of sul1, sul2, and sul3 in AGS, which increases the risk of sulfonamide antibiotic resistance. In AGS, Opitutaceae, Xanthomonas, Spartobacteria and Mesorhizobium were potential hosts for ARGs. This study provides theoretical references for the interaction of typical antibiotics and nitrogen in the biological treatment process of wastewater and bioremediation of natural water bodies.

Surgical resection and orbital iodine-125 brachytherapy for orbital malignancy: a novel treatment for orbital lymphoma.

OBJECTIVES: Orbital lymphoma is one of the most common adult orbital malignancies, accounting for approximately 10% of all orbital tumors. This study aimed to analyze the effects of surgical resection and orbital iodine-125 brachytherapy implantation for orbital lymphoma. PATIENTS AND METHODS: This was a retrospective study. Clinical data of 10 patients were collected from October 2016 to November 2018 and followed up to March 2022. Patients underwent the primary surgery for maximal safe removal of the tumor. After a pathologic diagnosis of a primary orbital lymphoma was established, iodine-125 seed tubes were designed based on the tumor size and invasion range, and direct vision was placed into the nasolacrimal canal or/and under the orbital periosteum around the resection cavity during the secondary surgery. Then, follow-up data, including the general situation, ocular condition, and tumor recurrence, were recorded. RESULTS: Of the 10 patients, the pathologic diagnoses included extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (6 cases), small lymphocytic lymphoma (1 case), mantle cell lymphoma (2 cases), and diffuse large B-cell lymphoma (1 case). The number of seeds implanted ranged from 16 to 40. The follow-up period ranged between 40 and 65 months. All patients in this study were alive and well had tumors that were completely controlled. No tumor recurrences or metastases occurred. Three patients had dry eye syndrome and two patients had abnormal facial sensation. No patient had radiodermatitis involving the skin around the eye, and no patient had radiation-related ophthalmopathy. CONCLUSIONS: Based on preliminary observations, iodine-125 brachytherapy implantation appeared to be a reasonable alternative to external irradiation for orbital lymphoma.

Nitrenoid from Oxime: A Practical Synthesis of Planar Chiral Ferrocenyl Phenanthridines via Nitrene-Involved Ring-Expansion Reaction.

Nitrenes and nitrenoids are highly reactive species and the proposed key intermediates in nitrogen-containing heterocyclic compound synthesis. In this work, we developed a practical method for the synthesis of phenanthridines by the reaction of oximes and Grignard reagents (with or without diethylzinc) via ring-expansion of magnesium coordinated nitrenoid complex as the key step. The method has been used to synthesize optically active planar chiral ferrocenyl phenanthridines.

Tandem Reduction, Ammonolysis, Condensation, and Deamination Reaction for Synthesis of Benzothiadiazines and 1-(Phenylsulfonyl)-1H-benzimidazoles.

A novel route for a SnCl2-promoted tandem reduction, ammonolysis, condensation, and deamination reaction which uses nitrile and 2-nitro-N-phenylbenzenesulfonamide/N-(2-nitrophenyl)benzenesulfonamide to synthesize derivatives of benzothiadiazine/1-(phenylsulfonyl)-1H-benzimidazole has been developed. The method features convenient operation and good functional group tolerance. In addition, it employs unsensitive and inexpensive SnCl2/i-PrOH as the reaction reagent and provides a direct approach for the synthesis of pharmaceutically important targets.

Application of an arched, Ni-Ti shape-memory connector in repairing distal tibiofibular syndesmosis ligament injury.

OBJECTIVE: To investigate the clinical effect of internal fixation of a Ni-Ti arched shape-memory connector in the treatment of distal tibiofibular syndesmosis ligament injury. METHODS: From January 2013 to January 2016, 108 cases of ankle fracture with distal tibiofibular syndesmosis ligament injury in our hospital were selected, and all of them were fixed with ASCs or screw fixation. The functional evaluation and efficacy evaluation were performed according to the Olerud Molander Ankle Score (Omas) and SF-36. At the same time, follow-ups recorded the incidence of postoperative complications: osteoarthritis, superficial infection, symptomatic hard and soft tissue irritation, early removal and poor reduction of internal fixation, and later loss of reduction. RESULTS: In the ASC(Ni-Ti Arched shape-memory Connector) group, the incidence of symptomatic hardware, soft tissue or superficial infection decreased to 2.77%(from 13.8% or 11.1% in SCREW group). The early removal rate(2.77%) of internal fixation was also lower than that of the screw group. While the incidence of osteoarthritis is 13.8% in SCREW group, the incidence of osteoarthritis in the later follow-up was also as low as 1.38% in ASC group. Loss of fracture reduction due to removal of the fixation device for the distal tibiofibular syndesmosis ligament was not observed in the ASC group. With two postoperative scoring systems (OMAS and SF-36), patients in the ASC group significantly get higher score than that in SCREW group. CONCLUSION: The design of the Ni-Ti arched shape-memory connector can be adapted to the irregular anatomical structure of the malleolus and the ability to continue to contract by body temperature. The use of ASCs in fixation of articular ligaments can preserve a slight range of motion, and the results suggest that ASCs can effectively reduce the incidence of fixation looseness, fracture, infection and other complications.

Cu-Catalyzed cis-selective ring-opening cross-coupling of an oxabicyclic olefin with an organoboron reagent.

The Cu(i)-catalyzed ring-opening cross-coupling of an oxabicyclic olefin with an organoboron reagent provides access to cis-2-aryl-1,2-dihydronaphthalen-1-ol derivatives, in contrast to the exclusive trans-selectivity in related Cu-catalyzed reactions with Grignard reagents. DFT calculations suggest that the reaction possibly proceeds via boronic ester by-product assisted ring-opening as an alternative pathway to the canonical ß-oxygen elimination as the rate-determining step.

Ursodeoxycholic acid alleviates nonalcoholic fatty liver disease by inhibiting apoptosis and improving autophagy via activating AMPK.

Ursodeoxycholic acid (UDCA), first identified in bear bile, was widely used in cholestatic liver diseases. Our previous studies have suggested UDCA may exert favorable influence on hepatic steatosis. However, the molecular mechanism remains elusive. Given the role of autophagy and apoptosis dysregulation in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and pharmacological effects of UDCA on modulating autophagy, apoptosis. we sought to investigate whether UDCA had therapeutic effect on NAFLD and its mechanism of modulating autophagy, apoptosis. Our finding revealed that UDCA exerted obviously favorable influence on hepatic steatosis in NAFLD rats by activating AMP-activated protein kinase (AMPK). Mechanistic studies indicated UDCA inhibited apoptosis and improved autophagy by influencing Bcl-2/Beclin-1 and Bcl-2/Bax complex interaction. Importantly, above-mentioned influence of UDCA on autophagy, apoptosis and Bcl-2/Beclin-1, Bcl-2/Bax complex interaction in NAFLD were partly counteracted by AMPK inhibitor compound C(CC). In conclusion, UDCA exerts favorable influence on hepatic steatosis in NAFLD rats, which is attributable to apoptosis inhibition and autophagy induction by influencing Bcl-2/Beclin-1 complex and Bcl-2/Bax complex interaction via activating AMPK, indicating that UDCA may be a promising therapeutic target for NAFLD.

Inhibition of p62/SQSTM1 sensitizes small-cell lung cancer cells to cisplatin-induced cytotoxicity by targeting NEDD9 expression.

Drug resistance is the leading cause for rapid progression and relapse in small-cell lung cancer (SCLC) patients. Thus overcoming drug resistance still remains to be urgently resolved during SCLC treatment. Here, we found p62/SQSTM1 was enriched in SCLC spheroids, a subpopulation possessing cancer stem-like properties, which is responsible for cancer relapse and metastasis. Subsequent functional assays in vitro showed that short hairpin RNA (shRNA)-mediated p62 knockdown increased sensitivity of SCLC cell lines to cisplatin (DDP), whereas lentivirus-mediated p62 ectopic overexpression diminished DDP-induced cytotoxicity in both NCI-H446 and NCI-H1688 cell lines. Moreover, ectopic p62 overexpression promoted DDP resistance of NCI-H446 cells-derived tumor xenografts in immunodeficient mice in vivo, as indicated by accelerated tumor growth rate and reduced fluorescent activity of cleaved caspase-3. Gene expression profiling analysis revealed that p62 was positively correlated with neuronal precursor cell-expressed, developmentally downregulated gene 9 (NEDD9) expression level. Consistently, NEDD9 messenger RNA (mRNA) level was decreased upon p62 suppression by small interfering RNA (siRNA) and increased with p62 transient overexpression in SCLC cell lines, suggesting that p62 positively regulated NEDD9 mRNA. Depletion of NEDD9 by siRNA, to a large extent, reversed p62-overexpressed SCLC cells to DDP-induced cytotoxicity, implying NEDD9 might act as a downstream target which was in charge of p62-mediated DDP resistance. Taken together, our findings uncovered a previously unknown role of p62 in the regulation of SCLC drug resistance, assigning p62 as an attractive target for SCLC treatment.

A gene-based survival score for lung adenocarcinoma by multiple transcriptional datasets analysis.

BACKGROUND: Lung adenocarcinoma (LUAD) remains a crucial factor endangering human health. Gene-based clinical predictions could be of great help for cancer intervention strategies. Here, we tried to build a gene-based survival score (SS) for LUAD via analyzing multiple transcriptional datasets. METHODS: We first acquired differentially expressed genes between tumors and normal tissues from intersections of four LUAD datasets. Next, survival-related genes were preliminarily unscrambled by univariate Cox regression and further filtrated by LASSO regression. Then, we applied PCA to establish a comprehensive SS based on survival-related genes. Subsequently, we applied four independent LUAD datasets to evaluate prognostic prediction of SS. Moreover, we explored associations between SS and clinicopathological features. Furthermore, we assessed independent predictive value of SS by multivariate Cox analysis and then built prognostic models based on clinical stage and SS. Finally, we performed pathway enrichments analysis and investigated immune checkpoints expression underlying SS in four datasets. RESULTS: We established a 13 gene-based SS, which could precisely predict OS and PFS of LUAD. Close relations were elicited between SS and canonical malignant indictors. Furthermore, SS could serve as an independent risk factor for OS and PFS. Besides, the predictive efficacies of prognostic models were also reasonable (C-indexes: OS, 0.7; PFS, 0.7). Finally, we demonstrated enhanced cell proliferation and immune escape might account for high clinical risk of SS. CONCLUSIONS: We built a 13 gene-based SS for prognostic prediction of LUAD, which exhibited wide applicability and could contribute to LUAD management.

Biases of Happy Faces in Face Classification Processing of Depression in Chinese Patients.

We explored the face classification processing mechanism in depressed patients, especially the biases of happy faces in face classification processing of depression. Thirty patients with the first episode of depression at the First Affiliated Hospital of Harbin Medical University were selected as the depression group, while healthy people matched for age, gender, and educational level were assigned to the control group. The Hamilton Depression Scale and Hamilton Anxiety Scale were used to select the subjects; then, we used the forced face classification paradigm to collect behavioral (response time and accuracy) and event-related potential (ERP) data of the subjects. The differences between the groups were estimated using a repeated measurement analysis of variance. The total response time of classified faces in the depression group was longer than that in the control group, the correct rate was lower, and the difference was statistically significant (P < 0.05). N170 component analysis demonstrated that the latency of the depression group was prolonged, and the difference was statistically significant (P < 0.05). When classifying happy faces, the depressed patients demonstrated a decrease in N170 amplitude and a prolongation of latency in some brain regions compared with the healthy individuals. The cognitive bias in depression may be due to prolonged processing of positive facial information and difficulty in producing positive emotional responses.

Ectopic expression of miR-944 impairs colorectal cancer cell proliferation and invasion by targeting GATA binding protein 6.

miR-944 is a microRNA that has been reported to play different important roles in the progression of cancer. Colorectal cancer (CRC) is a common cancer worldwide. A recent study has confirmed that miR-944 plays a tumour suppressive role in CRC. However, biological functions and the mechanism of miR-944 in CRC are poorly understood. Real-time reverse transcription polymerase chain reaction of 100 CRC tissues showed that miR-944 expression is frequently downregulated and is negatively associated with the T is the primary tumor, N is the lymph node, and M is the distant metastasis (TNM) stage (P = 0.009), depth of invasion (P = 0.001), and lymph node status (P = 0.002). Overexpression of mir-944 significantly impaired the functions of proliferation, migration and invasion in CRC cells, while these functions increased in knockdown experiments. GATA binding protein 6 (GATA6) knockdown can reverse the CRC cells functions induced by miR-944 inhibitor. Mechanistically, a Dual-Luciferase Reporter Assay showed that miR-944 is structurally combined with GATA6 and interacts with downstream proteins (CRT and p-AKT) in CRC cells. In conclusion, these findings indicated that miR-944 may be a tumour suppressor and could likely be used as a prognostic predictor and novel therapeutic target for CRC.

TMEM206 promotes the malignancy of colorectal cancer cells by interacting with AKT and extracellular signal-regulated kinase signaling pathways.

BACKGROUND: The roles of TMEM206, a new transmembrane protein, in cancer, including colorectal cancer (CRC), are unknown. Related family members, including TMEM16A, TMEM132A, and TMEM176B, have been shown to be involved in various biological behaviors. In addition, TMEM88 has been reported to promote non-small-cell lung cancer. In this study, we examined the roles of TMEM206 in CRC. METHOD: Real-time reverse transcription polymerase chain reaction was used to measure TMEM206 messenger RNA (mRNA) levels in clinical specimens and transfected cell lines. Immunohistochemistry was used to determine the relationship between TMEM206 expression levels and clinical data. Plasmids and small interfering RNA were used to upregulate and silence TMEM206, respectively. Protein expression levels and signaling pathway modulation were validated through western blot analysis. Colony formation, MTT, cell migration and invasion assays, and flow cytometry analyses were used to test the potential roles of TMEM206 in CRC. Co-immunoprecipitation was used to evaluate the interaction between TMEM206 and AKT. RESULTS: Investigation of the clinical significance of TMEM206 expression in CRC tissues revealed that TMEM206 mRNA and protein levels were higher in CRC tissues than in paired normal adjacent tissues (p < 0.05). TMEM206 overexpression was positively associated with T stage of cancer and UICC stage ( p < 0.05) and negatively related to differentiation of CRC ( p = 0.015). Upregulation or silencing of TMEM206 promoted or inhibited the proliferation of CRC cells and positively or negatively regulated the levels of phospho-AKT and downstream signaling pathway components (phospho-glycogen synthase kinase 3ß and cyclin D1), respectively. Moreover, silencing of TMEM206 in cell lines arrested CRC cells in the G1 stage of the cell-cycle. In addition, upregulating or silencing TMEM206 increased or decreased cell invasion and migration in vitro and positively or negatively altered levels of the phospho-extracellular signal-regulated kinase (ERK) and phospho-focal adhesion kinase 397, respectively. Co-immunoprecipitation demonstrated that AKT and TMEM206 proteins interacted. Furthermore, TMEM206 promoted the development and progression of CRC by enhancing the interactions between the AKT and ERK signaling pathways. CONCLUSION: TMEM206 controlled the progression of CRC by accelerating CRC cell proliferation and promoting CRC cell migration and invasion. The target of TMEM206 may be AKT, which is known to be involved in modulating the biological behaviors of various cancers.

ZC3H13 suppresses colorectal cancer proliferation and invasion via inactivating Ras-ERK signaling.

ZC3H13 is a canonical CCCH zinc finger protein, which harbors a somatic frame-shift mutation in colorectal cancer (CRC). However, its expression and biological function were still uncertain. In the current study, we found that ZC3H13 was served as a tumor suppressor in CRC cells, which decreased the expression of Snail, Cyclin D1, and Cyclin E1, and increased the expression of Occludin and Zo-1 through inactivating Ras-ERK signaling pathway. Furthermore, reduction of ZC3H13 associated with advanced TNM stage (p = 0.02), positive regional lymph node metastasis ( p = 0.01). Taken together, the current study indicated that ZC3H13 may be an upstream regulator of Ras-ERK signaling pathway and suppressed invasion and proliferation of CRC.

STYK1/NOK correlates with ferroptosis in non-small cell lung carcinoma.

Serine Threonine Tyrosine Kinase 1 (STYK1) presents oncogenic properties in many studies, and emerging evidence suggests that ferroptosis serve as a novel tumor suppressor. However, the interplay between STYK1 and ferroptosis in NSCLC remains unclear. Our aim is to illustrate the expression of ferroptotic regulator Glutathione peroxidase 4 (GPX4) in NSCLC and the relationship between STYK1 and ferroptosis. Herein, results based on ONCOMINE database, clinical specimens, and cellular manipulation revealed GPX4 was upregulated in NSCLC tissues and cell lines, and high GPX4 expression predicted worse prognosis. High STYK1 expression predicted worse OS and was related to high GPX4 in NSCLC tissues; overexpression of STYK1 in lung cancer cell line SW900 upregulated the expression of GPX4, promoted proliferation, and attenuated diverse mitochondrial abnormalities specific to ferroptosis, whereas knockdown of GPX4 exacerbated such attenuations without affecting cell proliferation. Taken together, ferroptosis as an anti-tumor factor is inhibited in NSCLC, and targeting ferroptosis could be a novel therapeutic strategy for the management of NSCLC; furthermore, regulating ferroptosis could be another cancerous mechanism of STYK1.