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1.
Nat Commun ; 15(1): 2551, 2024 Mar 21.
Article in English | MEDLINE | ID: mdl-38514606

ABSTRACT

Eukaryotic initiation translation factor 3 subunit h (EIF3H) plays critical roles in regulating translational initiation and predicts poor cancer prognosis, but the mechanism underlying EIF3H tumorigenesis remains to be further elucidated. Here, we report that EIF3H is overexpressed in colorectal cancer (CRC) and correlates with poor prognosis. Conditional Eif3h deletion suppresses colorectal tumorigenesis in AOM/DSS model. Mechanistically, EIF3H functions as a deubiquitinase for HAX1 and stabilizes HAX1 via antagonizing ßTrCP-mediated ubiquitination, which enhances the interaction between RAF1, MEK1 and ERK1, thereby potentiating phosphorylation of ERK1/2. In addition, activation of Wnt/ß-catenin signaling induces EIF3H expression. EIF3H/HAX1 axis promotes CRC tumorigenesis and metastasis in mouse orthotopic cancer model. Significantly, combined targeting Wnt and RAF1-ERK1/2 signaling synergistically inhibits tumor growth in EIF3H-high patient-derived xenografts. These results uncover the important roles of EIF3H in mediating CRC progression through regulating HAX1 and RAF1-ERK1/2 signaling. EIF3H represents a promising therapeutic target and prognostic marker in CRC.


Subject(s)
Colorectal Neoplasms , MAP Kinase Signaling System , Humans , Animals , Mice , Phosphorylation , Cell Transformation, Neoplastic/genetics , Carcinogenesis , Wnt Signaling Pathway , Eukaryotic Initiation Factor-3/genetics , Eukaryotic Initiation Factor-3/metabolism , Colorectal Neoplasms/pathology , Mitogen-Activated Protein Kinase Kinases/metabolism , Cell Line, Tumor , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Adaptor Proteins, Signal Transducing/metabolism
2.
Cell Oncol (Dordr) ; 2024 Feb 23.
Article in English | MEDLINE | ID: mdl-38393513

ABSTRACT

PURPOSE: Sunitinib is a recommended drug for metastatic renal cell carcinoma (RCC). However, the therapeutic potential of sunitinib is impaired by toxicity and resistance. Therefore, we seek to explore a combinatorial strategy to improve sunitinib efficacy of low-toxicity dose for better clinical application. METHODS: We screen synergistic reagents of sunitinib from a compound library containing 1374 FDA-approved drugs by in vitro cell viability evaluation. The synergistically antiproliferative and proapoptotic effects were demonstrated on in vitro and in vivo models. The molecular mechanism was investigated by phosphoproteomics, co-immunoprecipitation, immunofluorescence and western-blot assays, etc. RESULTS: From the four-step screening, nilotinib stood out as a potential synergistic killer combined with sunitinib. Subsequent functional evaluation demonstrated that nilotinib and sunitinib synergistically inhibit RCC cell proliferation and promote apoptosis in vitro and in vivo. Mechanistically, nilotinib activates E3-ligase HUWE1 and in combination with sunitinib renders MCL-1 for degradation via proteasome pathway, resulting in the release of Beclin-1 from MCL-1/Beclin-1 complex. Subsequently, Beclin-1 induces complete autophagy flux to promote antitumor effect. CONCLUSION: Our findings revealed that a novel mechanism that nilotinib in combination with sunitinib overcomes sunitinib resistance in RCC. Therefore, this novel rational combination regimen provides a promising therapeutic avenue for metastatic RCC and rationale for evaluating this combination clinically.

3.
Int J Mol Sci ; 24(23)2023 Nov 27.
Article in English | MEDLINE | ID: mdl-38069131

ABSTRACT

Penile cancer (PC) is a rare male malignant tumor, with early lymph node metastasis and poor prognosis. Human papillomavirus (HPV) plays a key role in the carcinogenesis of PC. This review aims to summarize the association between HPV infection and PC in terms of virus-host genome integration patterns (the disrupted regions in the HPV and PC genome), genetic alterations, and epigenetic regulation (methylation and microRNA modification) occurring in HPV and PC DNA, as well as tumor immune microenvironment reprogramming. In addition, the potential of HPV vaccination strategies for PC prevention and treatment is discussed. Understanding of the HPV-related multidimensional mechanisms and the application of HPV vaccines will promote rational and novel management of PC.


Subject(s)
Papillomavirus Infections , Papillomavirus Vaccines , Penile Neoplasms , Humans , Male , Female , Papillomavirus Infections/complications , Papillomavirus Infections/prevention & control , Papillomavirus Infections/genetics , Penile Neoplasms/prevention & control , Penile Neoplasms/genetics , Epigenesis, Genetic , Carcinogenesis/genetics , Papillomavirus Vaccines/therapeutic use , Papillomaviridae/genetics , Tumor Microenvironment
4.
Acta Pharm Sin B ; 13(8): 3382-3399, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37655321

ABSTRACT

Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.

5.
Adv Sci (Weinh) ; 10(27): e2300759, 2023 09.
Article in English | MEDLINE | ID: mdl-37544925

ABSTRACT

Numerous studies have demonstrated that individual proteins can moonlight. Eukaryotic Initiation translation factor 3, f subunit (eIF3f) is involved in critical biological functions; however, its role independent of protein translation in regulating colorectal cancer (CRC) is not characterized. Here, it is demonstrated that eIF3f is upregulated in CRC tumor tissues and that both Wnt and EGF signaling pathways are participating in eIF3f's oncogenic impact on targeting phosphoglycerate dehydrogenase (PHGDH) during CRC development. Mechanistically, EGF blocks FBXW7ß-mediated PHGDH ubiquitination through GSK3ß deactivation, and eIF3f antagonizes FBXW7ß-mediated PHGDH ubiquitination through its deubiquitinating activity. Additionally, Wnt signals transcriptionally activate the expression of eIF3f, which also exerts its deubiquitinating activity toward MYC, thereby increasing MYC-mediated PHGDH transcription. Thereby, both impacts allow eIF3f to elevate the expression of PHGDH, enhancing Serine-Glycine-One-Carbon (SGOC) signaling pathway to facilitate CRC development. In summary, the study uncovers the intrinsic role and underlying molecular mechanism of eIF3f in SGOC signaling, providing novel insight into the strategies to target eIF3f-PHGDH axis in CRC.


Subject(s)
Colorectal Neoplasms , Signal Transduction , Humans , Epidermal Growth Factor , Serine
6.
Environ Chem Lett ; : 1-32, 2023 Jun 15.
Article in English | MEDLINE | ID: mdl-37362014

ABSTRACT

The rise of global waste and the decline of fossil fuels are calling for recycling waste into energy and materials. For example, rice straw, a by-product of rice cultivation, can be converted into biogas and by-products with added value, e.g., biofertilizer, yet processing rice straw is limited by the low energy content, high ash and silica, low nitrogen, high moisture, and high-quality variability. Here, we review the recycling of rice straw with focus on the global and Chinese energy situations, conversion of rice straw into energy and gas, biogas digestate management, cogeneration, biogas upgrading, bioeconomy, and life cycle assessment. The quality of rice straw can be improved by pretreatments, such as baling, ensiling, and co-digestion of rice straw with other feedstocks. The biogas digestate can be used to fertilize soils. The average annual potential energy of collectable rice straw, with a lower heating value of 15.35 megajoule/kilogram, over the past ten years (2013-2022) could reach 2.41 × 109 megajoule.

7.
J Biol Chem ; 299(7): 104854, 2023 07.
Article in English | MEDLINE | ID: mdl-37224962

ABSTRACT

Functional depletion of the U1 small nuclear ribonucleoprotein (snRNP) with a 25 nt U1 AMO (antisense morpholino oligonucleotide) may lead to intronic premature cleavage and polyadenylation of thousands of genes, a phenomenon known as U1 snRNP telescripting; however, the underlying mechanism remains elusive. In this study, we demonstrated that U1 AMO could disrupt U1 snRNP structure both in vitro and in vivo, thereby affecting the U1 snRNP-RNAP polymerase II interaction. By performing chromatin immunoprecipitation sequencing for phosphorylation of Ser2 and Ser5 of the C-terminal domain of RPB1, the largest subunit of RNAP polymerase II, we showed that transcription elongation was disturbed upon U1 AMO treatment, with a particular high phosphorylation of Ser2 signal at intronic cryptic polyadenylation sites (PASs). In addition, we showed that core 3'processing factors CPSF/CstF are involved in the processing of intronic cryptic PAS. Their recruitment accumulated toward cryptic PASs upon U1 AMO treatment, as indicated by chromatin immunoprecipitation sequencing and individual-nucleotide resolution CrossLinking and ImmunoPrecipitation sequencing analysis. Conclusively, our data suggest that disruption of U1 snRNP structure mediated by U1 AMO provides a key for understanding the U1 telescripting mechanism.


Subject(s)
Morpholinos , Oligonucleotides, Antisense , RNA Precursors , Ribonucleoprotein, U1 Small Nuclear , Morpholinos/metabolism , Oligonucleotides, Antisense/metabolism , Oligonucleotides, Antisense/pharmacology , Polyadenylation , Ribonucleoprotein, U1 Small Nuclear/genetics , Ribonucleoprotein, U1 Small Nuclear/metabolism , RNA Polymerase II/genetics , RNA Polymerase II/metabolism , RNA Precursors/metabolism , Humans , HeLa Cells , Gene Knockdown Techniques , Cleavage And Polyadenylation Specificity Factor , Cleavage Stimulation Factor/metabolism , Transcription, Genetic/drug effects
8.
Respir Res ; 24(1): 111, 2023 Apr 15.
Article in English | MEDLINE | ID: mdl-37061730

ABSTRACT

BACKGROUND: Non-small cell lung cancer (NSCLC) is the main type of the most common malignant tumor in the world. Previous studies have shown that the expression level of mitochondrial creatine kinase 1 (CKMT1) is abnormal in NSCLC, but the mechanism of its effect remains unclear. Therefore, in this study, we intend to clarify the potential mechanism of CKMT1 in NSCLC and provide the theoretical basis for the clinical application of CKMT1. METHODS: The function of CKMT1 in NSCLC was identified by analyzing the GEO dataset and evaluating using in vitro and in vivo models. Protein mass spectrometry was used to find proteins interacting with CKMT1, and Co-immunoprecipitation (Co-IP) and GST-pull down experiments were used to verify the interaction between proteins. The immunofluorescence (IF) assay was used to explore the functional position of CKMT1 in cells. The effect of CKMT1 expression level on the efficacy of paclitaxel (TAX) in the treatment of NSCLC was analyzed by a combined TAX experiment in vivo and in vitro. RESULTS: CKMT1 expression was increased in NSCLC and CKMT1 promoted the proliferation of NSCLC cells in vitro and in vivo. CKMT1 knockdown resulted in a significantly increased G0/G1 fraction and decreased S phase cell fraction, indicating G1 phase arrest. Mechanically, the cyclin-dependent kinase 4 (CDK4) was identified to interact with CKMT1, and the crucial binding areas were focused on the DH domain of CKMT1 and the N- and C-terminal of CDK4. A fraction of the CDK4 proteins colocalize and interact with the CKMT1 at mitochondria, the level of phosphorylated CDK4 was regulated by CKMT1. Hence, the decrease in CKMT1 expression level could increase the antitumor effect of G2/M cell cycle antagonist-TAX in NSCLC in vitro and in vivo. CONCLUSIONS: CKMT1 could interact with CDK4 in mitochondria and regulate the phosphorylated level of CDK4, thus contributing to the proliferation and cell cycle transition of NSCLC cells. And CKMT1 could be a potential target to improve the sensitivity of chemotherapy based on TAX.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell Cycle , Cell Line, Tumor , Cell Proliferation , Creatine Kinase, Mitochondrial Form , Cyclin-Dependent Kinase 4/genetics , Lung Neoplasms/genetics , Lung Neoplasms/pathology
9.
Biochem Pharmacol ; 211: 115498, 2023 05.
Article in English | MEDLINE | ID: mdl-36913990

ABSTRACT

Despite the use of targeted therapy in non-small cell lung cancer (NSCLC) patients, cisplatin (DDP)-based chemotherapy is still the main option. However, DDP resistance is the major factor contributing to the failure of chemotherapy. In this study, we tried to screen DDP sensitizers from an FDA-approved drug library containing 1374 small-molecule drugs to overcome DDP resistance in NSCLC. As a result, disulfiram (DSF) was identified as a DDP sensitizer: DSF and DDP had synergistic anti-NSCLC effects, which are mainly reflected in inhibiting tumor cell proliferation, plate colony formation and 3D spheroidogenesis and inducing apoptosis in vitro, as well as the growth of NSCLC xenografts in mice. Although DSF has recently been reported to promote the antitumor effect of DDP by inhibiting ALDH activity or modulating some important factors or pathways, unexpectedly, we found that DSF reacted with DDP to form a new platinum chelate, Pt(DDTC)3+, which might be one of the important mechanisms for their synergistic effect. Moreover, Pt(DDTC)3+ has a stronger anti-NSCLC effect than DDP, and its antitumor activity is broad-spectrum. These findings reveal a novel mechanism underlying the synergistic antitumor effect of DDP and DSF, and provide a drug candidate or a lead compound for the development of a new antitumor drug.


Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Mice , Animals , Cisplatin/pharmacology , Cisplatin/metabolism , Disulfiram/pharmacology , Platinum/pharmacology , Carcinoma, Non-Small-Cell Lung/metabolism , Lung Neoplasms/metabolism , Antineoplastic Agents/pharmacology , Cell Proliferation , Drug Resistance, Neoplasm , Cell Line, Tumor
10.
Open Life Sci ; 18(1): 20220551, 2023.
Article in English | MEDLINE | ID: mdl-36816800

ABSTRACT

This study investigated the effect of combined thymosin α1 and vitamin C (Tα1 + VitC) on the immunological responses of septic rats. Five groups were designed. The septic model was established by the cecal ligation puncture (CLP) method. The sham group did not undergo CLP, the model group was given normal saline solution, the Tα1 group was given Tα1 (200 µg/kg), the VitC group was given VitC (200 mg/kg), and the Tα1 + VitC group was given Tα1 + VitC. Specimens for immunological analyses were collected at 6, 12, 24, and 48 h posttreatment in each group except for the sham group (only at 48 h). CD4 + CD25 + T cells in the peripheral blood and dendritic cell (DC) proportions in the spleen were analyzed by flow cytometry. Tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), transforming growth factor-ß (TGF-ß1), and nuclear factor kappa-B (NF-κB) were measured by ELISA. CD4 + CD25 + T cells and OX62 + DCs levels significantly increased in the model group and decreased in the Tα1 and/or VitC treatment groups. Similarly, the levels of TNF-α, IL-6, TGF-ß1, and NF-κB significantly increased in the model group and decreased in the Tα1, VitC, and Tα1 + VitC groups, indicating that combined Tα1 and VitC therapy may help regulate the immunological state of patients with sepsis, thereby improving prognosis.

11.
Shanghai Kou Qiang Yi Xue ; 32(6): 609-614, 2023 Dec.
Article in Chinese | MEDLINE | ID: mdl-38494969

ABSTRACT

PURPOSE: To investigate the prognosis of advanced oral squamous cell carcinoma (AOSCC) patients undergoing neck dissection with sternocleidomastoid muscle (SCM) preservation and resection. METHODS: From January 2013 to June 2017, a total of 235 AOSCC patients(stage Ⅲ and stage Ⅳ) who were diagnosed and underwent neck dissection at the Department of Oral and Maxillofacial Surgery, College and Hospital of Stomatology, Guangxi Medical University, were collected and followed-up. The differences in overall survival(OS), local recurrence-free survival (LRFS) and regional recurrence-free survival (RRFS) were compared between different surgical procedures. SPSS 25.0 software package was used for statistical analysis. RESULTS: Among 235 patients with postoperative follow-up, 101 patients retained the SCM during operation, and 134 patients had SCM removed. There was no significant difference in 5-year survival rate and 5-year regional recurrence rate between the SCM preservation group and the SCM resection group. Kaplan-Meier method of univariate analysis showed that SCM preservation or resection had no significant difference in OS, LRFS and RRFS. Cox multivariate regression analysis results showed that there was no significant difference between different surgical procedures in OS, LRFS and RRFS, while N stage and postoperative chemoradiotherapy were independent influencing factors for OS, LRFS and RRFS in AOSCC patients. CONCLUSIONS: Neck dissection with SCM preservation in AOSCC patients has no effect on survival and recurrence (including local recurrence and regional recurrence). It is feasible for AOSCC patients to undergo SCM-preserving neck dissection when metastatic cervical lymph nodes do not invade SCM. N stage and postoperative chemoradiotherapy affect the prognosis of AOSCC patients.


Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Mouth Neoplasms , Humans , Neck Dissection/methods , Squamous Cell Carcinoma of Head and Neck/pathology , Carcinoma, Squamous Cell/surgery , Carcinoma, Squamous Cell/pathology , Mouth Neoplasms/surgery , Mouth Neoplasms/pathology , Retrospective Studies , China , Prognosis , Cohort Studies , Head and Neck Neoplasms/surgery , Head and Neck Neoplasms/pathology , Muscles/pathology , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/surgery , Neoplasm Staging
12.
Mol Ther Oncolytics ; 26: 330-346, 2022 Sep 15.
Article in English | MEDLINE | ID: mdl-36090478

ABSTRACT

The use of radiotherapy for hypopharyngeal cancer (HC) treatment is increasing, and it is currently the primary treatment option for this cancer. However, radioresistance occurs in a proportion of patients. Here, we found that radiation increased proteasomal gene expression and that proteasome assembly was dependent on the induction of transcription factor NRF1 in HC. Through screening assays, we identified a mechanism by which proteasome-mediated degradation of DEP domain-containing mTOR-interacting protein (DEPTOR) contributes to the elevation of mTORC1 signaling after radiation. Therefore, after treatment with proteasome inhibitors (PIs), stabilization of DEPTOR inhibited mTORC1 signaling elevated by radiation and ultimately sensitized HC to radiotherapy. Mechanically, PIs not only interrupted the deubiquitination and degradation of DEPTOR but also suppressed the ubiquitination of DEPTOR mediated by ß-TrCP. Clinically, the high levels of DEPTOR in HC cells were associated with sensitivity to radiotherapy and favorable prognosis. Stabilizing DEPTOR through targeting proteasome-mediated degradation is a potential strategy for sensitizing HC to radiotherapy.

13.
J Environ Manage ; 320: 115895, 2022 Oct 15.
Article in English | MEDLINE | ID: mdl-35944326

ABSTRACT

Digestate generated from anaerobic digestion (AD) has been widely used as digestate fertilizer (DF) for plant growth, but its application should be comprehensively investigated. This study evaluates the effects of different amounts of DF on crop growth, nutrient use efficiency (NUE), soil properties, and potential negative impacts of DF application (salinity and heavy metals (HMs)) with two different crops (Eggplant and Shanghai cabbage). In eggplant cultivation, the yield increased with the increase of DF amount, and the yield of the DF-680 group was the highest (65.4 t/ha) under the highest fertilizer amount. However, due to high ammonia volatilization loss and excessive application, the NUE of DF was only about half of that of chemical fertilizer (CF). Significantly different from eggplant, the high application amount of DF resulted in yield reduction in Shanghai cabbage cultivation. The yield and NUE of the DF-170 group were the highest, the yield was 46.5 t/ha, and the NUE was more than twice compared to CF. Moreover, DF can raise soil nitrogen storage and alleviate soil acidification caused by fertilization in both batches of cultivation. Nevertheless, the electrical conductivity (EC) value of the soil was increased by 2-3 times, and the long-term application may lead to soil salinization. On the other hand, the increase of DF application elevated the content of copper (Cu), zinc (Zn), and cadmium (Cd) in soil significantly but did not cause HMs contamination in crops and tillage soil. In summary, reasonable application amounts and methods should be considered when applying DF.


Subject(s)
Fertilizers , Metals, Heavy , Agriculture/methods , China , Crops, Agricultural , Fertilizers/analysis , Metals, Heavy/analysis , Nitrogen/analysis , Risk Assessment , Soil/chemistry , Vegetables
14.
Environ Res ; 212(Pt D): 113404, 2022 09.
Article in English | MEDLINE | ID: mdl-35568236

ABSTRACT

Bioenergy is a promising solution for greenhouse gas (GHG) emissions mitigation. However, the emissions resulting from the different production stages must be quantified and evaluated. The life cycle assessment (LCA) method was used to compare and quantify the environmental burdens of three rice straw (RS) utilization scenarios for producing biogas, briquette fuel, and syngas. To our knowledge, this is the first study that applies the LCA approach to assess these three bioenergy scenarios in a single study where the main goal was to determine the most sustainable option. A total of 10 mid-point impact categories were investigated. The results indicated that the three scenarios achieved net positive energy and net negative GHG balances. The briquette fuel scenarios had the highest net energy balance (11,115 MJ/tonne dry RS), while the syngas scenario had the highest net GHG (-2,315 kg CO2-eq./tonne dry RS). Moreover, the syngas scenario was the most beneficial to the environment, achieving negative results in 9 out of the 10 impact categories; the largest was marine ecotoxicity (-853,897 kg 1,4-DB-eq./tonne dry RS). The biogas scenario achieved emission savings in 3 out of the 10 categories. Although the briquette fuel scenario had no negative values in the 10 categories, its overall contribution to environmental burdens was relatively low. Overall, the order of the three scenarios in terms of the most sustainable option is syngas > briquette fuel > biogas.


Subject(s)
Greenhouse Gases , Oryza , Animals , Biofuels , Greenhouse Effect , Life Cycle Stages
15.
RNA Biol ; 19(1): 686-702, 2022.
Article in English | MEDLINE | ID: mdl-35491945

ABSTRACT

It has recently been shown that CFIm25, a canonical mRNA 3' processing factor, could play a variety of physiological roles through its molecular function in the regulation of mRNA alternative polyadenylation (APA). Here, we used CRISPR/Cas9-mediated gene editing approach in human embryonic stem cells (hESCs) for CFIm25, and obtained three gene knockdown/mutant cell lines. CFIm25 gene editing resulted in higher proliferation rate and impaired differentiation potential for hESCs, with these effects likely to be directly regulated by the target genes, including the pluripotency factor rex1. Mechanistically, we unexpected found that perturbation in CFIm25 gene expression did not significantly affect cellular mRNA 3' processing efficiency and APA profile. Rather, we provided evidences that CFIm25 may impact RNA polymerase II (RNAPII) occupancy at the body of transcribed genes, and promote the expression level of a group of transcripts associated with cellular proliferation and/or differentiation. Taken together, these results reveal novel mechanisms underlying CFIm25's modulation in determination of cell fate, and provide evidence that the process of mammalian gene transcription may be regulated by an mRNA 3' processing factor.


Subject(s)
Polyadenylation , Stem Cells , Animals , Gene Knockdown Techniques , Humans , Mammals/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , mRNA Cleavage and Polyadenylation Factors/metabolism
16.
Article in English | MEDLINE | ID: mdl-35410081

ABSTRACT

A perennial question for the pharmaceutical industry has been excessive drug prices. To alleviate patients' burden of expensive medical bills and increase the affordability of medicines, China adopted the Two-Invoice System (TIS) in drug procurement for public medical institutions in 2017. In this paper, we study the impact of the TIS on pharmaceutical manufacturers' selling expenses. Using a Difference-in-Differences (DID) methodology and a sample of the A-share pharmaceutical manufacturing firms listed on the Shanghai Stock Exchange and Shenzhen Stock Exchange from the years 2014 to 2020, we find that the TIS leads to a significant increase in pharmaceutical manufacturers' selling expenses but gradually weakens over time. In addition, we further explore whether the impact of the TIS on pharmaceutical manufacturers' selling expenses is affected by the pharmaceutical manufacturers' previous drug circulation mode. The results indicate that the TIS could significantly increase the pharmaceutical manufacturers' selling expenses in the agency mode group. However, there is no evidence to support the TIS having the same effect in the direct sales office model group.


Subject(s)
Commerce , Drug Industry , China , Costs and Cost Analysis , Humans , Pharmaceutical Preparations
17.
Cancers (Basel) ; 13(23)2021 Dec 03.
Article in English | MEDLINE | ID: mdl-34885212

ABSTRACT

Human papillomavirus (HPV) is a significant etiologic driver of penile squamous cell carcinoma (PSCC). The integration pattern of HPV and its carcinogenic mechanism in PSCC remain largely unclear. We retrospectively reviewed 108 PSCC cases who received surgery between 2008 and 2017. Using high-throughput viral integration detection, we identified 35 HPV-integrated PSCCs. Unlike cervical cancer, the HPV E2 oncogene was not prone to involvement in integration. Eleven of the 35 (31.4%) HPV-integrated PSCCs harbored intact HPV E2; these tumors had lower HPV E6 and E7 expression and higher expression of p53 and pRb proteins than those with disrupted E2 did (p < 0.001 and p = 0.024). Integration breakpoints are preferentially distributed in or near host genes, including previously reported hotspots (KLF5, etc.) and newly identified hotspots (CADM2, etc.), which are mainly involved in oncogenic signaling pathways (MAPK, JAK/STAT, etc.). Regarding the phosphorylation levels of JNK, p38 was higher in HPV-positive tumors with MAPK-associated integration than those in HPV-positive tumors with other integration and those in HPV-negative tumors. In vitro, KLF5 knockdown inhibited proliferation and invasion of PSCC cells, while silencing CADM2 promoted migration and invasion. In conclusion, this study enhances our understanding of HPV-induced carcinogenesis in PSCC, which may not only rely on the E6/E7 oncogenes, but mat also affect the expression of critical genes and thus activate oncogenic pathways.

18.
Front Nutr ; 8: 702096, 2021.
Article in English | MEDLINE | ID: mdl-34722601

ABSTRACT

Biogas slurry, a byproduct of biogas plants, is considered a high-quality bio-organic fertilizer. Despite providing nutrients to crops, biogas slurry may contain a high concentration of heavy metals, leading to food safety problems and endangering human health if such metals are absorbed by plants. Therefore, biogas slurry should undergo systematic risk assessment prior to direct use on farmland to ensure its safety for soils and crops. In this study, the risk of applying biogas slurry in peanut cultivation was comprehensively evaluated. Based on nitrogen contents, different concentrations of biogas slurry were applied in peanut cultivation. The results achieved herein showed that the application of biogas slurry as a nutrient supplier in peanut cultivation would significantly affect the physical and chemical properties of soil and characteristics of the plant and the quality of peanuts. Although the heavy metal content of biogas slurry was within the permitted range, it had potential risks to human health and the environment. Principal component analysis (PCA) showed that biogas slurry was the primary source of heavy metals in soil. After the application of biogas slurry, the contents of As and Hg in the soil increased significantly, which were 11.12 and 26.67 times higher than those in the control soil. The contents of Cu, Zn, Pb, Cd, and As in peanut kernel samples under different levels of biogas slurry application were all lower than the maximum permissible limit set by the Standardization Administration of China. In contrast, the content of Hg in peanut kernels was higher than the maximum permissible limit value of 0.02 mg/kg. Peanut had a higher enrichment capacity of Cd and Zn and a higher migration capacity of Pb. The health risk assessment showed that the long-term consumption of peanuts grown with a high dosage of biogas slurry would be harmful to the health of children aged 2-6 years with a large consumption level.

19.
Ying Yong Sheng Tai Xue Bao ; 32(10): 3661-3670, 2021 Oct.
Article in Chinese | MEDLINE | ID: mdl-34676728

ABSTRACT

Due to the short-term observation record of the normalized difference vegetation index (NDVI), the research on long-term NDVI changes is scarce, which limits our understanding of the impacts of NDVI changes in the context of global warming. In this study, a regional tree-ring chronology was developed based on the tree-ring samples of Pinus tabuliformis in the middle Qinling Mountains. The results showed that tree-ring width of P. tabuliformis was significantly positively correlated with May-July NDVI (r=0.624, P<0.01, n=34). The Sig-Free tree-ring width chronology was used to reconstruct May-July NDVI during the period 1825-2018, which explained 38.9% of the total NDVI variance. Results of spatial analysis showed that the reconstructed series could better represent the NDVI changes in the study area. There were six high NDVI periods and five low NDVI periods in the past 194 years. The vegetation grew best in 2006-2018, indicating vegetation cove-rage in the middle of Qinling Mountains had been improved during the warming hiatus. Low NDVI periods in the reconstruction series were consistent with drought over much of study area. Results of wavelet analysis indicated the existence of 2-4 years and 12-16 years cycles in the reconstruction series. SEA analysis showed that the reconstruction series decreased significantly in the El Nino year, while increased significantly in the first to third years after the La Nina event. The growth of P. tabuliformis was predicted to increase slightly under the SSP2-4.5, SSP3-7.0 and SSP5-8.5 scenarios.


Subject(s)
Pinus , Droughts , Global Warming , Spatial Analysis , Wavelet Analysis
20.
Shanghai Kou Qiang Yi Xue ; 30(3): 316-322, 2021 Jun.
Article in Chinese | MEDLINE | ID: mdl-34476453

ABSTRACT

PURPOSE: To analyze the opening of mid-palatal suture, transverse changes in dental and dentoalveolar measurements and shift of midfacial bony structures induced by maxillary skeletal expansion (MSE) with cone-beam CT (CBCT), and to evaluate the effect of maxillary skeletal expansion and its influence on adjacent bony structures in adults. METHODS: The study sample consisted of 12 adult patients with maxillary transverse deficiency (4 males, 8 females) at a mean age of (21.17±4.13) years old. All patients were treated with MSE. After treatment, the posterior crossbite was corrected, and the width of the maxillary arch was achieved the optimal width. Pre- and post-treatment CBCT exams were taken before and after MSE treatment. Multiplanar coronal and axial slices obtained from CBCT images were used to measure the changes in transverse widths, angular changes and tooth inclination with Dolphin Imaging 11.9. SPSS 26.0 software package was used for statistical analysis. RESULTS: After MSE treatment, the anterior nasal spine width increased by (2.38±1.01) mm, posterior nasal spine width increased by (2.25±1.08) mm (P<0.01). The inter-crown and inter-apex distance at the first molar increased by (5.56±1.38) mm and (4.14±1.29) mm, respectively (P<0.01). No significant difference was seen in terms of tooth inclination of the first molar(P>0.05). Pterygoid process angle, pterygoid process width, anterior inter-maxillary distance, upper and lower inter-zygomatic distance were significantly larger after treatment (P<0.01), while the inter-temporal distance and bilateral zygomaticomaxillary angle remained unchanged(P>0.05). CONCLUSIONS: MSE has a favorable effect in adult patients with parallel skeletal expansion of the mid-palatal suture achieved after expansion. The teeth present with certain buccal inclination but show no significant movement relative to the alveolar bone. The midfacial bony structures also shift in three-dimensional under the effect of the expansion force.


Subject(s)
Palatal Expansion Technique , Palate , Adult , Cone-Beam Computed Tomography , Female , Humans , Male , Maxilla/diagnostic imaging , Sutures
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