A Chemoselective Enrichment Strategy for In-Depth Coverage of the Methyllysine Proteome.

Proteomics is a powerful method to comprehensively understand cellular posttranslational modifications (PTMs). Owing to low abundance, tryptic peptides with PTMs are usually enriched for enhanced coverage by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Affinity chromatography for phosphoproteomes by metal-oxide and pan-specific antibodies for lysine acetylome allow identification of tens of thousands of modification sites. Lysine methylation is a significant PTM; however, only hundreds of methylation sites were identified by available approaches. Herein we report an aryl diazonium based chemoselective strategy that enables enrichment of monomethyllysine (Kme1) peptides through covalent bonds with extraordinary sensitivity. We identified more than 10000 Kme1 peptides from diverse cell lines and mouse tissues, which implied a wide lysine methylation impact on cellular processes. Furthermore, we found a significant amount of methyl marks that were not S-adenosyl methionine (SAM)-dependent by isotope labeling experiments.

Neoadjuvant chemotherapy is linked to an amended anti-tumorigenic microenvironment in gastric cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is a frequently intervention for patients with locally advanced gastric cancer (GC). Nevertheless, its impact on the tumor immune microenvironment remains unclear. METHODS: We used immunohistochemistry to identify T-cell subpopulations, tumor-associated neutrophils (TANs), and tumor-associated macrophages (TAMs) in the GC microenvironment (GCME) among paired samples (pre-chemotherapy and post-chemotherapy) from 48 NAC-treated patients. Multiplex immunofluorescence (mIF) was performed to assess immune biomarkers, including CK, CD4, CD8, FOXP3, PD1, PD-L1, CD163, CD86, myeloperoxidase and Arginase-1 in paired samples from 6 GC patients whose response to NAC were rigorously defined. RESULTS: NAC was intricately linked to enhanced CD8+:CD4+ ratio, reduced CD163+ M2-like macrophages, augmented CD86+ M1: CD163+ M2-like macrophage ratio, and diminished FOXP3+ regulatory T cells (T-regs) and TANs density. Based on mIF, PD1+CD8+T-cells, FOXP3+T-regs, PD-L1+ TANs, and CD163+ M2-like macrophages exhibited marked reduction and greater co-localization with tumor cells following NAC. The pre-NAC FOXP3+ T-regs and CD163+ M2-like macrophages content was substantially elevated in the response cohort, whereas, the post-NAC CD8+:CD4+ and CD86+ M1: CD163+ M2-like macrophage ratios were intricately linked to the tumor pathologic response. We observed greater CD163+ M2-like macrophages and tumor cells co-localization following NAC, which was correlated with tumor pathologic response. Lastly, multivariate analysis revealed that post-NAC CD8+:CD4+ and CD86+ M1: CD163+ M2-like macrophage ratios were stand-alone indicators of positive patient prognosis. CONCLUSIONS: NAC converts the GCME to an anti-tumorigenic state that is conducive to enhanced patient outcome. These finding can significantly benefit the future planning of highly efficacious and personalized GC immunotherapy.

Tribuloside acts on the PDE/cAMP/PKA pathway to enhance melanogenesis, melanocyte dendricity and melanosome transport.

ETHNOPHARMACOLOGICAL RELEVANCE: Tribuloside, a natural flavonoid extracted from Chinese medicine Tribulus terrestris L., has shown potent efficacy in treating various diseases. In China, the fruits of Tribulus terrestris L. have long been utilized for relieving headache, dizziness, itchiness, and vitiligo. Water-based extract derived from Tribulus terrestris L. can enhance melanogenesis in mouse hair follicle melanocytes by elevating the expression of α-melanocyte stimulating hormone (α-MSH) and melanocortin-1 recepter (MC-1R). Nevertheless, there is a lack of information regarding the impact of tribuloside on pigmentation in both laboratory settings and living organisms. AIM OF THE STUDY: The present research aimed to examine the impact of tribuloside on pigmentation, and delve into the underlying mechanism. MATERIALS AND METHODS: Following the administration of tribuloside in human epidermal melanocytes (HEMCs), we utilized microplate reader, Masson-Fontana ammoniacal silver stain, transmission electron microscopy (TEM) and scanning electron microscopy (SEM) to measure melanin contents, dendrite lengths, melanosome counts; L-DOPA oxidation assay to indicate tyrosinase activity, Western blotting to evaluate the expression of melanogenic and associated phosphodiesterase (PDE)/cyclic adenosine monophosphate (cAMP)/cyclic-AMP dependent protein kinase A (PKA) pathway proteins. A PDE-Glo assay to verify the inhibitory effect of tribuloside on PDE was also conducted. Additionally, we examined the impact of tribuloside on the pigmentation in both zebrafish model and human skin samples. RESULTS: Tribuloside had a notable impact on the production of melanin in melanocytes, zebrafish, and human skin samples. These functions might be attributed to the inhibitory effect of tribuloside on PDE, which could increase the intracellular level of cAMP to stimulate the phosphorylation of cAMP-response element binding (CREB). Once activated, it induced microphthalmia-associated transcription factor (MITF) expression and increased the expression of tyrosinase, Rab27a and cell division cycle protein 42 (Cdc42), ultimately facilitating melanogenesis, melanocyte dendricity, and melanin transport. CONCLUSION: Tribuloside acts on the PDE/cAMP/PKA pathway to enhance melanogenesis, melanocyte dendricity, and melanosome transport; meanwhile, tribuloside does not have any toxic effects on cells and may be introduced into clinical prescriptions to promote pigmentation.

Meta analysis of ovulation induction effect and pregnancy outcome of acupuncture & moxibustion combined with clomiphene in patients with polycystic ovary syndrome.

Objective: Using Mesh Meta Analysis to evaluate the efficacy of Acupuncture & Moxibustion, Clomiphene, Acupuncture & Moxibustion combined with Clomiphene for treating Polycystic Ovary Syndrome (PCOS), in order to provide evidence-based medical evidence for whether to recommend Acupuncture & Moxibustion or Combine western medicine to treat PCOS. Methods: Eight databases including The Cochrane Library, Pubmed, Embase, Web of Science, CNKI, Wanfang Date, VIP and CBM were searched by computer. The included research period is from the establishment of the database to May 2023, which concerned with randomized controlled trials involving Acupuncture & Moxibustion, Clomiphene, Acupuncture & Moxibustion combined with Clomiphene on ovulation induction and pregnancy outcome in patients with PCOS. The duration of the research paper is from 2016 to 2023.The inclusion criteria refer to the Rotterdam standards issued by the European Center for Human Reproduction and Embryology and the American Society of Reproductive Medicine in January 2003, or the Expert Consensus on the Diagnosis and Treatment of Polycystic Ovarian Syndrome by the Endocrinology Group of the Obstetrics and Gynecology Branch of the Chinese Medical Association. Simultaneously exclude related diseases, repetitive literature, as well as literature with incomplete abstract information and no original data provided. Two researchers independently screened the literature, extracted data, and evaluated the risk of bias included in the study, using Stata17.0 software for a mesh meta-analysis. Results: Six randomized controlled trials were included, covering 1410 PCOS patients. Three interventions included Acupuncture & Moxibustion, Clomiphene, Acupuncture & Moxibustion combined with Clomiphene. Mesh Meta Analysis showed that in terms of improving ovulation rate, there was no statistical difference between Acupuncture & Moxibustion (A), Clomiphene (B), Clomiphene combined with Acupuncture & Moxibustion (C) (P>0.05).Acupuncture & Moxibustion (A) versus Clomiphene (B) [MD=0.15,95% CI (-0.51,0.80)], Acupuncture & Moxibustion (A) versus Clomiphene combined with Acupuncture & Moxibustion (C) [MD=1.60,95% CI (0.97,2.23)], Clomiphene (B) versus Clomiphene combined with Acupuncture & Moxibustion (C) [MD=1.45,95% CI (0.91,1.99)]. In terms of pregnancy outcome, the difference between the three intervention methods was statistically significant (P<0.05). Acupuncture & Moxibustion (A) versus Clomiphene (B) [MD=-0.80,95% CI (-1.84,0.23)], Acupuncture & Moxibustion (A) versus Clomiphene combined with Acupuncture & Moxibustion (C) [MD=0.29,95% CI (-0.73,1.30)], and Clomiphene (B) versus Clomiphene combined with Acupuncture & Moxibustion (C) [MD=1.09,95% CI (0.39,1.79)], The order of pregnancy rate from high to low is Acupuncture & Moxibustion combined with Clomiphene (C), Acupuncture & Moxibustion (A), Clomiphene (C).In terms of influencing endometrial thickness, the difference between the three intervention methods was statistically significant (P<0.05). Acupuncture & Moxibustion (A) versus Clomiphene (B) [MD=-0.84,95% CI (-1.87,0.19)], Acupuncture & Moxibustion (A) versus Acupuncture & Moxibustion combined with Clomiphene (C) [MD=0.26,95% CI (-1.01,1.53)], Clomiphene (B) versus Acupuncture & Moxibustion combined with Clomiphene (C) [MD=1.10,95% CI (0.36,1.84)], Acupuncture & Moxibustion combined with Clomiphene (C) has the best effect on improving endometrial thickness. In subgroup analysis, the effect of Acupuncture & Moxibustion treatment frequency on ovulation rate and pregnancy rate was not statistically significant. The combination of Acupuncture & Moxibustion, Electroacupuncture and warm Acupuncture & Moxibustion has no effect on the pregnancy rate, but the combination of Electroacupuncture and Clomiphene has the best effect on improving the ovulation rate. In the observation of adverse reactions, compared with clomiphene alone, Acupuncture & Moxibustion combined with Clomiphene can reduce the occurrence of Luteinized Unruptured Follicle Syndrome (LUFS) and Ovarian Hyperstimulation Syndrome (OHSS), and reduce the occurrence of physical adverse reactions such as nausea, vomiting, headache and dermatitis. Conclusion: Acupuncture & Moxibustion is effective in improving the ovulation promoting effect and pregnancy outcome of PCOS patients. The ovulation promoting effect of Acupuncture & Moxibustion or combined with Clomiphene is similar to that of Clomiphene alone, but Acupuncture & Moxibustion combined with Clomiphene has more advantages in improving the pregnancy rate of PCOS, and it also can reduce the adverse reactions of Clomiphene alone. Acupuncture & Moxibustion can be used as a recommended treatment for PCOS. More cases should also be included in the subgroup analysis to study the impact of Acupuncture & Moxibustion programs on clinical efficacy and further optimize the Acupuncture & Moxibustion treatment program. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/#myprospero, identifier (CRD42023433057).

Research progress of metabolomics in cervical cancer.

INTRODUCTION: Cervical cancer threatens women's health seriously. In recent years, the incidence of cervical cancer is on the rise, and the age of onset tends to be younger. Prevention, early diagnosis and specific treatment have become the main means to change the prognosis of cervical cancer patients. Metabolomics research can directly reflect the changes of biochemical processes and microenvironment in the body, which can provide a comprehensive understanding of the changes of metabolites in the process of disease occurrence and development, and provide new ways for the prevention and diagnosis of diseases. OBJECTIVES: The aim of this study is to review the metabolic changes in cervical cancer and the application of metabolomics in the diagnosis and treatment. METHODS: PubMed, Web of Science, Embase and Scopus electronic databases were systematically searched for relevant studies published up to 2022. RESULTS: With the emergence of metabolomics, metabolic regulation and cancer research are further becoming a focus of attention. By directly reflecting the changes in the microenvironment of the body, metabolomics research can provide a comprehensive understanding of the patterns of metabolites in the occurrence and development of diseases, thus providing new ideas for disease prevention and diagnosis. CONCLUSION: With the continuous, in-depth research on metabolomics research technology, it will bring more benefits in the screening, diagnosis and treatment of cervical cancer with its advantages of holistic and dynamic nature.

Triterpenoid Compounds from Cyclocarya paliurus: A Review of Their Phytochemistry, Quality Control, Pharmacology, and Structure-Activity Relationship.

Cyclocarya paliurus (Batalin) Iljinskaja (C. paliurus) is a single species of Cyclocarya paliurus in Juglandaceae. It is a unique rare medicinal plant resource in China that is mainly distributed in the south of China. The leaves of C. paliurus, as a new food ingredient, are processed into tea products in daily life. Triterpenoids are the main active ingredient in C. paliurus. So far, 164 triterpenoid compounds have been isolated and identified from C. paliurus, which are included 3,4-seco-dammaranes, dammaranes, oleanane, ursane, lupinanes, taraxeranes, and norceanothanes. Modern pharmacological studies manifested that these ingredients have a wide range of pharmacological activities both in vitro and in vivo, such as reducing blood sugar, lowering blood lipids, and anti-tumor, anti-inflammatory, anti-oxidant, and other activities. In addition, current results indicate that the pharmacological mechanisms of triterpenoids were closely related to their chemical structure, molecular signaling pathways, and the expression of related proteins. In order to further study C. paliurus based on the current research situation, this review summarizes the prospect and systematic summary of the triterpenes of C. paliurus from the aspects of structural characteristics, quality control, biological activity, and the structure-activity relationship, which provide a reference for further research and application of the triterpenoids from C. paliurus in the field of functional food and medicine.

Occurrence and influencing factors of cyclosporine A on the kidney injury following allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis.

OBJECTIVE: Whether cyclosporine A (CsA) is a risk factor of kidney injury after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has not been determined. We aim to comprehensively review the correlation and influencing factors between CsA and kidney injury in patients following allo-HSCT. METHODS: We searched PubMed, Embase (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), CNKI, VIP, Wanfang and CBM Database from inception to March 2022. Two researchers independently conducted literature screening, data extraction and quality assessment. Qualitative and quantitative methods were combined to analyze the data. RESULTS: We included a total of 30 studies. Meta-analyses of total incidence of kidney injury related to CsA was 37.0% [95% CI (25.4%, 48.6%); n = 15]. The proportion of CsA-related acute kidney injury to total acute kidney injury following allo-HSCT was 59.7% [95% CI (49.1%, 70.3%); n = 9]. One study found that AKI had a significant association with CsA in multivariate analysis [RR = 6.173; 95% CI (4.032, 9.434)]. With respect to cyclosporine combination and nephrotoxicity, 6/9 studies demonstrated that the concomitant medications for CsA (especially aminoglycoside antibiotics and amphotericin B) had negative effect on kidney functions related to CsA in allo-HSCT patients. No consensus was reached for "dose of CsA", "duration of CsA use", "comorbidities" and "CsA levels" across studies. CONCLUSIONS: CsA may be a risk factor for kidney injury in patients following allo-HSCT, especially the concomitant use of CsA and nephrotoxic medications.

The PRX-1/TLR4 axis promotes hypoxia-induced radiotherapy resistance in non-small cell lung cancer by targeting the NF-κB/p65 pathway.

Hypoxic lung cancer cells are highly resistant to radiation. Peroxiredoxin-1 (PRX-1), a transcriptional coactivator that enhances the DNA-binding activity of serum reactive factor, has been identified as a target for radiotherapy sensitization, but the underlying molecular mechanism remains unclear. This study aimed to investigate the influence of PRX-1 on radiotherapy sensitivity in hypoxic tumors. Hypoxic lung cancer cells exhibited radiotherapy-resistant phenotypes after irradiation, including increased proliferation, DNA damage repair, cell migration, invasion and stemness. Radio-resistant hypoxic lung cancer cells showed high expression levels of PRX-1. Furthermore, we observed that PRX-1 bound to the promoter region of TRL4 (-300 to -600) and promoted its transcription and expression and that PRX-1/TRL4 activated the NF-κB/p65 signaling pathway. Increased radiotherapy resistance of hypoxic lung cancer cells increased their ability to proliferate, migrate, and maintain stemness in vivo and in vitro. These findings suggest that PRX-1/TRL4 could be used as a target for the treatment of radiotherapy-resistant lung cancer cells and further provide a theoretical basis for the clinical treatment of hypoxic lung cancer cells.

A simplified non-coplanar volumetric modulated arc therapy for the whole brain radiotherapy with hippocampus avoidance.

Purpose: To evaluate the feasibility of using a simplified non-coplanar volumetric modulated arc therapy (NC-VMAT) and investigate its dosimetric advantages compared with intensity modulated radiation therapy (IMRT) and coplanar volumetric modulated arc therapy (C-VMAT) for hippocampal-avoidance whole brain radiation therapy (HA-WBRT). Methods: Ten patients with brain metastase (BM) were included for HA-WBRT. Three treatment plans were generated for each case using IMRT, C-VMAT, and NC-VMAT, respectively. Results: The dosimetric results of the three techniques complied roughly with the RTOG 0933 criteria. After dose normalization, the V30Gy of whole brain planned target volume (WB-PTV) in all the plans was controlled at 95%. Homogeneity index (HI) of WB-PTV was significantly reduced in NC-VMAT (0.249 ± 0.017) over IMRT (0.265 ± 0.020, p=0.005) and C-VMAT (0.261 ± 0.014, p=0.020). In terms of conformity index (CI), NC-VMAT could provide a value of 0.821 ± 0.010, which was significantly superior to IMRT (0.788 ± 0.019, p<0.001). According to D2% of WB-PTV, NC-VMAT could provide a value of 35.62 ± 0.37Gy, significantly superior to IMRT (36.43 ± 0.65Gy, p<0.001). According to D50% of WB-PTV, NC-VMAT can achieve the lowest value of 33.18 ± 0.29Gy, significantly different from IMRT (33.47 ± 0.43, p=0.034) and C-VMAT (33.58 ± 0.37, p=0.006). Regarding D2%, D98%, and Dmean of hippocampus, NC-VMAT could control them at 15.57 ± 0.18Gy, 8.37 ± 0.26Gy and 11.71 ± 0.48Gy, respectively. D2% and Dmean of hippocampus for NC-VMAT was significantly lower than IMRT (D2%: 16.07 ± 0.29Gy, p=0.001 Dmean: 12.18 ± 0.33Gy, p<0.001) and C-VMAT (D2%: 15.92 ± 0.37Gy, p=0.009 Dmean: 12.21 ± 0.54Gy, p<0.001). For other organs-at-risk (OARs), according to D2% of the right optic nerves and the right lenses, NC-VMAT had the lowest values of 31.86 ± 1.11Gy and 7.15 ± 0.31Gy, respectively, which were statistically different from the other two techniques. For other organs including eyes and optic chiasm, NC-VMAT could achieve the lowest doses, different from IMRT statistically. Conclusion: The dosimetry of the three techniques for HA-WBRT could roughly comply with the proposals from RTOG 0933. After dose normalization (D95%=30Gy), NC-VMAT could significantly improve dose homogeneity and reduce the D50% in the brain. Besides, it can reduce the D2% of the hippocampus, optic nerves, and lens. With this approach, an efficient and straightforward plan was accomplished.

The price and affordability of essential medicines, progress and regional distribution in China: a systematic review.

Background: Essential medicine is a vital component to assure universal access to quality healthcare. However, the trend of affordability to essential medicines in China and its regional differences were not yet fully understood. This study aimed to systematically evaluate the price and affordability of essential medicines, their progress, and regional distribution in China in the last decades. Methods: We searched seven databases and three websites for potentially eligible studies from inception until March 2022. Studies on the price and affordability of essential medicines investigated in China were included. Median and interquartile range (IQR) was used to describe the price and affordability of essential medicines, and compared in three periods, before 2009, from 2009 to 2014, and from 2015 to 2019. Subgroup analysis was performed to examine the price and affordability by regions, health facilities, and ATC categories of medicines. The study was registered with PROSPERO (CRD42022310173). Results: A total of 65 studies including 11,639 health facilities investigated between 2006 and 2019 were included in this review. Median price ratios (MPR) and affordability of essential medicines were reported in 44 studies and 50 studies, respectively. The median MPRs of essential medicines in China was 1.59 (IQR: 5.39), with a tendency to rise first and then fall from 2006 to 2019. And the median affordability was equal to 0.88 (IQR: 2.58) days' wage of the lowest paid unskilled government worker, but steadily rose from 2006 to 2019. Subgroup analysis showed that the affordability in the western region (1.40, IQR: 2.88), urban area (0.95, IQR: 2.80), private sector (0.90, IQR: 2.30), of originator brands (OB) (2.90, IQR: 6.68), and antineoplastic and immunomodulating agents (5.68, IQR: 56.47) were worse than their counterparts. Conclusion: The prices of essential medicine were higher than international level, the overall affordability of essential medicines in China is acceptable but poor in the western region, for OB drugs and anti-cancer medicines. Further national essential medicine policies are needed to reduce regional disparities and improve the affordability of expensive drugs. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/#recordDetails.

Polyacetylene Isomers Isolated from Bidens pilosa L. Suppress the Metastasis of Gastric Cancer Cells by Inhibiting Wnt/ß-Catenin and Hippo/YAP Signaling Pathways.

(E)-7-Phenyl-2-hepten-4,6-diyn-1-ol (1) and (Z)-7-Phenyl-2-hepten-4,6-diyn-1-ol (2) are isomeric natural polyacetylenes isolated from the Chinese medicinal plant Bidens pilosa L. This study first revealed the excellent anti-metastasis potential of these two polyacetylenes on human gastric cancer HGC-27 cells and the distinctive molecular mechanisms underlying their activities. Polyacetylenes 1 and 2 significantly inhibited the migration, invasion, and adhesion of HGC-27 cells at their non-toxic concentrations in a dose-dependent manner. The results of a further mechanism investigation showed that polyacetylene 1 inhibited the expressions of Vimentin, Snail, ß-catenin, GSK3ß, MST1, YAP, YAP/TAZ, and their phosphorylation, and upregulated the expression of E-cadherin and p-LATS1. In addition, the expressions of various downstream metastasis-related proteins, such as MMP2/7/9/14, c-Myc, ICAM-1, VCAM-1, MAPK, p-MAPK, Sox2, Cox2, and Cyr61, were also suppressed in a dose-dependent manner. These findings suggested that polyacetylene 1 exhibited its anti-metastasis activities on HGC-27 cells through the reversal of the EMT process and the suppression of the Wnt/ß-catenin and Hippo/YAP signaling pathways.

Caryophyllene-type sesquiterpenes from the endophytic fungus Pestalotiopsis lespedezae through an OSMAC approach.

Two new caryophyllene-type sesquiterpenes pestalotiopsins U and V (1 and 2) and three known compounds pestalotiopsin B (7), pestaloporinate B (8), and pestalotiopsin C (9) were isolated by the cultivation of the endophytic fungus Pestalotiopsis lespedezae on solid rice medium, while four additional new caryophyllene pestalotiopsins W-Z (3-6) were obtained when 3.5% NaI was added to the fungal culture medium. The structures of the new compounds were determined by HRESIMS and 1D/2D nuclear magnetic resonance data. Compounds 1-9 were tested for cytotoxicity against the mouse lymphoma cell line L5178Y, but only 6 displayed significant activity with an IC50 value of 2.4 µM.

Accessibility of essential anticancer medicines for children in the Sichuan Province of China.

Background: Compared with high-income countries, the survival rate of childhood cancer is lower in low- and middle-income countries. Access to essential anticancer medicines is an indispensable component of pediatric cancer treatment, which is still a big challenge in low- and middle-income countries. Objective: To assess the accessibility of essential anticancer medicines for children in public hospitals in the Sichuan Province of China. Methods: Based on the data of the Sichuan Province Drug Use Monitoring Platform in 2020, a retrospective study was conducted to investigate the original brands and generics of 34 anticancer and three supportive essential medicines for children (a total of 97 specific strengths) in Sichuan Province. The availability, price, and affordability of surveyed medicines were evaluated in all 152 tertiary public hospitals (120 general hospitals, 31 children's hospitals, and one cancer hospital) that could diagnose and treat cancer for children. Results: The average availability of generics and original brands was 18.5% and 2.6%, respectively. In regions with different gross domestic product (GDP) per capita levels, the average availability was similar, but the city with lower GDP per capita levels had fewer tertiary public hospitals. The prices of most original brands were higher than the lowest-priced generics, and the median price ratios of 31 lowest-priced generics and 16 original brands were 0.744 (P25~P75, 0.446~2.791) and 2.908 (1.719~6.465). After paying medical insurance for medicines, the affordability of essential anticancer medicines was improved. The monthly medicine cost did not exceed 10% of the monthly household income for 78.9% (30/38) of the lowest-priced generics and 50.0% (8/16) of the original brands. Conclusion: The availability of lowest-priced generics was higher than original brands in public hospitals, but the availability of both was low, which was similar to previous studies in low- and middle-income countries. About half of the lowest-priced generics and 87.5% of the original brands cost more than 1.5 times the International Reference Price. Although the National Basic Medical Insurance greatly improved the affordability of essential anticancer medicines for children, higher subsidies for essential medicines for cancer treatment to limit catastrophic health expenditures are still recommended.

Retraction Notice to: MicroRNA-140 Inhibits the Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer.

[This retracts the article DOI: 10.1016/j.omtn.2017.12.022.].

Nigrosporins B, a Potential Anti-Cervical Cancer Agent, Induces Apoptosis and Protective Autophagy in Human Cervical Cancer Ca Ski Cells Mediated by PI3K/AKT/mTOR Signaling Pathway.

Nigrosporins B, an anthraquinone derivative obtained from the secondary metabolites of marine fungus Nigrospora oryzae. In this study, we characterized the distinctive anti-cancer potential of Nigrosporins B in vitro and underlying molecular mechanisms in human cervical cancer Ca Ski cells for the first time. The results of MTT assay showed that Nigrosporins B significantly inhibited the proliferation of multiple tumor cells in a dose-dependent manner, especially for the Ca Ski cells with an IC50 of 1.24 µM. Nigrosporins B exerted an apoptosis induction effect on Ca Ski cells as confirmed by flow cytometry, AO/EB dual fluorescence staining, mitochondrial membrane potential analysis and western blot assay. In addition, Nigrosporins B induced obvious autophagy accompanied with the increase of autophagic vacuoles and the acceleration of autophagic flux as indicated by Cyto-ID staining, mRFP-GFP-LC3 adenovirus transfection and western blot analysis. Interestingly, the combination of Nigrosporins B with the three autophagy inhibitors all significantly enhanced the cytotoxicity of Nigrosporins B on Ca Ski cells, indicating that the autophagy induced by Nigrosporins B might protect Ca Ski cells from death. Furthermore, we found that Nigrosporins B inhibited the phosphorylation of PI3K, AKT, mTOR molecules and increased the protein expression levels of PTEN and p-AMPKα in a dose-dependent manner, suggesting that Nigrosporins B induced apoptosis and protective autophagy through the suppression of the PI3K/AKT/mTOR signaling pathway. Together, these findings revealed the anti-cervical cancer effect of Nigrosporins B and the underlying mechanism of action in Ca Ski cells, it might be as a promising alternative therapeutic agent for human cervical cancer.

Polymorphism analysis and expression profile of the estrogen receptor 2 gene in Leizhou black duck.

Our previous study on the ovarian transcriptomic analysis in Leizhou black duck revealed that the ESR2 gene was involved in hormone regulation in reproduction and the estrogen signaling pathway related to reproductive performance was enriched. This suggested that ESR2 may have a functional role in the reproductive performance of the Leizhou black duck. Thus, this study aimed at evaluating the polymorphism of the ESR2 gene and its association with egg-laying traits and the distribution pattern of ESR2 mRNA in laying and non-laying Leizhou black ducks. In this study, genomic DNA was extracted from blood samples of 101 Leizhou black ducks to identify single nucleotide polymorphisms (SNPs) of the ESR2 gene to elucidate molecular markers highly associated with egg-laying traits. Four each of laying and non-laying Leizhou black ducks were selected to collect different tissues to analyze the ESR2 gene expression. A total of 23 SNPs were identified and association analysis of the single SNP sites showed that SNPs g.56805646 T>C and exon 3-20G>A were significantly (P < 0.05) associated with egg weight. Ducks with CT and AG genotypes had significantly higher (P < 0.05) egg weights than their respective other genotypes. Haplotype association analysis of g.56805646 T>C and exon 3-20G>A showed that the haplotypes were significantly associated with egg weight. Higher egg weight was seen in individuals with H3H4 haplotypes. In the hypothalamus-pituitary-gonadal (HPG) axis, the results of qRT/PCR showed that ESR2 mRNA was significantly (P < 0.05) expressed in the ovaries of both duck groups than in the hypothalamus and pituitary. In the oviduct, ESR2 was significantly (P < 0.05) higher in the infundibulum and magnum of laying and non-laying ducks respectively. This study provides a molecular marker for selecting Leizhou black ducks for egg production. In addition, it offers theoretical knowledge for studying the related biological functions of the ESR2 gene at the cellular level.

Catastrophic health expenditure, incidence, trend and socioeconomic risk factors in China: A systematic review and meta-analysis.

Objective: To evaluate the incidence and trend of catastrophic health expenditures (CHE) in China over the past 20 years and explore the socioeconomic factors affecting China's CHE rate. Methods: The systematic review was conducted according to the Cochrane Handbook and reported according to PRISMA. We searched English and Chinese literature databases, including PubMed, EMbase, Web of Science, China National Knowledge Infrastructure (CNKI), Wan Fang, China Science and Technology Journal Database (CQVIP), and CBM (Sino Med), for empirical studies on the CHE rate in China and its associated socioeconomic factors from January 2000 to June 2020. Two reviewers conducted the study selection, data extraction, and quality appraisal. The secular trend of the CHE rate was examined, and factors associated with CHE were explored using subgroup analysis and meta-regression. Results: A total of 118 eligible studies with 1,771,726 participants were included. From 2000 to 2020, the overall CHE rate was 25.2% (95% CI: 23.4%-26.9%) in China. The CHE rate continued to rise from 13.0% in 2000 to 32.2% in 2020 in the general population. The CHE rate was higher in urban areas than in rural areas, higher in the western than the northeast, eastern, and central region, in the elderly than non-elderly, in low-income groups than non-low-income groups, in people with cancer, chronic infectious disease, and cardio-cerebrovascular diseases (CCVD) than those with non-chronic disease group, and in people with NCMS than those with URBMI and UEBMI. Multiple meta-regression analyses found that low-income, cancer, CCVD, unspecified medical insurance type, definition 1 and definition 2 were correlated with the CHE rate, while other factors were all non-significantly correlated. Conclusion: In the past two decades, the CHE rate in China has been rising. The continuous rise of health expenditures may be an important reason for the increasing CHE rate. Age, income level, and health status affect the CHE rate. Therefore, it is necessary to find ways to meet the medical needs of residents and, at the same time, control the unreasonable rapid increase in health expenditures in China.

Immune checkpoint blockade for locally advanced or recurrent/metastatic cervical cancer: An update on clinical data.

Immunotherapy has shown great promise in the field of oncology, and recent clinical trials have illustrated that immune checkpoint blockade (ICB) is safe and effective at treating a range of tumor types. Cervical cancer (CC) is the fourth most common malignancy in women. However, first-line treatments for locally advanced cervical cancer (LACC) and recurrent/metastatic (R/M) CC have limited efficacy. Thus, it is necessary to explore new treatment approaches. The National Comprehensive Cancer Network (NCCN) currently recommends pembrolizumab, a programmed cell death protein 1 (PD-1) monoclonal antibody, as a first line therapy for individuals with R/M CC. This study reviews the progress of ICB therapy for LACC and R/M CC and describes the current status of the combination of ICB therapy and other therapeutic modalities, including radiotherapy, chemotherapy, targeted therapy, and other immunotherapies. The focus is placed on studies published since 2018 with the aim of highlighting novel CC-specific immunotherapeutic approaches and treatment targets.

Case report: Primary intracranial mucosa-associated lymphoid tissue lymphoma presenting as two primary tumors involving the cavernous sinus and extra-axial dura, respectively.

Primary intracranial mucosa-associated lymphoid tissue (MALT) lymphoma is a rare type of brain tumor, with only a few reported cases worldwide that mostly have only one lesion with conventional magnetic resonance imaging (MRI) findings. Here, we present a special case of intracranial MALT lymphoma with two mass lesions radiographically consistent with meningiomas on MRI before the operation. A 66-year-old woman was admitted to the hospital with intermittent right facial pain for 1 year, aggravated for the last month. Brain MRI showed two extracerebral solid masses with similar MR signal intensity. One mass was crescent-shaped beneath the skull, and the other was in the cavernous sinus area. Lesions showed isointensity on T1WI and T2WI and an intense homogeneous enhancement after contrast agent injection. Both lesions showed hyperintensity in amide proton transfer-weighted images. The two masses were all surgically resected. The postoperative pathology indicated extranodal marginal zone B-cell lymphoma of MALT. To improve awareness of intracranial MALT lymphoma in the differential diagnosis of extra-axial lesions among clinicians, we present this report and briefly summarize previously reported cases to describe the clinical, pathological, radiological, and treatment features.

ATG 4B Serves a Crucial Role in RCE-4-Induced Inhibition of the Bcl-2-Beclin 1 Complex in Cervical Cancer Ca Ski Cells.

RCE-4, a steroidal saponin isolated from Reineckia carnea, has been studied previously and has exhibited promising anti-cervical cancer properties by inducing programmed cell death (PCD) of Ca Ski cells. Considering the cancer cells developed various pathways to evade chemotherapy-induced PCD, there is, therefore, an urgent need to further explore the potential mechanisms underlying its actions. The present study focused on targeting the Bcl-2-Beclin 1 complex, which is known as the key regulator of PCD, to deeply elucidate the molecular mechanism of RCE-4 against cervical cancer. The effects of RCE-4 on the Bcl-2-Beclin 1 complex were investigated by using the co-immunoprecipitation assay. In addition, autophagy-related genes (ATG) were also analyzed due to their special roles in PCD. The results demonstrated that RCE-4 inhibited the formation of the Bcl-2-Beclin 1 complex in Ca Ski cells via various pathways, and ATG 4B proteins involved in this process served as a key co-factor. Furthermore, based on the above, the sensitivity of RCE-4 to Ca Ski cells was significantly enhanced by inhibiting the expression of the ATG 4B by applying the ATG 4B siRNA plasmid.