A novel RIPK1 inhibitor reduces GVHD in mice via a nonimmunosuppressive mechanism that restores intestinal homeostasis.

Intestinal epithelial cells (IECs) are implicated in the propagation of T-cell-mediated inflammatory diseases, including graft-versus-host disease (GVHD), but the underlying mechanism remains poorly defined. Here, we report that IECs require receptor-interacting protein kinase-3 (RIPK3) to drive both gastrointestinal (GI) tract and systemic GVHD after allogeneic hematopoietic stem cell transplantation. Selectively inhibiting RIPK3 in IECs markedly reduces GVHD in murine intestine and liver. IEC RIPK3 cooperates with RIPK1 to trigger mixed lineage kinase domain-like protein-independent production of T-cell-recruiting chemokines and major histocompatibility complex (MHC) class II molecules, which amplify and sustain alloreactive T-cell responses. Alloreactive T-cell-produced interferon gamma enhances this RIPK1/RIPK3 action in IECs through a JAK/STAT1-dependent mechanism, creating a feed-forward inflammatory cascade. RIPK1/RIPK3 forms a complex with JAK1 to promote STAT1 activation in IECs. The RIPK1/RIPK3-mediated inflammatory cascade of alloreactive T-cell responses results in intestinal tissue damage, converting the local inflammation into a systemic syndrome. Human patients with severe GVHD showed highly activated RIPK1 in the colon epithelium. Finally, we discover a selective and potent RIPK1 inhibitor (Zharp1-211) that significantly reduces JAK/STAT1-mediated expression of chemokines and MHC class II molecules in IECs, restores intestinal homeostasis, and arrests GVHD without compromising the graft-versus-leukemia (GVL) effect. Thus, targeting RIPK1/RIPK3 in IECs represents an effective nonimmunosuppressive strategy for GVHD treatment and potentially for other diseases involving GI tract inflammation.

Research on the status and influencing factors of maternal health literacy among postpartum women in urban villages.

AIM: To comprehensively identify the status and influencing factors on maternal health literacy among postpartum women in Guangzhou urban villages. DESIGN: An explanatory sequential mixed-method research was conducted from November 2021 to July 2022. METHODS: The quantitative survey was conducted among postpartum women in Guangzhou urban villages using the convenience sampling principle, and a questionnaire survey was used to reflect the status and influencing factors on maternal health literacy. The qualitative interview conducted purposive sampling based on the survey and semi-structured interviews with women to supplement the non-quantifiable influencing factors. RESULTS: The quantitative survey showed that the maternal health literacy score of 501 women was 193.84 ± 22.23. The quantitative results suggested that ethnicity, education, income, household registration, delivery mode and social support were important influencing factors (p < .15). The qualitative interviews were conducted with 16 women and revealed three themes and eight sub-themes, including demographic factors (ethnicity, education, income, occupation and family history), pregnancy factors (delivery mode and pregnancy complications) and social factors (social support), which influenced maternal health literacy through three routes: women's motivation, access and ability in screening health information. CONCLUSION: Maternal health literacy among postpartum women in urban villages needs to be improved, especially critical health literacy. Maternal and infant workers need to guide women to develop appropriate health information concepts and consider the realistic knowledge needs of women in different socio-cultural and economic backgrounds. They should also construct a comprehensive social support system for women to better improve maternal health literacy. IMPACT: Highlights the positive benefits of maternal health literacy among postpartum women, as preparation for providing accurate and effective maternal and child health education services. PATIENT OR PUBLIC CONTRIBUTION: The information on maternal health literacy in this study was based on an interview with postpartum women in Guangzhou urban villages during the study period.

Preparation and Antioxidant Activity of New Carboxymethyl Chitosan Derivatives Bearing Quinoline Groups.

A total of 16 novel carboxymethyl chitosan derivatives bearing quinoline groups in four classes were prepared by different synthetic methods. Their chemical structures were confirmed by Fourier-transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), and elemental analysis. The antioxidant experiment results in vitro (including DPPH radical scavenging ability, superoxide anion radical scavenging ability, hydroxyl radical scavenging ability, and ferric reducing antioxidant power) demonstrated that adding quinoline groups to chitosan (CS) and carboxymethyl chitosan (CMCS) enhanced the radical scavenging ability of CS and CMCS. Among them, both N, O-CMCS derivatives and N-TM-O-CMCS derivatives showed DPPH radical scavenging over 70%. In addition, their scavenging of superoxide anion radicals reached more than 90% at the maximum tested concentration of 1.6 mg/mL. Moreover, the cytotoxicity assay was carried out on L929 cells by the MTT method, and the results indicated that all derivatives showed no cytotoxicity (cell viability > 75%) except O-CMCS derivative 1a, which showed low cytotoxicity at 1000 µg/mL (cell viability 50.77 ± 4.67%). In conclusion, the carboxymethyl chitosan derivatives bearing quinoline groups showed remarkable antioxidant ability and weak cytotoxicity, highlighting their potential use in food and medical applications.

Discovery, optimization and evaluation of isothiazolo[5,4-b]pyridine derivatives as RIPK1 inhibitors with potent in vivo anti-SIRS activity.

Receptor-interacting protein kinase-1 (RIPK1) is involved in the necroptosis pathway, which regulates inflammatory signaling and cell death in a variety of diseases, including inflammatory and neurodegenerative disorders. We identified a novel hit compound 36 by a cell-based screening assay (anti-necroptosis EC50 = 58 nM). Starting from compound 36, we designed a series of scaffolds to improve anti-necroptosis activity, physicochemical properties and metabolic stability. The isothiazolo[5,4-b]pyridine backbone proved to be a promising scaffold which provided a number of potent necroptosis inhibitors. Compound 56, for example, effectively blocked necroptosis in both human and mouse cells (EC50 = 1-5 nM). A binding assay showed that compound 56 potently binds to RIPK1 (Kd = 13 nM), but not RIPK3 (Kd > 10,000 nM). Kinase functional assay (ADP-Glo) confirmed that compound 56 inhibits RIPK1 phosphorylation with an IC50 at 5.8 nM. Importantly, compound 56 displayed excellent cross-species liver microsomal metabolic stability (t1/2 > 90 min). Furthermore, compound 56 exhibited favorable in vitro safety profiles in hERG and CYP assays. Finally, pre-treatment with 56 significantly reduced hypothermia and lethal shock in the systemic inflammatory response syndrome mice model. Taken together, compound 56 represented a promising prototype for the development of therapeutic agent to treat inflammation-related diseases.

The Accuracy Assessment of the PREM and AK135-F Radial Density Models.

The Earth's synthetic density and gravitational models can be used to validate numerical methods for global (or large-scale) gravimetric forward and inverse modelling formulated either in the spatial or spectral domains. The Preliminary Reference Earth Model (PREM) density parameters can be adopted as a 1-D reference density model and further refined using more detailed 2-D or 3-D crust and mantle density models. Alternatively, the AK135-F density parameters can be used for this purpose. In this study, we investigate options for a refinement of the Earth's synthetic density model by assessing the accuracy of available 1-D density models, specifically the PREM and AK135-F radial density parameters. First, we use density parameters from both models to estimate the Earth's total mass and compare these estimates with published results. We then estimate the Earth's gravity field parameters, particularly the geoidal geopotential number W0 and the mean gravitational attraction and compare them with published values. According to our results, the Earth's total mass from the two models (the PREM and the AK135-F) differ less than 0.02% and 0.01%, respectively, when compared with the value adopted by the International Astronomical Union (IAU). The geoidal geopotential values of the two models differ from the value adopted by the IAU by less than 0.1% and 0.04%, respectively. The values of the mean gravitational attraction of the two models differ less than 0.02% and 0.08%, respectively, when compared with the value obtained from the geocentric gravitational constant and the Earth's mean radius. These numerical findings ascertain that the PREM and AK135-F density parameters are suitable for defining a 1-D reference density model.

Fucoidan Protects against Doxorubicin-Induced Cardiotoxicity by Reducing Oxidative Stress and Preventing Mitochondrial Function Injury.

Doxorubicin (DOXO) is a potent chemotherapeutic drug widely used to treat various cancers. However, its clinical application is limited due to serious adverse effects on dose-dependent cardiotoxicity. Although the underlying mechanism has not been fully clarified, DOXO-induced cardiotoxicity has been mainly attributed to the accumulation of reactive oxygen species (ROS) in cardiomyocytes. Fucoidan, as a kind of sulphated polysaccharide existing in numerous brown seaweed, has potent anti-oxidant, immune-regulatory, anti-tumor, anti-coagulate and anti-viral activities. Here, we explore the potential protective role and mechanism of fucoidan in DOXO-induced cardiotoxicity in mice. Our results show that oral fucoidan supplement exerts potent protective effects against DOXO-induced cardiotoxicity by reducing oxidative stress and preventing mitochondrial function injury. The improved effect of fucoidan on DOXO-induced cardiotoxicity was evaluated by echocardiography, cardiac myocytes size and cardiac fibrosis analysis, and the expression of genes related to cardiac dysfunction and remodeling. Fucoidan reduced the ROS content and the MDA levels but enhanced the activity of antioxidant enzymes GSH-PX and SOD in the mouse serum in a DOXO-induced cardiotoxicity model. In addition, fucoidan also increased the ATP production capacity and restored the levels of a mitochondrial respiratory chain complex in heart tissue. Collectively, this study highlights fucoidan as a potential polysaccharide for protecting against DOXO-induced cardiovascular diseases.

Expression of COX-2 and Nrf2/GPx3 in the anterior vaginal wall tissues of women with pelvic organ prolapse.

PURPOSE: To evaluate COX-2 and Nrf2/GPx3 expressions in the lamina propria of the anterior vaginal wall tissues of women with and without pelvic organ prolapse (POP). METHODS: Tissue samples of anterior vaginal wall were examined using HE staining, immuohistochemical staining and Western blot for the expressions of COX-2/PGE2, Nrf2/GPx3, MMP2, TIMP1, collagen I and collagen III (n = 35, per group). RESULTS: Compared with control group, collagen fibers of the anterior vaginal wall were disorganized and discontinuous. Expressions of Nrf2, GPx3, TIMP1, collagen I and collagen III were found significantly lower in POP group (P < 0.05); while, expressions of COX-2, PGE2, and MMP2 were found significantly higher in POP group (P < 0.05). Statistically significant correlations of COX-2 and Nrf2/GPx3 were showed (P < 0.01). CONCLUSION: We found that the interaction between inflammation and oxidative stress was closely related to the development of POP. This study demonstrates that COX-2 and Nrf2 pathways may be involved in pathogenesis of POP, as promising potential therapeutic targets and agents.

Doxorubicin sensitizes cancer cells to Smac mimetic via synergistic activation of the CYLD/RIPK1/FADD/caspase-8-dependent apoptosis.

Smac/Diablo is a pro-apoptotic protein via interaction with inhibitors of apoptosis proteins (IAPs) to relieve their inhibition of caspases. Smac mimetic compounds (also known as antagonists of IAPs) mimic the function of Smac/Diablo and sensitize cancer cells to TNF-induced apoptosis. However, the majority of cancer cells are resistant to Smac mimetic alone. Doxorubicin is a widely used chemotherapeutic drug and causes adverse effect of cardiotoxicity in many patients. Therefore, it is important to find strategies of combined chemotherapy to increase chemosensitivity and reduce the adverse effects. Here, we report that doxorubicin synergizes with Smac mimetic to trigger TNF-mediated apoptosis, which is mechanistically distinct from doxorubicin-induced cell death. Doxorubicin sensitizes cancer cells including human pancreatic and colorectal cancer cells to Smac mimetic treatment. The combined treatment leads to synergistic induction of TNFα to initiate apoptosis through activating NF-κB and c-Jun signaling pathways. Knockdown of caspase-8 or knockout of FADD significantly blocked apoptosis synergistically induced by Smac mimetic and doxorubicin, but had no effect on cell death caused by doxorubicin alone. Moreover, Smac mimetic and doxorubicin-induced apoptosis requires receptor-interacting protein kinase 1 (RIPK1) and its deubiquitinating enzyme cylindromatosis (CYLD), not A20. These in vitro findings demonstrate that combination of Smac mimetic and doxorubicin synergistically triggers apoptosis through the TNF/CYLD/RIPK1/FADD/caspase-8 signaling pathway. Importantly, the combined treatment induced in vivo synergistic anti-tumor effects in the xenograft tumor model. Thus, the combined therapy using Smac mimetic and doxorubicin presents a promising apoptosis-inducing strategy with great potential for the development of anti-cancer therapy.

Novel biomarkers containing citrullinated peptides for diagnosis of systemic lupus erythematosus using protein microarrays.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterised by autoantibody production. This study aims to identify biomarkers involving citrullinated peptides that can be used for SLE diagnosis. METHODS: After a negative selection step with serum from healthy controls (HCs), a phage library of 12 peptides was used for three rounds of screening with sera from 30 SLE patients. After four rounds of biopanning, 21 positive peptides were sequenced. We produced 37-feature arrays containing 16 recombinant citrullinated peptides. The microarrays were tested with an independent validation set of serum samples from 50 HCs, 60 SLE patients, and 60 rheumatoid arthritis (RA) patients. RESULTS: Microarray analysis showed that the positive rates of 13S1212Cit3-IgM (60.0%), 13S1210-IgG (43.33%), and 13S1212Cit3-IgG (41.67%) were increased in SLE patients compared with HCs and RA patients. The area under the receiver operating characteristic curve (AUC) was 0.770, 0.687 and 0.698, respectively. The combination of 13S1212Cit3-IgM and 13S1210-IgG (termed COPSLE, for combination of peptides for SLE) was more efficient for SLE diagnosis, with a larger AUC (0.830) and a positive rate of 73.33%. COPSLE could be used to identify 80.0% of SLE patients who were negative for anti-Smith (Sm), anti-double-stranded DNA (ds-DNA), and anticardiolipin (ACA). The Spearman rank correlation indicated that COPSLE increased with albumin, serum level of C3 and platelet distribution width, but had negative correlations with decreased C3 and discoid lupus. CONCLUSIONS: A citrullinated/non-citrullinated peptide panel is a valuable diagnostic marker of SLE, even for patients who are negative for anti-Sm, anti-ds-DNA and ACA.

Characterization of a Carbonyl Reductase from Rhodococcus erythropolis WZ010 and Its Variant Y54F for Asymmetric Synthesis of (S)-N-Boc-3-Hydroxypiperidine.

The recombinant carbonyl reductase from Rhodococcus erythropolis WZ010 (ReCR) demonstrated strict (S)-stereoselectivity and catalyzed the irreversible reduction of N-Boc-3-piperidone (NBPO) to (S)-N-Boc-3-hydroxypiperidine [(S)-NBHP], a key chiral intermediate in the synthesis of ibrutinib. The NAD(H)-specific enzyme was active within broad ranges of pH and temperature and had remarkable activity in the presence of higher concentration of organic solvents. The amino acid residue at position 54 was critical for the activity and the substitution of Tyr54 to Phe significantly enhanced the catalytic efficiency of ReCR. The kcat/Km values of ReCR Y54F for NBPO, (R/S)-2-octanol, and 2-propanol were 49.17 s-1 mM-1, 56.56 s-1 mM-1, and 20.69 s-1 mM-1, respectively. In addition, the (S)-NBHP yield was as high as 95.92% when whole cells of E. coli overexpressing ReCR variant Y54F catalyzed the asymmetric reduction of 1.5 M NBPO for 12 h in the aqueous/(R/S)-2-octanol biphasic system, demonstrating the great potential of ReCR variant Y54F for practical applications.

Identification of heat shock protein 27 as a novel autoantigen of Behçet's disease.

OBJECTIVE: The aim of this study was to identify candidate pathogenic autoantigens of Behçet's disease (BD) in pathogen-stimulated target cells. METHODS: First, three cell lines were used as target cells to screen autoantibody. Second, selected target cells were simulated with pathogens. Third, western blotting was used for detecting the auto-antigens in cell extracts. Next, immunoprecipitation was performed and the amino-acid sequences of target antigens were analyzed by LC-MALDI-TOF/TOF. Then, the potential target antigen was expressed, purified, and immunologically confirmed. And finally, an ELISA kit was developed and clinically validated through the assessments of 456 clinical samples with BD. RESULTS: One antigen with a molecular weight of approximately 27-kDa was identified as heat shock protein 27 (HSP27). The reactivity of serum IgG against recombinant human HSP27 was detected in 52 of 91 BD patients (57%), 66 of 92 rheumatoid arthritis (RA) patients (72%), 32 of 90 Sjogren syndrome (SS) patients (36%), 22 of 92 systemic lupus erythematosus (SLE) patients (24%) and 0 of 91 healthy controls (HC). The reactivity of BD serum IgG antibodies against HSP27 was significantly higher than SLE (P<0.0001) SS (P<0.0001) and HC (P<0.0001). CONCLUSIONS: This study identified HSP27 as a candidate endothelial cell autoantigen of BD, which is interesting and probably worth further exploration.

Effect of mode of delivery on postpartum weight retention: A systematic review and meta-analysis.

OBJECTIVE: Retention of weight gained over pregnancy increases the risk of long-term obesity and related health concerns. While many risk factors for this postpartum weight retention have been examined, the role of mode of delivery in this relationship remains controversial. We carried out a systematic review and meta-analysis to determine the effect of mode of delivery on postpartum weight retention. METHODS: Ten electronic databases including PubMed, Cochrane Library, EMBASE, Web of Science, MEDLINE, CINAHL, China National Knowledge Infrastructure (CNKI), Wan-Fang database, the VIP database and China Biology Medicine Database (CBM) were searched from inception through November 2022. Review Manager 5.4 was used to pool the study data and calculate effect sizes. For dichotomous data, the odds ratio and 95 % confidence interval were used to report the results. For continuous data, the mean difference (MD) and 95 % confidence interval were used to report the results. The outcomes were the amount of postpartum weight retention and the number or proportion of women who experienced postpartum weight retention. The Newcastle- Ottawa Scale (NOS) and GRADE Guidelines were used to assess the methodological quality of the included studies. FINDINGS: A total of 16 articles were included in the systematic review and 13 articles were included in the meta-analysis. The results showed that the mode of delivery had a significant effect on postpartum weight retention, women who delivered by caesarean section were more likely to experience postpartum weight retention compared to those who delivered vaginally. Sensitivity analysis showed that the results were stable and credible. CONCLUSION: Due to the limitations of this study, the findings need to be treated with caution. And, to better prevent the postpartum weight retention, future practice and research need to further focus on upstream modifiable factors.

Synthesis, antimicrobial activity, antioxidant activity and molecular docking of novel chitosan derivatives containing glycine Schiff bases as potential succinate dehydrogenase inhibitors.

Succinate dehydrogenase (SDH) is an important inner mitochondrial membrane-bound enzyme involved in redox reactions during the tricarboxylic acid cycle. Therefore, a series of novel chitosan derivatives were designed and synthesized as potential microbicides targeting SDH and precisely characterized by FTIR, 1H NMR and SEM. Their antifungal and antibacterial activities were evaluated against Botrytis cinerea, Fusarium graminearum, Staphylococcus aureus and Escherichia coli. The bioassays revealed that these chitosan derivatives exerted significant antifungal effects, with four of the compounds achieving 100 % inhibition of Fusarium graminearum merely at a concentration of 0.5 mg/mL. Additionally, CSGDCH showed 79.34 % inhibition of Botrytis cinerea at a concentration of 0.1 mg/mL. In vitro antibacterial tests revealed that CSGDCH and CSGDBH have excellent Staphylococcus aureus and Escherichia coli inhibition with MICs of 0.0156 mg/mL and 0.03125 mg/mL, respectively. Molecular docking studies have been carried out to explore the binding energy and binding mode of chitosan and chitosan derivatives with SDH. The analyses indicated that chitosan derivatives targeted the active site of the SDH protein more precisely, disrupting its normal function and ultimately repressing the growth of microbial cells. Furthermore, the chitosan derivatives were also evaluated biologically for antioxidation, and all of these compounds had a greater degree of reducing power, superoxide radical, hydroxyl radical and DPPH-radical scavenging activity than chitosan. This research has the potential for the development of agricultural antimicrobial agents.

A novel chitosan antioxidant bearing sulfhydryl group: Synthesis, characterization and activity assessment.

To improve the antioxidant activity, sulfhydryl groups (-SH) were introduced into chitosan. Acylated chitosan derivatives, chitosan cationic salt derivatives, hydroxypropyl trimethylammonium chloride chitosan quaternary ammonium salt (HACC) derivatives and N,N,N-trimethyl chitosan iodine (TMC) derivatives were obtained. The chitosan derivatives were characterized by FTIR and 1H NMR to confirm the successful synthesis. Ellman's reagent was used to determine that the compound contained free sulfhydryl groups. The water solubility and thermal stability of chitosan and derivatives were evaluated. The antioxidant activities of the derivatives were verified, including DPPH radical scavenging activity, superoxide anion radical scavenging activity and reducing power activity. The novel chitosan derivatives showed excellent antioxidant activities. Toxicity assay used L929 cells proved that the derivatives had no significant toxic. The results showed that the chitosan derivatives bearing sulfhydryl groups described in this paper has a certain antioxidant effect, which provides a practical approach for further study of chitosan.

Highly efficient semiconductor modules making controllable parallel microchannels for non-compressible hemorrhages.

Nature makes the most beautiful solution to involuted problems. Among them, the parallel tubular structures are capable of transporting fluid quickly in plant trunks and leaf stems, which demonstrate an ingenious evolutionary design. This study develops a mini-thermoelectric semiconductor P-N module to create gradient and parallel channeled hydrogels. The modules decrease quickly the temperature of polymer solution from 20 °C to -20 °C within 5 min. In addition to the exceptional liquid absorption rate, the foams exhibited shape memory mechanics. Our mini device universally makes the inspired structure in such as chitosan, gelatin, alginate and polyvinyl alcohol. Non-compressible hemorrhages are the primary cause of death in emergency. The rapid liquid absorption leads to fast activation of coagulation, which provides an efficient strategy for hemostasis management. We demonstrated this by using our semiconductor modules on collagen-kaolin parallel channel foams with their high porosity (96.43%) and rapid expansion rate (2934%). They absorb liquid with 37.25 times of the own weight, show 46.5-fold liquid absorption speed and 24-fold of blood compared with random porous foams. These superior properties lead to strong hemostatic performance in vitro and in vivo.

Risk-stratified CA125 screening integrating CA125 trajectories, trajectory-specific progression and transvaginal ultrasound for ovarian cancer.

BACKGROUNDS: Cancer antigen 125 (CA125) is widely used for screening ovarian cancer (OC), yet its effectiveness remains debated. Potential factors may include ineffective cut-off value for CA125 in screening, as well as a lack of consideration for CA125 trajectories and trajectory-specific progression. METHODS: Based on data from multiple rounds of CA125 tests and transvaginal ultrasound (TVU) examinations conducted on 28,456 women in the PLCO Trial, time-dependent receiver-operating-characteristic curves (ROCs) and area-under-the-curves (tdAUCs) analyses were employed to identify the optimal CA125 cut-off values for OC screening. Participants were categorized into four CA125 trajectories: stable negative CA125 (CA125SN), loss of positive CA125 (CA125LP), stable positive CA125 (CA125SP), and gain of positive CA125 (CA125GP). The associations between different CA125 trajectories, trajectory-specific progression indicators, and OC risk were explored. The effectiveness of risk-stratified CA125 screening, incorporating CA125 trajectories, trajectory-specific progression, and TVU, was evaluated using hazard ratio and 95% confidence intervals [HR (95%CIs)], with adjustments for potential confounders. RESULTS: After a median follow-up of 14.8 years for OC incidence and 23.8 years for OC mortality, 250 OC cases and 218 OC deaths were identified. The tdAUC for 10-year OC incidence with CA125 was 0.663, with an optimal cut-off value of 13.00 U/ml. Trajectory analyses showed that both CA125SP and CA125GP were significantly associated with increased risks of OC incidence [HRs (95%CIs): 2.00(1.47-2.73) and 3.06(2.25-4.16)] and mortality [HRs (95%CIs):1.58(1.13-2.21) and 2.60(1.87-3.62)] compared to CA125SN. Trajectory-specific progression analyses identified relative velocity as the optimal progression indicators for both CA125SP and CA125GP (tdAUCs: 0.712 and 0.767), with optimal cut-off values of 9% and 32% per year, respectively. Positive progression was associated with significantly increased risks of OC incidence [HRs (95%CI): 7.26(4.00-13.17) and 3.83(1.96-7.51) CA125GP and CA125SP] and mortality [HRs (95%CI): 8.03(4.15-15.56) and 6.04(2.78-13.14)] compared to negative progression. Optimized risk-stratified CA125 screening, which integrated CA125 trajectories, trajectory-specific progression, and TVU, reduced missed OC by 3.6% and improved accuracy compared to traditional screening methods. CONCLUSIONS: Incorporating CA125 trajectories and trajectory-specific progression into screening protocols enhances the identification of the population at high-risk of OC. An optimized screening strategy, which includes these factors along with TVU, is recommended to improve the effectiveness of OC screening.

Preliminary effects of risk-adapted PSA screening for prostate cancer after integrating PRS-specific and age-specific variation.

Background: Although the risk of prostate cancer (PCa) varies across different ages and genetic risks, it's unclear about the effects of genetic-specific and age-specific prostate-specific antigen (PSA) screening for PCa. Methods: Weighed and unweighted polygenic risk scores (PRS) were constructed to classify the participants from the PLCO trial into low- or high-PRS groups. The age-specific and PRS-specific cut-off values of PSA for PCa screening were determined with time-dependent receiver-operating-characteristic curves and area-under-curves (tdAUCs). Improved screening strategies integrating PRS-specific and age-specific cut-off values of PSA were compared to traditional PSA screening on accuracy, detection rates of high-grade PCa (Gleason score ≥7), and false positive rate. Results: Weighted PRS with 80 SNPs significantly associated with PCa was determined as the optimal PRS, with an AUC of 0.631. After stratifying by PRS, the tdAUCs of PSA with a 10-year risk of PCa were 0.818 and 0.816 for low- and high-PRS groups, whereas the cut-off values were 1.42 and 1.62 ng/mL, respectively. After further stratifying by age, the age-specific cut-off values of PSA were relatively lower for low PRS (1.42, 1.65, 1.60, and 2.24 ng/mL for aged <60, 60-64, 65-69, and ≥70 years) than high PRS (1.48, 1.47, 1.89, and 2.72 ng/mL). Further analyses showed an obvious interaction of positive PSA and high PRS on PCa incidence and mortality. Very small difference in PCa risk were observed among subgroups with PSA (-) across different age and PRS, and PCa incidence and mortality with PSA (+) significantly increased as age and PRS, with highest risk for high-PRS/PSA (+) in participants aged ≥70 years [HRs (95%CI): 16.00 (12.62-20.29) and 19.48 (9.26-40.96)]. The recommended screening strategy reduced 12.8% of missed PCa, ensured high specificity, but not caused excessive false positives than traditional PSA screening. Conclusion: Risk-adapted screening integrating PRS-specific and age-specific cut-off values of PSA would be more effective than traditional PSA screening.

Metadherin confers chemoresistance of cervical cancer cells by inducing autophagy and activating ERK/NF-κB pathway.

Overexpression of metadherin (MTDH) has been reported in many solid tumors and implicated in chemoresistance. This study aimed to examine MTDH expression in cervical cancer tissues and explore its role in chemoresistance of cervical cancer. MTDH expression in cervical cancer biopsies and several cervical cancer cell lines was detected by immunoblotting and immunohistochemisty. MTDH expression level was experimentally modulated in HeLa cells to determine the effects on chemoresistance to cisplatin. The results showed that MTDH expression was higher in tissues from both cervical squamous carcinoma and cervical adenocarcinoma, compared to normal cervical tissues. MTDH expression was not correlated to patient age or cervical cancer grade, although nuclear MTDH expression was correlated with poor differentiation of cervical cancer. In SiHa, HeLa, CasKi, and C33A cells, MTDH expression level was positively correlated with chemoresistance to cisplatin. MTDH increased autophagy in HeLa cells, which was associated with decreased cleavage of Caspase-3 and the activation of EER/NF-κB pathway. In conclusion, MTDH expression is high in cervical cancer, and it contributes to chemoresistance of cervical cancer. MTDH could be utilized as a therapeutic target to overcome chemoresistance of cervical cancer.

Precolumn derivatization LC-MS/MS method to simultaneous quantitation of 10 monosaccharides in rat plasma.

Monosaccharides are essential for maintaining the normal physiological functions of living organisms. Under disease states, metabolic disorders in vivo will inevitably affect the levels of monosaccharides, which brings the possibility of monosaccharides as a biomarker of some diseases. In this study, a method was developed and validated for simultaneously determining 10 monosaccharides (glucose, galactose, mannose, rhamnose, fucose, xylose, iduronic acid, glucuronic acid, N-acetylgalactosamine and N-acetylglucosamine) in SD rat plasma using liquid chromatography-tandem mass spectrometry. The method employed 1-phenyl-3-methyl-5-pyrazolone (PMP) as a derivatization reagent, considerably improved the chromatographic retention and ionization efficiency of monosaccharides. After protein precipitation of plasma samples, monosaccharides and isotope internal standards were derivatized and liquid-liquid extraction was performed to remove excess PMP. To achieve the baseline separation of several isomers, the resulting derivatives were chromatographed on a Bridged ethyl hybrid (BEH) Phenyl column using gradient elution with a total run time of 8 min. The method was linear within the range of 0.0100-5.00 µg/mL for rhamnose, 0.0500-25.0 µg/mL for fucose, xylose, iduronic acid, glucuronic acid, N-acetylgalactosamine and N-acetylglucosamine, 1.00-500 µg/mL for galactose, 10.0-5000 µg/mL for mannose, and 50.0-25,000 µg/mL for glucose. And the accuracy and precision verification of surrogate matrix samples and plasma samples met the required criteria. The method has been used successfully to study the effect of hepatic insufficiency on monosaccharide levels in rats. It was found that the concentration of glucuronic acid in SD rat plasma was abnormally increased in rats with liver injury.