Association between systemic inflammatory response index and bone turnover markers in Chinese patients with osteoporotic fractures: a retrospective cross-sectional study.

Background: The systemic inflammatory response index (SIRI) is a novel composite biomarker of inflammation. However, there is limited information on its use in the context of osteoporotic fractures. Hence, this study aimed to investigate the association between baseline SIRI values and bone turnover markers (BTMs) in Chinese patients diagnosed with osteoporotic fractures (OPFs), to offer a more precise method for assessing bone health and inflammation in clinical settings. Methods: A retrospective cross-sectional study was conducted on 3,558 hospitalized patients with OPFs who required surgery or hospitalization at the First People's Hospital of Kunshan City from January 2017 to July 2022. Baseline measurements of SIRI, ß-CTX (beta-C-terminal telopeptide of type I collagen), and P1NP (procollagen type I N-terminal propeptide) were obtained. The analyses were adjusted for variables, including age, sex, body mass index (BMI), and other initial laboratory and clinical findings. Furthermore, multivariable logistic regression, smooth curve fitting, and threshold analysis were also performed. Results: The results revealed a negative correlation between baseline SIRI values and both ß-CTX and P1NP levels. After adjusting for covariates in the regression analysis, each unit increase in SIRI was found to be inked to a reduction of 0.04 (ß = -0.04; 95% confidence interval [CI], -0.05 to -0.03; with p-value <0.001) in ß-CTX levels and a decrease of 3.77 (ß = 3.77; 95% CI, 5.07 to 2.47; with p-value <0.001) in P1NP levels. Furthermore, a curvilinear relationship and threshold effect were also identified. Turning points were identified at SIRI values of 1.41 and 1.63 on the adjusted smooth curve. Conclusion: The results showed a negative correlation between the baseline SIRI value and ß-CTX level, as well as the level of P1NP. This suggests a possible link between the systemic inflammatory response and reduced bone metabolism. If these findings are verified, SIRI has the potential to function as a predictive indicator for BTMs. Nevertheless, additional research is necessary to verify these findings.

Identification of T2W hypointense ring as a novel noninvasive indicator for glioma grade and IDH genotype.

BACKGROUND: This study aimed to evaluate the T2W hypointense ring and T2-FLAIR mismatch signs in gliomas and use these signs to construct prediction models for glioma grading and isocitrate dehydrogenase (IDH) mutation status. METHODS: Two independent radiologists retrospectively evaluated 207 glioma patients to assess the presence of T2W hypointense ring and T2-FLAIR mismatch signs. The inter-rater reliability was calculated using the Cohen's kappa statistic. Two logistic regression models were constructed to differentiate glioma grade and predict IDH genotype noninvasively, respectively. Receiver operating characteristic (ROC) analysis was used to evaluate the developed models. RESULTS: Of the 207 patients enrolled (119 males and 88 females, mean age 51.6 ± 14.8 years), 45 cases were low-grade gliomas (LGGs), 162 were high-grade gliomas (HGGs), 55 patients had IDH mutations, and 116 were IDH wild-type. The number of T2W hypointense ring signs was higher in HGGs compared to LGGs (p < 0.001) and higher in the IDH wild-type group than in the IDH mutant group (p < 0.001). There were also significant differences in T2-FLAIR mismatch signs between HGGs and LGGs, as well as between IDH mutant and wild-type groups (p < 0.001). Two predictive models incorporating T2W hypointense ring, absence of T2-FLAIR mismatch, and age were constructed. The area under the ROC curve (AUROC) was 0.940 for predicting HGGs (95% CI = 0.907-0.972) and 0.830 for differentiating IDH wild-type (95% CI = 0.757-0.904). CONCLUSIONS: The combination of T2W hypointense ring, absence of T2-FLAIR mismatch, and age demonstrate good predictive capability for HGGs and IDH wild-type. These findings suggest that MRI can be used noninvasively to predict glioma grading and IDH mutation status, which may have important implications for patient management and treatment planning.

Artemisinins ameliorate polycystic ovarian syndrome by mediating LONP1-CYP11A1 interaction.

Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic ovaries. Despite its high prevalence, specific pharmacologic intervention for PCOS is challenging. In this study, we identified artemisinins as anti-PCOS agents. Our finding demonstrated the efficacy of artemisinin derivatives in alleviating PCOS symptoms in both rodent models and human patients, curbing hyperandrogenemia through suppression of ovarian androgen synthesis. Artemisinins promoted cytochrome P450 family 11 subfamily A member 1 (CYP11A1) protein degradation to block androgen overproduction. Mechanistically, artemisinins directly targeted lon peptidase 1 (LONP1), enhanced LONP1-CYP11A1 interaction, and facilitated LONP1-catalyzed CYP11A1 degradation. Overexpression of LONP1 replicated the androgen-lowering effect of artemisinins. Our data suggest that artemisinin application is a promising approach for treating PCOS and highlight the crucial role of the LONP1-CYP11A1 interaction in controlling hyperandrogenism and PCOS occurrence.

α-SMA+ cancer-associated fibroblasts increased tumor enhancement ratio on contrast-enhanced multidetector-row computed tomography in stages I-III colon cancer.

BACKGROUND AND AIM: Our prior research revealed that the tumor enhancement ratio (TER) on triphasic abdominal contrast-enhanced MDCT (CE-MDCT) scans was a prognostic factor for patients with stages I-III colon cancer. Building upon this finding, the present study aims to investigate the proteomic changes in colon cancer patients with varying TER values. METHODS: TER was analyzed on preoperative triphasic CE-MDCT scans of 160 stages I-III colon cancer patients. The survival outcomes of those in the low-TER and high-TER groups were compared. Proteomic analysis on colon cancer tissues was performed by mass spectrometry (MS) and verified by immune-histological chemistry (IHC) assays. In vivo, mouse xenograft models were employed to test the function of target proteins identified through the MS. CE-MDCT scans were conducted on mice xenografts, and the TER values were compared. RESULTS: Patients in the high-TER group had a significantly worse prognosis than those in the low-TER group. Proteomic analysis of colon cancer tissues revealed 153 differentially expressed proteins between the two groups. A correlation between TER and the abundance of α-SMA protein in tumor tissue was observed. IHC assays further confirmed that α-SMA protein expression was significantly increased in high-TER colon cancer, predominantly in cancer-associated fibroblasts (CAFs) within the cancer stroma. Moreover, CAFs promoted the growth of CRC xenografts in vivo and increased TER. CONCLUSIONS: Our study identified the distinct protein changes in colon cancer with low and high TER for the first time. The presence of CAFs may promote the growth of colon cancer and contribute to an increased TER.

Association of 25-hydroxyvitamin D levels with lipid profiles in osteoporosis patients: a retrospective cross-sectional study.

BACKGROUND: In the literature, scarce data investigate the link between 25-hydroxyvitamin D (25[OH]D) and blood lipids in the osteoporosis (OP) population. 25(OH)D, as a calcium-regulating hormone, can inhibit the rise of parathyroid hormone, increase bone mineralization to prevent bone loss, enhance muscle strength, improve balance, and prevent falls in the elderly. This retrospective cross-sectional study aimed to investigate the association between serum 25(OH)D levels and lipid profiles in patients with osteoporosis, with the objective of providing insight for appropriate vitamin D supplementation in clinical settings to potentially reduce the incidence of cardiovascular disease, which is known to be a major health concern for individuals with osteoporosis. METHODS: This is a retrospective cross-sectional study from the Affiliated Kunshan Hospital of Jiangsu University, including 2063 OP patients who received biochemical blood analysis of lipids during hospitalization from January 2015 to March 2022. The associations between serum lipids and 25(OH)D levels were examined by multiple linear regression. The dependent variables in the analysis were the concentrations of serum lipoprotein, total cholesterol (TC), triglycerides (TGs), apolipoprotein-A, lipoprotein A, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol (LDL-C). The independent variable was the concentration of blood serum 25(OH)D. At the same time, age, body mass index, sex, time and year of serum analysis, primary diagnosis, hypertension, diabetes, statins usage, beta-C-terminal telopeptide of type I collagen, procollagen type I N-terminal propeptide were covariates. Blood samples were collected in the early morning after the overnight fasting and were analyzed using an automated electrochemiluminescence immunoassay on the LABOSPECT 008AS platform (Hitachi Hi-Tech Co., Ltd., Tokyo, Japan). The generalized additive model was further applied for nonlinear associations. The inception result for smoothing the curve was evaluated by two-piecewise linear regression exemplary. RESULTS: Our results proved that in the OP patients, the serum 25(OH)D levels were inversely connected with blood TGs concentration, whereas they were positively associated with the HDL, apolipoprotein-A, and lipoprotein A levels. In the meantime, this research also found a nonlinear relationship and threshold effect between serum 25(OH)D and TC, LDL-C. Furthermore, there were positive correlations between the blood serum 25(OH)D levels and the levels of TC and LDL-C when 25(OH)D concentrations ranged from 0 to 10.04 ng/mL. However, this relationship was not present when 25(OH)D levels were higher than 10.04 ng/mL. CONCLUSIONS: Our results demonstrated an independent relationship between blood lipids and vitamin D levels in osteoporosis patients. While we cannot establish a causal relationship between the two, our findings suggest that vitamin D may have beneficial effects on both bone health and blood lipid levels, providing a reference for improved protection against cardiovascular disease in this population. Further research, particularly interventional studies, is needed to confirm these associations and investigate their underlying mechanisms.

Lead exposure suppresses the Wnt3a/ß-catenin signaling to increase the quiescence of hematopoietic stem cells via reducing the expression of CD70 on bone marrow-resident macrophages.

Lead (Pb) is a heavy metal highly toxic to human health in the environment. The aim of this study was to investigate the mechanism of Pb impact on the quiescence of hematopoietic stem cells (HSC). WT C57BL/6 (B6) mice treated with 1250 ppm Pb via drinking water for 8 weeks had increased the quiescence of HSC in the bone marrow (BM), which was caused by the suppressed activation of the Wnt3a/ß-catenin signaling. Mechanically, a synergistic action of Pb and IFNγ on BM-resident macrophages (BM-Mφ) reduced their surface expression of CD70, which thereby dampened the Wnt3a/ß-catenin signaling to suppress the proliferation of HSC in mice. In addition, a joint action of Pb and IFNγ also suppressed the expression of CD70 on human Mφ to impair the Wnt3a/ß-catenin signaling and reduce the proliferation of human HSC purified from umbilical cord blood of healthy donors. Moreover, correlation analyses showed that the blood Pb concentration was or tended to be positively associated with the quiescence of HSC, and was or tended to be negatively associated with the activation of the Wnt3a/ß-catenin signaling in HSC in human subjects occupationally exposed to Pb. Collectively, these data indicate that an occupationally relevant level of Pb exposure suppresses the Wnt3a/ß-catenin signaling to increase the quiescence of HSC via reducing the expression of CD70 on BM-Mφ in both mice and humans.

Enhancement of root sulfur metabolic pathway by overexpression of OAS-TL3 to increase total soybean seed protein content.

Sulfur is essential for plant growth, and the uptake of sulfate by plant roots is the primary source of plant sulfur. Previous studies have shown that the OAS-TL gene is a key enzyme in the sulfur metabolic pathway and regulates cysteine (Cys) synthase production. However, the interaction mechanism of the glycine max OAS-TL3 Cys synthase (OAS-TL3) gene on soybean root morphology construction and seed protein accumulation is unclear. This study shows that mutant M18 has better root growth and development, higher seed protein content, and higher methionine (Met) content in sulfur-containing amino acids than wild-type JN18. By transcriptome sequencing, the differentially expressed OAS-TL3 gene was targeted in the mutant M18 root line. The relative expression of the OAS-TL3 gene in roots, stems, and leaves during the seedling, flowering, and bulking stages of the OAS-TL3 gene overexpression lines is higher than that of the recipient material. Compared to the recipient material JN74, the enzymatic activities, Cys, and GSH contents of OAS-TL are higher in the sulfur metabolic pathway of seedling roots. The receptor material JN74 is exogenously applied with different concentrations of reduced glutathione. The results demonstrate a positive correlation between reduced glutathione on total root length, projected area, surface area, root volume, total root tip number, total bifurcation number, and total crossing number. The Met and total protein contents of sulfur-containing amino acids in soybean seeds of the OAS-TL3 gene overexpression lines are higher than those of the recipient material JN74, while the gene-edited lines show the opposite results. In conclusion, the OAS-TL3 gene positively regulates soybean root growth, root activity, and the content of Met in the seeds through the OAS-TL-Cys-GSH pathway. It breaks the limitation of other amino acids and facilitates the increase of total seed protein content. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-022-01348-y.

[A Retrospective Study on the Efficacy and Safety of Idarubicin Combined with High-Dose Cytarabine Consolidation in Patients with Acute Myeloid Leukemia over 60 Years of Age in First Remission].

OBJECTIVE: To evaluate the efficacy and safety of idarubicin combined with high-dose cytarabine as a post-remission therapy for elderly patients with acute myeloid leukemia (AML). METHODS: From November 2017 to June 2021, 24 AML patients aged ≥60 years who were in complete remission for the first time were enrolled in consolidation chemotherapy with idarubicin (10 mg/m2 intravenously once for day 1) combined with high-dose cytarabine (1.5 g/m2 intravenously over 3 hours every 12 hours for day 1-3), and the efficacy and safety were observed. RESULTS: Among the 24 patients, there were 12 males and 12 females, the median age was 65 (60-78) years old, and the median follow-up time was 23.3 (2-42.7) months. By the end of the follow-up, 15 patients relapsed and 11 patients died. The median disease-free survival (DFS) was 9 months and there were 3 cases of 2-year DFS. The median overall survival (OS) was 16.2 months, and there were 4 cases of 2-year OS. In terms of safety, 6 patients had grade 1-2 non-hematological adverse reactions, 12 patients had grade 3-4 hematological adverse reactions, and a total of 6 patients developed infection after consolidation chemotherapy. Multivariate analysis showed that two induction cycles and high-risk cytogenetic abnormalities were the adverse factors of DFS and OS in elderly patients with AML in this study. CONCLUSION: For AML patients ≥60 years old in first complete remission, idarubicin combined with high-dose cytarabine as post-remission therapy has a better safety, but compared with other regimens does not improve the prognosis of elderly patients, which needs further exploration.

An initial study on the predictive value using multiple MRI characteristics for Ki-67 labeling index in glioma.

BACKGROUND AND PURPOSE: Ki-67 labeling index (LI) is an important indicator of tumor cell proliferation in glioma, which can only be obtained by postoperative biopsy at present. This study aimed to explore the correlation between Ki-67 LI and apparent diffusion coefficient (ADC) parameters and to predict the level of Ki-67 LI noninvasively before surgery by multiple MRI characteristics. METHODS: Preoperative MRI data of 166 patients with pathologically confirmed glioma in our hospital from 2016 to 2020 were retrospectively analyzed. The cut-off point of Ki-67 LI for glioma grading was defined. The differences in MRI characteristics were compared between the low and high Ki-67 LI groups. The receiver operating characteristic (ROC) curve was used to estimate the accuracy of each ADC parameter in predicting the Ki-67 level, and finally a multivariate logistic regression model was constructed based on the results of ROC analysis. RESULTS: ADCmin, ADCmean, rADCmin, rADCmean and Ki-67 LI showed a negative correlation (r = - 0.478, r = - 0.369, r = - 0.488, r = - 0.388, all P < 0.001). The Ki-67 LI of low-grade gliomas (LGGs) was different from that of high-grade gliomas (HGGs), and the cut-off point of Ki-67 LI for distinguishing LGGs from HGGs was 9.5%, with an area under the ROC curve (AUROC) of 0.962 (95%CI 0.933-0.990). The ADC parameters in the high Ki-67 group were significantly lower than those in the low Ki-67 group (all P < 0.05). The peritumoral edema (PTE) of gliomas in the high Ki-67 LI group was higher than that in the low Ki-67 LI group (P < 0.05). The AUROC of Ki-67 LI level assessed by the multivariate logistic regression model was 0.800 (95%CI 0.721-0.879). CONCLUSIONS: There was a negative correlation between ADC parameters and Ki-67 LI, and the multivariate logistic regression model combined with peritumoral edema and ADC parameters could improve the prediction ability of Ki-67 LI.

PDE4 inhibitor Roflumilast modulates inflammation and lipid accumulation in PCOS mice to improve ovarian function and reduce DHEA-induced granulosa cell apoptosis in vitro.

This study was implemented to address the role of Roflumilast in polycystic ovary syndrome (PCOS) as well as to discuss its reaction mechanism in vivo and in vitro. In vivo, mice were administrated with 6 mg dehydroepiandrosterone (DHEA) per 100 g body weight and fed with 60% high fat diet to induce PCOS. The expression of phosphodiesterases 4 (PDE4) was assessed with RT-qPCR. The ovary pathology was observed by hematoxylin and eosin staining and follicles were counted. Enzyme-linked immunosorbent assay was adopted for the estimation of progesterone, testosterone and inflammatory factors and lipid accumulation was observed by Oil Red O staining. With the application of reverse transcription-quantitative PCR (RT-qPCR) and western blot, the messenger RNA (mRNA) and protein expressions of low-density lipoprotein receptor (LDLR) was resolved. In vitro, Cell counting kit-8 and flow cytometry analysis were applied for the assessment of cell proliferation and apoptosis. The proliferation- and apoptosis-related proteins were appraised with western blot. Additionally, the expressions of PDE-4 at both mRNA and protein levels were tested with RT-qPCR and western blot. Here, it was discovered that PDE4 was greatly elevated in PCOS mice and DHEA-induced ovarian granulosa cells (KGN). In PCOS mice, PDE4 was negative correlated with progesterone and had positive correlation with testosterone. Roflumilast could enhanced progesterone expression, increased the number of primary follicles, preantral follicles and antral follicles but reduced testosterone and decreased the number of cystic follicles in PCOS mice. It was also testified that Roflumilast could inhibit the release of inflammatory factors and lipid accumulation in PCOS mice. Besides, the proliferation of DHEA-induced KGN cells was enhanced while the apoptosis was declined by Roflumilast, accompanied by elevated contents of PCNA, Ki67 and antiapoptotic protein Bcl-2. Collectively, Roflumilast inhibited inflammation and lipid accumulation in PCOS mice to improve ovarian function and reduce DHEA-induced granulosa cell apoptosis.

Preoperative and Noninvasive Prediction of Gliomas Histopathological Grades and IDH Molecular Types Using Multiple MRI Characteristics.

Background and Purpose: Gliomas are one of the most common tumors in the central nervous system. This study aimed to explore the correlation between MRI morphological characteristics, apparent diffusion coefficient (ADC) parameters and pathological grades, as well as IDH gene phenotypes of gliomas. Methods: Preoperative MRI data from 166 glioma patients with pathological confirmation were retrospectively analyzed to compare the differences of MRI characteristics and ADC parameters between the low-grade and high-grade gliomas (LGGs vs. HGGs), IDH mutant and wild-type gliomas (IDHmut vs. IDHwt). Multivariate models were constructed to predict the pathological grades and IDH gene phenotypes of gliomas and the performance was assessed by the receiver operating characteristic (ROC) analysis. Results: Two multivariable logistic regression models were developed by incorporating age, ADC parameters, and MRI morphological characteristics to predict pathological grades, and IDH gene phenotypes of gliomas, respectively. The Noninvasive Grading Model classified tumor grades with areas under the ROC curve (AUROC) of 0.934 (95% CI=0.895-0.973), sensitivity of 91.2%, and specificity of 78.6%. The Noninvasive IDH Genotyping Model differentiated IDH types with an AUROC of 0.857 (95% CI=0.787-0.926), sensitivity of 88.2%, and specificity of 63.8%. Conclusion: MRI features were correlated with glioma grades and IDH mutation status. Multivariable logistic regression models combined with MRI morphological characteristics and ADC parameters may provide a noninvasive and preoperative approach to predict glioma grades and IDH mutation status.

Tumor enhancement ratio on preoperative abdominal contrast-enhanced CT scan for predicting recurrence risk in stage II colon cancer.

PURPOSE: The identification of high recurrence risk stage II colon cancer patients was critical to adjuvant chemotherapy decision. However, current definition of high-risk features remains inadequate. This study aimed to construct a model for predicting recurrence risk based on tumor enhancement ratio (TER) on abdominal contrast-enhanced CT scan. METHOD: 282 stage II colon cancer patients were included and randomly divided into training and validation sets in the ratio of 7:3. TER was calculated using maximum tumor attenuation value in contrast-enhanced CT scan divided by the minimum. Kaplan-Meier survival analyses were adopted to evaluate the prognostic value of variables. A model based on TER was built to predict recurrence risk through the LASSO Cox model. The recurrence risk score of patients was calculated based on this model. RESULTS: The optimal cut-off value of TER was 1.83 derived from the time-dependent ROC (tdROC) curve. Patients with high-TER showed increasingly poorer disease-free survival (DFS) in both training (p < 0.001) and validation (p < 0.001) sets. A model was built based on TER demonstrated satisfactory performance to recurrence risk prediction (C-index: 0.784 in the training set and 0.725 in the validation set). Patients were regrouped into modified high-risk and non-high risk according to recurrence risk score (cut-off value: 1.75) and a significant DFS difference was observed (training set: p < 0.001; validation set: p < 0.001). CONCLUSION: TER can serve as a high-risk feature of stage II colon cancer. And a model based on TER provided a new approach to assess recurrence risk of stage II disease.

Prostaglandin E2 receptor 3 promotes M1 macrophages polarization in unexplained recurrent pregnancy loss.

Unexplained recurrent pregnancy loss (uRPL) is associated with macrophage polarization, which can be modulated by prostaglandin E2 (PGE2). Our previous study demonstrated that PGE2 receptor 3 (EP3) signaling is induced in the first-trimester placentas of uRPL patients compared with its expression in healthy controls. However, whether EP3 plays a role in macrophage polarization at the maternal-fetal interface of uRPL women remains unknown. The positive expression of EP3 in decidual macrophages was confirmed by double immunofluorescence staining in the first-trimester placentas collected from uRPL patients and healthy controls. Antibodies CD68, iNOS, and CD163 were used as immunofluorescence marker for decidual macrophages, M1, and M2 macrophages. To clarify the effects of EP3 on macrophage polarization, THP-1 monocyte cells were applied as M0 macrophages after phorbol 12-myristate 13-acetate (PMA) treatment for in vitro study. The mRNA levels of representative M1 markers (interleukin-1ß and interleukin-6) and M2 markers (interleukin-10 and arginase-1) were quantified with qPCR in M0 macrophages being stimulated with sulprostone (an EP3 agonist) or L-798,106 (an EP3 antagonist). We found that EP3 expression was upregulated in the decidual macrophages of first-trimester placentas from uRPL patients compared with healthy controls. Furthermore, EP3 expression was increased in M1 macrophages compared with that in M2 macrophages in first-trimester placentas of uRPL patients. Sulprostone intensified the mRNA levels of IL-6 together with interferon-γ, whereas L-798,106 stimulated the mRNA expression of IL-10 and Arg-1 in a dose-dependent manner.

Application of Multiparametric Magnetic Resonance Imaging to Monitor the Early Antitumor Effect of CuS@GOD Nanoparticles in a 4 T1 Breast Cancer Xenograft Model.

BACKGROUND: We have developed hybrid nanoparticles (NPs) by co-loading copper sulfide (CuS) NPs and glucose oxidase (GOD) (CuS@GOD NPs) to explore their antitumor properties. PURPOSE: To investigate the feasibility of using multiparametric magnetic resonance imaging (MRI) including intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and R2 * mapping to quantitatively assess the early antitumor effect of CuS@GOD NPs. STUDY TYPE: Prospective. ANIMAL MODEL: The orthotopic BALB/c mice 4 T1 breast cancer model. The 4 T1 xenografts in group 1 mice received normal saline, group 2 received CuS@GOD NPs, group 3 received CuS NPs plus laser, and group 4 received CuS@GOD NPs plus laser (n = 28 for each group). FIELD STRENGTH/SEQUENCE: A 3.0 T/IVIM-DWI MRI single-shot echo-planar imaging, R2 * mapping spoiled gradient recalled echo (SPGR) sequence, T2-weighted images (T2WI) and T1-weighted images (T1WI) fast spin echo (FSE) sequence. ASSESSMENT: The IVIM-DWI and R2 * mapping were performed before and after treatment at 0 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, and 24 hours in four groups and the MRI parameters were obtained. Correlation analysis between the MRI parameters and histological analyses was conducted. STATISTICAL TESTS: One-way ANOVA, Pearson's correlation analysis, two independent samples t test, intraclass correlation coefficient. P < 0.05 was considered to be statistically significant. RESULTS: In group 4, the tumoral D value was significantly higher than that of group 2 at 24 hours (0.541 ± 0.065 vs. 0.492 ± 0.051). The f value of group 4 was significantly lower than that of groups 1 and 2 at 2 hours (10.83 ± 2.16 vs. 14.28 ± 1.86, 16.67 ± 3.53, respectively). The R2 * value was significantly increased at 0 hour in group 4 compared to that of groups 1 and 2 (64.552 ± 4.663 vs. 42.441 ± 1.516, 43.165 ± 1.709, respectively). D, f, and R2 * were correlated with the histological staining results (r = 0.695-0.970). DATA CONCLUSION: The IVIM-DWI-derived D and f and R2 * mapping-derived R2 * could monitor early response to CuS@GOD NPs treatment in vivo. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Prostaglandin E2 Receptor 4 (EP4) Affects Trophoblast Functions via Activating the cAMP-PKA-pCREB Signaling Pathway at the Maternal-Fetal Interface in Unexplained Recurrent Miscarriage.

Implantation consists of a complex process based on coordinated crosstalk between the endometrium and trophoblast. Furthermore, it is known that the microenvironment of this fetal-maternal interface plays an important role in the development of extravillous trophoblast cells. This is mainly due to the fact that tissues mediate embryonic signaling biologicals, among other molecules, prostaglandins. Prostaglandins influence tissue through several cell processes including differentiation, proliferation, and promotion of maternal immune tolerance. The aim of this study is to investigate the potential pathological mechanism of the prostaglandin E2 receptor 4 (EP4) in modulating extravillous trophoblast cells (EVTs) in unexplained recurrent marriage (uRM). Our results indicated that the expression of EP4 in EVTs was decreased in women experiencing uRM. Furthermore, silencing of EP4 showed an inhibition of the proliferation and induced apoptosis in vitro. In addition, our results demonstrated reductions in ß- human chorionic gonadotropin (hCG), progesterone, and interleukin (IL)-6, which is likely a result from the activation of the cyclic adenosine monophosphate (cAMP)- cAMP-dependent protein kinase A (PKA)-phosphorylating CREB (pCREB) pathway. Our data might provide insight into the mechanisms of EP4 linked to trophoblast function. These findings help build a more comprehensive understanding of the effects of EP4 on the trophoblast at the fetal-maternal interface in the first trimester of pregnancy.

A predictive model for early recurrence of colorectal-cancer liver metastases based on clinical parameters.

BACKGROUND: The prognosis for patients with colorectal-cancer liver metastases (CRLM) after curative surgery remains poor and shows great heterogeneity. Early recurrence, defined as tumor recurrence within 6 months of curative surgery, is associated with poor survival, requiring earlier detection and intervention. This study aimed to develop and validate a bedside model based on clinical parameters to predict early recurrence in CRLM patients and provide insight into post-operative surveillance strategies. MATERIAL AND METHODS: A total of 202 consecutive CRLM patients undergoing curative surgeries between 2012 and 2019 were retrospectively enrolled and randomly assigned to the training (n = 150) and validation (n = 52) sets. Baseline information and radiological, pathological, and laboratory findings were extracted from medical records. Predictive factors for early recurrence were identified via a multivariate logistic-regression model to develop a predictive nomogram, which was validated for discrimination, calibration, and clinical application. RESULTS: Liver-metastases number, lymph-node suspicion, neurovascular invasion, colon/rectum location, albumin and post-operative carcinoembryonic antigen, and carbohydrate antigen 19-9 levels (CA19-9) were independent predictive factors and were used to construct the nomogram for early recurrence after curative surgery. The area under the curve was 0.866 and 0.792 for internal and external validation, respectively. The model significantly outperformed the clinical risk score and Beppu's model in our data set. In the lift curve, the nomogram boosted the detection rate in post-operative surveillance by two-fold in the top 30% high-risk patients. CONCLUSION: Our model for early recurrence in CRLM patients after curative surgeries showed superior performance and could aid in the decision-making for selective follow-up strategies.

Prognostic Significance of Immune Checkpoints HLA-G/ILT-2/4 and PD-L1 in Colorectal Cancer.

Immune checkpoint inhibitors (ICIs) have become a promising area of research for cancer treatment. In addition to the well-known ICIs targeting PD-1/PD-L1, HLA-G/ILT-2/-4 is relatively new immune checkpoint that has been evaluated in early clinical trials in patients with advanced solid tumors. In this study, the expression of HLA-G (n=157), ILT-2/4 (n=82), and PD-L1 (n=70) in epithelial cell adhesion molecule (EpCAM)-positive colorectal cancer (CRC) cells was analyzed by multicolor flow cytometry, and the prognostic significance of these molecules was evaluated. In EpCAM+ CRC cells, the median percentages of HLA-G, ILT-2, ILT-4, and PD-L1 were 14.90%, 67.70%, 8.55% and 80.30%, respectively. In addition, a positive correlation was observed between them (all p<0.001). Higher levels of these immune checkpoint proteins are associated with lymph node metastasis. In addition to the AJCC stage (p=0.001), Kaplan-Meier survival analysis showed that higher levels of HLA-G (p=0.041), ILT-2 (p=0.060), ILT-4 (p<0.001), PD-L1 (p=0.012), HLA-GILT4 (p<0.001) and ILT-2ILT-4 (p<0.001) were significantly associated with shorter survival of CRC patients. When CRC patients were stratified by early and advanced AJCC stages, HLA-G levels were only related to the survival among CRC patients with early disease stage (p=0.024), while ILT-4 levels were significant for both CRC patients with early (p=0.001) and advanced (p=0.020) disease stages. Multivariate cox regression analysis revealed that advanced AJCC stage (HR=2.435; p=0.005) and higher ILT-4 levels (HR=2.198; p=0.063) were independent risk factors for poor outcomes in patients with CRC. In summary, among the immune checkpoints, HLA-G/ILT-2/4 and PD-L1, ILT-4 is the most significant prognostic indicator of CRC. This finding indicated that a combination of immunotherapy strategies, such as ILT-4 blockade, could improve the clinical outcomes in patients with cancer. Moreover, multicolor flow cytometry can be employed as a reliable and efficient, alternative to immunohistochemistry, for evaluating the immune checkpoint proteins expressed in tumor lesions.

Do the existing staging systems for primary liver cancer apply to combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma?

BACKGROUND: The incidence of combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma (cHCC-ICC) is relatively low, and the knowledge about the prognosis of cHCC-ICC remains obscure. In the study, we aimed to screen existing primary liver cancer staging systems and shed light on the prognosis and risk factors for cHCC-ICC. METHODS: We retrospectively reviewed 206 cHCC-ICC patients who received curative surgical resection from April 1999 to March 2017. The correlation of survival measures with the histological types or with tumor staging systems was determined and predictive values of tumor staging systems with cHCC-ICC prognosis were compared. RESULTS: The histological type was not associated with overall survival (OS) (P = 0.338) or disease-free survival (DFS) (P = 0.843) of patients after curative surgical resection. BCLC, TNM for HCC, and TNM for ICC stages correlated with both OS and DFS in cHCC-ICC (all P < 0.05). The predictive values of TNM for HCC and TNM for ICC stages were similar in terms of predicting postoperative OS (P = 0.798) and DFS (P = 0.191) in cHCC-ICC. TNM for HCC was superior to BCLC for predicting postoperative OS (P = 0.022) in cHCC-ICC. CONCLUSION: The TNM for HCC staging system should be prioritized for clinical applications in predicting cHCC-ICC prognosis.

Identification of an Immune-Related Gene Signature to Improve Prognosis Prediction in Colorectal Cancer Patients.

BACKGROUND: Despite recent advance in immune therapy, great heterogeneity exists in the outcomes of colorectal cancer (CRC) patients. In this study, we aimed to analyze the immune-related gene (IRG) expression profiles from three independent public databases and develop an effective signature to forecast patient's prognosis. METHODS: IRGs were collected from the ImmPort database. The CRC dataset from The Cancer Genome Atlas (TCGA) database was used to identify a prognostic gene signature, which was verified in another two CRC datasets from the Gene Expression Omnibus (GEO). Gene function enrichment analysis was conducted. A prognostic nomogram was built incorporating the IRG signature with clinical risk factors. RESULTS: The three datasets had 487, 579, and 224 patients, respectively. A prognostic six-gene-signature (CCL22, LIMK1, MAPKAPK3, FLOT1, GPRC5B, and IL20RB) was developed through feature selection that showed good differentiation between the low- and high-risk groups in the training set (p < 0.001), which was later confirmed in the two validation groups (log-rank p < 0.05). The signature outperformed tumor TNM staging for survival prediction. GO and KEGG functional annotation analysis suggested that the signature was significantly enriched in metabolic processes and regulation of immunity (p < 0.05). When combined with clinical risk factors, the model showed robust prediction capability. CONCLUSION: The immune-related six-gene signature is a reliable prognostic indicator for CRC patients and could provide insight for personalized cancer management.

Intratumor Heterogeneity of HLA-G Expression in Cancer Lesions.

Signaling pathway between human leukocyte antigen (HLA)-G and immune inhibitory receptors immunoglobulin-like transcript (ILT)-2/4 has been acknowledged as one of immune checkpoints, and as a potential target for cancer immunotherapy. Like other immune checkpoints, inter- and even intratumor heterogeneity of HLA-G could render a rather complexity for HLA-G-target immunotherapy. However, little information for intratumor heterogeneity of HLA-G is available. In this study, HLA-G expression in a serial section of colorectal cancer (CRC) lesions from three CRC patients (each sample with serial section of 50 slides, 10 randomized slides for each antibody), three different locations within a same sample (five CRC), and three case-matched blocks that each includes 36 esophageal cancer samples, were evaluated with immunohistochemistry using anti-HLA-G antibodies (mAbs 4H84, MEM-G/1 and MEM-G/2 probing for all denatured HLA-G isoforms, 5A6G7, and 2A12 probing for denatured HLA-G5 and HLA-G6 isoforms). Our results revealed that, in addition to the frequently observed inter-tumor heterogeneity, intratumor heterogeneous expression of HLA-G is common in different areas within a tumor in CRC and esophageal cancer samples included in this study. Moreover, percentage of HLA-G expression probed with different anti-HLA-G antibodies also varies dramatically within a tumor. Given HLA-G has been considered as an important immune checkpoint, intratumor heterogeneity of HLA-G expression, and different specificity of anti-HLA-G antibodies being used among studies, interpretation and clinical significance of HLA-G expression in cancers should be with caution.