Design, Synthesis, and Biological Evaluation of HDAC Inhibitors Containing Natural Product-Inspired N-Linked 2-Acetylpyrrole Cap.

Drawing inspiration from the structural resemblance between a natural product N-(3-carboxypropyl)-2-acetylpyrrole and phenylbutyric acid, a pioneer HDAC inhibitor evaluated in clinical trials, we embarked on the design and synthesis of a novel array of HDAC inhibitors containing an N-linked 2-acetylpyrrole cap by utilizing the pharmacophore fusion strategy. Among them, compound 20 exhibited potential inhibitory activity on HDAC1, and demonstrated notable potency against RPMI-8226 cells with an IC50 value of 2.89 ± 0.43 µM, which was better than chidamide (IC50 = 10.23 ± 1.02 µM). Western blot analysis and Annexin V-FTIC/propidium iodide (PI) staining showed that 20 could enhance the acetylation of histone H3, as well as remarkably induce apoptosis of RPMI-8226 cancer cells. The docking study highlighted the presence of a hydrogen bond between the carbonyl oxygen of the 2-acetylpyrrole cap group and Phe198 of the HDAC1 enzyme in 20, emphasizing the crucial role of introducing this natural product-inspired cap group. Molecular dynamics simulations showed that the docked complex had good conformational stability. The ADME parameters calculation showed that 20 possesses remarkable theoretical drug-likeness properties. Taken together, these results suggested that 20 is worthy of further exploration as a potential HDAC-targeted anticancer drug candidate.

Immunosuppressive Breviane Spiroditerpenoids from Penicillium bialowiezense Isolated from a Medicinal Plant.

Breviane spiroditerpenoids are a small group of structurally interesting and complex meroterpenoids. This work focused on an endophytic fungus Penicillium bialowiezense ZBWPQ-27 that was isolated from a medicinal plant Euphorbia neriifolia, leading to the isolation of 15 breviane spiroditerpenoids with four types of polycyclic systems (1-6 and 9-17), and two new carotane sesquiterpenoids (7 and 8). The structures including absolute configurations of the new compounds 1-8 were elucidated by spectroscopic data analysis and electronic circular dichroism (ECD) calculations. In addition, the misassigned NMR data of several resonances of the 5-methyl-TAL motif (E ring) in those of known brevianes (9-15) were corrected by spectroscopic data analysis. Biological tests revealed that brevianes with the type A ring system (6/6/6/5/6) showed moderate to significant immunosuppressive activities, and compound 11 displayed the most potent inhibitory activities against concanavalin A (ConA)-induced T cell proliferation (IC50 4.1 ± 0.2 µM) and lipopolysaccharide (LPS)-induced B cell proliferation (IC50 4.6 ± 0.2 µM), with good SI values of 28 ± 2 and 25 ± 4, respectively.

Anti-Inflammatory Salicin Derivatives from the Barks of Salix tetrasperma.

The genus Salix L. is traditionally used in folk medicine to alleviate pain caused by various kinds of inflammation. In the present study, 10 undescribed salicin derivatives along with 5 known congeners were isolated from the barks of Salix tetrasperma, and their structures were elucidated by spectroscopic analyses, single-crystal X-ray diffraction, electronic circular dichroism (ECD) calculations, and chemical conversions. Compounds 4-6 significantly inhibited NO production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages, and the most active 4 obviously suppressed the production of IL-1ß and IL-6 and decreased iNOS and COX-2 expression in a dose-dependent manner. Further Western blotting analysis revealed that the anti-inflammatory mechanism of 4 is possibly mediated through the MAPK and NF-κB signaling pathways.

Monoterpenoid indole alkaloids from Alstonia scholaris and their Toxoplasma gondii inhibitory activity.

Nine previously unreported various types of monoterpenoid indole alkaloids, together with seven known analogues were isolated from the stem barks of Alstonia scholaris through a silica gel free methodology. The structures of 1-9 were elucidated by spectroscopic data analysis, electronic circular dichroism calculations, and single-crystal X-ray diffraction. Compound 1 is a modified echitamine-type alkaloid with a novel 6/5/5/7/6/6 hetero hexacyclic bridged ring system, and 8 and 9 exist as a zwitterion and trifluoroacetate salt, respectively. The anti-Toxoplasma activity of all isolates on infected Vero cells were evaluated, which revealed that compound 14 at 0.24 µM displayed potent activity. This study expanded the structural diversity of alkaloids of A. scholaris, and presented their potential application in anti-Toxoplasma drug development.

Anti-factor Xa level monitoring of low-molecular-weight heparin for prevention of venous thromboembolism in critically ill patients (AXaLPE): protocol of a randomised, open-label controlled clinical trial.

INTRODUCTION: Whether and when to monitor the amount of anti-factor Xa (aFXa) activity in critically ill patients with complex diseases to prevent venous thromboembolism (VTE) remain unclear. This study is a randomised controlled trial to investigate the effect of aFXa level monitoring on reducing VTE and to establish a new method for accurately preventing VTE in critically ill patients with low-molecular-weight heparin (LMWH). METHODS AND ANALYSIS: A randomised controlled trial is planned in two centres with a planned sample size of 858 participants. Participants will be randomly assigned to three groups receiving LMWH prophylaxis at a 1:1:1 ratio: in group A, peak aFXa levels will serve as the guide for the LMWH dose; in group B, the trough aFXa levels will serve as the guide for the LMWH dose; and in group C, participants serving as the control group will receive a fixed dose of LMWH. The peak and trough aFXa levels will be monitored after LMWH (enoxaparin, 40 mg, once daily) reaches a steady state for at least 3 days. The monitoring range for group A's aFXa peak value will be 0.3-0.5 IU/mL, between 0.1 and 0.2 IU/mL is the target range for group B's aFXa trough value. In order to reach the peak or trough aFXa levels, groups A and B will be modified in accordance with the monitoring peak and trough aFXa level. The incidence of VTE will serve as the study's primary outcome indicator. An analysis using the intention-to-treat and per-protocol criterion will serve as the main outcome measurement. ETHICS AND DISSEMINATION: The Xuanwu Hospital Ethics Committee of Capital Medical University and Peking University First Hospital Ethics Committee have approved this investigation. It will be released in all available worldwide, open-access, peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05382481.

Diterpenoids from Euphorbia lactea and their anti-HIV-1 activity.

Nine undescribed diterpenoids, euphlactenoids A-I (1-9), including four ingol-type diterpenoids (1-4) with a 5/3/11/3-tetracyclic framework and five ent-pimarane-type diterpenoids (5-9), together with thirteen known diterpenoids (10-22), were identified from the leaves and stems of Euphorbia lactea Haw. The structures and absolute configurations of compounds 1-9 were unequivocally elucidated on the basis of spectroscopic analysis, ECD calculations and single crystal X-ray diffraction. Compounds 3 and 16 showed anti-HIV-1 effects with IC50 values of 1.17 µM (SI = 16.54) and 13.10 µM (SI = 1.93), respectively.

Circular RNA ACACA negatively regulated p53-modulated mevalonate pathway to promote colorectal tumorigenesis via regulating miR-193a/b-3p/HDAC3 axis.

This study aimed to explore the biological functions and underlying mechanism of circRNA acetyl-CoA carboxylase alpha (circACACA) in colorectal cancer (CRC). The RNA and protein levels were detected by qRT-PCR and western blot assays. The malignant capacities of CRC cells were analyzed by cell counting kit-8 (CCK-8), colony formation, flow cytometry, and transwell assays. The target relationship between miR-193a/b-3p and circACACA/histone deacetylase 3 (HDAC3) was determined by luciferase reporter assay and RNA immunoprecipitation. The binding of HDAC3 to the p53 promoter was validated by chromatin immunoprecipitation (ChIP). CRC cell growth and lung metastasis were evaluated in nude mice in vivo. High expression of circACACA was found in CRC tissues and cells, which was closely associated with the advanced tumor, lymph node, metastasis (TNM) stage, metastasis, and low overall survival rate. circACACA downregulation effectively delayed CRC cell proliferation and metastasis, but triggered apoptosis via inactivating the mevalonic acid (MVA) pathway. However, circACACA overexpression resulted in the opposite effects. Mechanistically, circACACA enhanced HDAC3 expression through sponging miR-193a/b-3p, which activated the MVA pathway via inhibiting the acetylation and transcription of p53. Moreover, rescue experiments confirmed that miR-193a/b-3p inhibition reversed the inhibitory effect of circACACA deficiency on CRC growth and metastasis. Moreover, circACACA overexpression-mediated malignant phenotypes of CRC cells were abrogated by HDAC3 knockdown. circACACA promoted CRC progression via regulating the miR-193a/b-3p/HDAC3/p53 axis to activate the MVA pathway, providing evidence for circACACA as a promising therapeutic target for CRC.

The new 'coN' staging system combining lymph node metastasis and tumour deposit provides a more accurate prognosis for TNM stage III colon cancer.

OBJECTIVE: Despite controversy over its origin and definition, the significance of tumour deposit (TD) has been underestimated in the tumour node metastasis (TNM) staging system for colon cancer, especially in stage III patients. We aimed to further confirm the prognostic value of TD in stage III colon cancer and to establish a more accurate 'coN' staging system combining TD and lymph node metastasis (LNM). METHODS: Information on stage III colon cancer patients with a definite TD status was retrospectively collected from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2017. The effect of TD on prognosis was estimated using Cox regression analysis. Maximally selected rank statistics were used to select the optimal cut-off value of TD counts. The predictive power of conventional N staging and the new coN staging was evaluated and compared by Akaike's information criterion (AIC), Harrell's concordance index (C-index) and time-dependent receiver operating characteristic (ROC) curves. Clinicopathological data of stage III colon cancer patients in the Xiangya database from 2014 to 2018 were collected to validate the coN staging system. RESULTS: A total of 39,185 patients with stage III colon cancer were included in our study: 38,446 in the SEER cohort and 739 in the Xiangya cohort. The incidence of TD in stage III colon cancer was approximately 30% (26% in SEER and 30% in the Xiangya database). TD was significantly associated with poorer overall survival (OS) (HR = 1.37, 95% CI 1.31-1.44, p < 0.001 in SEER). The optimal cut-off value of TD counts was 4, and the patients were classified into the TD0 (count = 0), TD1 (count = 1-3) and TD2 (count ≥ 4) groups accordingly. The estimated 5-year OS was significantly different among the three groups (69.4%, 95% CI 68.8%-70.0% in TD0; 60.5%, 95% CI 58.9%-62.2% in TD1 and 42.6%, 95% CI 39.2%-46.4% in TD2, respectively, p < 0.001). The coN system integrating LNM and TD was established, and patients with stage III colon cancer were reclassified into five subgroups (coN1a, coN1b, coN2a, coN2b and coN2c). Compared with conventional N staging, the coN staging Cox model had a smaller AIC (197097.581 vs. 197358.006) and a larger C-index (0.611 vs. 0.601). The AUCs of coN staging at 3, 5 and 7 years were also greater than those of conventional N staging (0.6305, 0.6326, 0.6314 vs. 0.6186, 0.6197, 0.6160). Concomitant with the SEER cohort results, the coN staging Cox model of the Xiangya cohort also had a smaller AIC (2883.856 vs. 2906.741) and a larger C-index (0.669 vs. 0.633). Greater AUCs at 3, 5 and 7 years for coN staging were also observed in the Xiangya cohort (0.6983, 0.6774, 0.6502 vs. 0.6512, 0.6368, 0.6199). CONCLUSIONS: Not only the presence but also the number of TDs is associated with poor prognosis in stage III colon cancer. A combined N staging system integrating LNM and TD provides more accurate prognostic prediction than the latest AJCC N staging in stage III colon cancer.

CT radiomics identifying non-responders to neoadjuvant chemoradiotherapy among patients with locally advanced rectal cancer.

BACKGROUND AND PURPOSE: Early detection of non-response to neoadjuvant chemoradiotherapy (nCRT) for locally advanced colorectal cancer (LARC) remains challenging. We aimed to assess whether pretreatment radiotherapy planning computed tomography (CT) radiomics could distinguish the patients with no response or no downstaging after nCRT from those with response and downstaging after nCRT. MATERIALS AND METHODS: Patients with LARC who were treated with nCRT were retrospectively enrolled between March 2009 and March 2019. Traditional radiological characteristics were analyzed by visual inspection and radiomic features were analyzed through computational methods from the pretreatment radiotherapy planning CT images. Differentiation models were constructed using radiomic methods and clinicopathological characteristics for predicting non-response to nCRT. Model performance was assessed for classification efficiency, calibration, discrimination, and clinical application. RESULTS: This study enrolled a total of 215 patients, including 151 patients in the training cohort (50 non-responders and 101 responders) and 64 patients in the validation cohort (21 non-responders and 43 responders). For predicting non-response, the model constructed with an ensemble machine learning method had higher performance with area under the curve (AUC) values of 0.92 and 0.89 as compared to the model constructed with the logistic regression method (AUC: 0.72 and 0.71 for the training and validation cohorts, respectively). Both decision curve and calibration curve analyses confirmed that the ensemble machine learning model had higher prediction performance. CONCLUSION: Pretreatment CT radiomics achieved satisfying performance in predicting non-response to nCRT and could be helpful to assist in treatment planning for patients with LARC.

Application of Radiomics in Predicting Treatment Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer: Strategies and Challenges.

Neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision is the standard treatment for locally advanced rectal cancer (LARC). A noninvasive preoperative prediction method should greatly assist in the evaluation of response to nCRT and for the development of a personalized strategy for patients with LARC. Assessment of nCRT relies on imaging and radiomics can extract valuable quantitative data from medical images. In this review, we examined the status of radiomic application for assessing response to nCRT in patients with LARC and indicated a potential direction for future research.

The Association of R-Loop Binding Proteins Subtypes with CIN Implicates Therapeutic Strategies in Colorectal Cancer.

Chromosomal instability (CIN) covers approximately 65 to 70% of colorectal cancer patients and plays an essential role in cancer progression. However, the molecular features and therapeutic strategies related to those patients are still controversial. R-loop binding proteins (RLBPs) exert significant roles in transcription and replication. Here, integrative colorectal cancer proteogenomic analysis identified two RLBPs subtypes correlated with distinct prognoses. Cluster I (CI), represented by high expression of RLBPs, was associated with the CIN phenotype. While Cluster II (CII) with the worst prognosis and low expression of RLBPs was composed of a high percentage of patients with mucinous adenocarcinoma or right-sided colon cancer. The molecular feature analysis revealed that the active RNA processing, ribosome synthesis, and aberrant DNA damage repair were shown in CI, a high inflammatory signaling pathway, and lymphocyte infiltration was enriched in CII. In addition, we revealed 42 tumor-associated RLBPs proteins. The CI with high expression of tumor-associated proteins was sensitive to drugs targeting genome integrity and EGFR in both cell and organoid models. Thus, our study unveils a significant molecular association of the CIN phenotype with RLBPs, and also provides a powerful resource for further functional exploration of RLBPs in cancer progression and therapeutic application.

EPSTI1 as an immune biomarker predicts the prognosis of patients with stage III colon cancer.

Objective: The poor prognosis and heterogeneity of stage III colon cancer (CC) suggest the need for more prognostic biomarkers. The tumor microenvironment (TME) plays a crucial role in tumor progression. We aimed to explore novel immune infiltration-associated molecules that serve as potential prognostic and therapeutic targets. Methods: TME immune scores were calculated using "TMEscore" algorithm. Differentially expressed genes between the high and low TME immune score groups were identified and further investigated through a protein-protein interaction network and the Molecular Complex Detection algorithm. Cox regression, meta-analysis and immunohistochemistry were applied to identify genes significantly correlated with relapse-free survival (RFS). We estimated immune infiltration using three different algorithms (TIMER 2.0, CIBERSORTx, and TIDE). Single-cell sequencing data were processed by Seurat software. Results: Poor RFS was observed in the low TME immune score groups (log-rank P < 0.05). EPSTI1 was demonstrated to be significantly correlated with RFS (P < 0.05) in stage III CC. Meta-analysis comprising 547 patients revealed that EPSTI1 was a protective factor (HR = 0.79, 95% CI, 0.65-0. 96; P < 0.05)). More immune infiltrates were observed in the high EPSTI1 group, especially M1 macrophage and myeloid dendritic cell infiltration (P < 0.05). Conclusion: The TME immune score is positively associated with better survival outcomes. EPSTI1 could serve as a novel immune prognostic biomarker for stage III CC.

m6A Methyltransferase KIAA1429 Regulates the Cisplatin Sensitivity of Gastric Cancer Cells via Stabilizing FOXM1 mRNA.

Although cisplatin is frequently used to treat gastric cancer, the resistance is the main obstacle for effective treatment. mRNA modification, N6-methyladenosine (m6A), is involved in the tumorigenesis of many types of cancer. As one of the largest m6A methyltransferase complex components, KIAA1429 bridges the catalytic m6A methyltransferase components, such as METTL3. In gastric cancer, KIAA1429 was reported to promote cell proliferation. However, whether KIAA1429 is involved in the resistance of gastric cancer to cisplatin remains unclear. Here, we generated cisplatin resistant gastric cancer cell lines, and compared the m6A content between resistant cells and wild type cells. The m6A content as well as KIAA1429 expression are higher in resistant cells. Interestingly, the expression of KIAA1429 was significantly increased after cisplatin treatment. We then used shRNA to knockdown KIAA1429 and found that resistant cells responded more to cisplatin treatment after KIAA1429 depletion, while overexpression of KIAA1429 decreased the sensitivity. Moreover, we identified a putative p65 binding site on the promoter area of KIAA1429 and ChIP assay confirmed the binding. p65 depletion decreased the expression of KIAA1429. YTHDF1 is the most abundant m6A "reader" that interacts with m6A modified mRNA. Mechanistically, YTHDF1 was recruited to the 3'-untranslated Region (3'-UTR) of transcriptional factor, FOXM1 by KIAA1429 and stabilized FOXM1 mRNA. More importantly, KIAA1429 knockdown increased the sensitivity of resistant cells to cisplatin in vivo. In conclusion, our results demonstrated that KIAA1429 facilitated cisplatin resistance by stabilizing FOXM1 mRNA in gastric cancer cells.

Pre-Treatment Computed Tomography Radiomics for Predicting the Response to Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer: A Retrospective Study.

Background and Purpose: Computerized tomography (CT) scans are commonly performed to assist in diagnosis and treatment of locally advanced rectal cancer (LARC). This study assessed the usefulness of pretreatment CT-based radiomics for predicting pathological complete response (pCR) of LARC to neoadjuvant chemoradiotherapy (nCRT). Materials and Methods: Patients with LARC who underwent nCRT followed by total mesorectal excision surgery from July 2010 to December 2018 were enrolled in this retrospective study. A total of 340 radiomic features were extracted from pretreatment contrast-enhanced CT images. The most relevant features to pCR were selected using the least absolute shrinkage and selection operator (LASSO) method and a radiomic signature was generated. Predictive models were built with radiomic features and clinico-pathological variables. Model performance was assessed with decision curve analysis and was validated in an independent cohort. Results: The pCR was achieved in 44 of the 216 consecutive patients (20.4%) in this study. The model with the best performance used both radiomics and clinical variables including radiomic signatures, distance to anal verge, lymphocyte-to-monocyte ratio, and carcinoembryonic antigen. This combined model discriminated between patients with and without pCR with an area under the curve of 0.926 and 0.872 in the training and the validation cohorts, respectively. The combined model also showed better performance than models built with radiomic or clinical variables alone. Conclusion: Our combined predictive model was robust in differentiating patients with and without response to nCRT.

The survival impact of radiotherapy on synchronous metastatic rectal cancer: metastatic site can serve for radiotherapy-decision.

Purpose: The metastatic site seems to represent a malignancy with a different biological characteristic. Radiotherapy, as a successful, well-tolerated, cost-effective and time-efficient intervention, is able to provide clear benefits for the treatment of locally advanced rectal cancer and has become an essential component of palliative oncology care. The real-world effect of radiotherapy on the survival outcomes of metastatic rectal cancer (mRC) patients might do exist and was worth exploring. Patients and methods: Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database in this retrospective analysis. The statistical methods included Pearson's chi-square test, Log-rank test, Cox regression model and propensity score matching (PSM). Results: The multivariable Cox regression displayed that radiotherapy may not be used as a prognostic factor for mRC (p=0.057). However, radiotherapy may be associated with the prognosis if the metastatic site was excluded from the multivariate analysis (p<0.001). Radiotherapy seemed to fail to improve OS before PSM (p<0.001) and after PSM without the metastatic site as a matching factor (p<0.001). Nevertheless, there was no significant survival difference between radiotherapy and non-radiotherapy cohort after PSM with the metastatic site as a matching factor (p=0.057). All of M1a rectal cancer patients appear to obtain survival benefit from radiotherapy without the impact of PSM (p<0.001). Notwithstanding, radiotherapy was associated with improved OS of patients with rectal liver-limited metastasis (p=0.023) and did not appear to provide survival benefit for rectal lung-limited (p=0.386) and other-limited metastasis (p=0.385). Both of M1b mRC with and without liver metastasis did not seem to obtain survival benefit from radiotherapy. Conclusions: Carefully selected data from the SEER database suggested that radiotherapy appears to improve overall survival only in patients with rectal liver-limited metastasis.

Diterpenoids from Sauropus spatulifolius Leaves with Antimicrobial Activities.

As a plant used in both food and medicine, Sauropus spatulifolius is consumed widely as a natural herbal tea, food source, and Chinese medicine. Inspired by its extensive applications, we conducted a systematic phytochemical study of the leaves of S. spatulifolius. Thirteen new diterpenoids, sauspatulifols A-M (1-13), including four ent-cleistanthane-type diterpenoids (1-4), eight 15,16-di-nor-ent-cleistanthane-type diterpenoids (5-12), and one 17-nor-ent-pimarane-type diterpenoid (13) as well as one known diterpenoid, cleistanthol (14), were isolated. All of these diterpenoids feature a 2α,3α-dihydroxy unit within the A ring, and their structures were elucidated by spectroscopic data analysis, electronic circular dichroism calculations, and single-crystal X-ray diffraction analysis. Compound 14 displayed moderate inhibitory activity against Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, and Shigella flexneri with the same minimum inhibitory concentration value of 12 µg/mL as well as activity against vesicular stomatitis virus and influenza A virus.

Optimization of tourism routes in Lushunkou District based on ArcGIS.

With the advancements and developments in China's tourism industry, various autonomous forms of tourism have been gaining prominence. As such, to facilitate tourists and provide them with maximum experience while economizing on time and cost is essential. One approach toward achieving this is the optimization of tourism routes. However, so far the studies on this approach have focused primarily on inland tourist sites and have lacked a geographic perspective. Therefore, this study undertook the tourism resource data of Lushunkou District of 2020, used the ArcGIS accessibility evaluation model to analyze tourism resources, and finally used the Vehicle Routing Problem of network analysis technology to optimize the tourism route of Lushunkou District and obtain the general overall intellectual framework and technical methods for tourism route optimization. The results showed that the ArcGIS accessibility evaluation model could be used to integrate resources in the tourism area before using the Vehicle Routing Problem to optimize the analysis of tourism routes, thereby enabling the separation of different types of tourism. These divisions were based on the Vehicle Routing Problem to optimize routes for one-day and two-day tours. A new method and model for optimization for tourism routes was constructed to provide a basis and reference for the optimization of tourism routes in similar cities. The observations and results of the present study can facilitate the government in developing the tourism industry and maximizing the benefits obtained from them. Further, travel agencies and tourists will have the provision of designing optimum tourism routes.

SIK2 maintains breast cancer stemness by phosphorylating LRP6 and activating Wnt/ß-catenin signaling.

Breast cancer stem cells (BCSCs) are the main drivers of recurrence and metastasis. However, commonly used drugs rarely target BCSCs. Via screenings, we found that Salt-inducible kinase 2 (SIK2) participated in breast cancer (BC) stemness maintenance and zebrafish embryos development. SIK2 was upregulated in recurrence samples. Knockdown of SIK2 expression reduced the proportion of BCSCs and the tumor initiation of BC cells. Mechanistically, SIK2, phosphorylated by CK1α, directly phosphorylated LRP6 in a SIK2 kinase activity-dependent manner, leading to Wnt/ß-catenin signaling pathway activation. ARN-3236 and HG-9-91-01, inhibitors of SIK2, inhibited LRP6 phosphorylation and ß-catenin accumulation and disturbed stemness maintenance. In addition, the SIK2-activated Wnt/ß-catenin signaling led to induction of IDH1 expression, causing metabolic reprogramming in BC cells. These findings demonstrate a novel mechanism whereby Wnt/ß-catenin signaling pathway is regulated by different kinases in response to metabolic requirement of CSCs, and suggest that SIK2 inhibition may potentially be a strategy for eliminating BCSCs.

Oophorectomy for ovarian torsion - should this be abandoned?

BACKGROUND: Management of ovarian torsion ranges from de-torsion to oophorectomy and is dependent on various factors. Oophorectomy can have significant implications for fertility and general health, thus requiring careful consideration. AIMS: We evaluate the management of ovarian torsion at a tertiary hospital over a ten-year period and identify the predictors of oophorectomy in ovarian torsion cases. MATERIALS AND METHODS: Inpatient notes of patients who underwent surgical management for acute ovarian torsion at a tertiary hospital in Victoria, Australia, were reviewed, from January 2008 to June 2018. We reported the incidence and predictors of oophorectomy and ovarian ischaemia and current practices in oophoropexy. RESULTS: Our analysis included 159 patients. The incidence of oophorectomy was 47%. After confounders were adjusted, increasing age was the only significant predictor for oophorectomy. The adjusted odds ratio of having an oophorectomy based on age alone was 1.10 for each year increase in age between the ages of 15 and 68 (P = 0.001, 95% confidence interval 1.04-1.16). Of those with oophorectomy, 57% had ischaemia confirmed histologically. There were no significant predictors for ischaemia. CONCLUSION: The incidence of oophorectomy in this audit is comparable to reported incidences in current literature. However, with increasing evidence to support ongoing ovarian function even in cases where ischaemia is histologically confirmed, this incidence could be lowered. Age was the only variable that was found to have a significant effect on the incidence of oophorectomy.