Precise lymph node biopsy for endometrial cancer confined to the uterus: Analysis of 43 clinical cases.

OBJECTIVE: To explore a precise association between tumor location and lymph node (LN) biopsy algorithm in uterine confined endometrial cancer (EC). MATERIALS AND METHODS: Patients with EC treated in the Department of Obstetrics and Gynecology, South Branch of Fujian Provincial Hospital were included in this observational retrospective study. Based on the procedure of treatment, patients were separated to stage I (2015.07-2019.09) and stage II (2019.09-2021.9). In each stage, patients were separated to high and low-risk group by the predicted results. Patients in the high-risk group received systematic lymphadenectomy in stage I and sentinel lymph node (SLN) dissection in stage II. The efficiency of lymph node metastasis (LNM) detection rates was compared between stage I and stage II cases. Precise lymph node biopsy algorithm was also constructed based on the outcomes of stage II. RESULTS: Overall, 43 patients, 28 in stage I and 15 in stage II, were included in the study. No recurrence or death cases had been found within follow-up terms. Based on the difference in the detection efficiency of LNM (p > 0.05), there was no difference between two stages. Thus, systematic lymphadenectomy and SLN biopsy provided similar success rates. The location of tumor site was also important for deciding whether pelvic or para-aortic SLN should be sampled for LNM. CONCLUSIONS: Precise SLN biopsy for EC confined to the uterus showed comparable LNM detection rate as systematic lymphadenectomy. EC location may be used to determine whether pelvic or para-aortic SLN sampling should be conducted for treatment.

Discovery of potent immune-modulating molecule taccaoside A against cancers from structures-active relationships of natural steroidal saponins.

BACKGROUND: In recent years, the T-cell therapy and immune checkpoint inhibitors toward CTLA-4 and PD-1/PD-L1 axis antibody therapy have acquired encouraging success. However, most of patients were still not benefited with lots of troubles, such as low penetration of tissues/cells, strong immunogenicity and cytokine release syndrome, and long manufacturing process and expensive costs. By contrast, the immune-modulating small molecules possessed natural advantages to overcome these obstacles and might achieve greater success. PURPOSE: Exploring the potent immune-modulating natural small molecules and revealing what kinds of molecules or structures with the immunomodulatory activity against cancers. METHODS: A novel non-cytotoxic T-cell immunomodulating screening model was used to identify the cytotoxic/selective/immunomodulatory bioactivity for 148 natural steroidal saponins. The structure-activity relationships (SARs) research was used to reveal the key groups for immunomodulation/cytotoxicity/selectivity. The negative selection was used to isolate and purify the T-cell. The cell viability assay was used to measure the anti-cancer effect in vitro. The ELISA assay was used to detect the cytokines for IL-1ß, IL-6, TNF-α, IFN-γ, IL-12, perforin and granzyme B (GZMB). The western blotting assay was used to research the immunomodulatory mechanism. The siRNA knockdown was used to generate the IFN-γ resistant melanoma cells. The NOG immune-deficient mice were used to evaluate the anti-tumor efficacy in vivo. The peripheral blood samples from 10 cancer patients were used to detect the broad population anti-tumor efficacy. RESULTS: It was reported that the correlation among structures and immunomodulation/ cytotoxicity/selectivity, in which opening ring-F with 26-O-glucopyranosyl, disaccharide and trisaccharide chains at C-3, steric hindrance and polarity of C-22 were key immunomodulatory groups. Moreover, taccaoside A was identified as the most potent candidate against cancer cells, including non-small cell lung cancer, triple negative breast cancer, and the IFN-γ resistant melanoma, partly through enhancing T lymphocyte mTORC1-Blimp-1 signal to secrete GZMB. Besides, 10 patients derived T-cell also would be modulated against cancer cells in vitro. Moreover, the overall survival was great extended (>140 days vs 93 days) with nearly 100% tumor burden disappearance (0 mm3vs 1006 ± 79.5 mm3) in mice. CONCLUSION: This work demonstrated one possibility for this concerned purpose, and identified a potent immune-modulating natural molecule taccaoside A, which might contribute to cancer immunotherapy in future.

Synthesis and biological evaluation of thieno[3,2-c]pyrazol-3-amine derivatives as potent glycogen synthase kinase 3ß inhibitors for Alzheimer's disease.

Glycogen synthase kinase 3ß (GSK-3ß) catalyses the hyperphosphorylation of tau protein in the Alzheimer's disease (AD) pathology. A series of novel thieno[3,2-c]pyrazol-3-amine derivatives were designed and synthesised and evaluated as potential GSK-3ß inhibitors by structure-guided drug rational design approach. The thieno[3,2-c]pyrazol-3-amine derivative 16b was identified as a potent GSK-3ß inhibitor with an IC50 of 3.1 nM in vitro and showed accepted kinase selectivity. In cell levels, 16b showed no toxicity on the viability of SH-SY5Y cells at the concentration up to 50 µM and targeted GSK-3ß with the increased phosphorylated GSK-3ß at Ser9. Western blot analysis indicated that 16b decreased the phosphorylated tau at Ser396 in a dose-dependent way. Moreover, 16b effectively increased expressions of ß-catenin as well as the GAP43, N-myc, and MAP-2, and promoted the differentiated neuronal neurite outgrowth. Therefore, the thieno[3,2-c]pyrazol-3-amine derivative 16b could serve as a promising GSK-3ß inhibitor for the treatment of AD.

A Unique GSK-3ß inhibitor B10 Has a Direct Effect on Aß, Targets Tau and Metal Dyshomeostasis, and Promotes Neuronal Neurite Outgrowth.

Due to the complicated pathogenesis of Alzheimer's disease (AD), the development of multitargeted agents to simultaneously interfere with multiple pathological processes of AD is a potential choice. Glycogen synthase kinase-3ß (GSK-3ß) plays a vital role in the AD pathological process. In this study, we discovered a novel 1H-pyrrolo[2,3-b]pyridine derivative B10 as a GSK-3ß inhibitor that features with a quinolin-8-ol moiety to target the metal dyshomeostasis of AD. B10 potently inhibited GSK-3ß with an IC50 of 66 ± 2.5 nM. At the concentration of 20 µM, B10 increased ß-catenin abundance (ß-catenin/GAPDH: 0.83 ± 0.086 vs. 0.30 ± 0.016), phosphorylated GSK-3ß at Ser9 (p-GSK-3ß/GAPDH: 0.53 ± 0.045 vs. 0.35 ± 0.012), and decreased the phosphorylated tau level (p-tau/GAPDH: 0.33 ± 0.065 vs. 0.83 ± 0.061) in SH-SY5Y cells. Unlike other GSK-3ß inhibitors, B10 had a direct effect on Aß by inhibiting Aß1-42 aggregation and promoting the Aß1-42 aggregate disassociation. It selectively chelated with Cu2+, Zn2+, Fe3+, and Al3+, and targeted AD metal dyshomeostasis. Moreover, B10 effectively increased the mRNA expression of the recognized neurogenesis markers, GAP43, N-myc, and MAP-2, and promoted the differentiated neuronal neurite outgrowth, possibly through the GSK-3ß and ß-catenin signal pathways. Therefore, B10 is a potent and unique GSK-3ß inhibitor that has a direct on Aß and serves as a multifunctional anti-AD agent for further investigations.

Synthesis and evaluation of novel GSK-3ß inhibitors as multifunctional agents against Alzheimer's disease.

To target the multi-facets of Alzheimer's disease (AD), a series of novel GSK-3ß inhibitors containing the 2,3-diaminopyridine moiety were designed and synthesized. The amide derivatives 5a-f showed moderate potency against GSK-3ß with weak Cu2+, Zn2+ and Al3+ chelating ability. The imine derivatives 9a, 9b and 9e were potent GSK-3ß inhibitors and selective Cu2+and Al3+ chelators. The 1,2-diamine derivatives 10a-e were strong metal-chelators, but decreased or lost their GSK-3ß inhibitory potency. In vitro, compounds 9a, 9b and 9e, especially 9b, exhibited good Cu2+-induced Aß aggregation inhibition, Cu2+-Aß complex disaggregation, ROS formation inhibition, and antioxidant activities. In cells, compounds 9a, 9b and 9e can inhibit tau protein phosphorylation and protect neuro cells against Cu2+-Aß1-42 and H2O2-induced cell damage. Furthermore, compound 9b was predicted to have the ability to pass the BBB with drug likeness properties. Therefore, compound 9b might be a good lead for the development of novel GSK-3ß inhibitors targeting multi-facets of AD.

Effects of calcium fertilizer application on absorption and distribution of nutrients in peanut under salt stress.

In order to solve the problems of nutrient absorption and accumulation and provide theoretical basis for rational amount of calcium fertilization of peanut in saline land, the effects of calcium fertilizer application on absorption and accumulation of nutrients including nitrogen, phosphorus, potassium, calcium and magnesium in peanut under salt stress were examined. Using 'Huayu 25' as experimental material, four Ca levels [T1 (0), T2 (75), T3 (150) and T4 (225) kg·hm-2 CaO] were set under 0.3% salt stress in a pot experiment. The results showed that nutrient contents in peanut followed the order of nitrogen > potassium > calcium > phosphorus > magnesium. At the seedling stage, leaves were the absorption center of nitrogen and calcium, while stems were the center of phosphorus, potassium and magnesium, with nearly half of nutrient accumulation being distributed in the corresponding growth center. At mature stage, the absorption centers of nitrogen, phosphorus and potassium were transferred to pod. The accumulation of nitrogen and phosphorus in seed kernel reached to 72.3%-78.9%. The absorption centers of calcium and magnesium was still in the leaves and stems, with a distribution ratio of 49.8% and 32.6%, respectively. Salt stress significantly inhibited nutrient absorption and distribution in peanut, especially decreased the nitrogen accumulation in leaves and seed kernels. However, salt stress increased the magnesium accumulation in pod. Exogenous calcium application had significant positive effect on absorption and accumulation of nitrogen, phosphorus, calcium and magnesium in different organs of peanut under salt stress. It had significant adjustment on phosphorus accumulation in seed kernel, which was increased by more than 50%. Appropriate calcium content could significantly promote the peanut nutrient absorption and accumulation under salt stress and improve the distribution ratio of nitrogen, phosphorus, potassium in mature pods of peanut. According to the responses of nutrient absorption and distribution, the optimized application amount for calcium fertilizer under 0.3% salt stress was 150 kg·hm-2 CaO.

[Features of contrast-enhanced ultrasound imaging in malignant lymphoma after treatment with integrated Chinese and Western medicine].

OBJECTIVE: To investigate the typical features of contrast-enhanced ultrasound imaging in malignant lymphoma after treatment with integrated Chinese and Western medicine. METHODS: Ten patients with malignant lymphoma after different treatment cycles were examined with contrast-enhanced sonography, including 21 lymphnodes (in the neck, space of iliac blood vessels, retroperitoneum) and 7 spleen infiltrations. RESULTS: The blood flow pattern distribution in lymph node before freatment was significantly different from that after trentment showed either by color Doppler flow imaging (CDFI) or by contrast-enhanced ultrasound (CEUS, P < 0.05), and the difference in splenic lesion was shown by CEUS (P < 0.05). CONCLUSION: Contrast-enhanced ultrasound imaging is a valuable tool for the follow-ups of malignant lymphoma after chemotherapy and guiding subsequent treatment.

[Diagnosis of thyroid space-occupying lesions using real-time contrast-enhanced ultrasonography with sulphur hexafluoride microbubbles].

OBJECTIVE: To explore the value of contrast-enhanced ultrasound (CEUS) in the diagnosis of thyroid occupied lesions with injection of sulphur hexafluoride microbubbles. METHODS: Fifty nine cases of conventional ultrasonic diagnosis of thyroid lesions in patients with 73 lesions re-sulfur hexafluoride microbubble ultrasound contrast real-time inspection, the use of CEUS and contrast pulse sequencing (CPS). RESULTS: Seventy-three lesions were satisfied with the dynamic contrast perfusion imaging. Ultrasound contrast prompted the 15 lesions (13 cases) of malignant lesions by postoperative pathology confirmed papillary thyroid carcinoma, ultrasound images showed a low or mixed echo, boundary ambiguity, accompanied by Microcalcification foci, blood flow distribution I rank or grade III. Ultrasound prompted 58 lesions (46 cases) of benign lesions, blood flow distribution of grade II or III, the performance of a variety of two-dimensional ultrasound image, showing cystic, solid or liquid-solid mass, border clearance. Contrast with the surrounding thyroid tissue, lesionsor=20 mm papillary thyroid carcinoma, manifested prior to the beginning of the adjacent thyroid substance to enhance and dissection, showing the form of high-enhanced perfusion; thyroid follicular adenoma as early as the beginning of the adjacent thyroid substance to enhance and dissection, mass retained within the contrast agent longer time, showing the form of high-enhanced perfusion; nodular goiter enhanced for thyroid nodules and adjacent synchronization started to pick up in real terms, after the 6 lesions showed nodular contrast slightly earlier than the adjacent thyroid substance started to pick up, 28 lesions with synchronous real beginning of the adjacent thyroid dissection, 11 lesions of nodular dissipated early on (started receding time < or = 25 s) adjacent to thyroid substance. CONCLUSION: The real-time CEUS with injecting sulphur hexafluoride microbubbles is valuable in the diagnosis and differential diagnosis of the thyroid occupied lesions.