Synthesis and structure-activity relationship study of a potent MHO7 analogue as potential anti-triple negative breast cancer agent.

Triple-negative breast cancer (TNBC) is the most aggressive, high recurrence and metastatic breast cancer subtype. There are few safe and effective therapeutic drugs for treatment of TNBC. The marine natural product MHO7 has been determined to be a potential antitumor agent. However, its moderate activity and complex structure hampered its clinical application. In this study, a series of novel derivatives with modification on C24 of MHO7 were first synthesized. Some of the analogues were significantly more potent than MHO7 against all selected breast cancer cell lines. Among them, compound 4m had the best activity, and its IC50 value against TNBC was up to 0.51 µM. A whole-genome transcriptomic analysis shown that the mechanism of compound 4m against TNBC cells was similar with that of parent compound MHO7. Subsequent cellular mechanism studies showed that compound 4m could induce apoptosis of MDA-MB-231 cells through mitochondria pathway and cause G1 phase arrest. Moreover, 4m could disrupt the expressions of MAPK/Akt pathway-associated proteins (p-p38 and p-Akt) and remarkably increase the ratio of Bax to Bcl-2 and activate cleaved caspase 3/9/PARP. Importantly, 4m could influence the expression of Smad 7, and p-Smad 3 to inhibit TNBC cells metastasis. Stability assays in rat plasma and liver microsomes indicated that 4m still have room for further optimization. And the results of the online molinspiration software predicted that 4m has desirable physicochemical properties but some properties still have violation from the Lipinski rule of five. Overall, the modification on C24 of MHO7 was a promising way for developing novel anti-TNBC agents with considerable potential for optimization.

Design and synthesis of marine sesterterpene analogues as novel estrogen receptor α degraders for breast cancer treatment.

Targeted protein degradation using small molecules is an intriguing strategy for drug development. The marine sesterterpene compound MHO7 had been reported to be a potential ERα degradation agent. In order to further improve its biological activity, two series of novel MHO7 derivatives with long side chains were designed and identified as novel selective estrogen receptor down-regulators (SERDs). The growth inhibition activity of the novel SERD compounds were significantly affected by the type and length of the side chain. Most of the derivatives were significantly more potent than MHO7 against both drug-sensitive and drug-resistant breast cancer cells. Among them, compound 16a, with IC50 values of 0.41 µM against MCF-7 cell lines and 9.6-fold stronger than MHO7, was the most potential molecule. A whole-genome transcriptomic analysis of MCF-7 cells revealed that the mechanism of 16a against MCF-7 cell was similar with that of MHO7. The estrogen signaling pathway was the most affected among the disturbed genes, but the ERα degradation activity of 16a was observed higher than that of MHO7. Other effects of 16a were confirmed similar with MHO7, which means that the basic mechanisms of the derivatives are the same with the ophiobolin backbone, i.e. the degradation of ERα is mediated via proteasome-mediated process, the induction of apoptosis and the cell cycle arrest at the G1 phase. Meanwhile, a decrease of mitochondrial membrane potential and an increase of cellular ROS were also detected. Based on these results, as a novel modified ophiobolin derived compound, 16a may warrant further exploitation as a promising SERD candidate agent for the treatment of breast cancer.

Clinicopathological Characteristics and Prognosis of Hepatoid Adenocarcinoma of the Stomach: Evaluation of a Pooled Case Series.

Hepatoid adenocarcinoma of the stomach (HAS) is an extremely rare and unique gastric malignancy. The present study aimed to examine the relevance of the clinicopathological characteristics of HAS with patient prognosis. We retrospectively reviewed clinical data of 34 HAS patients treated at our institution between January 2010 and December 2016, as well as 294 cases reported prior to 2017 in research databases. Among these patients, 45.6% (115/252) had lesions in the gastric antrum and 77.0% (235/305) were male. Elevated levels of serum alpha-fetoprotein (AFP) were detected in most patients (75/93, 80.6%). Vascular invasion (199/286, 69.6%), lymph node metastasis (222/283, 78.4%), and preoperative distant metastasis (121/328, 36.9%) were commonly observed. The 5-year disease-free survival (DFS) and disease-specific survival (DSS) were 20.7% and 29.2%, respectively. DFS and DSS of patients receiving neoadjuvant therapy were significantly higher than those of patients receiving postoperative adjuvant therapy [DFS: P<0.001, hazard ratio (HR)=-1.831, 95% confidence interval (CI): 0.060-0.429; DSS: P<0.001, HR=-2.185, 95% CI: 0.032-0.401]. In conclusion, HAS exhibits distinct clinicopathological characteristics and a strikingly worse prognosis when compared with common gastric cancer. Complete surgery, early pTNM stage, and adjuvant therapy may predict a more favorable prognosis. Neoadjuvant therapy is strongly recommended for patients with lymph node metastasis or/and preoperative distant metastasis.

[Effect of protecting parathyroid in situ in the operation of total thyroidectomy].

OBJECTIVE: To evaluate the effect of protecting parathyroid glands in situ in the operation of total thyroidectomy by detecting parathyroid hormone after the operation. METHODS: In the surgical team, 1019 consecutive patients with thyroid diseases were treated with total thyroidectomy. During the operation, parathyroid glands were protected in situ with correctly identifying the parathyroid glands, precisely dissecting its envelope and protecting its blood supply. Serum calcium level and parathyroid hormone were measured before and 24 hours after operation. The patients who had symptomatic hypocalcemia or hypoparathyroidism were given supportive treatment and followed-up. RESULTS: At least one of the parathyroid glands was preserved and remained in situ in all cases. Eighty-nine cases (8.7%) had decreased parathyroid hormone levels and 42 cases (4.1%) had complicated symptomatic hypocalcemia. The symptoms of hypocalcemia in all these cases could be controlled by supportive treatment, and serum calcium level and parathyroid hormone had all recovered 1 - 6 months later. If 3 and 4 parathyroid were conserved in situ, the postoperative complication rate was significantly lower than those with 1 and 2 parathyroid conserved (decreased PTH 69/999 vs 20/20, symptoms of hypocalcemia 25/999 vs 17/20, all P < 0.01). CONCLUSION: The techniques to protect parathyroid glands in situ are effective measure to prevent the postoperative hypoparathyroidism in total thyroidectomy.