Targeting Prostaglandin E2 Receptor EP2 for Treatment of High-Risk Neuroblastoma

Prostaglandin E2 (PGE2) is a predominant proinflammatory regulator that plays pivotal roles in regulating tumor cell proliferation, migration, and invasion. It fosters an inflammation-enriched microenvironment that facilitates angiogenesis and immune evasion. Neuroblastoma (NB) is a lethal pediatric malignancy. PGE2 has been reported to promote high-risk NB proliferation and progression. However, the PGE2 receptor subtype (EP1-EP4) which potentially contributed to NB growth remained elusive. In this research, at first, we demonstrated that EP2 receptor was highly correlated with NB aggressiveness, and acted as a predominant Gαs-coupled receptor mediating PGE2-initiated cyclic AMP (cAMP) signaling in NB cells with high-risk factors, including chromosome 11q deletion and MYCN amplification. CRISPR/Cas9 induced EP2 knockout blocked the development of NB xenografts in athymic nude mice. Additionally, EP2 conditional knockdown prevented established tumors from progressing in vivo. Pharmacological inhibition of EP2 by our recently developed antagonist TG6-129 substantially suppressed the NB tumor growth in both nude mice and syngeneic immunocompetent hosts, with the observable anti-inflammatory, anti-angiogenic, and apoptotic effects. Next, based on the scaffold of TG6-129, we developed, and identified a novel robust EP2 antagonizing compound GLL-618. GLL-618 demonstrated enhanced EP2 binding potency. Meanwhile, it also showed advanced pharmacokinetic features such as prolonged plasma half-life and im-proved bioavailability. Applied as a single treatment reagent, GLL-618 could significantly inhibited high-risk NB neuro-spheres development and suppressed high-risk NB xenograft tumors growth by 50%. Subsequently, we combined GLL-618 with vincristine, a prevalently used chemotherapy drug for the treatment of high-risk NB. GLL-618 could synergistically increase the anti-tumor effect of vincristine, which was evidenced by an overall 70% tumor weight reduction at the treatment endpoint in an immunocompetent allograft model, accompanied with quenched proinflammatory signaling within the tumor microenvironment and elevated expression of apoptotic markers. In conclusion, this study suggested that the PGE2/EP2 signaling pathway might contribute to NB development and progression. EP2 inhibition with our drug-like compounds could be potentially applied as an alternative, and adjunctive treatment strategy for this deadly pediatric cancer

Identification of a Novel UT-B Urea Transporter in Human Urothelial Cancer

The urea transporter UT-B is widely expressed and has been studied in erythrocyte, kidney, brain and intestines. Interestingly, UT-B gene has been found more abundant in bladder than any other tissue. Recently, gene analyses demonstrate that SLC14A1 (UT-B) gene mutations are associated with bladder cancer, suggesting that urea transporter UT-B may play an important role in bladder carcinogenesis. In this study, we examined UT-B expression in bladder cancer with human primary bladder cancer tissues and cancer derived cell lines. Human UT-B has two isoforms. We found that normal bladder expresses long form of UT-B2 but was lost in 8 of 24 (33%) or significantly downregulated in 16 of 24 (67%) of primary bladder cancer patients. In contrast, the short form of UT-B1 lacking exon 3 was detected in 20 bladder cancer samples. Surprisingly, a 24-nt in-frame deletion in exon 4 in UT-B1 (UT-B1Δ24) was identified in 11 of 20 (55%) bladder tumors. This deletion caused a functional defect of UT-B1. Immunohistochemistry revealed that UT-B protein levels were significantly decreased in bladder cancers. Western blot analysis showed a weak UT-B band of 40 kDa in some tumors, consistent with UT-B1 gene expression detected by RT-PCR. Interestingly, bladder cancer associate UT-B1Δ24 was barely sialylated, reflecting impaired glycosylation of UT-B1 in bladder tumors. In conclusion, SLC14A1 gene and UT-B protein expression are significantly changed in bladder cancers. The aberrant UT-B expression may promote bladder cancer development or facilitate carcinogenesis induced by other carcinogens

Faster NTRU-based Bootstrapping in less than 4 ms

Bootstrapping is a critical technique in constructing fully homomorphic encryption (FHE), which serves to refresh the noise in FHE ciphertexts, enabling an arbitrary number of homomorphic operations. Among published results, the TFHE-rs library [Zam22] offers the fastest bootstrapping implementation on CPU platforms by taking advantage of AVX-512 instructions. In this paper, we improve the efficiency of the bootstrapping algorithm based on the NTRU problem. First, we introduce the approximate gadget decomposition method tailored for NTRU ciphertext, reducing the number of NTT operations required for external products. Second, by integrating the approximate decomposition and key unrolling techniques, we improve the performance of CMux-based blind rotation. Third, for the automorphism-based blind rotation method, we present a hybrid window size technique that reduces the number of automorphisms by 34% compared to recent work [XZD+23](in Crypto23). Subsequently, we implement the proposed bootstrapping algorithm on the CPU platform with AVX instructions. Experimental results demonstrate that our method only takes 3.8ms, which achieves a 1.8× speedup compared to the TFHE-rs library. Finally, we propose an efficient FPGA accelerator based on the CMux method, which not only achieves the best performance but also exhibits high throughput advantages. Our accelerator can improve performance by 2x compared to state-of-the-art FPGA implementations (e.g., FPT)

LmbU, a Cluster-Situated Regulator for Lincomycin, Consists of a DNA-Binding Domain, an Auto-Inhibitory Domain, and Forms Homodimer

Few studies were reported about the regulatory mechanism of lincomycin biosynthesis since it was found in 1962. Although we have proved that a cluster-situated regulator (CSR) LmbU (GenBank Accession No. ABX00623.1) positively modulates lincomycin biosynthesis in Streptomyces lincolnensis NRRL 2936, the molecular mechanism of LmbU regulation is still unclear. In this study, we demonstrated that LmbU binds to the target lmbAp by a central DNA-binding domain (DBD), which interacts with the binding sites through the helix-turn-helix (HTH) motif. N-terminal of LmbU includes an auto-inhibitory domain (AID), inhibiting the DNA-binding activity of LmbU. Without the AID, LmbU variant can bind to its own promoter. Interestingly, compared to other LmbU homologs, the homologs within the biosynthetic gene clusters (BGCs) of known antibiotics generally contain N-terminal AIDs, which offer them the abilities to play complex regulatory functions. In addition, cysteine 12 (C12) has been proved to be mainly responsible for LmbU homodimer formation in vitro. In conclusion, LmbU homologs naturally exist in hundreds of actinomycetes, and belong to a new regulatory family, LmbU family. The present study reveals the DBD, AID and dimerization of LmbU, and sheds new light on the regulatory mechanism of LmbU and its homologs

Identification of a Novel UT-B Urea Transporter in Human Urothelial Cancer

The urea transporter UT-B is widely expressed and has been studied in erythrocyte, kidney, brain and intestines. Interestingly, UT-B gene has been found more abundant in bladder than any other tissue. Recently, gene analyses demonstrate that SLC14A1 (UT-B) gene mutations are associated with bladder cancer, suggesting that urea transporter UT-B may play an important role in bladder carcinogenesis. In this study, we examined UT-B expression in bladder cancer with human primary bladder cancer tissues and cancer derived cell lines. Human UT-B has two isoforms. We found that normal bladder expresses long form of UT-B2 but was lost in 8 of 24 (33%) or significantly downregulated in 16 of 24 (67%) of primary bladder cancer patients. In contrast, the short form of UT-B1 lacking exon 3 was detected in 20 bladder cancer samples. Surprisingly, a 24-nt in-frame deletion in exon 4 in UT-B1 (UT-B1 1 24) was identified in 11 of 20 (55%) bladder tumors. This deletion caused a functional defect of UT-B1. Immunohistochemistry revealed that UT-B protein levels were significantly decreased in bladder cancers. Western blot analysis showed a weak UT-B band of 40 kDa in some tumors, consistent with UT-B1 gene expression detected by RT-PCR. Interestingly, bladder cancer associate UT-B1 1 24 was barely sialylated, reflecting impaired glycosylation of UT-B1 in bladder tumors. In conclusion, SLC14A1 gene and UT-B protein expression are significantly changed in bladder cancers. The aberrant UT-B expression may promote bladder cancer development or facilitate carcinogenesis induced by other carcinogens.Emory URC grant; NIH [R01-DK087838, R01-DK89828, R01-DK41707]; China Scholarship Council (CSC) under the State Scholarship FundSCI(E)ARTICLE

A new species of the genus Leptolalax (Anura: Megophryidae) from Guangxi, China

Yuan, Zhiyong, Sun, Ruida, Chen, Jinmin, Rowley, Jodi J. L., Wu, Zhengjun, Hou, Shaobing, Wang, Shaoneng, Che, Jing (2017): A new species of the genus Leptolalax (Anura: Megophryidae) from Guangxi, China. Zootaxa 4300 (4): 551-570, DOI: https://doi.org/10.11646/zootaxa.4300.4.

FIGURE 3 in A new species of the genus Leptolalax (Anura: Megophryidae) from Guangxi, China

FIGURE 3. (A) Dorsal view, (B) lateral view, (C) Ventral view, (D) dorsolateral view, (E) dorsal view of thighs and (F) posterioventral view of thighs in the holotype (KIZ046696) of Leptolalax maoershanensis sp. nov. in life.Published as part of Yuan, Zhiyong, Sun, Ruida, Chen, Jinmin, Rowley, Jodi J. L., Wu, Zhengjun, Hou, Shaobing, Wang, Shaoneng & Che, Jing, 2017, A new species of the genus Leptolalax (Anura: Megophryidae) from Guangxi, China, pp. 551-570 in Zootaxa 4300 (4) on page 558, DOI: 10.11646/zootaxa.4300.4.5, http://zenodo.org/record/84014

FIGURE 4 in A new species of the genus Leptolalax (Anura: Megophryidae) from Guangxi, China

FIGURE 4. (A) Dorsal and (B) ventral views of the hand, and (C) dorsal and (D) ventral views of the foot in the holotype (KIZ046696) of Leptolalax maoershanensis sp. nov. in life.Published as part of Yuan, Zhiyong, Sun, Ruida, Chen, Jinmin, Rowley, Jodi J. L., Wu, Zhengjun, Hou, Shaobing, Wang, Shaoneng & Che, Jing, 2017, A new species of the genus Leptolalax (Anura: Megophryidae) from Guangxi, China, pp. 551-570 in Zootaxa 4300 (4) on page 559, DOI: 10.11646/zootaxa.4300.4.5, http://zenodo.org/record/84014