Abstract
MTAP deletion is common in about 15% of all human cancers and coincides with the deletion of tumor suppressor locus containing CDKN2A/B. Methylthioadenosine (MTA), the substrate of MTAP, ...accumulates as a result of MTAP deletion. Increased levels of MTA result in partial inhibition of the PRMT5 enzyme by competing with S-adenosylmethionine (SAM, the methyl donor for PRMT5 substrate) due to structural similarity. Cancer cell lines with MTAP-deletion exhibit profound sensitivity to PRMT5 inhibition, suggesting MTAPnull-selective PRMT5 inhibitors have the potential to treat patients with MTAP deficiency (Kryukov et al., 2016). We identified CTS3157 as an orally bioavailable small molecule MTA-cooperative PRMT5 inhibitor that binds to PRMT5-MTA complex and inhibits PRMT5 enzymatic activity. Cell-based assays revealed that CTS3157 demonstrated potent PRMT5 inhibition as evidenced by suppression of symmetric dimethylarginine (SDMA) and cell growth inhibitory activity for MTAP-deleted cell lines over isogenic MTAPWT cell lines. Moreover, CTS3157 series compounds exhibited strong cell growth inhibition in a diverse panel of MTAPnull human tumor cell lines across several lineages. In vivo, CTS3157 demonstrated potent antitumor response after once-daily oral administration in MTAP-deleted xenograft models. The anti-tumor activity is correlated with PRMT5 modulation as measured by reduced SDMA levels. At molecular level, PRMT5 inhibition by CTS3157 resulted in massive RNA splicing defects and differentially expressed genes involving key cellular activities in MTAPnull cells. In summary, MTAPnull-selective PRMT5 inhibitor CTS3157 showed strong and durable antitumor responses in vitro and in vivo in MTAP-deleted tumors across diverse lineages. CTS3157 is an effective and promising therapeutics against MTAP-deleted tumors.
Citation Format: Long Wang, Yilin Liu, Hui Shi, Yuanyuan Liu, Qiugeng Ouyang, Jiannan Guo, Yiqin Wang, Youzhen Wang, Guoliang Xu, Yuan Mi, Haiping Wu. CTS3157, a novel MTA-cooperative PRMT5 inhibitor for targeting MTAP-deleted human tumors. abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6273.
•The variants in FIX’s SP cause HB at the stage of posttranscription, translation, and posttranslational processing.•The missense variants in FIX’s SP mainly disturb the cotranslational translocation ...and/or cleavage of SP.
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Signal peptide (SP) is essential for protein secretion, and pathogenic variants in the SP of factor IX (FIX) have been identified in hemophilia B (HB). However, the underlying mechanism for the genotype-phenotype correlation of these variants has not been well studied. Here, we systematically examined the effects of 13 pathogenic point variants in the SP of FIX using different approaches. Our results showed that these point variants lead to HB by missense variants and/or aberrant premessenger RNA (pre-mRNA) splicing. The missense variants in a hydrophobic core (h-region) mainly affected the cotranslational translocation function of the SP, and those in C-terminal containing cleavage site (c-region) caused FIX deficiency mainly by disturbing the cotranslational translocation and/or cleavage of the SP. Almost absolute aberrant pre-mRNA splicing was only observed in variants of c.82T>G, but a slight change of splicing patterns was found in variants of c.53G>T, c.77C>A, c.82T>C, and c.83G>A, indicating that these variants might have different degrees of impact on pre-mRNA splicing. Although two 6-nt deletion aberrant pre-mRNA splicing products caused FIX deficiency by disturbing the SP cleavage, they could produce some functional mature FIX, and vitamin K could increase the secretion of functional FIX. Taken together, our data indicated that pathogenic variants in the SP of FIX caused HB through diverse molecular mechanisms or even a mixture of several mechanisms, and vitamin K availability could be partially attributed to varying bleeding tendencies in patients carrying the same variant in the SP.
Our previous study has demonstrated that TF/FVIIa and protease-activated receptor 2 (PAR2) are closely related to the proliferation and migration of colon cancer cell line SW620. However, the ...detailed signaling cascades and underlying molecular mechanisms remain unclear. This study has investigated whether extracellular signal-regulated kinase 1 and 2 (ERK1/2) and nuclear factor kappaB (NF-κB) signaling pathways are involved in the events. The results revealed that PAR2-activating peptide (PAR2-AP) or FVIIa elicited time-dependent upregulation of ERK1/2 phosphorylation in SW620 cells, and the effect of FVIIa was significantly attenuated by anti-TF antibody. PAR2-AP or FVIIa also increased NF-κB (p65/RelA) levels among cell nuclear proteins and simultaneously decreased IκB-α levels in the cytoplasmic proteins. Such effects of FVIIa can be inhibited with anti-PAR2 or anti-TF antibodies. While ERK1/2 inhibitor (U0126) intervened with the regulatory effects of PAR2-AP and FVIIa on IκB-α/NF-κB (p65/Rel) expression in the cells, NF-κB inhibitor (PDTC) partially blocked the enhancing effects of PAR2-AP and FVIIa on the proliferating and migratory ability of SW620 cells. Furthermore, the regulatory effects of PAR2-AP and FVIIa on expressions of certain proteins (IL-8, caspase-7, and TF) were also significantly abolished by PDTC. Collectively, the data in this study suggest that the interaction between FVIIa and TF induces PAR2 activation, thereby triggers the ERK1/2 and IκB-α/NF-κB signal transduction pathway to regulate the gene expression of IL-8, TF, and caspase-7, and ultimately promotes SW620 cell proliferation and migration.
Existing RNA in situ imaging strategies mostly utilize parallel repetitive nucleic acid self-assembly to achieve multiple analysis, with limitations of complicated systems and cumbersome steps. Here, ...a Cas9 code key system with key probe (KP) encoder and CRISPR/Cas9 signal exporter is developed. This system triggers T-protospacer adjacent motif (T-PAM structural transitions of multiple KP encoders to form coding products with uniform single-guide RNA (sgRNA) target sequences as tandem nodes. Only single sgRNA/Cas9 complex is required to cleave multiple coding products, enabling efficient "many-to-one" tandem signaling, and non-collateral cleavage activity-dependent automatic signaling output through active introduction of mismatched bases. Compared with conventional parallel multiple signaling analysis model, the proposed system greatly simplifies reaction process and enhances detection efficiency. Further, a rapid multiple RNA in situ imaging system is developed by combining the Cas9 code key system with a T-strand displacement amplification (T-SDA) signal amplifier. The constructed system is applied to tumor cells and clinicopathology slices, generating clear multi-mRNA imaging profiles in less than an hour with just one step. Therefore, this work provides reliable technical support for clinical tumor typing and molecular mechanism investigation.
Purpose
Sleep disturbance is significantly associated with overall morbidity, mortality, and quality of life in end-stage renal disease patients. Although it was reported that the prevalence of poor ...sleep quality was 41–83% in hemodialysis patients, sleep disturbance was not well understood in peritoneal dialysis (PD) patients, especially in Asian PD patients. The present study attempted to assess the prevalence and related risk factors of sleep disturbance among continuous ambulatory peritoneal dialysis (CAPD) patients in Guangzhou, southern China.
Methods
Pittsburgh Sleep Quality Index (PSQI) was used to assess the sleep quality in eligible 212 CAPD patients (53.3% men), average age 49.9 ± 16.7 years.
Results
The average global PSQI score of the CAPD patients was 9.5 ± 5.2, with 171 (80.4%) poor sleepers (PSQI scores > or = 5). The PSQI score was negatively correlated with serum albumin (
r
= −0.21,
P
= 0.003) subjective global assessment (SGA) score (
r
= −0.27,
P
= 0.001) and positively correlated with age (
r
= 0.34,
P
< 0.001
)
, high-sensitivity C-reactive protein (
r
= 0.20,
P
= 0.008
)
, level of calcium × phosphate product (
r
= 0.19,
P
= 0.009
)
, cardiovascular disease (
r
= 0.17,
P
= 0.019
)
, Charlson comorbidity index score (
r
= 0.21,
P
= 0.004), malnutrition–inflammation score (MIS) (
r
= 0.31,
P
< 0.001), and duration on CAPD (
r
= 0.20,
P
= 0.005). In multiple analysis, old age, high calcium × phosphate product, low SGA score (β = −0.23,
P
= 0.042), and high MIS (β = 0.30,
P
= 0.007) were independent predictors of sleep disturbance in CAPD patients.
Conclusion
We clearly demonstrated the novel relationship of malnutrition and calcium × phosphate product with poor sleep quality in CAPD patients, which may be a part of the explanation for the strong links between sleep quality and overall morbidity and mortality.
Our study aimed to evaluate clinical outcomes of patients transferred to peritoneal dialysis (PD) because of complications related to hemodialysis (HD). ♢
In a 1:2 matched case-control study, we ...compared patient and technique survival between patients initially treated with HD for at least 3 months and then transferred to PD (transfer group) and patients started on and continuing with PD (no-transfer group). ♢
All baseline characteristics except for initial residual urinary output were comparable between the groups. Compared with patients in the transfer group, patients in the no-transfer group had a higher initial daily residual urinary output 850 mL (range: 600 - 1250 mL) vs 0 mL (range: 0 - 775 mL/d), p = 0.000. The main reasons for transfer to PD were vascular access problems and cardiovascular disease. Patient survival and technique failure rates did not significantly differ between the groups (p > 0.05). The 1-, 3-, and 5-year patient survival rates were 80.0%, 53.7%, and 27.6% in the transfer group and 89.7%, 60.2%, and 43.1% in the no-transfer group. Age (per 10 years) and serum albumin were independent risk factors for long-term survival in PD patients. Relative risk of either death or technique failure was not significantly increased in patients transferred from HD. ♢
Patients who transferred to PD after failing HD had outcomes on PD similar to those for patients who started with and were maintained on PD. Age (per 10 years) and serum albumin were independent risk factors for long-term survival in PD patients.
The novel nano-ultrafine powders for the preparation of CaCu3Ti4O12 ceramic were prepared by the sol-gel method and citrate auto-ignition method. The obtained precursor powders were pressed, sintered ...at 1000 deg C to fabricate microcrystal CaCu3Ti4O12 ceramic. The microcrystalline phase of CaCu3Ti4O12 was confirmed by X-ray powder diffraction (XRD). The morphology and size of the grains of the powders and ceramics under different heat treatments were observed using scanning electron microscopy (SEM). The relative dielectric constant of the ceramic sintered at 1000 deg C was measured with a magnitude of more than 104 at room temperature, which was approaching to those of Pb-containing complex perovskite ceramics, and the loss tangent was less than 0.20 in a broad frequency region. The relative dielectric constant and loss tangent were also compared with that of CaCu3Ti4O12 ceramic prepared by other reported methods.
Portal vein tumor thrombus (PVTT) is very common and it plays a major role in the prognosis and clinical staging of hepatocellular carcinoma (HCC). We have published the first version of the ...guideline in 2016 and revised in 2018. Over the past several years, many new evidences for the treatment of PVTT become available, especially for the advent of new targeted drugs and immune checkpoint inhibitors which have further improved the prognosis of PVTT. So, the Chinese Association of Liver Cancer and Chinese Medical Doctor Association revised the 2018 version of the guideline to adapt to the development of PVTT treatment. Future treatment strategies for HCC with PVTT in China would depend on new evidences from more future clinical trials.
A novel adsorbent, TiO
2
/eggshell composite, was synthesized by sol–gel method, and characterized by XRD and FTIR. The removal of
60
Co(II) from aqueous solution by TiO
2
/eggshell was studied as a ...function of contact time, pH, ionic strength, foreign ions, humic substances and temperature. The results indicated that the sorption of
60
Co(II) on TiO
2
/eggshell was strongly dependent on pH and ionic strength. The Langmuir, Freundlich and D-R models were applied to simulate the sorption of
60
Co(II) at temperatures of 303.15, 323.15 and 343.15 K. The thermodynamic parameters (Δ
H
0
, Δ
S
0
, Δ
G
0
) calculated from the temperature dependent sorption isotherms indicated that the sorption process of
60
Co(II) on TiO
2
/eggshell was endothermic and spontaneous. At low pH, the sorption of
60
Co(II) was dominated by outer-sphere surface complexation or ion exchange, whereas inner-sphere surface complexation was the main sorption mechanism at high pH. TiO
2
/eggshell composites have good potentialities for cost-effective disposal of
60
Co(II) bearing wastewaters.
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