Dopamine and cyclic adenosine monophosphate-regulated phosphoprotein with an apparent Mr of 32000 promotes colorectal cancer growth.

BACKGROUND: Dopamine and cyclic adenosine monophosphate (cAMP)-regulated phosphoprotein with an apparent Mr of 32000 (DARPP-32) is a protein that is involved in regulating dopamine and cAMP signaling pathways in the brain. However, recent studies have shown that DARPP-32 is also expressed in other tissues, including colorectal cancer (CRC), where its function is not well understood. AIM: To explore the effect of DARPP-32 on CRC progression. METHODS: The expression levels of DARPP-32 were assessed in CRC tissues using both quantitative polymerase chain reaction and immunohistochemistry assays. The proliferative capacity of CRC cell lines was evaluated with Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays, while apoptosis was measured by flow cytometry. The migratory and invasive potential of CRC cell lines were determined using wound healing and transwell chamber assays. In vivo studies involved monitoring the growth rate of xenograft tumors. Finally, the underlying molecular mechanism of DARPP-32 was investigated through RNA-sequencing and western blot analyses. RESULTS: DARPP-32 was frequently upregulated in CRC and associated with abnormal clinicopathological features in CRC. Overexpression of DARPP-32 was shown to promote cancer cell proliferation, migration, and invasion and reduce apoptosis. DARPP-32 knockdown resulted in the opposite functional effects. Mechanistically, DARPP-32 may regulate the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway in order to carry out its biological function. CONCLUSION: DARPP-32 promotes CRC progression via the PI3K/AKT signaling pathway.

CircGPRC5A enhances colorectal cancer progress by stabilizing PPP1CA and inducing YAP dephosphorylation.

BACKGROUND: With the advancements in bioinformatic technology, an increasing number of circular RNAs (circRNAs) have been discovered and their crucial roles in the development and progression of various malignancies have been confirmed through multiple pathways. However, the specific mechanisms involving protein-binding circRNAs in colorectal cancer (CRC) remain largely unexplored. METHODS: Differential circRNA expression was assessed using a human circRNA microarray in five CRC tissue and paired normal samples. CircGPRC5A expression was then confirmed in the CRC tissues and paired normal samples using qRT-PCR. The biological function of circGPRC5A in CRC were studied in vitro and in vivo. Western blotting, fluorescence in situ hybridization, immunofluorescence, RNA pulldown, mass spectrometry, immunoprecipitation, quantitative phosphoproteomics, and RNA-binding protein immunoprecipitation assays were used to study circGPRC5A. RESULTS: Our analysis revealed that circGPRC5A expression was higher in CRC tissues compared to normal tissues and was associated with tumor size, tumor stage and lymph node status. CircGPRC5A promoted CRC cell proliferation, migration, and metastasis in vitro and in vivo. CircGPRC5A could stabilize PPP1CA protein by inhibiting the binding between UBA1 and PPP1CA, and increasing YAP dephosphorylation. CONCLUSIONS: Our study revealed that circGPRC5A plays an essential function in CRC progression by stabilizing PPP1CA protein and enhancing YAP dephosphorylation. CircGPRC5A could act as a novel and potential target for CRC.

Effect of neoadjuvant chemotherapy combined with arterial chemoembolization on short-term clinical outcome of locally advanced gastric cancer.

BACKGROUND: The purpose of this study was to explore the short-term efficacy and safety of neoadjuvant chemotherapy combined with arterial chemoembolization for locally advanced gastric cancer (LAGC). METHODS: We retrospectively analyzed the clinical data of 203 patients with LAGC who received neoadjuvant therapy from June 2019 to December 2021. The patients were divided into a neoadjuvant chemotherapy combined with arterial chemoembolization group (combined group, n = 102) and a neoadjuvant chemotherapy group (conventional group, n = 101). The adverse events of chemotherapy, postoperative complications and pathological complete response (pCR) rate were compared between the two groups. Univariate and multivariate analyses were performed to evaluate the potential factors affecting pCR. RESULTS: A total of 78.8% of the patients were in clinical stage III before neoadjuvant therapy. A total of 52.2% of the patients underwent surgery after receiving two cycles of neoadjuvant therapy. There were 21.2% patients with ≥ grade 3 (CTCAE 4.0) adverse events of chemotherapy and 11.3% patients with Clavien-Dindo classification ≥ grade 3 postoperative complications. Compared with the conventional group, the combination group did not experience an increase in the adverse events of chemotherapy or postoperative complications. The pCR rate in the combined group was significantly higher than that in the conventional group (16.7% vs. 4.95%, P = 0.012). The multivariate analysis showed that arterial chemoembolization, pre-treatment neutrophil-to-lymphocyte ratio (NLR) and pre-treatment platelet-to-lymphocyte ratio (PLR) were independent factors affecting pCR. CONCLUSION: Neoadjuvant chemotherapy combined with arterial chemoembolization contributed to improving the pCR rate of LAGC patients. Arterial chemoembolization, pre-treatment NLR and pre-treatment PLR were also predictors of pCR.

[The characteristics of vestibular-evoked myogenic potentials in unilateral Meniere's disease patients at different clinical stages].

Objective:This study was to retrospectively analyze the results of vestibular-evoked myogenic potentials（VEMP） in unilateral Meniere's disease（MD） patients. Methods:The clinical assessment results of MD patients who visited the department between January 2016 to February 2022 were reviewed. Unilateral MD patients who met the inclusion and exclusion criteria were divided into three groups according to clinical stages, namely, group 1（stage Ⅰ+ stage Ⅱ）, group 2（stage Ⅲ） and group 3（stage Ⅳ）. The normal value data were used to investigate the incidence of abnormal P1 and N1 latencies, abnormal P1-N1 interwave latency, and abnormal interaural amplitude asymmetry ratio（IAR）. Afterwards, considering all the above mentioned parameters, the VEMP result of each patient was graded into four levels（grade 1 means VEMP result is normal, grade 2, 3 and 4 means the VEMP result is abnormal in different degrees）. The correlation between VEMP result level and pure tone average（PTA） of MD patients in different clinical stages was examined. Results:The prevalence of cVEMP in three groups was 84.2%, 70.0% and 33.3%, respectively（P<0.05）. The prevalence of oVEMP in three groups was 63.2%, 34.0% and 16.7%, respectively（P<0.05）. The incidence of abnormal P1 latency, N1 letancy and P1-N1 interwave latency of cVEMP was 21.1%, 26.3% and 24.6%, respectively. The incidence of abnormal P1 latency, N1 latency and interwave latency of oVEMP was 15.6%, 43.8% and 3.1%, respectively. The incidence of abnormal cVEMP IAR in group 1, group 2 and group 3 was 6.7%, 21.2% and 33.3%, respectively（P>0.05）. The incidence of abnormal IAR of oVEMP in group 1, group 2 and group 3 was 16.7%, 23.1% and 0, respectively（P>0.05）. cVEMP and oVEMP result levels were significantly correlated with PTA（r=0.339, P<0.01; r=0.362, P<0.01 ）, respectively. Conclusion:With the progression of MD, the function of saccule-vestibular inferior nerve pathway and utricle-vestibular superior nerve pathway would deteriorate in the same way as hearing.

CRISPR-based knockout screening identifies the loss of MIEF2 to enhance oxaliplatin resistance in colorectal cancer through inhibiting the mitochondrial apoptosis pathway.

The first-line anticancer agent oxaliplatin (OXL) is the preferred drug for treating colorectal cancer (CRC); however, the development of drug resistance is common in patients treated with OXL, which considerably reduces the efficacy of OXL-based regimens. By performing genome-wide CRISPR/Cas9 library knockdown screening, we found that mitochondrial elongation factor 2 (MIEF2) was among the top candidate genes. The OXL-resistant cell lines and organoids developed in the present study showed stable but low expression of MIEF2. Reduced MIEF2 expression may enhance CRC resistance to OXL by reducing mitochondrial stability and inhibiting apoptosis by decreasing cytochrome C release. In conclusion, among the different biomarkers of OXL resistance in CRC, MIEF2 may serve as a specific biomarker of OXL responsiveness and a potential target for the development of therapies to improve chemotherapeutic effectiveness.

Neutral Antiaromatic Bis(1,2-dithiolene)-Chelated Nickel Complexes Bearing Multiradical Characters.

Metal-organic complexes with radical characteristics are unique species attracting immense attention in recent years due to their peculiar properties and promising applicability in a wide variety of innovative research fields. However, the reported complexes typically do not exceed diradicality. This study systematically investigates a series of square planar neutral Ni-bis(1,2-dithiolene) and Ni-bis(1,2-dioxolene) complexes with linear, branched, and macrocyclic configurations via ab initio calculations. The linear Ni-complexes display strong singlet diradical characters, while their branched counterparts can also exhibit moderate singlet multiradical characters. Importantly, the macrocyclic Ni-complexes can possess extremely strong singlet multiradical characters up to dodeca-radicality along with their global antiaromaticity and hence strong induced ring current in the presence of an external magnetic field, ascribed to the localization of unpaired α and ß electrons residing in the highest few molecular orbitals at different molecular sites, minimizing their coupling and annihilation. Our work represents the first indication in the rational design of novel multiradical neutral antiaromatic macrocyclic complexes for potential applications in molecular machines and electronic devices.

[Influence of hot-humid stress and acclimation on airway mucus production in lungs of mice].

OBJECTIVE: To study the change of airway mucus secretion under a high temperature and humidity environment, and explore the effects of hot-humid stress and acclimation on the morbidity and mortality of respiratory disease. METHODS: Forty-five BABL/c mice were randomly divided into five groups:normal group, hot-humid group I, hot-humid group Ⅱ, hot-humid group Ⅲ, hot-humid group IV, with 9 mice in each group. Mice in normal group were continuously placed in the common environment and sacrificed after 7 days. Mice in other groups were housed in a temperature-and-humidity-controlled environment (33℃±0.5℃, 95%±5%). Mice in hot-humid group I, hot-humid group Ⅱ, hot-humid group Ⅲ and hot-humid group IV were sacrificed after 12 hours, 24 hours, 4 days, 7 days respectively. The protein expression of mucin 5AC(MUC5AC)、epidermal growth factor receptor (EGFR)、aquaporin 1(AQP1) and aquaporin 5(AQP5) in lung were tested by immunohistochemisty. RESULTS: After housed in a high temperature and humidity environment, immunohistochemisty revealed a significant increase of AQP5 12 h later, MUC5AC and EGFR 24 h later, compared with normal group(P<0.05). There was a significant decrease of MUC5AC 7 d later, compared with normal group(P<0.05). There was no significant difference in MUC5AC, EGFR and AQP5 expression among all groups at other time points. There was no difference of AQP1 in humid heat groups, compared with normal group, but a significant decrease in humid heat Ⅲ and IV groups, compared with humid heat I and Ⅱ groups. CONCLUSIONS: These findings indicate that hot-humid stress induces mucus hypersecretion in airways, which may be related to the up-regulation of EGFR and down-regulation of AQP5 in MUC5AC. Although acclimation mitigates above-mentioned response, a series of more complex responses may be induced if still in the hot-humid environment.

The amido-bridged zirconocene's reactivity and catalytic behavior for ethylene polymerization.

Reaction of the amido-bridged zirconium complex (CpSiMe(2)NSiMe(2)Cp)ZrCH(3) (1) (Cp = C(5)H(4)) with half an equivalent of B(C(6)F(5))(3) or Ph(3)CB(C(6)F(5))(4) afforded the binuclear zirconium complexes [(CpSiMe(2)NSiMe(2)Cp)Zr)(2)(mu-CH(3))][RB(C(6)F(5))(3)] (2a, R = CH(3), 2b, R = C(6)F(5)) with a methyl group as the bridge between the two zirconium atoms. In the presence of one equivalent of B(C(6)F(5))(3) or Ph(3)C(C(6)F(5))(4), 1 was transformed to the zwitterionic complexes [(CpSiMe(2)NSiMe(2)Cp)Zr][RB(C(6)F(5))(3)] (3a, R = CH(3), 3b, R = C(6)F(5)) which are free of a metal-bound sigma-alkyl ligand. 2b is stable with Me(3)Al while 3b combined with Me(3)Al to form a hetero-binuclear complex [(CpSiMe(2)NSiMe(2)Cp)Zr(mu-CH(3))]Al(CH(3))(2)][B(C(6)F(5))(4)] (4) as shown by NMR spectroscopy at room temperature. Treatment of 2a or 3a with an excess of Me(3)Al led to (CpSiMe(2)NSiMe(2)Cp)Zr(C(6)F(5)) (5) through a group exchange process. 2b, 3a and 5 have been characterized by X-ray diffraction studies. 2b, 2b, 3a and 3b were highly active catalysts for ethylene polymerization and copolymerization with 1-octene in the presence of trialkylaluminium, but the binuclear zirconium complexes (2a and 2b) showed higher activities than their mononuclear counterparts 3a and 3b. Polymerization activities varied with the trialkylaluminiums and increased with the trialkylaluminium concentration applied in the system. The product existed mainly in the form of Al(PE)(3) with polymeric chains, and its molecular weight and distribution were greatly influenced by the type and amount of trialkylaluminium applied in the catalytic system.

Highly efficient asymmetric Lewis acid catalysis with platinum group complexes of conformationally flexible 1,3-butadiene-bridged diphosphines, NUPHOS.

[structure: see text] Palladium and platinum complexes of conformationally flexible 1,3-butadiene-bridged diphosphines NUPHOS can be resolved with (S)-BINOL at elevated temperatures to afford diastereopure delta-[(NUPHOS)M[(S)-BINOL]] (M = Pd, Pt). The homochiral Lewis acid complexes delta-[(NUPHOS)M][OTf](2), generated by protonation of delta-[(NUPHOS)M[(S)-BINOL]] with trifluoromethanesulfonic acid, catalyze the Diels-Alder reaction between acryloyl-N-oxazolidinones and cyclopentadiene to give ee values up to 96%. The corresponding enantiopure dichlorides delta-[(NUPHOS)PtCl(2)] react with AgClO(4) to form highly efficient catalysts that give good endo/exo selectivities and high endo enantioselectivity.