Development and validation of a federated learning framework for detection of subphenotypes of multisystem inflammatory syndrome in children.

Background: Multisystem inflammatory syndrome in children (MIS-C) is a severe post-acute sequela of SARS-CoV-2 infection. The highly diverse clinical features of MIS-C necessities characterizing its features by subphenotypes for improved recognition and treatment. However, jointly identifying subphenotypes in multi-site settings can be challenging. We propose a distributed multi-site latent class analysis (dMLCA) approach to jointly learn MIS-C subphenotypes using data across multiple institutions. Methods: We used data from the electronic health records (EHR) systems across nine U.S. children's hospitals. Among the 3,549,894 patients, we extracted 864 patients < 21 years of age who had received a diagnosis of MIS-C during an inpatient stay or up to one day before admission. Using MIS-C conditions, laboratory results, and procedure information as input features for the patients, we applied our dMLCA algorithm and identified three MIS-C subphenotypes. As validation, we characterized and compared more granular features across subphenotypes. To evaluate the specificity of the identified subphenotypes, we further compared them with the general subphenotypes identified in the COVID-19 infected patients. Findings: Subphenotype 1 (46.1%) represents patients with a mild manifestation of MIS-C not requiring intensive care, with minimal cardiac involvement. Subphenotype 2 (25.3%) is associated with a high risk of shock, cardiac and renal involvement, and an intermediate risk of respiratory symptoms. Subphenotype 3 (28.6%) represents patients requiring intensive care, with a high risk of shock and cardiac involvement, accompanied by a high risk of >4 organ system being impacted. Importantly, for hospital-specific clinical decision-making, our algorithm also revealed a substantial heterogeneity in relative proportions of these three subtypes across hospitals. Properly accounting for such heterogeneity can lead to accurate characterization of the subphenotypes at the patient-level. Interpretation: Our identified three MIS-C subphenotypes have profound implications for personalized treatment strategies, potentially influencing clinical outcomes. Further, the proposed algorithm facilitates federated subphenotyping while accounting for the heterogeneity across hospitals.

CISD2 promotes lung squamous carcinoma cell migration and invasion via the TGF-ß1-induced Smad2/3 signaling pathway.

BACKGROUND: Although aberrant expression of CDGSH iron sulfur domain 2 (CISD2) contributes to the tumorigenesis and progression of numerous human cancers, the biological function of CISD2 and its specific prognostic value in lung squamous cell carcinoma (LUSC) have yet to be comprehensively explored. The current study aimed to elucidate the role of CISD2 in LUSC as well as the underlying molecular mechanisms. METHODS: Immunohistochemistry was conducted to detect the protein expression of CISD2 and analyze whether high expression of CISD2 affects the overall survival (OS) of LUSC patients. Cell proliferation, colony formation, wound healing and Transwell invasion assays were performed to clarify whether CISD2 contributes to LUSC cell proliferation and disease progression. Quantitative real-time reverse transcription-PCR and western blot assays were used to detect the levels of transcription factors and key epithelial-mesenchymal transition (EMT)-related markers in LUSC cells after CISD2 knockdown and overexpression to determine whether CISD2 regulates transforming growth factor-beta (TGF-ß)-induced EMT in LUSC. RESULTS: Immunohistochemistry of human tissue microarrays containing 90 pairs of adjacent and cancerous tissues revealed that CISD2 is considerably overexpressed in LUSC and strongly linked to poor OS. Functional experiments suggested that silencing endogenous CISD2 inhibited the growth, colony formation, migration, and invasion of H2170 and H226 cell lines. Exogenous overexpression of CISD2 facilitated these phenotypes in SK-MES-1 and H2170 cells. Furthermore, CISD2 promoted EMT progression by increasing the expression of mesenchymal markers (N-cadherin, vimentin, Snail, and Slug) as well as SMAD2/3 and reducing the expression of the epithelial marker E-cadherin. Mechanistically, our studies provide the first evidence that CISD2 can promote EMT by enhancing TGF-ß1-induced Smad2/3 expression in LUSC cells. CONCLUSION: In conclusion, our research illustrates that CISD2 is highly expressed in LUSC and may facilitate LUSC proliferation and metastasis. Thus, CISD2 may serve as an independent prognostic marker and possible treatment target for LUSC.

Naturally occurring organobromine compounds (OBCs) including polybrominated dibenzo-p-dioxins in the marine sponge Hyrtios proteus from The Bahamas.

Halogenated natural products (HNPs) were identified from organic extracts of the marine sponge Hyrtios proteus from The Bahamas using gas chromatography with electron capture negative ion mass spectrometry and non-targeted gas chromatography with electron ionization mass spectrometry. The HNPs found have similar properties to anthropogenic persistent organic pollutants (POPs). Two ortho-methoxy brominated diphenyl ethers (MeO-BDEs) 2'-MeO-BDE 68 and 6-MeO-BDE 47 were the most abundant compounds. Fourteen other MeO-BDEs were detected along with several polybrominated dibenzo-p-dioxins (PBDDs) (1,3,7-triBDD, 1,3,6,8-tetraBDD and 1,3,7,9-tetraBDD) and MeO-PBDDs. Further analysis of a higher trophic level octopus (Octopus maya) from the same FAO fishing area showed that the major HNPs detected in Hyrtios proteus were also predominant. Moreover, HNPs were more than 30-fold higher in abundance than the major POPs in the octopus, i.e., polychlorinated biphenyls. Hence, Caribbean marine organisms, including those potentially used for food, harbor relatively high concentrations of HNPs.

CMPD1 inhibited human gastric cancer cell proliferation by inducing apoptosis and G2/M cell cycle arrest.

BACKGROUND: Gastric cancer occupies the fourth highest morbidity rate of cancers worldwide. Clinical therapies of gastric cancer remain limited because of uncertainty of mechanisms and shortness of effective medicine. Thus, new drug candidates for gastric cancer treatment is urgently needed. RESULTS: In this study, CMPD1 as a wildly used MK2 phosphorylation inhibitor was employed to find its impact on gastric cancer cell proliferation, apoptosis and cell cycle using colony formation assay and flow cytometry analysis. Along with its anti-proliferation effect on gastric cancer cell line MKN-45 and SGC7901, CMPD1 also induced massive apoptosis and significant G2/M phase arrest in a time-dependent and dose-dependent manner in MKN-45 cells respectively. Furthermore, Western blot confirmed that the expression of anti-apoptotic proteins Bcl-2 was decreased while BAX, cytochrome c release and cleaved PARP were increased. In addition, oncogene c-Myc was downregulated in response to CMPD1 treatment. CONCLUSIONS: Our results demonstrated that CMPD1 has anti-tumor effect on human gastric cancer cell line MKN-45 possibly via downregulating oncogene c-Myc expression and CMPD1 could be applied as a potential candidate for treating gastric malignancy. To the best of our knowledge, it is the first report of anti-tumor effect of CMPD-1 on human gastric cancer cells.

CMPD1 inhibited human gastric cancer cell proliferation by inducing apoptosis and G2/M cell cycle arrest

BACKGROUND: Gastric cancer occupies the fourth highest morbidity rate of cancers worldwide. Clinical therapies of gastric cancer remain limited because of uncertainty of mechanisms and shortness of effective medicine. Thus, new drug candidates for gastric cancer treatment is urgently needed. RESULTS: In this study, CMPD1 as a wildly used MK2 phosphorylation inhibitor was employed to find its impact on gastric cancer cell proliferation, apoptosis and cell cycle using colony formation assay and flow cytometry analysis. Along with its anti-proliferation effect on gastric cancer cell line MKN-45 and SGC7901, CMPD1 also induced massive apoptosis and significant G2/M phase arrest in a time-dependent and dose-dependent manner in MKN-45 cells respectively. Furthermore, Western blot confirmed that the expression of anti-apoptotic proteins Bcl-2 was decreased while BAX, cytochrome c release and cleaved PARP were increased. In addition, oncogene c-Myc was downregulated in response to CMPD1 treatment. CONCLUSIONS: Our results demonstrated that CMPD1 has anti-tumor effect on human gastric cancer cell line MKN- 45 possibly via downregulating oncogene c-Myc expression and CMPD1 could be applied as a potential candidate for treating gastric malignancy. To the best of our knowledge, it is the first report of anti-tumor effect of CMPD-1 on human gastric cancer cells.

Searching for a new family of insensitive high explosives by introducing N hybridization and N-oxides into a cage cubane.

A new family of energetic azacubane N-oxides were designed by introducing N-oxides into azacubanes and investigated by using density functional theory. Introducing the N-oxides into the azacubanes could improve their detonation performance significantly due to the increase of the OB and ρ but would also increase the sensitivity to some extent. These effects would be further enhanced as the numbers of N-oxides increase. Among all the designed azacubane N-oxides, D6-4 (1,3,5,7-tetraazacubane-1,3,5,7-tetraoxides) has higher detonation performance than one famous high explosive HMX (1,3,5,7-tetranitro-1,3,5,7-tetrazocane) and lower sensitivity than one very insensitive explosive TNT (1-methyl-2,4,6-trinitrobenzene), suggesting that its overall performance is outstanding and may be considered as the potential candidate of insensitive high explosives. The internal small cage C-N skeleton of D6-4 is surrounded by the external big cage hydrogen bonds and this special double cage structure may be an important reason why it has low sensitivity.