Development and validation of novel models for the prediction of intravenous corticosteroid resistance in acute severe ulcerative colitis using logistic regression and machine learning.

Background: The early prediction of intravenous corticosteroid (IVCS) resistance in acute severe ulcerative colitis (ASUC) patients remains an unresolved challenge. This study aims to construct and validate a model that accurately predicts IVCS resistance. Methods: A retrospective cohort was established, with consecutive inclusion of patients who met the diagnosis criteria of ASUC and received IVCS during index hospitalization in Peking Union Medical College Hospital between March 2012 and January 2020. The primary outcome was IVCS resistance. Classification models, including logistic regression and machine learning-based models, were constructed. External validation was conducted in an independent cohort from Shengjing Hospital of China Medical University. Results: A total of 129 patients were included in the derivation cohort. During index hospitalization, 102 (79.1%) patients responded to IVCS and 27 (20.9%) failed; 18 (14.0%) patients underwent colectomy in 3 months; 6 received cyclosporin as rescue therapy, and 2 eventually escalated to colectomy; 5 succeeded with infliximab as rescue therapy. The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and C-reactive protein (CRP) level at Day 3 are independent predictors of IVCS resistance. The areas under the receiver-operating characteristic curves (AUROCs) of the logistic regression, decision tree, random forest, and extreme-gradient boosting models were 0.873 (95% confidence interval [CI], 0.704-1.000), 0.648 (95% CI, 0.463-0.833), 0.650 (95% CI, 0.441-0.859), and 0.604 (95% CI, 0.416-0.792), respectively. The logistic regression model achieved the highest AUROC value of 0.703 (95% CI, 0.473-0.934) in the external validation. Conclusions: In patients with ASUC, UCEIS and CRP levels at Day 3 of IVCS treatment appeared to allow the prompt prediction of likely IVCS resistance. We found no evidence of better performance of machine learning-based models in IVCS resistance prediction in ASUC. A nomogram based on the logistic regression model might aid in the management of ASUC patients.

Circadian Clock and Sirtuins in Diabetic Lung: A Mechanistic Perspective.

Diabetes-induced tissue injuries in target organs such as the kidney, heart, eye, liver, skin, and nervous system contribute significantly to the morbidity and mortality of diabetes. However, whether the lung should be considered a diabetic target organ has been discussed for decades. Accumulating evidence shows that both pulmonary histological changes and functional abnormalities have been observed in diabetic patients, suggesting that the lung is a diabetic target organ. Mechanisms underlying diabetic lung are unclear, however, oxidative stress, systemic inflammation, and premature aging convincingly contribute to them. Circadian system and Sirtuins have been well-documented to play important roles in above mechanisms. Circadian rhythms are intrinsic mammalian biological oscillations with a period of near 24 h driven by the circadian clock system. This system plays an important role in the regulation of energy metabolism, oxidative stress, inflammation, cellular proliferation and senescence, thus impacting metabolism-related diseases, chronic airway diseases and cancers. Sirtuins, a family of adenine dinucleotide (NAD+)-dependent histone deacetylases, have been demonstrated to regulate a series of physiological processes and affect diseases such as obesity, insulin resistance, type 2 diabetes (T2DM), heart disease, cancer, and aging. In this review, we summarize recent advances in the understanding of the roles of the circadian clock and Sirtuins in regulating cellular processes and highlight the potential interactions of the circadian clock and Sirtuins in the context of diabetic lung.

Pravastatin alleviates lipopolysaccharide-induced placental TLR4 over-activation and promotes uterine arteriole remodeling without impairing rat fetal development.

Preeclampsia is associated with over-activation of the innate immune system in the placenta, in which toll-like receptor 4 (TLR4) plays an essential part. With their potent anti-inflammatory effects, statins have been suggested as potential prevention or treatment of preeclampsia, although evidence remains inadequate. Herewith, we investigated whether pravastatin could ameliorate preeclampsia-like phenotypes in a previously established lipopolysaccharide (LPS)-induced rat preeclampsia model, through targeting the TLR4/NF-κB pathway. The results showed that pravastatin reduced the blood pressure [maximum decline on gestational day (GD) 12, (101.33±2.49) mmHg vs. (118.3±1.37) mmHg, P<0.05] and urine protein level [maximum decline on GD9, (3,726.23±1,572.86) µg vs. (1,991.03±609.37) µg, P<0.05], which were elevated following LPS administration. Pravastatin also significantly reduced the rate of fetal growth restriction in LPS-treated rats (34.10% vs. 8.99%, P<0.05). Further pathological analyses suggested a restoration of normal spiral artery remodeling in preeclampsia rats by pravastatin treatment. These effects of pravastatin were associated with decreased TLR4/NF-κB protein levels in the placenta and IL-6/MCP-1 levels in serum. Additionally, no obvious abnormalities in fetal liver, brain, and kidney were found after administration of pravastatin. These results provide supportive evidence for use of pravastatin in preventing preeclampsia.

Prediction of boiling points of organic compounds by QSPR tools.

The novel electro-negativity topological descriptors of YC, WC were derived from molecular structure by equilibrium electro-negativity of atom and relative bond length of molecule. The quantitative structure-property relationships (QSPR) between descriptors of YC, WC as well as path number parameter P3 and the normal boiling points of 80 alkanes, 65 unsaturated hydrocarbons and 70 alcohols were obtained separately. The high-quality prediction models were evidenced by coefficient of determination (R(2)), the standard error (S), average absolute errors (AAE) and predictive parameters (Qext(2),RCV(2),Rm(2)). According to the regression equations, the influences of the length of carbon backbone, the size, the degree of branching of a molecule and the role of functional groups on the normal boiling point were analyzed. Comparison results with reference models demonstrated that novel topological descriptors based on the equilibrium electro-negativity of atom and the relative bond length were useful molecular descriptors for predicting the normal boiling points of organic compounds.

[Insulin-like growth factor 2 imprinting status and promoter usage in the placenta of macrosomia].

OBJECTIVE: To study the mechanism of marcosomia by investigating insulin-like growth factor 2 (IGF(2))imprinting status, expression level and the promoter usage in the placenta of macrosomia. METHODS: We selected heterozygous cases for Apa I polymorphism in exon 9 of IGF(2) gene and then analyzed its imprinting status in 168 placentas of macrosomia and normal pregnancies. IGF(2) transcription levels and promoter usages in macrosomic and normal placenta were evaluated by using semi-quantitative RT-PCR assay. RESULTS: Thirty specimens of macrosomic placenta and 30 of normal placenta were identified as heterozygous for IGF(2). All of the heterozygous specimens showed maintenance of imprinting. The expression of placental IGF(2) mRNA (2.2 +/- 1.2) was significantly higher in macrosomia than that of normal weight group (1.6 +/- 0.6, P < 0.05). Of four promoters, P4 was the most powerful, P3 was the second, and P2 was weakest. Transcripts from P1 were the fewest, and they were only detected in two specimens. The value of P4 was 2.06 +/- 1.26, P3 0.99 +/- 0.72, P2 0.20 +/- 0.20 in macrosomia group and P4 2.05 +/- 1.27, P3 0.98 +/- 0.80, P2 0.19 +/- 0.17 in normal group. There were no significant differences between two groups (P > 0.05). CONCLUSION: It is possible that over expression of IGF(2) in placenta contributes to macrosomia while the promoter usage and imprinting status are not associated with macrosomia.

[Loss of imprinting of IGF2 in cord blood of newborns of Chinese Han population].

OBJECTIVE: To study the imprinting status of IGF2 and phenotypes of loss of imprinting (LOI) in cord blood of neonates of Chinese Han population and to investigate relative factors to LOI. METHODS: Cord blood of 1010 Chinese Han newborns were collected and the imprinting status of IGF2 was detected by reverse transcription-PCR(RT-PCR) and restriction fragment length polymorphism.The relationships between LOI and fetal growth indices, features of parents and grandparents, clinical characteristics were analyzed. RESULTS: Of all cases, 42.8% (432/1010) were heterozygous for a polymorphism of Apa I site in exon 9 of IGF2, while 21.6%(66/306) displayed IGF2 LOI. Maternal factors including average age, gestational age, BMI pre-pregnancy, weight gain during pregnancy and the level of HB, HCT, and other indices of biochemistry in their second and third trimester were not correlated with LOI expression. However in newborns with fathers older than 35 yrs, 31.7%(19/60) displayed LOI, which was significantly more common than that in newborns with younger fathers (P< 0.05, chi square is 4.69). There were no difference in birth weight (BW) between normal imprinting and LOI groups. But if the newborn's weights were in 2500-2999 g, LOI was 6.25%(2/32), which was significantly lower than that in 3000 g group (P< 0.05, chi square is 4.89). In groups with BW being less than 2500 g and more than/equal to 4000 g, the LOI newborn's blood glucose was decreased significantly after 2 hrs (P< 0.01, t is 7.47 and 10.9). CONCLUSION: In newborns of Chinese Han population, 21.6% showed IGF2 LOI in cord blood. IGF2 LOI may have some influences on fetal growth. Paternal age is associated with LOI.

[Relationship between human herpesvirus 6 infection and oral squamous cell carcinoma].

OBJECTIVE: To study the relationship between human herpesvirus 6 (HHV-6) and oral squamous cell carcinoma. METHODS: The serum anti-HHV-6 antibody titers from oral squamous cell carcinoma patients and control subjects were detected by indirect immunofluorescence assay. HHV-6 DNA in peripheral blood mononuclear cells from oral squamous cell carcinoma patients and control subjects was amplified by PCR with primers from sequence of HHV-6 and the specificity was confirmed by Southern-blot hybridization with an internal probe oligonucleotide. An immunohistochemical staining using rabbit anti-HHV-6 antibody was used to detect HHV-6 antigen in oral tumor tissues from oral squamous cell carcinoma patients. RESULTS: Significantly higher proportion of patients with oral carcinoma (16/16) had IgG antibody to HHV-6 in sera compared with those (12/16) in control subjects, and geometric mean titer of these two groups was 1:118 and 1:64 respectively (P less than 0.05). The detectable rate of HHV-6 DNA in peripheral blood mononuclear cells for the above groups was 10/16 and 6/16 respectively (P less than 0.05). HHV-6 antigens were positive in 9 out of 12 oral tumor cases and in only 2 out of 8 pericancerous tissues the difference between these two groups was also significant (P less than 0.05). CONCLUSION: These results demonstrated the frequent presence of HHV-6 in oral squamous cell carcinoma, therefore, HHV-6 possibly play a role in the pathogenesis of oral squamous cell carcinoma.

Relationship between expression of CD44v6 and nm23-H1 and tumor invasion and metastasis in hepatocellular carcinoma.

AIM:To detect the expression of CD44v6 mRNA and nm23-H1 mRNA in hepatocellular carcinoma (HCC) by in situ hybridization, and to evaluate the relationship between their expression and also relationship between their expressions and tumor invasion and metastasis.METHODS:CD44v6 cDNA probe was synthesized with PCR technique and the nm23-H1 cRNA probe by in vitro transcription. The expression of CD44v6 mRNA and nm23-H1 mRNA was detected by in situ hybridization. RESULTS:In group with high invasion and metastasis potential, the positive rates of CD44v6 mRNA and nm23-H1 mRNA were 80% (8/10) and 40% (4/10),in group with poor invasion and metastasis potential, they were 21.7% (5/23) and 91.3% (21/23).There was a positive correlation between the expression of CD44v6 mRNA and tumor invasion and metastasis potential in HCC (P < 0.01), and a reverse correlation between the expression of nm23-H1 mRNA and tumor invasion and metastasis potential (P < 0.01) and a reverse correlation in the expression between CD44v6 mRNA and nm23-H1 mRNA in HCC (P < 0.01).CONCLUSION: Detection of CD44v6 mRNA and nm23-H1 mRNA may be useful for tumor invasion and metastasis in HCC.