Patients with ulcerative colitis have an increased risk of developing colitis-associated colon cancer (CACC). Changes in glycosylation of the oncoprotein MUC1 commonly occur in chronic inflammation, including ulcerative colitis, and this abnormally glycosylated MUC1 promotes cancer development and progression. It is not known what causes changes in glycosylation of MUC1. Gene expression profiling of myeloid cells in inflamed and malignant colon tissues showed increased expression levels of inflammatory macrophage–associated cytokines compared with normal tissues. We analyzed the involvement of macrophage-associated cytokines in the induction of aberrant MUC1 glycoforms. A coculture system was used to examine the effects of M1 and M2 macrophages on glycosylation-related enzymes in colon cancer cells. M2-like macrophages induced the expression of the glycosyltransferase ST6GALNAC1, an enzyme that adds sialic acid to O-linked GalNAc residues, promoting the formation of tumor-associated sialyl-Tn (sTn) O-glycans. Immunostaining of ulcerative colitis and CACC tissue samples confirmed the elevated number of M2-like macrophages as well as high expression of ST6GALNAC1 and the altered MUC1-sTn glycoform on colon cells. Cytokine arrays and blocking antibody experiments indicated that the macrophage-dependent ST6GALNAC1 activation was mediated by IL13 and CCL17. We demonstrated that IL13 promoted phosphorylation of STAT6 to activate transcription of ST6GALNAC1. A computational model of signaling pathways was assembled and used to test IL13 inhibition as a possible therapy. Our findings revealed a novel cellular cross-talk between colon cells and macrophages within the inflamed and malignant colon that contributes to the pathogenesis of ulcerative colitis and CACC. See related Spotlight on p. 160

Background The novel SARS-CoV-2 has caused the coronavirus disease 2019 (COVID-19) pandemic. Currently, with insufficient worldwide vaccination rates, identifying treatment solutions to reduce the impact of the virus is urgently needed. Method An adaptive, multicentric, open-label, and randomized controlled phase I/II clinical trial entitled the “SENTAD-COVID Study” was conducted by the Abu Dhabi Stem Cells Center under exceptional conditional approval by the Emirates Institutional Review Board (IRB) for COVID-19 Research Committee from April 4th to July 31st, 2020, using an autologous peripheral blood non-hematopoietic enriched stem cell cocktail (PB-NHESC-C) administered by compressor (jet) nebulization as a complement to standard care therapy. The primary endpoints include safety and efficacy assessments, adverse events, the mortality rate within 28 days, and the time to clinical improvement as measured by a 2-point reduction on a seven-category ordinal scale or discharge from the hospital whichever occurred first. Results The study included a total of 139 randomized COVID-19 patients, with 69 in the experimental group and 70 in the control group (standard care). Overall survival was 94.20% for the cocktail-treated group vs. 90.27% for the control group. Adverse events were reported in 50 (72.46%) patients receiving PB-NHESC-C and 51 (72.85%) in the control group (p = 0.9590), with signs and symptoms commonly found in COVID-19. After the first 9 days of the intervention, 67.3% of cocktail-treated patients recovered and were released from hospitals compared to 53.1% (RR = 0.84; 95% CI, 0.56–1.28) in the control group. Improvement, i.e., at least a 2-point reduction in the severity scale, was more frequently observed in cocktail-treated patients (42.0%) than in controls (17.0%) (RR = 0.69; 95% CI, 0.56–0.88). Conclusions Cocktail treatment improved clinical outcomes without increasing adverse events. Thus, the nebulization of PB-NHESC-C was safe and effective for treatment in most of these patients. Trial registration ClinicalTrials.gov. NCT04473170. It was retrospectively registered on July 16th, 2020.

Motivation Creating or extending computational models of complex systems, such as intra- and intercellular biological networks, is a time and labor-intensive task, often limited by the knowledge and experience of modelers. Automating this process would enable rapid, consistent, comprehensive, and robust analysis and understanding of complex systems. Results In this work, we present CLARINET (CLARIfying NETworks), a novel methodology and a tool for automatically expanding models using the information extracted from literature by machine reading. CLARINET creates collaboration graphs from the extracted events and uses several novel metrics for evaluating these events individually, in pairs, and in groups. These metrics are based on the frequency of occurrence and co-occurrence of events in literature, and their connectivity to the baseline model. We tested how well CLARINET can reproduce manually built and curated models, when provided with varying amount of information in the baseline model and in the machine reading output. Our results show that CLARINET can recover all relevant interactions that are present in the reading output and it automatically reconstructs manually built models with average recall of 80% and average precision of 70%. CLARINET is highly scalable, its average runtime is at the order of ten seconds when processing several thousand interactions, outperforming other similar methods. Availability https://bitbucket.org/biodesignlab/clarinet/src/master/

Pregnancy after the fifth delivery is viewed with anxiety, especially by obstetricians in developing countries working with inadequate facilities. High parity is still common with serious consequences to the fetus, the mother, the family and society. In the last 40 years, non-governmental, national and international efforts have been made to reduce fertility rates. We therefore intended to determine the trend in the grandmultiparity rates from 1 January 1987 to 31 December 1994 in the South Western part of Nigeria. The obstetric performance of these grandmultiparae in two different settings were to be compared. This was a retrospective, case-note analysis of all the grandmultiparae delivered at the University College Hospital (UCH) (Group A) and the Oluyoro Catholic Hospital (OCH) (Group B), both in Ibadan city. The former is a tertiary health care centre while the latter is a secondary centre. The socio-clinico-demographic characteristics of these patients were collated and analysis and comparison performed using EPI-INFO software. In Group A, 828 grandmultiparae were seen among 9215 deliveries, a rate of 8.99% (10.90% in 1987 to 3.36% in 1994). In Group B, there were 1940 cases among 22 587 deliveries, i.e. 8.59% (12.75% to 6.07%), respectively. The modal age group was 31-35 years, and women above 35 years formed one-third of cases. The parity group 5-7 was the most frequent in both groups (91.6% vs. 94.9%). Only two mothers (both in group B) had parity above 10. Booked patients formed a larger percentage in Group B than in Group A (85.8% vs. 69.7%, respectively). In Group B 85.9% had spontaneous vertex delivery as opposed to 66.3% in Group A. Caesarean section was the mode of delivery in 9.0% and 24.2% in Groups B and A, respectively. Equal percentages had breech delivery. The modal birth weight was 2.51-3.00 kg in both groups. Macrosomic babies formed 3.7% in Group A and 2.4% in Group B, while low birth weight babies formed 17.7% and 11.7% in Groups A and B, respectively. The crude perinatal death ratio was 123/1000 in Group A and 68/1000 in Group B. Antepartum haemorrhage, anaemia and premature rupture of membranes in Group A and anaemia, hypertension and antepartum haemorrhage in Group B were the most common pregnancy complications noted. In labour, abnormal lie/presentation, prolonged labour and premature labour in Group A and abnormal lie/presentation, antepartum haemorrhage and birth asphyxia in Group B formed the majority of the complications. The most common puerperal complications were primary postpartum haemorrhage, wound/genital sepsis in Group A and anaemia and primary postpartum haemorrhage in Group B, respectively. Maternal death ratio was 10.85/100 000 total deliveries in Group A and 35.42/100 000 in Group B. High parity is still common in developing countries, although the incidence is declining, with rates of 3.4% and 6.1% of total deliveries in Groups A and B, respectively. More patients are delivered per abdomen at UCH compared to OCH. The perinatal mortality rate is higher at UCH than OCH b...

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