CD44 variant expression and estrogen receptor status in breast cancer

To understand the relationship between CD44 gene expressionand an established variable associated with aggressive behaviourin human breast cancer, we have studied apanel of 6 breast cell lines and 40breast tumors selected primarily on the basis ofestrogen receptor (ER) status. CD44s (standard form) mRNAwas assessed by semi-quantitative RT-PCR, and CD44 variantsincorporating exon v7 or v10 were studied byRT-PCR and Southern blot. While CD44 expression wasnot influenced by estrogen in ER+ve MCF-7 cells,CD44s expression was slightly higher (up to 2fold) in ER–ve cells but there was amarked decrease in the range of CD44 variantsincorporating exons v7 or v10. In microdissected tumors,the levels of CD44s showed no correlation withER status but the pattern of expression oflarger forms of CD44 incorporating variant exons v7and v10 was significantly different (p=0.005and p=0.015, respectively) between ER+ve andER–ve tumors, reflecting the pattern seen in thecell lines. These findings suggest that the profileof CD44 expression in breast cancer may reflectcellular differentiation as indicated by the ER phenotype.The influence of these differences in CD44 expressionon the increased metastatic potential of ER negativebreast cancer remains to be determined.     

Loss of heterozygosity of 3p markers in neuroblastoma tumours implicate a tumour-suppressor locus distal to the FHIT gene.

Neuroblastoma is a heterogeneous childhood tumour of the sympathetic nervous system, in which deletions of chromosomal region 1p and amplification of the MYCN oncogene correlate with aggressive tumour behaviour. However, the majority of neuroblastoma tumours show neither of these aberrations, indicating that other chromosomal regions may be involved in tumorigenesis. Here, we report findings of loss of heterozygosity (LOH) on chromosome 3. In our neuroblastoma material, nine of 59 (15.3%) tested tumours showed allelic loss of chromosome 3p markers. We found significant clinical and biological differences between tumours with the loss of one entire chromosome 3 vs tumours with partial loss in chromosome region 3p. All children with tumours with whole chromosome 3 loss are long-term survivors, whereas all children with tumours showing partial 3p LOH have died from tumour progression. A consensus region found to be deleted in all the tumours with 3p deletions was defined by markers D3S1286 and D3S1295, i.e. 3p25.3-p14.3, distal to the FHIT gene.     

Prolonged pregnancy: evaluating gestation-specific risks of fetal and infant mortality

Objective To evaluate gestation-specific risks of stillbirth, neonatal and post-neonatal mortality.
Design Retrospective analysis of 171,527 notified births (1989–1991) and subsequent infant survival at one year, from community child health records.
Setting Notifications from maternity units in the North East Thames Region, London.
Main outcome measures The incidence of births, stillbirths, neonatal and post-neonatal deaths at each gestation after 28 completed weeks. Mortality rates per 1000 total or live births and per 1000 ongoing pregnancies at each gestation were calculated.
Results The rates of stillbirth at term (2.3 per 1000 total births) and post-term (1.9 per 1000 total births) were similar. When calculated per 1000 ongoing pregnancies, the rate of stillbirth increased six-fold from 0.35 per 1000 ongoing pregnancies at 37 weeks to 2.12 per 1000 ongoing pregnancies at 43 weeks of gestation. Neonatal and post-neonatal mortality rates fell significantly with advancing gestation, from 15 1.4 and 31.7 per 1000 live births at 28 weeks, to reach a nadir at 41 weeks of gestation (0.7 and 1.3 per 1000 live births, respectively), increasing thereafter in prolonged gestation to 1.6 and 2.1 per 1000 live births at 43 weeks of gestation. When calculated per 1000 ongoing pregnancies, the overall risk of pregnancy loss (stillbirth + infant mortality) increased eight-fold from 0.7 per 1000 ongoing pregnancies at 37 weeks to 5.8 per 1000 ongoing pregnancies at 43 weeks of gestation.
Conclusion The risks of prolonged gestation on pregnancy are better reflected by calculating fetal and infant losses per 1000 ongoing pregnancies. There is a significant increase in the risk of stillbirth, neonatal and post-neonatal mortality in prolonged pregnancy. This study provides accurate data on gestation-specific risks of pregnancy loss, enabling pregnant women and their carers to judge the appropriateness of obstetric intervention.     

Incidence of urinary incontinence and constipation during pregnancy and postpartum: survey of current findings at the Rotunda Lying-in Hospital

Objective To assess the impact of pregnancy upon continence and constipation.
Design A questionnaire survey.
Setting Maternity wards in the Rotunda Lying In Hospital, Dublin, Republic of Ireland.
Population 7771 women who were delivered of liveborn infants.
Methods Questionnaires were delivered and collected by physiotherapy staff as part of routine postnatal care.
Results Analysis of data using χ² tests showed significant differences between three parity groups [primigravidae, multigravidae (2–4) and multigravidae (5+)] for symptoms of both urinary incontinence (  χ²= 119.54  , df = 2, P = 0.000) and constipation (  χ²= 12.53  , df = 3, P = 0.002); the incidence of both constipation and urinary incontinence increased with parity.
Conclusion The results of this survey have emphasised the relation between parity and postpartum incontinence which stresses the importance of early diagnosis and intervention.     

Long-term results in children with AML: NOPHO-AML Study Group--report of three consecutive trials.

In all, 447 children with acute myeloid leukaemia (AML) have been treated on three consecutive NOPHO studies from July 1984 to December 2001. NOPHO-AML 84 was of moderate intensity with an induction of three courses of cytarabine, 6-thioguanine and doxorubicin followed by four consolidation courses with high-dose cytarabine. The 5-year event-free survival (EFS), disease free survival (DFS) and overall survival (OS) were 29, 37 and 38%. NOPHO-AML 88 was of high intensity with the addition of etoposide and mitoxantrone in selected courses during induction and consolidation. The interval between the induction courses should be as short as possible, that is, time intensity was introduced. The 5-year EFS, DFS and OS were 41, 48 and 46%. In NOPHO-AML 93, the treatment was stratified according to response to first induction course. The protocol utilised the same induction blocks as NOPHO-AML 88, but after the first block, children with a hypoplastic, nonleukaemic bone marrow were allowed to recover before the second block. Consolidation was identical with NOPHO-AML 88. The 5-year EFS, DFS and OS in NOPHO-AML 93 were 48, 52 and 65%. The new NOPHO-AML protocol has been based on experiences from previous protocols with stratification of patients with regard to in vivo response and specific cytogenetic aberrations.     

Food effects on tablet disintegration.

The aims of the present study was to investigate if food components, as represented by a multi-component nutritional drink for tube feeding, could affect tablet disintegration of standard tablets in vitro as well as in vivo and propose a mechanism for potential food effects on tablet disintegration. The tablet disintegration was delayed between 5 min and more than 1h in the simulated gastric fed medium compared to a simple buffer. This effect was dependent on the tablet composition. A similar delay in tablet disintegration was also found in vivo after administration of the nutritional drink to three Labradors as observed by removing the tablet from the stomach at different times through a gastric fistula. The delay in tablet disintegration appeared to be caused by precipitation of a film, mainly consisting of protein, on the tablet surface as indicated by disintegration studies with pure nutrients, identification by IR spectroscopy of contents of precipitates obtained in a model study were the nutrients were incubated with different tablet excipients and visual observations of tablets exposed to the simulated fed medium. The drug dissolution of a soluble compound, metoprolol tartrate, from a standard tablet was also strongly delayed in the simulated fed medium. In conclusion, food, could significantly delay tablet disintegration and drug dissolution in the stomach by formation of a film around the tablets. This effect could be monitored by a simple in vitro disintegration test using a test medium based on a nutritional drink. More studies are needed to investigate the significance of the slow tablet disintegrations on bioavailability and for which types of food the present effect occurs.     

Orange Fanta versus orange fruit: A novel measure of nutrition knowledge in Malawi

This paper introduces a novel survey instrument to identify distinct components of nutrition knowledge and test for links between knowledge and dietary choices in Southern Malawi. Our first aim is to distinguish respondents' familiarity with recommended behaviours, such as when to start breastfeeding or introduce solid foods, from respondents' factual knowledge about mechanisms, such as whether biscuits or papaya and orange fruit or orange Fanta contribute more to future health. We find knowledge of nutrition behaviours to be strongly associated with more schooling, older age, and being female, whereas knowledge of mechanisms is associated only with training and employment as a health professional. We then test whether this expanded definition of nutrition knowledge is associated with dietary intake when controlling for other factors and find no significant links in these data. Results point to the need for knowledge surveys and public health behaviour‐change campaigns to address the kinds of information that might have the most influence on actual behaviour, potentially including the mechanisms involved in food composition, food safety, and disease transmission.     

Understanding the Driving Forces That Trigger Mutations in SARS-CoV-2: Mutational Energetics and the Role of Arginine Blockers in COVID-19 Therapy

SARS-CoV-2 is a global challenge due to its ability to mutate into variants that spread more rapidly than the wild-type virus. Because the molecular biology of this virus has been studied in such great detail, it represents an archetypal paradigm for research into new antiviral drug therapies. The rapid evolution of SARS-CoV-2 in the human population is driven, in part, by mutations in the receptor-binding domain (RBD) of the spike (S-) protein, some of which enable tighter binding to angiotensin-converting enzyme (ACE2). More stable RBD-ACE2 association is coupled with accelerated hydrolysis of furin and 3CLpro cleavage sites that augment infection. Non-RBD and non-interfacial mutations assist the S-protein in adopting thermodynamically favorable conformations for stronger binding. The driving forces of key mutations for Alpha, Beta, Gamma, Delta, Kappa, Lambda and Omicron variants, which stabilize the RBD-ACE2 complex, are investigated by free-energy computational approaches, as well as equilibrium and steered molecular dynamic simulations. Considered also are the structural hydropathy traits of the residues in the interface between SARS-CoV-2 RBD and ACE2 protein. Salt bridges and π-π interactions are critical forces that create stronger complexes between the RBD and ACE2. The trend of mutations is the replacement of non-polar hydrophobic interactions with polar hydrophilic interactions, which enhance binding of RBD with ACE2. However, this is not always the case, as conformational landscapes also contribute to a stronger binding. Arginine, the most polar and hydrophilic among the natural amino acids, is the most aggressive mutant amino acid for stronger binding. Arginine blockers, such as traditional sartans that bear anionic tetrazoles and carboxylates, may be ideal candidate drugs for retarding viral infection by weakening S-protein RBD binding to ACE2 and discouraging hydrolysis of cleavage sites. Based on our computational results it is suggested that a new generation of “supersartans”, called “bisartans”, bearing two anionic biphenyl-tetrazole pharmacophores, are superior to carboxylates in terms of their interactions with viral targets, suggesting their potential as drugs in the treatment of COVID-19. In Brief: This in silico study reviews our understanding of molecular driving forces that trigger mutations in the SARS-CoV-2 virus. It also reports further studies on a new class of “supersartans” referred to herein as “bisartans”, bearing two anionic biphenyltetrazole moieties that show potential in models for blocking critical amino acids of mutants, such as arginine, in the Delta variant. Bisartans may also act at other targets essential for viral infection and replication (i.e., ACE2, furin cleavage site and 3CLpro), rendering them potential new drugs for additional experimentation and translation to human clinical trials.