Outcomes of higher-order multiple pregnancies in an Australian setting.

BACKGROUND: Higher-order multiple (HOM) pregnancies are associated with significant maternal and neonatal morbidity, especially consequent to preterm birth. Multi-fetal pregnancy reduction (MFPR) may be provided, though its benefits in prolonging gestation and improving neonatal outcomes must be weighed against its risks. AIMS: The aim was to compare outcomes of HOM pregnancies where expectant management was chosen (EM) with those where MFPR was provided. METHODS: The method involved a retrospective study of HOM pregnancies referred to a single quaternary hospital between 2007 and 2016. The primary outcome was gestational age. Secondary outcomes included miscarriage, nursery admission, hospital stay, Apgar scores, early fetal loss, stillbirth, neonatal death and composite fetal loss. RESULTS: Fifty-seven pregnancies were eligible for inclusion. Median gestation at birth (weeks) was significantly higher for MFPR (35.3 vs 33.1, P < 0.01). Pregnancies after MFPR were less likely to lead to preterm birth (63.2 vs 100.0%, P < 0.001), half as likely to birth before 34 weeks (31.6 vs 60.0%, P = 0.09) but similarly likely to extremely preterm birth (<28 weeks, 8.6 vs 10.5%, P = 0.58). Miscarriage was more likely after MFPR (13.6 vs 0%, P = 0.05). EM neonates were more likely to be admitted to the nursery (P < 0.01) and have longer hospital stay (29.6 vs 20.2 days, P = 0.05); however, they had similar Apgar scores. CONCLUSION: Our study demonstrates that MFPR is associated with an increase in gestational age, with a reduction by almost half of births before 34 weeks, but no difference in extremely preterm births; the latter represents the highest risk group. This should be used to guide management counselling for HOM pregnancies.

TUBB3/ßIII-tubulin acts through the PTEN/AKT signaling axis to promote tumorigenesis and anoikis resistance in non-small cell lung cancer.

ßIII-tubulin (encoded by TUBB3) expression is associated with therapeutic resistance and aggressive disease in non-small cell lung cancer (NSCLC), but the basis for its pathogenic influence is not understood. Functional and differential proteomics revealed that ßIII-tubulin regulates expression of proteins associated with malignant growth and metastases. In particular, the adhesion-associated tumor suppressor maspin was differentially regulated by ßIII-tubulin. Functionally, ßIII-tubulin suppression altered cell morphology, reduced tumor spheroid outgrowth, and increased sensitivity to anoikis. Mechanistically, the PTEN/AKT signaling axis was defined as a critical pathway regulated by ßIII-tubulin in NSCLC cells. ßIII-Tubulin blockage in vivo reduced tumor incidence and growth. Overall, our findings revealed how ßIII-tubulin influences tumor growth in NSCLC, defining new biologic functions and mechanism of action of ßIII-tubulin in tumorigenesis.

The cytoskeleton as a therapeutic target in childhood acute leukemia: obstacles and opportunities.

Antimitotic agents that interfere with the tubulin/microtubule system are important in the treatment of a range of cancers. Natural product tubulin-binding agents such as the Vinca alkaloids have proven highly effective in the treatment of leukemia. Improved understanding of the mechanisms of action of these and related drugs has led to the identification of distinct binding sites on tubulin that cause inhibition of spindle microtubule dynamics, mitotic arrest and cell death. Despite the efficacy of these agents, treatment failure caused by the emergence of drug resistant leukemic cells is a significant clinical problem. Alterations in the cellular target of tubulin-binding agents have been strongly implicated in resistance to these agents. This review will focus on the microtubule cytoskeleton and its role in drug resistance in leukemia. The identification of novel protein pathways involved in drug response and the development of new drugs targeted against microtubules, offers opportunities to treat resistant disease, improve outcome and potentially reduce toxicity for leukemia patients.

Transthyretin interacts with the lysosome-associated membrane protein (LAMP-1) in circulation.

LAMP-1 (lysosome-associated membrane protein), a major glycoprotein present in the lysosomal membrane, constitutes up to 50% of total membrane proteins. LAMP-1, expressed at the plasma membrane, is reported to be the major molecule expressing the sialyl-Lewis X antigen. Two forms of LAMP-1 exist; the full-length LAMP-1 [LAMP-1 (+Tail)] has a highly glycosylated lumenal domain, a membrane-spanning domain and a short cytoplasmic tail, and the truncated LAMP-1 [LAMP-1 (-Tail)] contains only the lumenal domain. Soluble LAMP-1 (+/-Tail) has been reported in circulation. LAMP-1 at the cell surface has been shown to interact with E-selectin and galectin and is proposed to function in cell-cell interactions. However, the functional role(s) of soluble LAMP-1 in circulation is unclear. To investigate the functional role of soluble LAMP-1 in circulation, recombinant LAMP-1 (-Tail) and LAMP-1 (+Tail) were produced in HT1080 cells. Two immune-quantification assays were developed to distinguish between the LAMP-1 forms. The interaction and aggregation properties of the different LAMP-1 forms were investigated using the immune-quantification assays. Only LAMP-1 (+Tail) was found to aggregate and interact with plasma proteins. Plasma proteins that interact with LAMP-1 were isolated by affinity chromatography with either the recombinant LAMP-1 (-Tail) or a synthesized peptide consisting of the 14 amino acids of the LAMP-1 cytoplasmic tail. Transthyretin was found to interact with the cytoplasmic tail of LAMP-1. Transthyretin exists as a homotetramer in plasma, as such may play a role in the aggregation of LAMP-1 in circulation.