ALDH5A1/miR-210 axis plays a key role in reprogramming cellular metabolism and has a significant correlation with glioblastoma patient survival.

BACKGROUND: Glioblastoma (GBM) is the most aggressive among the tumors of the central nervous system (CNS), and has a dismal prognosis. Altered metabolism, especially the increased rate of aerobic glycolysis promotes rapid proliferation of GBM cells. Here, we investigated the role of aldehyde dehydrogenase 5 family member A1 (ALDH5A1), a mitochondrial enzyme in the aspect of GBM metabolism. We also studied the regulatory mechanisms of altered ALDH5A1 expression in GBM. APPROACH AND RESULTS: We show that ALDH5A1 is significantly downregulated in GBM patients in a grade dependent manner as compared to control brain and its low expression is associated with poor prognosis. It is significantly downregulated under hypoxia and is a direct target of the hypoxia induced microRNA: miR-210. Ectopic overexpression of ALDH5A1 in GBM cell lines U-87 MG and T98G markedly reduced their proliferation, 3D spheroid forming ability, and formation of reactive oxygen species (ROS). ALDH5A1 upregulation increased the oxygen consumption rate (OCR), and reduced the extracellular acidification rate (ECAR) of GBM cells while miR-210 overexpression showed the opposite. A significant downregulation in the transcript levels of LDHA, PDK1, and SLC2A1; coupled with lower glucose uptake and lactate production upon ALDH5A1 overexpression reveals that ALDH5A1 significantly reduces the glycolytic capacity of GBM cells. Total ATP generated in 24 h was more when miR-210 was overexpressed, while a slight decrease in ATP formation was observed upon ALDH5A1 upregulation. Interestingly, we also observed that ALDH5A1 expression is elevated and miR-210 levels are downregulated in IDH-mutant glioma as compared to its wild-type form. CONCLUSION: Overall, our findings suggest that miR-210 mediated downregulation of ALDH5A1 plays a critical role in tumor metabolism and helps maintaining a high glycolytic phenotype in GBM.

Synthesis of 2,2-dimethyl-chroman-based stereochemically flexible and constrained anti-breast cancer agents.

Receptors are proteinous macromolecules which remain in the apo form under normal/unliganded conditions. As the ligand approaches, there are specific stereo-chemical changes in the apo form of the receptor as per the stereochemistry of a ligand. Accordingly, a series of substituted dimethyl-chroman-based stereochemically flexible and constrained Tamoxifen analogs were synthesized as anti-breast cancer agents. The synthesized compounds 19a-e, 20a-e, 21, and 22a-e, showed significant antiproliferative activity against estrogen receptor-positive (ER+, MCF-7) and negative (ER-, MDA MB-231) cells within IC50 value 8.5-25.0 µM. Amongst all, four potential molecules viz 19b, 19e, 22a, and 22c, were evaluated for their effect on the cell division cycle and apoptosis of ER+ and ER- cancer cells (MCF-7 & MDA MB-231cells), which showed that these compounds possessed antiproliferative activity through triggering apoptosis. In-silico docking experiments elucidated the possible affinity of compounds with estrogen receptors-α and -ß.

Synthesis of amide derivatives of 3-aryl-3H-benzopyrans as osteogenic agent concomitant with anticancer activity.

The present study reports a series of 3-aryl-3H-benzopyran-based amide derivatives as osteogenic agents concomitant with anticancer activity. Six target compounds viz 22e, 22f, 23i, and 24b-d showed good osteogenic activity at 1 pM and 100 pM concentrations. One of the potential molecules, 24b, effectively induced ALP activity and mRNA expression of osteogenic marker genes at 1 pM and bone mineralization at 100 pM concentrations. These molecules also presented significant growth inhibition of osteosarcoma (MG63) and estrogen-dependent and -independent (MCF-7 and MDA-MB-231) breast cancer cells. The most active compound, 24b, inhibited the growth of all the cancer cells within the IC50 10.45-12.66 µM. The mechanistic studies about 24b showed that 24b induced apoptosis via activation of the Caspase-3 enzyme and inhibited cancer cell migration. In silico molecular docking performed for 24b revealed its interaction with estrogen receptor-ß (ER-ß) preferentially.

High-quality large-scale electron-beam-written resonant filters for the long-wave infrared region.

We present new, to the best of our knowledge, large-scale, high-quality spectral filters operating in the long-wave infrared (LWIR) spectral region. We employ high-spatial resolution nanofabrication techniques to achieve large-area (12mm×12mm) spectrally tunable notch filters. Filter operation is based on the guided-mode resonance effect. The device structure consists of a germanium waveguide grating on top of a zinc selenide substrate. The filters reflect the incident broadband light at one (or more) narrow spectral bands while fully transmitting the rest. We tune the reflected wavelength by tilting the filter. Filters based on one-dimensional gratings are polarization sensitive. We fabricate prototype filters and characterize their polarization dependence and spectral tuning performance using a tunable quantum cascade laser system that spans the ∼7-13µm spectral band. We obtain an excellent agreement between the theoretical and experimental results.

Neurocritical care of high-risk infants during inter-hospital transport.

The centralisation of neonatal intensive care in recent years has improved mortality, particularly of extremely preterm infants, but similar improvements in morbidity, such as neurodevelopmental impairment, have not been seen. Integral to the success of centralisation are specialised neonatal transport teams who provide intensive care prior to and during retrieval of high-risk neonates when in-utero transfer has not been possible. Neonatal retrieval aims to stabilise the clinical condition and then transfer the neonate during a high-risk period for patient. Transport introduces the hazards of noise and vibration; acceleration and deceleration forces; additional handling and temperature fluctuations. The transport team must stabilise the infant fully prior to transport as when on the move they are limited by space and movement to effectively attend to clinical deterioration. Inborn infants have better neurodevelopmental outcome compared with the outborn and aetiology of this seems to be multifactorial with the impact of transport itself during critical illness, remaining unclear. To improve the neurological outcomes for transported infants, it seems imperative to integrate the advancing intensive care neuromonitoring tools into the transport milieu. This review examines current inter-hospital transport neuromonitoring and how new modalities might be applied to the neurocritical care delivered by specialist transport teams.

Notch filtering using a multiple passband AOTF in the SWIR region.

A notch filtering operation was accomplished using a TeO2 acousto-optic tunable filter (AOTF) with 16 simultaneous overlapping passbands in the shortwave infrared wavelength region. By switching off specific radio frequency signals applied to the AOTF, laser wavelengths corresponding to the inactive passbands are rejected, providing see-through capability with the remaining wavelengths. The rejection level was determined by leakage through the sidelobes of adjacent passbands, as was shown by theory and corresponding measurements. By switching off multiple passbands near the laser wavelength, the rejection level can be increased at the expense of reduced see-through capability. The AOTF imaging system used telecentric confocal optics that compensate for AOTF aberrations, which are severe at high sidelobe operation.

Transport of infants with congenital heart disease: benefits of antenatal diagnosis.

UNLABELLED: Infants with significant congenital heart disease (CHD) typically require transport from their birth centre to a regional paediatric cardiac centre. Antenatal diagnosis of CHD allows early pre-emptive stabilisation, and is associated with improved early clinical status. However, the effect of antenatal diagnosis on the transport characteristics of infants with CHD has not been previously investigated. The aim of this study was to compare the transport characteristics of infants with antenatal and postnatal diagnosis of CHD. This study is a retrospective cohort study of all infants of ≤10 days and ≥34 weeks of gestation with CHD admitted to the Royal Children's Hospital, Melbourne (RCH) over 5 years. Demographic, diagnosis, and transport data were recorded. Cases of complex CHD were included in this study. Of 320 infants with complex CHD, 198 (62 %) had antenatal diagnosis (ANdx) and 122 (38 %) had postnatal diagnosis (PNdx). There was no significant difference in sex, birth weight, or gestation between ANdx and PNdx groups. Average age of referral was 15 vs. 53.4 h in ANdx vs. PNdx groups. Aggregate transfer distance in the ANdx group was 2216 km and in the PNdx group was 10,274 km (P < 0.0001). Of the infants, 39 % in the PNdx group required highest-acuity "time critical" transports compared to 6 % of ANdx infants (P = 0.0001). Conversely, only 11 % of the infants in the PNdx group had lowest acuity "non-urgent" transfers, compared to 24 % of ANdx infants (P = 0.003). PNdx was associated with significantly higher rates of invasive ventilation (36 vs 20 %; P = 0.01) and higher rates of inotrope use (19 vs. 9 %; P = 0.007) during transport. CONCLUSIONS: Improved antenatal detection would allow for safer, less resource intense transfers of infants with CHD.

Improving diagnostic accuracy in the transport of infants with suspected duct-dependent congenital heart disease.

AIM: To identify factors that distinguish duct-dependent congenital heart disease (DDCHD) from non-DDCHD in newborn infants. METHOD: A retrospective, cohort study. The Newborn Emergency Transport Service, Victoria (NETS) is a retrieval service for all inter-hospital neonatal transfers, and the Royal Children's Hospital, Melbourne (RCH) is a paediatric cardiac referral centre for the state of Victoria, Australia. All infants ≤10 days and ≥34 weeks gestation with suspected CHD and/or persistent pulmonary hypertension of the newborn (PPHN), transferred by NETS from non-tertiary neonatal units to RCH, over a 4-year period. RESULTS: Of 142 eligible infants, 81 had DDCHD and 61 had non-DDCHD, of whom 51 had PPHN. Diagnostic accuracy of DDCHD by the NETS team was 77%. Presence of a heart murmur, abnormal pulses, upper and lower limb blood pressure (BP) difference >10 mmHg, cardiomegaly, initial SpO2 of <92%, PaO2 <50 mmHg, and pre-post ductal SpO2 difference >10% were significantly associated with DDHCD on univariate analysis. No single clinical finding was significantly associated with DDCHD on multivariate analysis. Labile SpO2 , abnormal lung parenchyma, mean BP <40 mmHg, pH <7.25, lactate >5 and FiO2 >0.5 were significantly associated with non-DDCHD, but at multivariate analysis only labile SpO2 and mean BP <40 mmHg were associated with non-DDCHD. CONCLUSIONS: Clinical diagnosis of DDCHD outside of a cardiac centre is challenging. No single factor predicts DDCHD. Combined interpretation of clinical, physiological and x-ray findings may assist.

Comparative sequence analysis in the exon 5 of growth hormone gene in the various livestock species of India.

The aim of the study was to identify genetic polymorphism in growth hormone (GH) gene locus of six different livestock species using PCR-Direct DNA sequencing method. In exon 5 of GH gene, 10 SNPs variants were identified in all livestock species studied, namely Bubalus bubalis, Bos indicus, Bos frontalis, Bos grunniens, Ovis aries, and Capra hircus. Four SNPs were observed in Bubalus bubalis, two SNPs in Bos indicus, one SNP in Ovis aries, and three SNPs in Capra hircus. No changes were observed in Bos grunniens and Bos frontalis when compared with the template sequence and the SNPs observed in the present investigation may be useful in the marker assisted selection.