Hospitalizations in Australian children with neuroblastoma: A population-based study.

BACKGROUND: An increasing number of children diagnosed with both low- and high-risk neuroblastoma are surviving. Yet, treatment can be intensive and often multimodal, especially for high-risk neuroblastoma, resulting in significant long-term health problems. We aimed to describe neuroblastoma survivors' pediatric hospitalizations, readmissions, and their associated costs. METHOD: We conducted a population-based study of all children (<18 years) residing in New South Wales (NSW), Australia, and hospitalized with a recorded diagnosis of neuroblastoma during 2001-2020. We used linked NSW Admitted Patient Data Collection and death registration data to examine the frequency, length of stay, and readmissions following the first admission when neuroblastoma was diagnosed (i.e., the index admission), and the associated hospitalization costs by age and timing postindex admission discharge. RESULTS: In total, 300 children (64% aged <3 years) were hospitalized for neuroblastoma over the study period. The median number of readmissions and length of stay within 2 years postdischarge were 17 (interquartile range IQR: 5.5-25) and 45.5 (IQR: 10-125) days, and median cost per child was AUD$124,058 (IQR $34,217-$264,627). Following discharge from the index admission, there were 7088 readmissions (median: 20 per child, IQR: 7-29). Fifty-eight percent of readmissions occurred within 1-year postdischarge, primarily due to fever, nausea, abdominal pain, and respiratory conditions. CONCLUSION: The burden of health problems requiring hospitalization among neuroblastoma survivors results in significant associated healthcare costs, warranting further efforts to optimize health care for neuroblastoma survivors that focuses on early intervention and long-term monitoring.

UPLC‒ESI‒MS/MS profiling of active polyphenolics in Morinda coreia leaf extract and in vitro antioxidant and antibacterial activity.

In this study, aqueous and methanol extracts of Morinda coreia (MC) leaves were tested for antioxidant and antibacterial activity under in vitro conditions. Phytochemical analysis using UPLC-ESI-MS revealed the presence of phenolics, flavonoids, alkaloids, glycosides, amino acids, proteins, saponins, and tannins. Under in vitro conditions, antioxidant test using DPPH, ABTS, and reducing power demonstrated that the plant leaves play a crucial role in antioxidant activity compared to the commercial antioxidant butylated hydroxytoluene (BHT). The ABTS and DPPH free radical scavenging activities showed that the IC50 values of the M. coreia methanol extract were 26.35 µg/mL and 200.23 µg/mL, respectively. The methanol extract of M. coreia contained higher levels of total phenols and flavonoids and higher free radical scavenging capacity than the aqueous extract. FTIR analysis of the methanol extract showed a substantial number of phenols in the functional groups of M. coreia leaves. The well diffusion assay using the methanolic extract of M. coreia (200 µg/mL) leaves showed antibacterial activity against Pseudomonas aeruginosa (19 ± 0.85 mm), Proteus sp. (20 ± 0.97 mm), Streptococcus sp. (21 ± 1.29 mm), and Enterobacter sp. (17 ± 0.2 mm). Thus, the present study revealed that the antibacterial and antioxidant activity of M. coreia leaf extract was due to the presence of 18 unknown and 15 primary known polyphenols.

Deciphering the fluorescence quenching potential of Croton bonplandianum leaves and detection of bioactive molecules using liquid chromatography and mass spectrometry.

In this study, liquid chromatography and mass spectrometry were used to screen the active phytochemicals and analyze antioxidant activity of Croton bonplandianum. In addition, cadmium telluride quantum dots were used to analyze the fluorescence quenching capabilities of Croton bonplandianum plants. UPLC-ESI-MS was used to screen polyphenols in the mass range of 100-2000, with both positive and negative ionizations. Based on molecular weight, 7-Spirostanoldihexoside isomer, Rutin, Quercetin hexoside, Kaempferol-3-O-(p-coumaroyl)-glucoside, Kaempferol, Quercetin, and (E) Catechin-(E) Gallocatechin were tentatively identified. In total, 63.34 mg of polyphenols and 20.36 mg of flavonoids were detected. Lipid peroxidation IC50 values were 212, 38, 56, and 365 g/mL for DPPH, ABTS, and superoxide radicals. Reducing power of the plant material showed the maximum absorbance of 0.56 in 500 µg/mL concentration. Furthermore, the plant extract quenched cadmium telluride quantum dots fluorescence in a dose dependent manner. The results from quenching concluded that Croton bonplandianum with QDs might be used as a drug targeting and delivery nanomaterial.

Nuclear Vav3 is required for polycomb repression complex-1 activity in B-cell lymphoblastic leukemogenesis.

Acute B-cell lymphoblastic leukemia (B-ALL) results from oligo-clonal evolution of B-cell progenitors endowed with initiating and propagating leukemia properties. The activation of both the Rac guanine nucleotide exchange factor (Rac GEF) Vav3 and Rac GTPases is required for leukemogenesis mediated by the oncogenic fusion protein BCR-ABL. Vav3 expression becomes predominantly nuclear upon expression of BCR-ABL signature. In the nucleus, Vav3 interacts with BCR-ABL, Rac, and the polycomb repression complex (PRC) proteins Bmi1, Ring1b and Ezh2. The GEF activity of Vav3 is required for the proliferation, Bmi1-dependent B-cell progenitor self-renewal, nuclear Rac activation, protein interaction with Bmi1, mono-ubiquitination of H2A(K119) (H2AK119Ub) and repression of PRC-1 (PRC1) downstream target loci, of leukemic B-cell progenitors. Vav3 deficiency results in de-repression of negative regulators of cell proliferation and repression of oncogenic transcriptional factors. Mechanistically, we show that Vav3 prevents the Phlpp2-sensitive and Akt (S473)-dependent phosphorylation of Bmi1 on the regulatory residue S314 that, in turn, promotes the transcriptional factor reprogramming of leukemic B-cell progenitors. These results highlight the importance of non-canonical nuclear Rho GTPase signaling in leukemogenesis.

PROState Pathway Embedded Comparative Trial: The IP3-PROSPECT study.

INTRODUCTION: The traditional double blind RCT is the 'gold standard' trial design. For a variety of reasons, these designs often fail to accrue enough participants to conclude. This is particularly challenging in localized prostate cancer. The cohort multiple randomised controlled trial (cmRCT) trial design may represent an alternative approach to delivering robust comparative data in prostate cancer. PATIENTS AND METHODS: IP3-PROSPECT is a cmRCT designed to test multiple prostate cancer interventions from eligible men in one cohort. Key to the design is two points of consent. First, at point of consent one, men referred for prostate cancer investigations are invited to join the cohort. They may then be randomly invited at a later date to consider an intervention at point of consent two. In the pilot phase we will test the acceptability and feasibility of developing the cohort. RESULTS: Acceptability and feasibility of the study will be measured by a combination of quantitative and qualitative methods. The primary outcome measure is the rate of consent to inclusion to the IP3-PROSPECT cohort. Secondary outcome measures include the completeness of data collection at sites and return rates of patient questionnaires. We will also interview patients and healthcare professionals to explore their thoughts on the implementation, practicality and efficiency of IP3-PROSPECT. CONCLUSION: The IP3-PROSPECT study will evaluate the cmRCT design in prostate cancer. Initially we will pilot the design, assessing for acceptability and feasibility. The cmRCT is an innovative design that offers potential for building a modern comparative evidence base for prostate cancer.

TLR4 signaling modulation of PGC1-α mediated mitochondrial biogenesis in the LPS-Chronic mild stress model: Effect of fluoxetine and pentoxiyfylline.

AIM: The addition of repeated lipopolysaccharide (LPS) to chronic mild stress was recently proposed in our lab as an alternative model of depression, highlighting the possible interaction between stress and immune-inflammatory pathways in predisposing depression. Given that CMS-induced depressive behavior was previously related to impaired hippocampal energy metabolism and mitochondrial dysfunction, our current study aimed to investigate the interplay between toll-like receptor 4 (TLR4) signaling and peroxisome proliferator-activated receptor gamma coactivators-1-alpha (PGC1-α) as a physiological regulator of energy metabolism and mitochondrial biogenesis in the combined LPS/CMS model. MAIN METHODS: Male Wistar rats were exposed to either LPS (50 µg/kg i.p.) over 2 weeks, CMS protocol for 4 weeks or LPS over 2 weeks followed by 4 weeks of CMS (LPS/CMS). Three additional groups of rats were exposed to LPS/CMS protocol and treated with either pentoxifylline (PTX), fluoxetine (FLX) or a combination of both. Rats were examined for behavioral, neurochemical, gene expression and mitochondrial ultra-structural changes. KEY FINDINGS: LPS/CMS increased the expression of TLR4 and its downstream players; MyD88, NFκB and TNF-α along with an escalation in hippocampal-energy metabolism and p-AMPK. Simultaneously LPS/CMS attenuated the expression of PGC1-α/NRF1/Tfam and mt-DNA. The antidepressant (AD) 'FLX', the TNF-α inhibitor 'PTX' and their combination ameliorated the LPS/CMS-induced changes. Interestingly, all the aforementioned changes induced by the LPS/CMS combined model were significantly less than those induced by CMS alone. SIGNIFICANCE: Blocking the TLR4/NFκB signaling enhanced the activation of the PGC1-α/NRF1/Tfam and mt-DNA content independent on the activation of the energy-sensing kinase AMPK.

A comparison study of cleanup techniques for oil spill treatment using magnetic nanomaterials.

Magnetic nanoparticles have been successfully used to recovery oil from oil spilled on water. Two different methods, floating and vortex, were employed to promote the interaction of four oil samples with different API (e.g., 10, 20, 28 and 45) spilled on seawater and deionized water with three magnetic materials, namely: magnetite nanoparticles (N); magnetic nanocomposites of yeast biomass provided by ethanol industry (Y); and magnetic nanocomposites of cork powder (C). The magnetic nanomaterials exposed to oil on water were taking out by a neodymium magnet, and the oil recoveries were determined by gravimetric analysis before and after lyophilization. The lyophilization was determinant to guarantee the accuracy of the experiments, and without this step, the masses of oil recovered would be overestimated due to the drag of water during the oil and magnetic material removal process. Three main factors, API, contact method and magnetic material, and two interactions (i.e., API × contact method, and contact method × magnetic material) presented a statistically significant effect on oil recovery. It was observed that oil recovery increases as API decreases, and it was possible to establish a model to predict the amount of recovered oil according to this effect. Higher oil recoveries were also obtained by magnetic nanocomposites of yeast biomass (Y), regardless of the contact method and type of water, recoveries of 23% and 100% for 45 and 10 API, respectively, employing around 20 mg of Y on 300 mg of spilled oil. These percentages correspond to 0.29 ±â€¯0.01 kg/kg and 15.98 kg/kg of recovering oil by the magnetic procedure. The increase of mass of magnetic material improved the recovery of oils with higher APIs. The reusability of the spent materials presents potential for its application in oil spill cleaning technologies.

Maternal first trimester serum levels of free-beta human chorionic gonadotrophin and male genital anomalies.

STUDY QUESTION: Are maternal first trimester levels of serum free-beta hCG associated with the development of hypospadias or undescended testis (UDT) in boys? SUMMARY ANSWER: Overall, first trimester maternal levels of serum free-beta hCG are not associated with hypospadias or UDT. However, elevated levels were found in severe phenotypes (proximal hypospadias and bilateral UDT) suggesting an altered pathway of hormonal release in early pregnancy. WHAT IS KNOWN ALREADY: Human chorionic gonadotrophin peaks in first trimester of pregnancy stimulating fetal testosterone production, which is key to normal male genital development. Endocrine-disrupting insults early in pregnancy have been associated with increased risk of common genital anomalies in males such as hypospadias and UDT. One plausible etiological pathway is altered release of hCG. STUDY DESIGN, SIZE, DURATION: We conducted a record-linkage study of two separate populations of women attending first trimester aneuploidy screening in two Australian states, New South Wales (NSW) and Western Australia (WA), in 2006-2009 and 2001-2003, respectively. PARTICIPANTS/MATERIALS, SETTING, METHODS: Included were women who gave birth to a singleton live born male infant. There were 12 099 boys from NSW and 10 518 from WA included, of whom 90 and 77 had hypospadias; and 107 and 109 UDT, respectively. Serum levels of free-beta hCG were ascertained from laboratory databases and combined with relevant birth outcomes and congenital anomalies via record linkage of laboratory, birth, congenital anomalies and hospital data. Median and quartile levels of gestational age specific free-beta hCG multiple of the median (MoM) were compared between affected and unaffected boys. Logistic regression was used to evaluate the association between levels of free-beta hCG MoM and hypospadias or UDT, stratified by suspected placental dysfunction and co-existing anomalies. Where relevant, pooled analysis was conducted. MAIN RESULTS AND THE ROLE OF CHANCE: There was no difference in median hCG levels amongst women with an infant with hypospadias (NSW = 0.88 MoM, P = 0.83; WA = 0.84 MoM, P = 0.76) or UDT (NSW = 0.89 MoM, P = 0.54; WA = 0.95 MoM, P = 0.95), compared with women with an unaffected boy (NSW = 0.92 MoM; WA = 0.88 MoM). Low (<25th centile) or high (>75th centile) hCG levels were not associated with hypospadias or UDT, nor when stratifying by suspected placental dysfunction and co-existing anomalies. However, there was a tendency towards high levels for severe types, although confidence intervals were wide. When combining NSW and WA results, high hCG MoM levels (>75th centile) were associated with increased risk of proximal hypospadias (odds ratio (OR) 4.34; 95% CI: 1.08-17.4) and bilateral UDT (OR 2.86; 95% CI: 1.02-8.03). LIMITATIONS, REASONS FOR CAUTION: There were only small numbers of proximal hypospadias and bilateral UDT in both cohorts and although we conducted pooled analyses, results reported on these should be interpreted with caution. Gestational age by ultrasound may have been inaccurately estimated in small and large for gestational age fetuses affecting hCG MoM calculation in those pregnancies. Despite the reliability of our datasets in identifying adverse pregnancy outcomes, we did not have pathology information to confirm tissue lesions in the placenta and therefore our composite outcome should be considered as a proxy for placental dysfunction. WIDER IMPLICATIONS OF THE FINDINGS: This is one of the largest population-based studies examining the association between maternal first trimester serum levels of free-beta hCG and genital anomalies-hypospadias and UDT; and the first to compare specific phenotypes by severity. Overall, our findings does not support the hypothesis that alteration in maternal hCG levels is associated with the development of male genital anomalies; however, high hCG free-beta levels found in severe types suggest different underlying etiology involving higher production and secretion of hCG. These findings require further exploration and replication. STUDY FUNDING/COMPETING INTERESTS: This work was funded by the National Health and Medical Research Council (NHMRC) grant APP1047263. N.N. is supported by a NHMRC Career Development Fellowship APP1067066. C.B. was supported by a NHMRC Principal Research Fellowship #634341. The funding agencies had no role in the design, analysis, interpretation or reporting of the findings. There are no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

Iron deficiency in early pregnancy using serum ferritin and soluble transferrin receptor concentrations are associated with pregnancy and birth outcomes.

BACKGROUND/OBJECTIVES: There are several biomarkers for measuring iron deficiency (ID) in pregnancy, but the prevalence of ID and its association with inflammation and adverse pregnancy outcomes is inconclusive. The aim of this work was to describe the prevalence and determinants of first trimester ID and associations with pregnancy and birth outcomes. SUBJECTS/METHODS: A record-linkage cohort study of archived serum samples of women attending first trimester screening and birth and hospital data to ascertain maternal characteristics and pregnancy outcomes. Sera were analysed for iron stores (ferritin; µg/l), lack of iron in the tissues (soluble transferrin receptor (sTfR); nmol/l) and inflammatory (C-reactive protein (CRP); mg/dl) biomarkers. Total body iron (TBI) was calculated from serum ferritin (SF) and sTfR concentrations. Multivariate logistic regression analysed risk factors and pregnancy outcomes associated with ID using the definitions: SF<12 µg/l, TfR ⩾ 21.0 nmol/l, and TBI<0 mg/kg. RESULTS: Of the 4420 women, the prevalence of ID based on ferritin, sTfR and TBI was 19.6, 15.3 and 15.7%, respectively. Risk factors of ID varied depending on which iron parameter was used and included maternal age <25 years, multiparity, socioeconomic disadvantage, high maternal body weight and inflammation. ID, defined by SF and TBI but not TfR, was associated with reduced risk of gestational diabetes mellitus (GDM). ID defined using TBI only was associated with increased risk of large-for-gestation-age (LGA) infants. CONCLUSIONS: Nearly one in five Australian women begin pregnancy with ID. Further investigation of excess maternal weight and inflammation in the relationships between ID and GDM and LGA infants is needed.

UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO.

The t(8;21) rearrangement, which creates the AML1-ETO fusion protein, represents the most common chromosomal translocation in acute myeloid leukemia (AML). Clinical data suggest that CBL mutations are a frequent event in t(8;21) AML, but the role of CBL in AML1-ETO-induced leukemia has not been investigated. In this study, we demonstrate that CBL mutations collaborate with AML1-ETO to expand human CD34+ cells both in vitro and in a xenograft model. CBL depletion by shRNA also promotes the growth of AML1-ETO cells, demonstrating the inhibitory function of endogenous CBL in t(8;21) AML. Mechanistically, loss of CBL function confers hyper-responsiveness to thrombopoietin and enhances STAT5/AKT/ERK/Src signaling in AML1-ETO cells. Interestingly, we found the protein tyrosine phosphatase UBASH3B/Sts-1, which is known to inhibit CBL function, is upregulated by AML1-ETO through transcriptional and miR-9-mediated regulation. UBASH3B/Sts-1 depletion induces an aberrant pattern of CBL phosphorylation and impairs proliferation in AML1-ETO cells. The growth inhibition caused by UBASH3B/Sts-1 depletion can be rescued by ectopic expression of CBL mutants, suggesting that UBASH3B/Sts-1 supports the growth of AML1-ETO cells partly through modulation of CBL function. Our study reveals a role of CBL in restricting myeloid proliferation of human AML1-ETO-induced leukemia, and identifies UBASH3B/Sts-1 as a potential target for pharmaceutical intervention.

High maternal iron status, dietary iron intake and iron supplement use in pregnancy and risk of gestational diabetes mellitus: a prospective study and systematic review.

AIM: High iron measured using dietary intake and biomarkers is associated with Type 2 diabetes. It is uncertain whether a similar association exists for gestational diabetes mellitus. The aim of this systematic review was to conduct a cohort study examining first trimester body iron stores and subsequent risk of gestational diabetes, and to include these findings in a systematic review of all studies examining the association between maternal iron status, iron intake (dietary and supplemental) and the risk of gestational diabetes. METHODS: Serum samples from women with first trimester screening were linked to birth and hospital records for data on maternal characteristics and gestational diabetes diagnosis. Blood was analysed for ferritin, soluble transferrin receptor and C-reactive protein. Associations between iron biomarkers and gestational diabetes were assessed using multivariate logistic regression. A systematic review and meta-analysis, registered with PROSPERO (CRD42014013663) included studies of all designs published in English from January 1995 to July 2015 that examined the association between iron and gestational diabetes and included an appropriate comparison group. RESULTS: Of 3776 women, 3.4% subsequently developed gestational diabetes. Adjusted analyses found increased odds of gestational diabetes for ferritin (OR 1.41; 95% CI 1.11, 1.78), but not for soluble transferrin receptor (OR 1.00; 95% CI 0.97, 1.03) per unit increase of the biomarker. Two trials of iron supplementation found no association with gestational diabetes. Increased risk of gestational diabetes was associated with higher levels of ferritin and serum iron and dietary haem iron intakes. CONCLUSIONS: Increased risk of gestational diabetes among women with high serum ferritin and iron levels and dietary haem iron intakes warrants further investigation.

Role of adenosine A2A receptor in cerebral ischemia reperfusion injury: Signaling to phosphorylated extracellular signal-regulated protein kinase (pERK1/2).

Following brain ischemia reperfusion (IR), the dramatic increase in adenosine activates A2AR to induce further neuronal damage. Noteworthy, A2A antagonists have proven efficacious in halting IR injury, however, the detailed downstream signaling remains elusive. To this end, the present study aimed to investigate the possible involvement of phospho-extracellular signal-regulated kinase (pERK1/2) pathway in mediating protection afforded by the central A2A blockade. Male Wistar rats (250-270 g) subjected to bilateral carotid occlusion for 45 min followed by a 24-h reperfusion period showed increased infarct size corroborating histopathological damage, memory impairment and motor incoordination as well as increased locomotor activity. Those events were mitigated by the unilateral intrahippocampal administration of the selective A2A antagonist SCH58261 via a decrease in pERK1/2 downstream from diacyl glycerol (DAG) signaling. Consequent to pERK1/2 inhibition, reduced hippocampal microglial activation, glial tumor necrosis factor-alpha (TNF-α) and brain-derived neurotropic factor (BDNF) expression, glutamate (Glu), inducible nitric oxide synthase (iNOS) and thiobarbituric acid reactive substances (TBARS) were evident in animals receiving SCH58261. Additionally, the anti-inflammatory cytokine interleukin-10 (IL-10) increased following nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). Taken all together, these events suppressed apoptotic pathways via a reduction in cytochrome c (Cyt. c) as well as caspase-3 supporting a crucial role for pERK1/2 inhibition in consequent reduction of inflammatory and excitotoxic cascades as well as correction of the redox imbalance.

Prevalence of functional bowel disorders and faecal incontinence: an Australian primary care survey.

AIM: Interest in functional bowel disorders (FBDs) and faecal incontinence (FI) has increased amongst coloproctologists. The study aimed to assess the prevalence of FBDs and FI (including its severity) among Australian primary healthcare seekers using objective criteria. METHOD: A cross-sectional survey was conducted in a primary care setting in Sydney, Australia. A self-administered questionnaire was used to collect demographic information and diagnose FBDs (irritable bowel syndrome, constipation, functional bloating and functional diarrhoea) based on Rome III criteria. The severity of FI was determined using the Vaizey incontinence score. Associations with medical/surgical history and healthcare utilization were assessed. RESULTS: Of 596 subjects approached, 396 (66.4%) agreed to participate. Overall, 33% had FBD and/or FI. Irritable bowel syndrome was present in 11.1% and these participants were more likely to report anxiety/depression (P < 0.01) and to have had a previous colonoscopy (P < 0.001) or cholecystectomy (P = 0.02). Functional constipation was present in 8.1%, and functional bloating and functional diarrhoea were diagnosed in 6.1%, and 1.5%, respectively. FI was present in 12.1% with the majority (52%) reporting moderate/severe incontinence (Vaizey score > 8). Participants with FI were more likely to have irritable bowel syndrome, urinary incontinence and previous anal surgery (P < 0.01). CONCLUSION: FBDs and FI are prevalent conditions amongst primary healthcare seekers and the needs of those affected appear to be complex given their coexisting symptoms and conditions. Currently, the majority do not reach colorectal services, although increased awareness by primary care providers could lead to sufferers being referred for specialist management.

Criticality of iron and its principal alloying elements.

Because modern technology depends on reliable supplies of a wide variety of materials and because of increasing concern about those supplies, a comprehensive methodology was created to quantify the degree of criticality of the metals of the periodic table. In this paper, we apply this methodology to iron and several of its main alloying elements (i.e., vanadium, chromium, manganese, and niobium). These elements represent the basic metals of any industrial society and are vital for national security and economic well-being. Assessments relating to the dimensions of criticality - supply risk, vulnerability to supply restriction, and environmental implications - for 2008 are made on the global level and for the United States. Evaluations of each of the multiple indicators are presented, with aggregate results plotted in "criticality space", together with Monte Carlo simulation-derived "uncertainty cloud" estimates. Iron has the lowest supply risk, primarily because of its widespread geological occurrence. Vanadium displays the highest cradle-to-gate environmental implications, followed by niobium, chromium, manganese, and iron. Chromium and manganese, both essential in steel making, display the highest vulnerability to supply restriction, largely because substitution or substitution at equal performance is not possible for all end-uses. From a comprehensive perspective, we regard the overall criticality as low for iron and modest for the alloying elements we evaluated.

Breast cancer-associated missense mutants of the PALB2 WD40 domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair.

Heterozygous carriers of germ-line mutations in the BRCA2/FANCD1, PALB2/FANCN and RAD51C/FANCO DNA repair genes have an increased lifetime risk of developing breast, ovarian and other cancers; bi-allelic mutations in these genes clinically manifest as Fanconi anemia (FA). Here, we demonstrate that RAD51C is part of a novel protein complex that contains PALB2 and BRCA2. Further, the PALB2 WD40 domain can directly and independently bind RAD51C and BRCA2. To understand the role of these homologous recombination (HR) proteins in DNA repair, we functionally characterize effects of missense mutants of the PALB2 WD40 domain that have been reported in breast cancer patients. In contrast to large truncations of PALB2, which display a complete loss of interaction, the L939W, T1030I and L1143P missense mutants/variants of the PALB2 WD40 domain are associated with altered patterns of direct binding to the RAD51C, RAD51 and BRCA2 HR proteins in biochemical assays. Further, the T1030I missense mutant is unstable, whereas the L939W and L1143P proteins are stable but partially disrupt the PALB2-RAD51C-BRCA2 complex in cells. Functionally, the L939W and L1143P mutants display a decreased capacity for DNA double-strand break-induced HR and an increased cellular sensitivity to ionizing radiation. As further evidence for the functional importance of the HR complex, RAD51C mutants that are associated with cancer susceptibility and FA also display decreased complex formation with PALB2. Together, our results suggest that three different cancer susceptibility and FA proteins function in a DNA repair pathway based upon the PALB2 WD40 domain binding to RAD51C and BRCA2.

Cytogenetic and anatomic behavior of cytochimeras and total polyploids in cassava.

Cassava periclinal cytochimeras, cultivars, and interspecific hybrid and polyploid types were studied in relation to embryonic, cytogenetic, and anatomical behavior. Their apical shoots, pollen grains, male and female buds, roots, stomata, and flowering period were analyzed. Chimeras exhibited increased size of L1 and L2 cells. Polyploidy led to enlargement of stomata in chimeras whereas L2 gave tetraploid chromosome configurations, tetrad irregularity, decrease of pollen viability, and increase in frequency of polyembryo sacs. The chimeric composition of tetraploids L1 and L2 and diploid L3 expressed a notable epigenetic effect seen in a marked enlargement of edible roots compared to total diploid. One of the chimeric types was accompanied by complete flowering inhibition. Pollen viability and diameter appeared to be reliable markers to determine ploidy levels.

Cassava interspecific hybrids with increased protein content and improved amino acid profiles.

Cassava (Manihot esculenta) is a principal food for large populations of poor people in the tropics and subtropics. Its edible roots are poor in protein and lack several essential amino acids. Interspecific hybrids may acquire high protein characteristics from wild species. We analyzed 19 hybrids of M. esculenta with its wild relative, M. oligantha, for crude protein, amino acid profile, and total cyanide. Some hybrids produced roots with high protein content of up to 5.7%, while the common cultivar that we examined had just 2.3% crude protein. The essential amino acids alanine, phenylalanine, and valine were detected in the hybrids. The sulfur-containing amino acids cysteine and methionine were found at relatively high concentrations in the roots of 4 hybrids. The proportion of lysine in one hybrid was 20 times higher than in the common cultivar. The levels of total cyanide ranged from 19.73 to 172.56 mg/kg and most of the roots analyzed were classified as "non-toxic" and "low toxic". Furthermore, 2 progenies showed reasonable levels of cyanide, but higher protein content and amino acid profile more advantageous than the common cassava.

Apomixis in cassava: advances and challenges.

Cassava is the most important staple crop in the Tropics and Subtropics. Apomixis may revolutionize its production due to various attributes. These potential advantages include production by true seed, maintaining cultivar superiority over generations without segregation, and avoiding contamination by bacteria and viruses. Historically, apomixis was initially observed by International Institute of Tropical Agriculture researchers, in the 1980s, in homogenous progeny of hybrid crosses. Later, from 1980 through 2010, apomixis was extensively studied by Universidade de Brasília, in order to determine contributing mechanisms and occurrence. Apomixis genes occur naturally at low frequencies in cultivated cassava and can be transferred by crosses with wild species. Apparently, apomixis in cassava is controlled by more than one recessive gene, which act in an additive form. Aneuploidy is associated with apomixis in cassava and can provide the double dosages necessary for recessive gene action. By using molecular techniques, genetic homogeneous progeny has been demonstrated, while embryonic exams have shown nucellar multiembryos. Polyploidy was found to increase apomixis percentage. From an evolutionary viewpoint, polyploidy has contributed to production of new species, when combined with apomixis. Recently, somatic embryos have been detected in the integument, revealing a rare model of apomixis that has only been documented in cassava.

First trimester screening of maternal placental protein 13 for predicting preeclampsia and small for gestational age: in-house study and systematic review.

OBJECTIVE: To describe normative levels of PP13 in first trimester of pregnancy and determine the accuracy of PP13 in predicting preeclampsia and small for gestational age (SGA) infants. METHODS: We measured PP13 in archived first trimester serum samples from an unselected maternal cohort of 2989 women. Associations of PP13 levels and diagnostic accuracy in predicting adverse pregnancy outcomes were assessed using multivariate logistic regression models. Due to inadequate number of cases we then conducted a systematic review and subsequent meta-analysis of predictive accuracy. Structured searches including all languages were completed in electronic databases and supplemented by cross-checking reference lists of relevant publications. Characteristics, data extraction and quality assessment of studies was conducted by independent assessors. RESULTS: Overall, 2678 women were included in the in-house study with 71 (2.7%) preeclampsia cases, 5 (0.2%) early-onset preeclampsia (≤34 weeks) cases; and 191 (7.1%) and 41 (1.5%) infants SGA<10th and <3rd centile. Median (IQR) normative level of PP13 in unaffected pregnancies was 53.5 (37.7-71.8) pg/ml. The area under the receiver operating characteristic curve (AUC) for multivariate models was 0.72 (95%CI 0.66-0.78) for preeclampsia; 0.82 (95%CI 0.63-0.99) for early-onset preeclampsia; 0.73 (95%CI 0.69-0.77) for SGA<10th centile; and 0.83 (95%CI 0.78-0.88) for SGA<3rd centile. Eight studies were included in the systematic review, normative levels of PP13 were assessed in four studies but these were variable; and meta-analysis was performed on seven studies. Sensitivity rates of PP13 based on 5% fixed false positive rates were 24%, 45% and 26% for preeclampsia, for early-onset preeclampsia and SGA, respectively. There was no evidence of between-study heterogeneity. CONCLUSIONS: First trimester PP13, in combination with maternal characteristics and other serum biomarkers was inadequate for screening purposes and predicting women at risk.

SCH58261 the selective adenosine A(2A) receptor blocker modulates ischemia reperfusion injury following bilateral carotid occlusion: role of inflammatory mediators.

In the present study, the effects of SCH58261, a selective adenosine A(2A) receptor antagonist that crosses the blood brain barrier (BBB) and 8-(4-sulfophenyl) theophylline (8-SPT), a non-selective adenosine receptor antagonist that acts peripherally, were investigated on cerebral ischemia reperfusion injury (IR). Male Wistar rats (200-250 g) were divided into four groups: (1) sham-operated (SO), IR pretreated with either (2) vehicle (DMSO); (3) SCH58261 (0.01 mg/kg); (4) 8-SPT (2.5 mg/kg). Animals were anesthetized and submitted to occlusion of both carotid arteries for 45 min. All treatments were administered intraperitoneally (i.p.) post carotid occlusion prior to exposure to a 24 h reperfusion period. Ischemic rats showed increased infarct size compared to their control counterparts that corroborated with histopathological changes as well as increased lactate dehydrogenase (LDH) activity in the hippocampus. Moreover, ischemic animals showed habituation deficit, increased anxiety and locomotor activity. IR increased hippocampal glutamate (Glu), GABA, glycine (Gly) and aspartate (ASP). SCH58261 significantly reversed these effects while 8-SPT elicited minimal change. IR raised myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), prostaglandin E2 (PGE2) accompanied by a decrease in interleukin-10 (IL-10), effects that were again reversed by SCH58261, but 8-SPT elicited less changes. Results from the present study point towards the importance of central blockade of adenosine A(2A) receptor in ameliorating hippocampal damage following IR injury by halting inflammatory cascades as well as modulating excitotoxicity.