bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome plasticity in Paramecium bursaria revealed by population genomics
Authors: Cheng Yu-Hsuan , Liu Chien-Fu Jeff , Yu Yen-Hsin , Jhou Yu-Ting , Fujishima Masahiro , Tsai Isheng Jason , Leu Jun-Yi
Published: November 2020

Background

Ciliates are an ancient and diverse eukaryotic group found in various environments. A unique feature of ciliates is their nuclear dimorphism, by which two types of nuclei, the diploid germline micronucleus (MIC) and polyploidy somatic macronucleus (MAC), are present in the same cytoplasm and serve different functions. During each sexual cycle, ciliates develop a new macronucleus in which newly fused genomes are extensively rearranged to generate functional minichromosomes. Interestingly, each ciliate species seems to have its way of processing genomes, providing a diversity of resources for studying genome plasticity and its regulation. Here, we sequenced and analyzed the macronuclear genome of different strains ofParamecium bursaria, a highly divergent species of the genusParameciumwhich can stably establish endosymbioses with green algae.

Results

We assembled a high-quality macronuclear genome ofP.bursariaand further refined genome annotation by comparing population genomic data. We identified several species-specific expansions in protein families and gene lineages that are potentially associated with endosymbiosis. Moreover, we observed an intensive chromosome breakage pattern that occurred during or shortly after sexual reproduction and contributed to highly variable gene dosage throughout the genome. However, patterns of copy number variation were highly correlated among genetically divergent strains, suggesting that copy number is adjusted by some regulatory mechanisms or natural selection. Further analysis showed that genes with low copy number variation among populations tended to function in basic cellular pathways, whereas highly variable genes were enriched in environmental response pathways.

Conclusions

We report programmed DNA rearrangements in theP.bursariamacronuclear genome that allow cells to adjust gene copy number globally according to individual gene functions. Our results suggest that large-scale gene copy number variation may represent an ancient mechanism for cells to adapt to different environments.
Two different clinical forms of squamous cell carcinoma (SCC) in the perineum and vulva of two mares
Authors: Raś Andrzej , Otrocka-Domagała Iwona , Raś-Noryńska Małgorzata
Published: November 2020

Background

Genital malignant neoplasms in mares are relatively rare. The treatment involve surgical removal of the tumour masses, chemotherapy or both.

Case presentation

Two elderly warmblood mares, aged 16 and 20 were presented in University Clinic with the lumpy lesions at the region of perineum and left labia. Surgical removals of tumour masses were performed on standing animals. Removed tissues were subjected to histopathological examination which confirmed SCC.

Conclusions

Clinical and ultrasound examination of reproductive organs in both mares showed no inflammatory or neoplastic changes. Both mares healed within 2 weeks after surgery and showed no signs of tumour recurrence for the following year despite no chemotherapy treatment.
Utility of a custom designed next generation DNA sequencing gene panel to molecularly classify endometrial cancers according to The Cancer Genome Atlas subgroups
Authors: Miller Eirwen M. , Patterson Nicole E. , Gressel Gregory M. , Karabakhtsian Rouzan G. , Bejerano-Sagie Michal , Ravi Nivedita , Maslov Alexander , Quispe-Tintaya Wilber , Wang Tao , Lin Juan , Smith Harriet O. , Goldberg Gary L. , Kuo Dennis Y. S. , Montagna Cristina
Published: November 2020

Background

The Cancer Genome Atlas identified four molecular subgroups of endometrial cancer with survival differences based on whole genome, transcriptomic, and proteomic characterization. Clinically accessible algorithms that reproduce this data are needed. Our aim was to determine if targeted sequencing alone allowed for molecular classification of endometrial cancer.

Methods

Using a custom-designed 156 gene panel, we analyzed 47 endometrial cancers and matching non-tumor tissue. Variants were annotated for pathogenicity and medical records were reviewed for the clinicopathologic variables. Using molecular characteristics, tumors were classified into four subgroups. Group 1 included patients with > 570 unfiltered somatic variants, > 9 cytosine to adenine nucleotide substitutions per sample, and < 1 cytosine to guanine nucleotide substitution per sample. Group 2 included patients with any somatic mutation in MSH2, MSH6, MLH1, PMS2. Group 3 included patients with TP53 mutations without mutation in mismatch repair genes. Remaining patients were classified as group 4. Analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, North Carolina, USA).

Results

Endometrioid endometrial cancers had more candidate variants of potential pathogenic interest (median 6 IQR 4.13 vs. 2 IQR 2.3; p < 0.01) than uterine serous cancers. PTEN (82% vs. 15%, p < 0.01) and PIK3CA (74% vs. 23%, p < 0.01) mutations were more frequent in endometrioid than serous carcinomas. TP53 (18% vs. 77%, p < 0.01) mutations were more frequent in serous carcinomas. Visual inspection of the number of unfiltered somatic variants per sample identified six grade 3 endometrioid samples with high tumor mutational burden, all of which demonstrated POLE mutations, most commonly P286R and V411L. Of the grade 3 endometrioid carcinomas, those with POLE mutations were less likely to have risk factors necessitating adjuvant treatment than those with low tumor mutational burden. Targeted sequencing was unable to assign samples to microsatellite unstable, copy number low, and copy number high subgroups.

Conclusions

Targeted sequencing can predict the presence of POLE mutations based on the tumor mutational burden. However, targeted sequencing alone is inadequate to classify endometrial cancers into molecular subgroups identified by The Cancer Genome Atlas.
KLHL17/Actinfilin, a brain-specific gene associated with infantile spasms and autism, regulates dendritic spine enlargement
Authors: Hu Hsiao-Tang , Huang Tzyy-Nan , Hsueh Yi-Ping
Published: November 2020

Background

Dendritic spines, the actin-rich protrusions emerging from dendrites, are the subcellular locations of excitatory synapses in the mammalian brain. Many actin-regulating molecules modulate dendritic spine morphology. Since dendritic spines are neuron-specific structures, it is reasonable to speculate that neuron-specific or -predominant factors are involved in dendritic spine formation. KLHL17 (Kelch-like 17, also known as Actinfilin), an actin-binding protein, is predominantly expressed in brain. Human genetic study has indicated an association of KLHL17/Actinfilin with infantile spasms, a rare form of childhood epilepsy also resulting in autism and mental retardation, indicating that KLHL17/Actinfilin plays a role in neuronal function. However, it remains elusive if and how KLHL17/Actinfilin regulates neuronal development and brain function.

Methods

Fluorescent immunostaining and electrophysiological recording were performed to evaluate dendritic spine formation and activity in cultured hippocampal neurons. Knockdown and knockout of KLHL17/Actinfilin and expression of truncated fragments of KLHL17/Actinfilin were conducted to investigate the function of KLHL17/Actinfilin in neurons. Mouse behavioral assays were used to evaluate the role of KLHL17/Actinfilin in brain function.

Results

We found that KLHL17/Actinfilin tends to form circular puncta in dendritic spines and are surrounded by or adjacent to F-actin. Klhl17 deficiency impairs F-actin enrichment at dendritic spines. Knockdown and knockout of KLHL17/Actinfilin specifically impair dendritic spine enlargement, but not the density or length of dendritic spines. Both N-terminal Broad-Complex, Tramtrack and Bric-a-brac (BTB) domain and C-terminal Kelch domains of KLHL17/Actinfilin are required for F-actin remodeling and enrichment at dendritic spines, as well as dendritic spine enlargement. A reduction of postsynaptic and presynsptic markers at dendritic spines and altered mEPSC profiles due to Klhl17 deficiency evidence impaired synaptic activity in Klhl17-deficient neurons. Our behavioral assays further indicate that Klhl17 deficiency results in hyperactivity and reduced social interaction, strengthening evidence for the physiological role of KLHL17/Actinfilin.

Conclusion

Our findings provide evidence that KLHL17/Actinfilin modulates F-actin remodeling and contributes to regulation of neuronal morphogenesis, maturation and activity, which is likely relevant to behavioral impairment in Klhl17-deficient mice.

Trial registration Non-applicable.
Aurora-B knockdown inhibits osteosarcoma metastasis by inducing autophagy via the mTOR/ULK1 pathway
Authors: Wu Xin , Liu Jia-ming , Song Hong-hai , Yang Qi-kun , Ying Hui , Tong Wei-lai , Zhou Yang , Liu Zhi-li
Published: November 2020

Background

Autophagy plays an essential role in metastasis of malignancies. Although our studies showed that Aurora-B facilitate pulmonary metastasis in OS, the mechanism of Aurora-B kinase on autophagy and metastasis in OS has not been explored.

Methods

Clinical-pathological parameters and follow-up information was collected in OS patients. Immunohistochemical staining was performed to detect Aurora-B and LC3 protein in OS tissues. Short hairpin RNA transfection was used to silence Aurora-B in OS cells. Real-time quantitative PCR (RT-qPCR) was performed to detect Aurora-B mRNA expression in OS cells. Aurora-B and autophagy related protein were measured by Western blot. Transmission electron microscopy and laser scanning confocal microscopy were performed to observe the formation of autophagosomes and autolysosomes. Migratory and invasive ability of OS cells were measured by Wound healing and transwell assays. Orthotopic xenograft model was used to evaluate the effect of autophagy mediated by Aurora-B inhibition on pulmonary metastasis of OS.

Results

The elevated expression of Aurora-B protein in OS tissues negatively associated with the overall survival of OS patients. Further investigation has found that Aurora-B expression was negatively correlative with autophagy related protein LC3 in OS patient tissues. Knockdown Aurora-B stimulates autophagy and inhibits migratory and invasive ability of OS cells. Mechanistically, Aurora-B knockdown suppressed the mTOR/ULK1 signaling pathway and reactivation of the mTOR/ULK1 pathway decreased autophagy level. Furthermore, the inhibition effect of silencing Aurora-B on migration and invasion of OS was reversed by chloroquine and mTOR activator in vitro and vivo.

Conclusions

Our results suggest that silencing of Aurora-B stimulate autophagy via decreasing mTOR/ULK1 and result in inhibiting OS metastasis. Targeted Aurora-B/mTOR/ULK1 pathway may be a promising treatment strategy for OS patients.
Plasmodium falciparum multidrug resistance gene-1 polymorphisms in Northern Nigeria: implications for the continued use of artemether-lumefantrine in the region
Authors: Adamu Auwal , Jada Mahmoud Suleiman , Haruna Hauwa Mohammed Sani , Yakubu Bassa Obed , Ibrahim Mohammed Auwal , Balogun Emmanuel Oluwadare , Sakura Takaya , Inaoka Daniel Ken , Kita Kiyoshi , Hirayama Kenji , Culleton Richard , Shuaibu Mohammed Nasir
Published: November 2020

Background

The analysis of single nucleotide polymorphism (SNPs) in drug-resistance associated genes is a commonly used strategy for the surveillance of anti-malarial drug resistance in populations of parasites. The present study was designed and performed to provide genetic epidemiological data of the prevalence of N86Y-Y184F-D1246Y SNPs in Plasmodium falciparum multidrug resistance 1 (pfmdr1) in the malaria hotspot of Northern Nigeria.

Methods

Plasmodium falciparum-positive blood samples on Whatman-3MM filter papers were collected from 750 symptomatic patients from four states (Kano, Kaduna, Yobe and Adamawa) in Northern Nigeria, and genotyped via BigDye (v3.1) terminator cycle sequencing for the presence of three SNPs in pfmdr1. SNPs in pfmdr1 were used to construct NYD, NYY, NFY, NFD, YYY, YYD, YFD and YFY haplotypes, and all data were analysed using Pearson Chi square and Fisher’s exact (FE) tests.

Results

The prevalence of the pfmdr1 86Y allele was highest in Kaduna (12.50%, 2 = 10.50, P = 0.02), whilst the 184F allele was highest in Kano (73.10%, 2 = 13.20, P = 0.00), and the pfmdr1 1246Y allele was highest in Yobe (5.26%, 2 = 9.20, P = 0.03). The NFD haplotype had the highest prevalence of 69.81% in Kano (2 = 36.10, P = 0.00), followed by NYD with a prevalence of 49.00% in Adamawa, then YFD with prevalence of 11.46% in Kaduna. The YYY haplotype was not observed in any of the studied states.

Conclusion

The present study suggests that strains of P. falciparum with reduced sensitivity to the lumefantrine component of AL exist in Northern Nigeria and predominate in the North-West region.
Defining malaria risks among forest workers in Aceh, Indonesia: a formative assessment
Authors: Ekawati Lenny L. , Johnson Kelly C. , Jacobson Jerry O. , Cueto Carmen A. , Zarlinda Iska , Elyazar Iqbal R. F. , Fatah Abdul , Sumiwi Maria E. , Noviyanti Rintis , Cotter Chris , Smith Jennifer L. , Coutrier Farah N. , Bennett Adam
Published: November 2020

Background

Following a dramatic decline of malaria cases in Aceh province, geographically-based reactive case detection (RACD) was recently evaluated as a tool to improve surveillance with the goal of malaria elimination. While RACD detected few cases in households surrounding index cases, engaging in forest work was identified as a risk factor for malaria and infections from Plasmodium knowlesi—a non-human primate malaria parasite—were more common than expected. This qualitative formative assessment was conducted to improve understanding of malaria risk from forest work and identify strategies for targeted surveillance among forest workers, including adapting reactive case detection.

Methods

Between June and August, 2016, five focus groups and 18 in-depth interviews with forest workers and key informants were conducted in each of four subdistricts in Aceh Besar and Aceh Jaya districts. Themes included: types of forest activities, mobility of workers, interactions with non-human primates, malaria prevention and treatment-seeking behaviours, and willingness to participate in malaria surveys at forest work sites and using peer-referral.

Results

Reported forest activities included mining, logging, and agriculture in the deep forest and along the forest fringe. Forest workers, particularly miners and loggers, described often spending weeks to months at work sites in makeshift housing, rarely utilizing mosquito prevention and, upon fever, self-medicating and seeking care from traditional healers or pharmacies rather than health facilities. Non-human primates are frequently observed near work sites, and most forest work locations are within a day’s journey of health clinics. Employers and workers expressed interest in undertaking malaria testing and in participating in survey recruitment by peer-referral and at work sites.

Conclusions

Diverse groups of forest workers in Aceh are potentially exposed to malaria through forest work. Passive surveillance and household-based screening may under-estimate malaria burden due to extended stays in the forest and health-seeking behaviours. Adapting active surveillance to specifically target forest workers through work-site screening and/or peer-referral appears promising for addressing currently undetected infections.
Evaluation of a single screen and treat strategy to detect asymptomatic malaria among pregnant women from selected health facilities in Lindi region, Tanzania
Authors: Kitojo Chonge , Chacky Frank , Kigadye Emmanuel S. , Mugasa Joseph P. , Lusasi Abdallah , Mohamed Ally , Walker Patrick , Reaves Erik J. , Gutman Julie R. , Ishengoma Deus S.
Published: November 2020

Background

In areas of high transmission, malaria in pregnancy (MiP) primarily causes asymptomatic infections; these infections nonetheless increase the risk of adverse maternal and fetal outcomes. In 2014, Tanzania initiated a single screening and treatment (SST) strategy for all pregnant women at their first antenatal care (ANC) visit using malaria rapid diagnostic tests (RDT) for surveillance purposes. However, there is paucity of data on the effectiveness of SST in the prevention of MiP. The objective of this study was to estimate the number of asymptomatic infections among pregnant women detected by SST, which would have been missed in the absence of the policy.

Methods

Data from pregnant women attending their first ANC visits between October 2017 and June 2018, including gestational age, history of fever, and RDT results, were abstracted from ANC registers in eight health centres in two randomly selected districts, Kilwa and Lindi, in Lindi Region. The proportion of symptomatic (with history of fever in the past 48 h) and asymptomatic pregnant women with positive RDTs were calculated and stratified by trimester (first, second and third). The study areas were categorized as low transmission with prevalence < 10% or moderate/high with ≥ 10%.

Results

Over the study period, 1,845 women attended their first ANC visits; 22.1% were in the first trimester (< 12 weeks gestation age). Overall 15.0% of the women had positive RDTs, and there was a trend towards higher malaria prevalence in the first (15.9%) and second (15.2%) trimesters, compared to the third (7.1%), although the differences were not statistically significant (p = 0.07). In total, 6.9% of women reported fever within the past 48 h and, of these, 96.1% were RDT positive. For every 100 pregnant women in the moderate/high and low transmission areas, SST identified 60 and 26 pregnant women, respectively, with asymptomatic infections that would have otherwise been missed. Among the 15.9% of women detected in the first trimester, 50.7% were asymptomatic.

Conclusion

In areas of moderate/high transmission, many infected women were asymptomatic, and would have been missed in the absence of SST. The benefits on maternal and fetal birth outcomes of identifying these infections depend heavily on the protection afforded by treatment, which is likely to be greatest for women presenting in the first trimester when intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine (SP) is contraindicated, and in areas with high SP resistance, such as most parts of Tanzania. An evaluation of the impact and cost-effectiveness of SST across different transmission strata is warranted.
Development of fluorescence/MR dual-modal manganese-nitrogen-doped carbon nanosheets as an efficient contrast agent for targeted ovarian carcinoma imaging
Authors: Han Cuiping , Xie Ting , Wang Keying , Jin Shang , Li Ke , Dou Peipei , Yu Nana , Xu Kai
Published: November 2020

Background

Development of sensitive and specific imaging approaches for the detection of ovarian cancer holds great promise for improving the therapeutic efficacy and the lifespan of the patients.

Results

In this study, manganese-nitrogen doped carbon nanosheets (Mn-N-CNSs) coupled with Anti-HE4 monoclonal antibody (Mn-N-CNSs@Anti-HE4) were synthesized for the specific and targeted fluorescence/MR dual-modal imaging of ovarian carcinoma. The prepared Mn-N-CNSs revealed excellent aqueous dispersity, good colloidal stability, great optical properties and high longtudinal relaxivity rate (r1 = 10.30 mM−1 s−1). Encouraged by the tunable photoluminiscence of the nanoprobe and Anti-HE4 targeting ligand, the ovarian carcinoma cells were specifically labeled by the Mn-N-CNSs@Anti-HE4 nanoprobe with multi-color fluorescences. Benefiting from the high r1 relaxivity, the nanoprobe exhibited targeted and enhanced MR contrast effect in the ovarian carcinoma cells and tumor bearing mice model. Besides, the high biocompatibility and easy excretion from the body of the nanoprobe were further confirmed in vivo.

Conclusion

The prepared Mn-N-CNSs@Anti-HE4 with excellent biocompatibility, high-performance and superior tumor-targeting ability provides a novel fluorescence/MR dual-modal nanoprobe for specific labeling and detection of ovarian carcinoma cells in vitro and in vivo.
Preparation of PLA/chitosan nanoscaffolds containing cod liver oil and experimental diabetic wound healing in male rats study
Authors: Khazaeli Payam , Alaei Maryam , Khaksarihadad Mohammad , Ranjbar Mehdi
Published: November 2020

Diabetes mellitus is one of the most common metabolic disorders. One of the important metabolic complications in diabetes is diabetic foot ulcer syndrome, which causes delayed and abnormal healing of the wound. The formulation of nanoscaffolds containing cod liver oil by altering the hemodynamic balance toward the vasodilators state, increasing wound blood supply, and altering plasma membrane properties, namely altering the membrane phospholipids composition, can be effective in wound healing. In this study, electrospinning method was used to produce poly lactic acid/chitosan nanoscaffolds as a suitable bio-substitute. After preparing the nanoscaffolds, the products were characterized with dynamic light scattering (DLS), transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Also optical properties of polymer and comparison between adsorption between single polymer and polymer-drug calculated with UV−Vis spectra. The structure and functional groups of the final products were characterized by Fourier-transform infrared spectroscopy (FT-IR) and energy dispersive spectroscopy (EDAX) as elemental analysis. The results showed that the optimum formulation of cod liver oil was 30%, which formed a very thin fiber that rapidly absorbed to the wound and produced significant healing effects. According to the results, poly lactic acid/chitosan nanoscaffolds containing cod liver oil can be a suitable bio-product to be used in treating the diabetic foot ulcer syndrome.
Understanding the influence of physical resources and social supports on primary food providers’ snack food provision: a discrete choice experiment
Authors: Johnson Brittany J. , Golley Rebecca K. , Zarnowiecki Dorota , Hendrie Gilly A. , Huynh Elisabeth K.
Published: November 2020

Background

Snack eating occasions contribute approximately a third of children’s energy intake, with approximately half of all unhealthy foods consumed during snack times. Therefore, it is critical to understand the drivers of primary food providers’ snack provision. The study aims were to determine the relative importance of physical resources and social supports when primary food providers are choosing snacks to provide to their child, and to investigate how these attributes differ in social versus non-social occasions, and between subgroups of primary food providers based on socio-economic position.

Methods

Primary food providers of three to seven-year olds completed an online discrete choice experiment, by making trade-offs when completing repeated, hypothetical choice tasks on the choice of snacks to provide to their child in: 1) non-social and 2) social condition. Choice tasks included two alternatives consisting of varying attribute (i.e. factor) levels, and an opt-out option. The order of conditions shown were randomized across participants. Multinomial logit model analyses were used to determine utility weights for each attribute.

Results

Two-hundred and twenty-five primary food providers completed the study, providing 1125 choice decisions per condition. In the non-social condition, the top three ranked attributes were type of food (utility weight 1.94, p < 0.001), child resistance (− 1.62, p < 0.001) and co-parent support (0.99, p < 0.001). In the social condition, top ranking attributes were child resistance (utility weight − 1.50, p < 0.001), type of food (1.38, p < 0.001) and co-parent support (1.07, p < 0.001). In both conditions, time was not a significant influence and cost was of lowest relative importance. Subgroup analyses revealed cost was not a significant influence for families from higher socio-economic backgrounds.

Conclusions

Type of food, child resistance and co-parent support were of greatest relative importance in primary food providers’ snack provision decision-making, regardless of social condition or socio-economic position. In designing future interventions to reduce unhealthy snacks, researchers should prioritize these influences, to better support primary food providers in changing their physical and social opportunity.

Trial registration

Australian New Zealand Clinical Trials Registry no. ACTR N12618001173280
Stillbirth 2010–2018: a prospective, population-based, multi-country study from the Global Network
Authors: McClure Elizabeth M. , Saleem Sarah , Goudar Shivaprasad S. , Garces Ana , Whitworth Ryan , Esamai Fabian , Patel Archana B. , Tikmani Shiyam Sunder , Mwenechanya Musaku , Chomba Elwyn , Lokangaka Adrien , Bose Carl L. , Bucher Sherri , Liechty Edward A. , Krebs Nancy F. , Yogesh Kumar S. , Derman Richard J. , Hibberd Patricia L. , Carlo Waldemar A. , Moore Janet L. , Nolen Tracy L. , Koso-Thomas Marion , Goldenberg Robert L.
Published: November 2020

Background

Stillbirth rates are high and represent a substantial proportion of the under-5 mortality in low and middle-income countries (LMIC). In LMIC, where nearly 98% of stillbirths worldwide occur, few population-based studies have documented cause of stillbirths or the trends in rate of stillbirth over time.

Methods

We undertook a prospective, population-based multi-country research study of all pregnant women in defined geographic areas across 7 sites in low-resource settings (Kenya, Zambia, Democratic Republic of Congo, India, Pakistan, and Guatemala). Staff collected demographic and health care characteristics with outcomes obtained at delivery. Cause of stillbirth was assigned by algorithm.

Results

From 2010 through 2018, 573,148 women were enrolled with delivery data obtained. Of the 552,547 births that reached 500 g or 20 weeks gestation, 15,604 were stillbirths; a rate of 28.2 stillbirths per 1000 births. The stillbirth rates were 19.3 in the Guatemala site, 23.8 in the African sites, and 33.3 in the Asian sites. Specifically, stillbirth rates were highest in the Pakistan site, which also documented a substantial decrease in stillbirth rates over the study period, from 56.0 per 1000 (95% CI 51.0, 61.0) in 2010 to 44.4 per 1000 (95% CI 39.1, 49.7) in 2018. The Nagpur, India site also documented a substantial decrease in stillbirths from 32.5 (95% CI 29.0, 36.1) to 16.9 (95% CI 13.9, 19.9) per 1000 in 2018; however, other sites had only small declines in stillbirth over the same period. Women who were less educated and older as well as those with less access to antenatal care and with vaginal assisted delivery were at increased risk of stillbirth. The major fetal causes of stillbirth were birth asphyxia (44.0% of stillbirths) and infectious causes (22.2%). The maternal conditions that were observed among those with stillbirth were obstructed or prolonged labor, antepartum hemorrhage and maternal infections.

Conclusions

Over the study period, stillbirth rates have remained relatively high across all sites. With the exceptions of the Pakistan and Nagpur sites, Global Network sites did not observe substantial changes in their stillbirth rates. Women who were less educated and had less access to antenatal and obstetric care remained at the highest burden of stillbirth.

Study registration

Clinicaltrials.gov (ID# NCT01073475).
Prevalence of clinically-evident congenital anomalies in the Western highlands of Guatemala
Authors: Figueroa Lester , Garces Ana , Hambidge K. Michael , McClure Elizabeth M. , Moore Janet , Goldenberg Robert , Krebs Nancy F.
Published: November 2020

Background

Congenital anomalies are a significant cause of death and disability for infants, especially in low and middle-income countries (LMIC), where 95% of all deaths due to anomalies occur. Limited data on the prevalence and survival of infants with congenital anomalies are available from Central America. Estimates have indicated that 53 of every 10,000 live births in Guatemala are associated with a congenital anomaly. We aim to report on the incidence and survival of infants with congenital anomalies from a population-based registry and classify the anomalies according to the International Classification of Disease, Tenth Revision (ICD-10).

Methods

We conducted a planned secondary analysis of data from the Maternal Newborn Health Registry (MNHR), a prospective, population-based study carried out by the Global Network for Women’s and Children’s Health Research in seven research sites. We included all deliveries between 2014 and 2018 in urban and rural settings in Chimaltenango, in the Western Highlands of Guatemala. These cases of clinically evident anomalies were reported by field staff and reviewed by medically trained staff, who classified them according to ICD – 10 categories. The incidence of congenital anomalies and associated stillbirth, neonatal mortality, and survival rates were determined for up to 42 days.

Results

Out of 60,142 births, 384 infants were found to have a clinically evident congenital anomaly (63.8 per 10,000 births). The most common were anomalies of the nervous system (28.8 per 10,000), malformations and deformations of the musculoskeletal system (10.8 per 10,000), and cleft lip and palate (10.0 per 10,000). Infants born with nervous system anomalies had the highest stillbirth and neonatal mortality rates (14.6 and 9.0 per 10,000, respectively).

Conclusions

This is the first population-based report on congenital anomalies in Guatemala. The rates we found of overall anomalies are higher than previously reported estimates. These data will be useful to increase the focus on congenital anomalies and hopefully increase the use of interventions of proven benefit.

Trial registration

ClinalTrial.gov ID: NCT01073475.
Serum biomarkers of the calcium-deficient rats identified by metabolomics based on UPLC/Q-TOF MS/MS
Authors: Meng Fanyu , Fan Lina , Sun Lin , Yu Qingli , Wang Maoqing , Sun Changhao
Published: November 2020

Background

We previously identified the urinary biomarkers to diagnose calcium deficiency and nutritional rickets by ultra-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF MS/MS). To find biomarkers of calcium deficiency and further confirm these biomarkers in serum, we performed serum metabolomics analysis of calcium-deficient rats.

Methods

A calcium-deficient rat model was established with a low-calcium diet for 12 weeks. Serum metabolomics based UPLC/Q-TOF MS/MS and multivariate statistical analysis was performed to identify the alterations in metabolites associated with calcium deficiency in rats.

Results

Bone mineral density, serum parathyroid hormone and alkaline phosphatase were significantly decreased in the low-calcium diet group (LCG) compared to the normal calcium diet group (NCG). Serum metabolic-profiling analysis could definitively distinguish between the LCG and NCG and identified 24 calcium-deficient biomarkers. Three metabolites (indoxyl sulfate, phosphate, and taurine) of the 24 biomarkers were found in our previous urinary metabolomics study of rats with a calcium deficiency and nutritional rickets. The areas under the curve (AUCs) of these three biomarkers were greater than 0.8, and the combination of any two biomarkers was higher than 0.95.

Conclusion

Dietary calcium deficiency induced the alterations of metabolites in the serum of rats, and the three identified biomarkers had relatively high diagnostic values for calcium deficiency in rats.
Dietary nutrient intake related to higher grade cervical intraepithelial neoplasia risk: a Chinese population-based study
Authors: Wang Zhe , Yang Aimin , Yang Jing , Zhao Weihong , Wang Zhilian , Wang Wei , Wang Jintao , Song Jinghui , Li Li , Lv Weiguo , Li Dongyan , Liu Huiqiang , Wang Chen , Hao Min
Published: November 2020

Background

Dietary nutrient intake plays a significant role in carcinogenesis. Few studies have investigated the association between dietary nutrient intake and cervical intraepithelial neoplasia (CIN) risk in China.

Methods

Data on 2304 women from an ongoing cohort comprising 40,000 women from China in 2014 were included. Study randomly selected 218 out of 2304 people as subjects during 2019. All participants were surveyed through in-person interviews, physical examinations, and laboratory tests. Clinical data were obtained from physical examinations and laboratory tests. Dietary intakes were assessed using a semiquantitative food frequency questionnaire. Nutrition intakes from 26 food sources were calculated using a comprehensive validated database. Descriptive statistics were used to describe the frequency and proportion, and mean and standard deviation of the demographic characteristics. Characteristics were examined for significant differences, and Pearson chi-square tests were used for categoric variables. Logistic regression was used to obtain odds ratios (ORs) and confidence intervals (CIs) for CIN risk in each nutrient intake quartile relative to that in the highest quartile.

Results

The food frequency questionnaire exhibited acceptable reproducibility and reasonable validity in assessing nutrient intakes among these women. After adjusting for multiple confounders, several dietary nutrients showed significant associations with CIN2+ risk. Low dietary folate intake was associated with the risk of CIN2+ (first versus fourth quartile: OR = 1.55, 95% CI 1.03–2.33). Similar results were also observed for vitamin B6 (OR = 1.63, 95% CI 1.08–2.46), vitamin C (OR = 1.59, 95% CI 1.05–2.42), niacin (OR = 1.65, 95% CI 1.08–2.51), and vitamin K (second versus fourth quartile: OR = 1.60, 95% CI 1.05–2.44).

Conclusions

Low folate; vitamin B6, C, and K; and niacin intakes were associated with CIN2+ risk. Nutrients may influence the development of higher grade CIN and cervical cancer.

Trial registration The study was registered in the Chinese Clinical Trial Register (ChiCTR-ROC-15006479) (https://www.chictr.org.cn).
Comprehensive 3D analysis of condylar morphology in adults with different skeletal patterns – a cross-sectional study
Authors: Santander Petra , Quast Anja , Olbrisch Carolin , Rose Marius , Moser Norman , Schliephake Henning , Meyer-Marcotty Philipp
Published: November 2020

Background

The correlation between individuals’ condylar morphology and their skeletal pattern is of great interest for treatment strategies ranging from orthodontic orthopaedics to orthognathic surgery. The objective of the present study was to investigate this relationship three-dimensionally.

Methods

A total of 111 adult patients (mean age = 27.0 ± 10.2 years) who underwent head computed tomography or cone beam computed tomography scans were included. Based on these data, 3D models of the skull and the condyles were calculated. The craniofacial skeleton was evaluated (1) transversally regarding skeletal symmetry (menton deviation), (2) sagittally regarding skeletal classes (Wits appraisal) and vertically regarding the inclination of the jaws (maxillomandibular plane angle). The condylar morphology was assessed (a) linearly by the condylar width, height and depth; (b) angularly by the antero-posterior and medio-lateral condylar inclination; and (c) volumetrically by the ratio of the condylar volume/mandibular volume (C/Mand).

Results

(1) Transversal: Asymmetric patients showed significantly higher discrepancies in the volumetric ratio C/Mand on the deviation and non-deviation side compared to symmetric patients. (2) Sagittal: Class III subjects demonstrated longer, more voluminous condyles with higher antero-posterior and medio-lateral inclination angles compared to Class II participants. (3) Vertical: Hyperdivergent subjects had smaller condyles with higher antero-posterior inclination angles than those of hypodivergent subjects. No interactions of skeletal class and vertical relationships regarding condylar morphology were observed.

Conclusions

This study demonstrates a clear correlation between pronounced skeletal patterns and condylar morphology in an adult population. The description of radiographic condyle characteristics in relation to the craniofacial morphology improves orthodontic treatment planning and could be helpful in the diagnosis of temporomandibular joint pathologies.
Audiological and otologic manifestations of glutaric aciduria type I
Authors: Chen Yen-Chi , Huang Chii-Yuan , Lee Yen-Ting , Wu Chia-Hung , Chang Sheng-Kai , Cheng Hsiu-Lien , Chang Po-Hsiung , Niu Dau-Ming , Cheng Yen-Fu
Published: November 2020

Background

Glutaric aciduria type 1 (GA-1) is a rare disease connected with speech delay and neurological deficits. However, the audiological and otologic profiles of GA-1 have not yet been fully characterized. To our knowledge, this is the largest study of comprehensive audiological and otologic evaluation in patients with GA-1 to date.

Methods

Thirteen patients diagnosed with GA-1 between January 1994 and December 2019 with audiological, radiological and genetic manifestations were retrospectively analyzed. Hearing tests were performed in all patients. MRI was performed for radiological evaluation.

Results

Hearing loss was found in 76.9% (10/13) of GA-1 patients, including slight hearing loss in 46.1% (6/13) of patients, mild hearing loss in 15.4% (2/13) of patients, and moderate hearing loss in 7.7% (1/13) of patients. Normal hearing thresholds were seen in 23% (3/13) of patients. Patients with intensive care unit (ICU) admission history showed significantly worse hearing than those without (29.17 ± 12.47 vs 13.56 ± 3.93 dB HL, 95% CI 2.92–24.70, p = 0.0176). One patient had moderate sensorineural hearing loss and a past history of acute encephalopathic crisis. No usual causative gene mutations associated with hearing loss were found in these patients. MRI showed a normal vestibulocochlear apparatus and cochlear nerve. One patient with extensive injury of the basal ganglia on MRI after acute encephalopathic crisis was found to have moderate sensorineural hearing loss. Two patients with disability scores above 5 were found to have mild to moderate hearing impairment. No obvious correlation between macrocephaly and hearing loss was found.

Conclusion

A high prevalence of hearing impairment is found in GA-1 patients. Adequate audiological evaluation is essential for these patients, especially for those after encephalopathic crises or with ICU admission history.
An evaluation of solid versus liquid transport media for high-risk HPV detection and cervical cancer screening on self-collected specimens
Authors:   CHIMUST group, Du Hui , Duan Xianzhi , Liu Yan , Shi Bin , Zhang Wei , Wang Chun , Qu Xinfen , Bao Juncui , Li Jingran , Zhao Chao , Jiang Jing , Liu Juan , Wu Kejia , Xiao Aimin , Duan Lvfang , Huang Xia , Bian Shuhuang , Zhang Lijie , Luo Hongxue , Wei Lihui , Belinson Jerome L. , Wu Ruifang
Published: November 2020

Background

The solid transport media is a small size card that allows fast, easy DNA extraction from a variety of biological samples. In 2016 we developed a solid media transport card; for that pilot study to control the self-collection we used a pseudo-self-collection technique. The current study expands this prior work using true self-collections and only the POI card, and aims to evaluate the solid media transport card to detect HR-HPV in self-samples compared to liquid transport media.

Methods

Ten thousand eight hundred eighty-five women between the ages of 30–59 with no screening for 3 years were enrolled. The self-collected sample was first applied to a new solid media transport card (Labeled as SC) then the brush placed in 6 ml ThinPrep liquid (Labeled as SL). Then a physician collected a direct endocervical specimen into ThinPrep liquid (Labeled as DL). Samples were tested with Cobas 4800 and the SeqHPV NGS assay for HR-HPV. Patients positive on any test were recalled for colposcopy and biopsy.

Results

Ten thousand three hundred thirty-nine participants had complete data. The mean age was 43.9 years. CIN 2+ rates were 1.4% (142/10339). The agreement in HPV detection between the two different self-sample collection media was also good (Cobas HPV kappa = 0.86; SeqHPV kappa = 0.98). Tested with Cobas, the sensitivity of Cobas-SL and Cobas-SC for CIN 2+ was95.07 and 94.37%; and for CIN3+ was 96.30, 96.30% respectively. The specificity of Cobas-SC, and Cobas-SL for CIN2+ was 88.74 and 87.35%; for CIN3 was 88.04and 86.65% respectively. Tested with SeqHPV, the sensitivity for CIN2+ of Seq-SC and Seq-SL was 95.77 and 96.48%; for CIN3+, both the SC and SL specimens had a sensitivity of 100%. The specificity for CIN2+ of Seq-SC and Seq-SL was 89.54 and 89.53%; for CIN3+ was 88.84,88.82% respectively. For both HR-HPV assays, the sensitivities were similar for the two self-sample media (SC vs SL, p = 1.00).

Conclusions

The solid transport card for collecting vaginal self-samples as accurate as liquid transport media assayed by two different PCR based HR-HPV tests. The solid transport media is a suitable medium for collecting and storing vaginal self-samples.
Phase II trial of carboplatin and bevacizumab in patients with breast cancer brain metastases
Authors: Leone Jose Pablo , Emblem Kyrre E. , Weitz Michelle , Gelman Rebecca S. , Schneider Bryan P. , Freedman Rachel A. , Younger Jerry , Pinho Marco C. , Sorensen A. Gregory , Gerstner Elizabeth R. , Harris Gordon , Krop Ian E. , Morganstern Daniel , Sohl Jessica , Hu Jiani , Kasparian Elizabeth , Winer Eric P. , Lin Nancy U.
Published: November 2020

Background

We aimed to examine the safety and efficacy of bevacizumab and carboplatin in patients with breast cancer brain metastases.

Methods

We enrolled patients with breast cancer and > 1 measurable new or progressive brain metastasis. Patients received bevacizumab 15 mg/kg intravenously (IV) on cycle 1 day 1 and carboplatin IV AUC = 5 on cycle 1 day 8. Patients with HER2-positive disease also received trastuzumab. In subsequent cycles, all drugs were administered on day 1 of each cycle. Contrast-enhanced brain MRI was performed at baseline, 24–96 h after the first bevacizumab dose (day + 1), and every 2 cycles. The primary endpoint was objective response rate in the central nervous system (CNS ORR) by composite criteria. Associations between germline VEGF single nucleotide polymorphisms (rs699947, rs2019063, rs1570360, rs833061) and progression-free survival (PFS) and overall survival (OS) were explored, as were associations between early (day + 1) MRI changes and outcomes.

Results

Thirty-eight patients were enrolled (29 HER2-positive, 9 HER2-negative); all were evaluable for response. The CNS ORR was 63% (95% CI, 46–78). Median PFS was 5.62 months and median OS was 14.10 months. As compared with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, patients with ECOG PS 1–2 had significantly worse PFS and OS (all P < 0.01). No significant associations between VEGF genotypes or early MRI changes and clinical outcomes were observed.

Conclusions

The combination of bevacizumab and carboplatin results in a high rate of durable objective response in patients with brain metastases from breast cancer. This regimen warrants further investigation.

Trial registration

NCT01004172. Registered 28 October 2009.
Navitoclax enhances the effectiveness of EGFR-targeted antibody-drug conjugates in PDX models of EGFR-expressing triple-negative breast cancer
Authors: Zoeller Jason J. , Vagodny Aleksandr , Daniels Veerle W. , Taneja Krishan , Tan Benjamin Y. , DeRose Yoko S. , Fujita Maihi , Welm Alana L. , Letai Anthony , Leverson Joel D. , Blot Vincent , Bronson Roderick T. , Dillon Deborah A. , Brugge Joan S.
Published: November 2020

Background

Targeted therapies for triple-negative breast cancer (TNBC) are limited; however, the epidermal growth factor receptor (EGFR) represents a potential target, as the majority of TNBC express EGFR. The purpose of these studies was to evaluate the effectiveness of two EGFR-targeted antibody-drug conjugates (ADC: ABT-414; ABBV-321) in combination with navitoclax, an antagonist of the anti-apoptotic BCL-2 and BCL-XL proteins, in order to assess the translational relevance of these combinations for TNBC.

Methods

The pre-clinical efficacy of combined treatments was evaluated in multiple patient-derived xenograft (PDX) models of TNBC. Microscopy-based dynamic BH3 profiling (DBP) was used to assess mitochondrial apoptotic signaling induced by navitoclax and/or ADC treatments, and the expression of EGFR and BCL-2/XL was analyzed in 46 triple-negative patient tumors.

Results

Treatment with navitoclax plus ABT-414 caused a significant reduction in tumor growth in five of seven PDXs and significant tumor regression in the highest EGFR-expressing PDX. Navitoclax plus ABBV-321, an EGFR-targeted ADC that displays more effective wild-type EGFR-targeting, elicited more significant tumor growth inhibition and regressions in the two highest EGFR-expressing models evaluated. The level of mitochondrial apoptotic signaling induced by single or combined drug treatments, as measured by DBP, correlated with the treatment responses observed in vivo. Lastly, the majority of triple-negative patient tumors were found to express EGFR and co-express BCL-XL and/or BCL-2.

Conclusions

The dramatic tumor regressions achieved using combined agents in pre-clinical TNBC models underscore the abilities of BCL-2/XL antagonists to enhance the effectiveness of EGFR-targeted ADCs and highlight the clinical potential for usage of such targeted ADCs to alleviate toxicities associated with combinations of BCL-2/XL inhibitors and systemic chemotherapies.
Human A-to-I RNA editing SNP loci are enriched in GWAS signals for autoimmune diseases and under balancing selection
Authors: Zhang Hui , Fu Qiang , Shi Xinrui , Pan Ziqing , Yang Wenbing , Huang Zichao , Tang Tian , He Xionglei , Zhang Rui
Published: November 2020

Background

Adenosine-to-inosine (A-to-I) RNA editing plays important roles in diversifying the transcriptome and preventing MDA5 sensing of endogenous dsRNA as nonself. To date, few studies have investigated the population genomic signatures of A-to-I editing due to the lack of editing sites overlapping with SNPs.

Results

In this study, we applied a pipeline to robustly identify SNP editing sites from population transcriptomic data and combined functional genomics, GWAS, and population genomics approaches to study the function and evolution of A-to-I editing. We find that the G allele, which is equivalent to edited I, is overrepresented in editing SNPs. Functionally, A/G editing SNPs are highly enriched in GWAS signals of autoimmune and immune-related diseases. Evolutionarily, derived allele frequency distributions of A/G editing SNPs for both A and G alleles as the ancestral alleles are skewed toward intermediate frequency alleles relative to neutral SNPs, a hallmark of balancing selection, suggesting that both A and G alleles are functionally important. The signal of balancing selection is confirmed by a number of additional population genomic analyses.

Conclusions

We uncovered a hidden layer of A-to-I RNA editing SNP loci as a common target of balancing selection, and we propose that the maintenance of such editing SNP variations may be at least partially due to constraints on the resolution of the balance between immune activity and self-tolerance.