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Background Massive occurrences of interstitial loss of heterozygosity (LOH) likely resulting from gene conversions were found by us in different cancers as a type of single-nucleotide variations (SNVs), comparable in abundance to the commonly investigated gain of heterozygosity (GOH) type of SNVs, raising the question of the relationships between these two opposing types of cancer mutations. Methods In the present study, SNVs in 12 tetra sample and 17 trio sample sets from four cancer types along with copy number variations (CNVs) were analyzed by AluScan sequencing, comparing tumor with white blood cells as well as tissues vicinal to the tumor. Four published “nontumor”-tumor metastasis trios and 246 pan-cancer pairs analyzed by whole-genome sequencing (WGS) and 67 trios by whole-exome sequencing (WES) were also examined. Results Widespread GOHs enriched with CG-to-TG changes and associated with nearby CNVs and LOHs enriched with TG-to-CG changes were observed. Occurrences of GOH were 1.9-fold higher than LOH in “nontumor” tissues more than 2 cm away from the tumors, and a majority of these GOHs and LOHs were reversed in “paratumor” tissues within 2 cm of the tumors, forming forward-reverse mutation cycles where the revertant LOHs displayed strong lineage effects that pointed to a sequential instead of parallel development from “nontumor” to “paratumor” and onto tumor cells, which was also supported by the relative frequencies of 26 distinct classes of CNVs between these three types of cell populations. Conclusions These findings suggest that developing cancer cells undergo sequential changes that enable the “nontumor” cells to acquire a wide range of forward mutations including ones that are essential for oncogenicity, followed by revertant mutations in the “paratumor” cells to avoid growth retardation by excessive mutation load. Such utilization of forward-reverse mutation cycles as an adaptive mechanism was also observed in cultured HeLa cells upon successive replatings. An understanding of forward-reverse mutation cycles in cancer development could provide a genomic basis for improved early diagnosis, staging, and treatment of cancers.

Intronic polymorphisms of the GABAA receptor β2 subunit gene (GABRB2) under adaptive evolution were associated with schizophrenia and reduced expression, especially of the long isoform which differs in electrophysiological properties from the short isoform. The present study was directed to examining the gene dosage effects of Gabrb2 in knockout mice of both heterozygous (HT) and homozygous (KO) genotypes with respect to possible schizophrenia-like and comorbid phenotypes. The KO mice, and HT mice to a lesser extent, were found to display prepulse inhibition (PPI) deficit, locomotor hyperactivity, stereotypy, sociability impairments, spatial-working and spatial-reference memory deficits, reduced depression and anxiety, and accelerated pentylenetetrazol (PTZ)-induced seizure. In addition, the KO mice were highly susceptible to audiogenic epilepsy. Some of the behavioral phenotypes showed evidence of imprinting, gender effect and amelioration by the antipsychotic risperidone, and the audiogenic epilepsy was inhibited by the antiepileptic diazepam. GABAergic parvalbumin (PV)-positive interneuron dystrophy, astrocyte dystrophy, and extensive microglia activation were observed in the frontotemporal corticolimbic regions, and reduction of newborn neurons was observed in the hippocampus by immunohistochemical staining. The neuroinflammation indicated by microglial activation was accompanied by elevated brain levels of oxidative stress marker malondialdehyde (MDA) and the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). These extensive schizophrenia-like and comorbid phenotypes brought about by Gabrb2 knockout, in conjunction with our previous findings on GABRB2 association with schizophrenia, support a pivotal role of GABRB2 in schizophrenia etiology.

Earlier, prominent occurrences of interstitial loss-of-heterozygosities (LOHs) were found in different cancers as a type of single-nucleotide-variations (SNVs), at rates far exceeding those of the commonly investigated gain-of-heterozygosities (GOHs) type of SNVs. Herein, such co-occurrences of LOHs and GOHs were confirmed in 102 cases of four cancer types analyzed with three different next-generation sequencing platforms, comparing non-tumor, paratumor, and tumor tissues with white-blood-cell controls; and in 246 pan-cancer cases of whole-genome tumor-control pairs. Unexpectedly, large numbers of SNVs enriched with CG>TG GOHs and copy-number-variations (CNVs) proximal to these GOHs were detected in the non-tumor tissues, which were extensively reversed in paratumors showing prominent TG>CG LOHs with proximal CNVs, and less so in tumors to form forward-reverse mutation cycles. Lineage effects in the reversions, likely resulting from directional selection, supported a sequential rather than parallel mode of evolution as described in a 'Stage Specific Populations' model of cancer development.

Background The prevalence of dementia is surging that results in huge service demand in the community care services. Dementia care competence of staff working in these settings is fundamental of the care quality. This project aims to examine the effects of staff training on their competence for the anticipated challenges in dementia care and explore how the training influence their care practices. Methods This study adopted a mixed methods triangulation design, including a prospective multi-center study with pre-test post-test evaluations and a narrative analysis of the participants’ reflective essays. Seventeen experienced health and social care professionals were trained as trainers at the Dementia Services Development Centre of the University of Stirling, UK. The trainers provided local facilitator training to staff members by using training materials that were culturally adapted to the local context. The facilitators were required to deliver 12 two-hour in-service training sessions for 6 months to their colleagues in a small group format in their respective workplace. Eventually a total of 1347 staff members from community care centers, day care centers, outreach teams and care homes of 70 non-government organizations in Hong Kong participated in the study between April 2017 and December 2018. Validated instruments were used to measure knowledge, attitude, sense of competence in dementia care and job satisfaction at the baseline and at 12-month follow-up. All participants were required to write a reflective essay to describe their experiences in dementia care by the end of the training. Results A total of 1264 participants, including 195 facilitators and 1069 learners, completed all assessment were included for analysis. Significant improvements were observed in all outcomes at the 12-month follow-up assessment ( P s ≤ .001). The magnitude of improvements in attitudes was the largest. The findings also showed that the effects of the training program significantly varied across different groups of learners in terms of age, occupation, work and training experience. Conclusions This community-wide large-scale project provided evidence that the train-the-trainer model and reflective learning are effective means to facilitate situated learning that promote awareness and understanding of dementia, and consequently enhance sustainability of changes in care practices.

A scarlet fever outbreak occurred in Hong Kong in 2011. The majority of cases resulted in the isolation of Streptococcus pyogenes emm12 with multiple antibiotic resistances. Phylogenetic analysis of 22 emm12 scarlet fever outbreak isolates, 7 temporally and geographically matched emm12 non-scarlet fever isolates, and 18 emm12 strains isolated during 2005-2010 indicated the outbreak was multiclonal. Genome sequencing of 2 nonclonal scarlet fever isolates (HKU16 and HKU30), coupled with diagnostic polymerase chain reaction assays, identified 2 mobile genetic elements distributed across the major lineages: a 64.9-kb integrative and conjugative element encoding tetracycline and macrolide resistance and a 46.4-kb prophage encoding superantigens SSA and SpeC and the DNase Spd1. Phenotypic comparison of HKU16 and HKU30 with the S. pyogenes M1T1 strain 5448 revealed that HKU16 displays increased adherence to HEp-2 human epithelial cells, whereas HKU16, HKU30, and 5448 exhibit equivalent resistance to neutrophils and virulence in a humanized plasminogen murine model. However, in contrast to M1T1, the virulence of HKU16 and HKU30 was not associated with covRS mutation. The multiclonal nature of the emm12 scarlet fever isolates suggests that factors such as mobile genetic elements, environmental factors, and host immune status may have contributed to the 2011 scarlet fever outbreak.

Malaria is a global health problem that threatens 300-500 million people and kills more than one million people annually. Disease control is hampered by the occurrence of multi-drug-resistant strains of the malaria parasite Plasmodium falciparum. Synthetic antimalarial drugs and malarial vaccines are currently being developed, but their efficacy against malaria awaits rigorous clinical testing. Artemisinin, a sesquiterpene lactone endoperoxide extracted from Artemisia annua L (family Asteraceae; commonly known as sweet wormwood), is highly effective against multi-drug-resistant Plasmodium spp., but is in short supply and unaffordable to most malaria sufferers. Although total synthesis of artemisinin is difficult and costly, the semi-synthesis of artemisinin or any derivative from microbially sourced artemisinic acid, its immediate precursor, could be a cost-effective, environmentally friendly, high-quality and reliable source of artemisinin. Here we report the engineering of Saccharomyces cerevisiae to produce high titres (up to 100 mg l-1) of artemisinic acid using an engineered mevalonate pathway, amorphadiene synthase, and a novel cytochrome P450 monooxygenase (CYP71AV1) from A. annua that performs a three-step oxidation of amorpha-4,11-diene to artemisinic acid. The synthesized artemisinic acid is transported out and retained on the outside of the engineered yeast, meaning that a simple and inexpensive purification process can be used to obtain the desired product. Although the engineered yeast is already capable of producing artemisinic acid at a significantly higher specific productivity than A. annua, yield optimization and industrial scale-up will be required to raise artemisinic acid production to a level high enough to reduce artemisinin combination therapies to significantly below their current prices.

Background Primary malignant tumors located near the acetabulum are usually managed by resection of the tumor with wide margins that include the acetabulum. These resections are deemed P2 resections by the Enneking and Dunham classification. There are various methods to perform the subsequent hip reconstruction. Unfortunately, there is no consensus as to the best management. In general, patients undergoing resection at this level will have substantial levels of pain and disability as measured by the Musculoskeletal Tumor Society (MSTS) scoring system. We believe there is a subset of patients whose tumors in this location can be resected while preserving all or most of the weightbearing acetabulum using navigation and careful surgical planning. Questions/purposes (1) What complications were associated with this resection; (2) what oncological outcomes (histological margins and local recurrence) were achieved; and (3) what is the function achieved by these patients? Methods This was a retrospective study of patients with periacetabular primary malignancy. From 2008 to 2014, we treated 12 patients who had periacetabular primary malignant tumors and in five, we performed resection with the weightbearing portion spared. During this period, our general indications to perform a resection that spared the acetabulum were the tumor with its resection margin not involving the weightbearing portion of the acetabulum. However, we did not perform this procedure in patients who had more cranial lesion involving the weightbearing portion or whose hip stability might be in question after the tumor excision. Three patients were women and the other two were men. Four were chondrosarcomas, whereas the other one was synovial sarcoma. Ages ranged from 46 to 60 years (average, 53 years). Minimum followup was 14 months (median, 37 months; range, 14–88 months); no patients were lost to followup before a 1-year minimum was achieved, and all patients have been seen within the last 9 months. Results There were no intraoperative or early postoperative complications. None of the five patients had a positive margin by histological assessment. No local recurrences were detected. The median functional score by MSTS was 28 out of 30 (range, 27–30). Conclusions The roof of the acetabulum is the weightbearing portion of the acetabulum. It also maintains the stability of the hip. With precise preoperative planning of the resection and accurate execution of the procedure, the hip-sparing approach through partial acetabular resection can be performed in selected patients with malignant periacetabular neoplasms. Navigation makes it possible to minimize the amount of bone resection. In this preliminary report of a small number of patients, we had adequate short-term local tumor control. We believe the function is good, but we do not have a comparison group of patients to document improved function. Level of Evidence Level IV, therapeutic study.

Gain-of-function kinase mutations are common in AML and usually portend an inferior prognosis. We reported a novel mechanism whereby kinase mutants induced intracellular alkalization characteristic in oncogenesis. Thirteen kinases were found to activate sodium/hydrogen exchanger (NHE1) in normal hematopoietic progenitors, of which FLT3-ITD, KRASG12D, and BTK phosphorylated NHE1 maintained alkaline intracellular pH (pHi) and supported survival of AML cells. Primary AML samples with kinase mutations also showed increased NHE1 phosphorylation and evidence of NHE1 addiction. Amiloride enhanced anti-leukemic effects and intracellular distribution of kinase inhibitors and chemotherapy. Co-inhibition of NHE1 and kinase synergistically acidified pHi in leukemia and inhibited its growth in vivo. Plasma from patients taking amiloride for diuresis reduced pHi of leukemia and enhanced cytotoxic effects of kinase inhibitors and chemotherapy in vitro. NHE1-mediated intracellular alkalization played a key pathogenetic role in transmitting the proliferative signal from mutated-kinase and could be exploited for therapeutic intervention in AML.

Rinse Weersma, Carl Anderson and colleagues report the results of a trans-ancestry association study of inflammatory bowel disease. They implicate 38 new susceptibility loci, and show that the variance explained by each IBD risk locus is consistent across diverse ancestries, with a few notable exceptions. Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency ( NOD2 ) or effect size ( TNFSF15 and ATG16L1 ) or a combination of these factors ( IL23R and IRGM ). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.

PurposeTo report the clinical outcomes of adalimumab in treating refractory Behcet’s disease (BD)-related uveitis in paediatric or adolescent patients.MethodsRetrospective review of five paediatric or adolescent patients with BD-related uveitis with a minimum follow-up of 24 months.ResultsDisease quiescence was observed in 9 (90%) of 10 eyes at 12 months. The mean number of relapses per year per patient was 5 (range, 3–7) before initiation of adalimumab treatment. This was reduced to 0.2 relapse per patient per year among the five patients during the first 24 months after starting adalimumab treatment. At baseline, 5 eyes had active retinal vasculitis. Retinal vasculitis resolved in all cases (100%) after starting adalimumab. The mean time to complete resolution of inflammation was 3.4 weeks. The mean ± standard deviation logMAR best-corrected visual acuity was 0.711 ± 0.63 at baseline and improved to 0.172 ± 1.04 at 12 months (P < 0.001). None of the patients developed any adverse events associated with adalimumab treatment.ConclusionAdalimumab was effective in preventing irreversible sight-threatening BD-related uveitis in paediatric or adolescent patients. Adalimumab appears to be a promising treatment option for young patients with recalcitrant BD-related uveitis and has a favourable safety profile.