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Summary In our study, we focused on a particular subtype of aggressive breast cancer called Triple-Negative Breast Cancer (TNBC). We investigated a complex series of events that contribute to poor outcomes in this disease and uncovered a crucial signaling cascade driving tumor growth and progression. At the core of this signaling cascade are three key proteins: SRC, AKT, and ERK2. Together, they form a pathway that activates a transcription factor called Slug. Transcription factors act like molecular switches, controlling the expression of genes. Once Slug is activated, it strongly suppresses genes that would normally restrict cell growth and cell spread. One of the genes downregulated by Slug is TGFB2-AS1. This product of the TGFB2-AS1 gene normally controls levels of its target protein called TGF-beta2 (TGFB2), a protein which has roles in cell growth, cell migration and differentiation. Slug downregulation of TGFB2-AS1 results in higher TGFB2 levels, and this in turn contributes to the uncontrolled growth and spread of cancer cells. TGFB2, and other proteins in this pathway (SRC, AKT, ERK2, and a Slug interactor called LSD1) all maintain the stability of Slug, meaning that Slug levels remain high and drive the aggressive features of this subtype of breast cancer. Overall, our research sheds light on the intricate molecular mechanisms driving aggressive TNBC. It also identifies potential targets for future therapies, aimed at disrupting this harmful signaling pathway and potentially improving patient outcomes for this disease.

Dryas octopetala L. var. asiatica (Nakai) Nakai 1918 is a dwarf shrub that mainly grow in alpine and arctic zones of the Northern Hemisphere, representing an endemic variety in Asia. In the present study, the complete chloroplast (cp) genome of D. octopetala var. asiatica was first characterized and used for its phylogenetic analysis. The cp genome span 158,271 bp with an overall GC content of 36.5%. A total of 129 genes were identified, including 84 protein-coding genes (PCGs), 37 tRNA genes, and 8 rRNA genes. In addition, repetitive sequences and microsatellites were detected within this species. Phylogenetic analysis involving 39 cp genomes from Rosaceae family indicated that D. octopetala var. asiatica was sister to the clade of Amygdaloideae. This study contributes fundamental insights into the cp genome of Dryas octopetala var. asiatica, which will have expanded its use in photosynthesis and evolutionary study.

Background: Insomnia is a prevalent health concern in the general population associated with a range of adverse health effects. New, effective, safe and low-cost treatments, suitable for long-term use, are urgently required. Previous studies have shown the potential of electrical vestibular nerve stimulation (VeNS) in improving insomnia symptoms, however only one sham-controlled trial has been conducted on people with chronic insomnia. Objectives/Hypothesis: Repeated VeNS delivered by the Modius Sleep device prior to sleep onset will show superior improvement in Insomnia Severity Index (ISI) scores over a 4-week period compared to sham stimulation. Methods: In this double-blinded, multi-site, randomised, sham-controlled study, 147 participants with moderate to severe insomnia (ISI≥15) were recruited and allocated a VeNS or a sham device (1:1 ratio) which they were asked to use at home for 30 min daily (minimum 5 days per week) for 4 weeks. Results: After 4 weeks, mean ISI score reduction was 2.26 greater in the VeNS treatment group than the sham group (p = 0.002). In the per protocol analysis, the treatment group had a mean ISI score decrease of 5.8 (95 % CI [-6.8, −4.81], approaching the clinically meaningful threshold of a 6-point reduction, with over half achieving a clinically significant decrease. Furthermore, the treatment group showed superior improvement to the sham group in the SF-36 (Quality of Life) energy/fatigue component (PP p = 0.004, effect size 0.26; ITT p = 0.006, effect size 0.22). Conclusions: Modius sleep has the potential to provide a viable, non-invasive and safe clinically meaningful alternative treatment option for insomnia.

Postharvest rot caused by various fungal pathogens is a damaging disease affecting kiwifruit production and quality, resulting in significant annual economic losses. This study focused on isolating the strain P3-1W, identified as Diaporthe eres, as the causal agent of ‘Hongyang’ postharvest rot disease in China. The investigation highlighted cell wall degrading enzymes (CWDEs) as crucial pathogenic factors. Specially, the enzymatic activities of cellulase, β-galactosidase, polygalacturonase, and pectin methylesterases peaked significantly on the second day after infection of D. eres P3-1W. To gain a comprehensive understanding of these CWDEs, the genome of this strain was sequenced using PacBio and Illumina sequencing technologies. The analysis revealed that the genome of D. eres P3-1W spans 58,489,835 bp, with an N50 of 5,939,879 bp and a GC content of 50.7%. A total of 15,407 total protein-coding genes (PCGs) were predicted and functionally annotated. Notably, 857 carbohydrate-active enzymes (CAZymes) were identified in D. eres P3-1W, with 521 CWDEs consisting of 374 glycoside hydrolases (GHs), 108 carbohydrate esterase (CEs) and 91 polysaccharide lyases (PLs). Additionally, 221 auxiliary activities (AAs), 91 glycosyltransferases (GTs), and 108 carbohydrate binding modules (CBMs) were detected. These findings offer valuable insights into the CAZymes of D. eres P3-1W.

Alternaria tenuissima can cause leaf spots and fruit decay in some economically important crops. Recently, this species was first reported as a causal agent causing fruit decay in postharvest kiwifruit. Here, a highly contiguous genome assembly 33.87 Mb in size was obtained by a combination of Illumina NovaSeq and PacBio SMRT sequencing methods, yielding five full chromosome-level sequences. This resource provides opportunities for a better understanding of the mechanisms that underpin the pathogenicity of A. tenuissima. [Figure: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Background: The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has posed unprecedented challenges to healthcare systems worldwide. Here, we have identified proteomic and genetic signatures for improved prognosis which is vital for COVID-19 research. Methods: We investigated the proteomic and genomic profile of COVID-19-positive patients (n = 400 for proteomics, n = 483 for genomics), focusing on differential regulation between hospitalised and non-hospitalised COVID-19 patients. Signatures had their predictive capabilities tested using independent machine learning models such as Support Vector Machine (SVM), Random Forest (RF) and Logistic Regression (LR). Results: This study has identified 224 differentially expressed proteins involved in various inflammatory and immunological pathways in hospitalised COVID-19 patients compared to non-hospitalised COVID-19 patients. LGALS9 (p-value < 0.001), LAMP3 (p-value < 0.001), PRSS8 (p-value < 0.001) and AGRN (p-value < 0.001) were identified as the most statistically significant proteins. Several hundred rsIDs were queried across the top 10 significant signatures, identifying three significant SNPs on the FSTL3 gene showing a correlation with hospitalisation status. Conclusions: Our study has not only identified key signatures of COVID-19 patients with worsened health but has also demonstrated their predictive capabilities as potential biomarkers, which suggests a staple role in the worsened health effects caused by COVID-19.

BackgroundHealth organizations and countries around the world have found it difficult to control the spread of COVID-19. To minimize the future impact on the UK National Health Service and improve patient care, there is a pressing need to identify individuals who are at a higher risk of being hospitalized because of severe COVID-19. Early targeted work was successful in identifying angiotensin-converting enzyme-2 receptors and type II transmembrane serine protease dependency as drivers of severe infection. Although a targeted approach highlights key pathways, a multiomics approach will provide a clearer and more comprehensive picture of severe COVID-19 etiology and progression. ObjectiveThe COVID-19 Response Study aims to carry out an integrated multiomics analysis to identify biomarkers in blood and saliva that could contribute to host susceptibility to SARS-CoV-2 and the development of severe COVID-19. MethodsThe COVID-19 Response Study aims to recruit 1000 people who recovered from SARS-CoV-2 infection in both community and hospital settings on the island of Ireland. This protocol describes the retrospective observational study component carried out in Northern Ireland (NI; Cohort A); the Republic of Ireland cohort will be described separately. For all NI participants (n=519), SARS-CoV-2 infection has been confirmed by reverse transcription-quantitative polymerase chain reaction. A prospective Cohort B of 40 patients is also being followed up at 1, 3, 6, and 12 months postinfection to assess longitudinal symptom frequency and immune response. Data will be sourced from whole blood, saliva samples, and clinical data from the electronic care records, the general health questionnaire, and a 12-item general health questionnaire mental health survey. Saliva and blood samples were processed to extract DNA and RNA before whole-genome sequencing, RNA sequencing, DNA methylation analysis, microbiome analysis, 16S ribosomal RNA gene sequencing, and proteomic analysis were performed on the plasma. Multiomics data will be combined with clinical data to produce sensitive and specific prognostic models for severity risk. ResultsAn initial demographic and clinical profile of the NI Cohort A has been completed. A total of 249 hospitalized patients and 270 nonhospitalized patients were recruited, of whom 184 (64.3%) were female, and the mean age was 45.4 (SD 13) years. High levels of comorbidity were evident in the hospitalized cohort, with cardiovascular disease and metabolic and respiratory disorders being the most significant (P

Abstract Genus Filipendula (Rosoideae, Rosaceae) comprises about 15 species and mainly distributed in Northern Hemisphere. The phylogenetic relationships based on the nrITS marker are not consistent with the traditional taxonomic systems of the genus. Here, we first analysed the complete chloroplast (cp) genomes of seven Filipendula species (including two varieties of F. palmate). Our results indicated that the cp genomes of Filipendula species had few changes in size, ranging from 154,205 bp to 154,633 bp and the average of 36.63% GC content. A total of 126 annotated genes had the identical order and orientation, implying that the cp genome structure of Filipendula species was rather conserved. However, the cp genomes of Filipendula species exhibited structural differences, including gene loss, transposition and inversion when compared to those of other genera of Rosoideae. Moreover, SSRs with the different number were observed in the cp genome of each Filipendula species and sequence divergence mainly occurred in noncoding regions, in which four mutational hotspots were identified. In contrast, only two positive selection genes (matK and rps8) were found. Phylogenetic and molecular-dating analysis indicated that Filipendula species were divergent from other genera of Rosoideae at about 82.88 Ma. Additionally, Filipendula species from East Asia were split at about 9.64 Ma into two major clades. These results provide a basis for further studying the infrageneric classification of Filipendula.

Abstract Background Spiraea is a genus of deciduous shrubs that contains 80-120 species, is mainly distributed in the Northern Hemisphere and has diversified in East Asia. Spiraea species are cultivated as ornamental plants and some are used in traditional herbal medicine. Based on morphological characteristics and genetic markers, phylogenetic classification exhibits low discriminatory power. Results In present study, we assembled and characterized the chloroplast (cp) genomes of ten Spiraea species and comparatively analysed with five reported cp genomes of this genus. The cp genomes of the fifteen Spiraea species, ranging from 155,904 to 158,637 bp in length, were very conserved and no structural rearrangements occurred. A total of 85 protein-coding genes (PCGs), 37 tRNAs and 8 rRNAs were annotated. We also examined 1,010 simple sequence repeat (SSR) loci, most of which had A/T base preference. Comparative analysis of cp genome demonstrated that single copy and non-coding regions were more divergent than the inverted repeats (IRs) and coding regions and six mutational hotspots were detected. Selection pressure analysis showed that all PCGs were under purifying selection. Phylogenetic analysis based on the complete cp genome data showed that Spiraea formed a monophyletic group and was further divided into two major clades. Infrageneric classification in each clade was supported with a high resolution value. Moreover, the phylogenetic trees based on each individual mutational hotspot segment and their combined dataset also consisted of two major clades, but most of the phylogenetic relationships of interspecies were not well supported. Conclusions Although the cp genomes of Spiraea species exhibited high conservation in genome structure, gene content and order, a large number of polymorphism sites and several mutation hotspots were identified in whole cp genomes, which might be sufficiently used as molecular markers to distinguish Spiraea species. Phylogenetic analysis based on the complete cp genome indicated that infrageneric classification in two major clades was supported with high resolution values. Therefore, the cp genome data of the genus Spiraea will be effective in resolving the phylogeny in this genus.

Alzheimer’s disease (AD) is a complex neurodegenerative condition that is characterized by the build-up of amyloid-beta plaques and neurofibrillary tangles. While multiple theories explaining the aetiology of the disease have been suggested, the underlying cause of the disease is still unknown. Despite this, several modifiable and non-modifiable factors that increase the risk of developing AD have been identified. To date, only eight AD drugs have ever gained regulatory approval, including six symptomatic and two disease-modifying drugs. However, not all are available in all countries and high costs associated with new disease-modifying biologics prevent large proportions of the patient population from accessing them. With the current patient population expected to triple by 2050, it is imperative that new, effective, and affordable drugs become available to patients. Traditional drug development strategies have a 99% failure rate in AD, which is far higher than in other disease areas. Even when a drug does reach the market, additional barriers such as high cost and lack of accessibility prevent patients from benefiting from them. In this review, we discuss how a stratified medicine drug repurposing approach may address some of the limitations and barriers that traditional strategies face in relation to drug development in AD. We believe that novel, stratified drug repurposing studies may expedite the discovery of alternative, effective, and more affordable treatment options for a rapidly expanding patient population in comparison with traditional drug development methods.

Abstract Gastric neuroendocrine carcinoma (GNEC) is a common type of neuroendocrine carcinoma (NEC) with a poor prognosis and limited therapeutic options. The underlying mechanisms of chemoresistance in patients with GNEC and those with NEC are largely unknown, and thus, reliable biomarkers and therapeutic targets that could improve treatment outcomes in patients with NECs are lacking. The aim of this study was to identify specific targets and investigate their roles in GNEC progression and treatment resistance. Differentially expressed genes (DEGs) were identified in GNEC specimens and were further analysed by focusing on their roles in chemoresistance. Gene Ontology (GO) and pathway enrichment analyses of GNEC DEGs revealed that synapse-related function was the most prominent cellular function perturbed in GNEC. SNAP25 was identified as the target gene involved in most of the enriched pathways. In vitro and in vivo experiments showed that SNAP25 plays a role in proliferation and chemoresistance in GNEC cell lines. AKT has been identified as a downstream target, and SNAP25 binds to AKT protein and promotes AKT protein half-life. Further analysis of other types of NEC as well as small cell lung cancer, which resembles NEC on a molecular level, has identified RUNDC3A as an upstream molecule that regulates SNAP25 expression and the associated phenotypes that could enhance chemoresistance in NECs. Our results show that SNAP25 expression in GNEC is mediated by RUNDC3A and promotes GNEC progression and chemoresistance via posttranslational modification of AKT. Thus, our results suggest that the RUNDC3A/SNAP25/Akt axis could be a potential therapeutic target in GNEC.

Paris stigmatosa is a new described species of Melanthiaceae. In this study, the complete chloroplast (cp) genome sequence of P. stigmatosa was first reported and characterized. The cp genome is 165,623 bp in length and contains a pair of inverted repeats (IRs, 34,165 bp) separated by a large (84,327 bp) and small (12,966 bp) single-copy regions. A total of 113 genes were predicted, including 79 protein-coding genes, 30 tRNA genes and 4 rRNA genes. The phylogenetic analysis suggested that P. stigmatosa is sister of the clade formed by P. marmorata and P. luquanensis.

BackgroundAnastomosing hemangioma (AH) is a rare vascular tumor and occurs in various organs. It is difficult to distinguish AH from malignant tumors even through multimodal imaging examination. AH located in the inguinal region is even rare. We present the diagnosis and treatment of a patient with spermatic cord AH in detail and conduct a literature review.Case ReportAn 84-year-old Chinese man had swelling pain in his right scrotum. A hard and fixed mass was palpable in the right inguinal region. Preoperative radiological examination considered it a neurogenic or vascular tumor. Malignant soft tissue sarcoma could not be excluded. He underwent radical inguinal right orchiectomy under intraspinal anesthesia. The diagnosis of spermatic cord AH was confirmed by pathological examination. The patient recovered uneventfully and remained disease-free during an 18-month follow-up.ConclusionSpermatic cord AH is quite rare and could be misdiagnosed as a malignant tumor. Pathological evidence might be necessary. The optimal choice of treatment should be determined through a comprehensive assessment of both tumor and patient factors.

The long dormancy period of Paris polyphylla var. yunnanensis seeds affects the supply of this scarce plant, which is used as an important traditional Chinese medicine. Mature seeds with a globular embryo and germinating seeds with developed embryo were used to explore the mechanisms of seed germination in this species. The protein profiles between the mature and germinating seeds were compared using the isobaric tags for relative and absolute quantification (iTRAQ) approach. Of the 4,488 proteins identified, a total of 1,305 differentially expressed proteins (DEPs) were detected. A Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of these DEPs indicated that metabolic pathways and the biosynthesis of secondary metabolites were the two top pathways. Additionally, phytohormone quantification shows that the abscisic acid (ABA) level significantly decreased, whereas the GA3 level dramatically increased among nine endogenous gibberellins (GAs), resulting in a significant increase of the GA3/ABA ratio in germinating seeds. The biosynthesis pathways of carotenoid as a precursor for ABA production and GA were further analyzed, and showed that proteinic expressions of the candidate genes in the two pathways did not correlate with the transcriptional abundances. However, 9-cis-epoxycarotenoid dioxygenase (NCED), a rate limited enzyme for ABA biosynthesis, was significantly decreased in mRNA levels in germinating seeds. By contrast, gibberellin 20-oxidase (GA20ox), a key enzyme GA biosynthesis, exhibited the major increase in one copy and a slight decrease in three others at the protentional level in germinating seeds. Gibberellin 2-oxidase (GA2ox), an inactivate enzyme in bioactive GAs, has the tendency to down-regulate in mRNA or at the proteinic level in germinating seeds. Altogether, these results suggested that the analyses of ABA and GA levels, the GA3/ABA ratio, and the expressional patterns of their regulatory genes may provide a novel mechanistic understanding of how phytohormones regulate seed germination in P. polyphylla var. yunnanensis.

Abstract We hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.

Amila Suraweera et al. use a range of biochemical and in vitro cellular assays to examine the role of the COMMD4 in DNA repair. Their results suggest that COMMD4 interacts with the histone H2A-H2B during repair of double-stranded DNA breaks, thereby maintaining genomic stability by regulating chromatin structure.

Abstract. Background. Renal cell carcinoma (RCC) has the propensity to lead to venous tumor thrombus (VTT). Nephrectomy with tumor thrombectomy is an effective treatment option but is a technically challenging surgical procedure that is accompanied by a high rate of complications. The aims of this study were to investigate pre-operative imaging parameters for the assessment of inferior vena cava (IVC) wall invasion due to a tumor thrombus in patients with RCC and to identify predictors from the intra-operative findings. Methods. Clinical and imaging data were collected from 110 patients who underwent nephrectomy with IVC tumor thrombectomy (levels I–IV) for RCC and IVC tumor thrombus at the Peking University Third Hospital between May 2015 and March 2018. Univariable and multivariable logistic regression and receiver operating characteristic curves were used to assess the correlations between pre-operative imaging features and intra-operative macroscopic invasions of the IVC wall by tumor thrombus. Results. Among the 110 patients, 41 underwent partial or segmental resection of IVC. There were univariate associations of pre-operative imaging parameters that could be used to predict the need for IVC resection, including those of the Mayo classification, maximum anterior-posterior (AP) diameter of the renal vein at the renal vein ostium (RVo), maximum AP diameter of the VTT at the RVo and IVC occlusion. For the multivariable analysis, the AP diameter of the VTT at the RVo and IVC occlusion were associated with a significantly increased risk of invasion of the IVC wall by tumor thrombus. The optimum imaging thresholds included an AP diameter of the VTT at the RVo larger than 17.0 mm and the presence of IVC occlusion, with which we predicted invasions of the IVC wall requiring IVC resection. The probabilities of intra-operative IVC resection for patients without both independent factors, with an AP diameter of the VTT at the RVo larger than 17.0 mm, with IVC occlusion, and with both concurrent factors were 5%, 23%, 56%, and 66%, respectively. Conclusion. An increase in the AP VTT diameter at the RVo and the presence of complete occlusion of the IVC are independent risk factors for a high probability of IVC wall invasion by tumor thrombus.

Abstract Background Many antipsychotics elevate prolactin, a hormone implicated in breast cancer aetiology however no studies have investigated antipsychotic use in patients with breast cancer. This study investigated if antipsychotic use is associated with an increased risk of cancer-specific mortality among breast cancer patients. Methods A cohort of 23,695 women newly diagnosed with a primary breast cancer between 1st January 1998 and 31st December 2012 was identified from the UK Clinical Practice Research Datalink linked to English cancer-registries and followed for until 30th September 2015. Time-dependent Cox proportional hazards models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer-specific mortality comparing use of antipsychotics with non-use, overall, and by prolactin elevating activitiy. Analyses were repeated restricting to patients with a history of severe mental illness to control for potential confounding by indication. Results In total 848 patients were prescribed an antipsychotic and of which 162 died due to their breast cancer. Compared with non-use, antipsychotic use was associated with an increased risk of breast-cancer specific mortality (HR 2.25, 95%CI 1.90–2.67), but this did not follow a dose response relation. Restricting the cohort to patients with severe mental illness attenuated the association between antipsychotic use and breast cancer-specific mortality (HR 1.11, 95%CI 0.58–2.14). Conclusions In this population-based cohort of breast cancer patients, while the use of antipsychotics was associated with increased breast cancer-specific mortality, there was a lack of a dose response, and importantly null associations were observed in patients with severe mental illness, suggesting the observed association is likely a result of confounding by indication. This study provides an exemplar of confounding by indication, highlighting the importance of consideration of this important bias in studies of drug effects in cancer patients.

Abstract. Background. Radical nephrectomy and thrombectomy is the standard surgical procedure for the treatment of renal cell carcinoma (RCC) with tumor thrombus (TT). But the estimation of intra-operative blood loss is only based on the surgeon's experience. Therefore, our study aimed to develop Peking University Third Hospital score (PKUTH score) for the prediction of intra-operative blood loss volume in radical nephrectomy and thrombectomy. Methods. The clinical data of 153 cases of renal mass with renal vein (RV) or inferior vena cava tumor thrombus admitted to Department of Urology, Peking University Third Hospital from January 2015 to May 2018 were retrospectively analyzed. The total amount of blood loss during operation is equal to the amount of blood sucked out by the aspirator plus the amount of blood in the blood-soaked gauze. Univariate linear analysis was used to analyze risk factors for intra-operative blood loss, then significant factors were included in subsequent multivariable linear regression analysis. Results. The final multivariable model included the following three factors: open operative approach (P

The genomic heterogeneity of clear cell renal cell carcinoma (ccRCC) across populations is poorly understood. Here, the authors analyse a cohort of Chinese ccRCC cases revealing a mutational signature associated with aristolochic acid exposure, and higher mutational burden and enrichment for BAP1 and SETD2 mutations in ccRCC cases associated with tumor thrombus.

Gastric neuroendocrine carcinoma (GNEC) is rare cancer detected in the stomach. Previously, we demonstrated that the poorer prognosis of GNEC patients compared with gastric adenocarcinoma (GAC) patients was probably due to the lack of response to chemotherapy. Thus, it is crucial to study the specific GNEC gene expression pattern and investigate chemoresistance mechanism of GNEC. The transcriptome of GNEC patients was compared with that of GAC patients using RNA-seq. The KEGG analysis was employed to explore the specific differential expression gene function enrichment pattern. In addition, the transcriptomes of two GNEC cell lines, ECC10 and ECC12, were also compared with those of two GAC cell lines, MGC-803 and AGS, using RNA-seq. Comparing patient samples and cell lines transcriptome data, we try to uncover the potential targets and pathways which may affect the chemoresistance of GNEC. By combing all transcriptome data, we identified 22 key genes that were specifically up-regulated in GNEC. This panel of genes probably involves in the chemoresistance of GNEC. From our current experimental data, NeuroD1, one of the 22 genes, is associated with the prognosis of GNEC patients. Knockdown of NeuroD1 enhanced the sensitivity to irinotecan of GNEC cell lines. Our research sheds light in identifying a panel of novel therapeutic target specifically for GNEC clinical treatment which has not been reported before.

Mutation of the nuclear envelope protein, barrier-to-autointegration factor 1 (Banf1), has previously been associated with the development of ageing associated diseases in a human progeria syndrome. Here, the authors reveal the functional link between Banf1-regulated, PARP1-directed repair of oxidative lesions.

Sorbus L. is a genus of controversy on its taxonomic concept due to great variations in morphological characteristics. Sorbus sensu stricto species, being monophyletic, are characterized as pinnate leaves. However, phylogenetic relationships of these species are somewhat fluid based on morphological characteristics and genetic markers. In this study, the chloroplast (cp) genomes of eight Sorbus s. str. species were characterized and compared with those of twelve released species in this genus. Our results indicated that the plastomes of the twenty Sorbus species had a conserved quadripartite structure, and 129 annotated genes had the same order and showed a good collinearity. Additionally, numerous SSRs were observed in the cp genome of each Sorbus species; most of the sequence variations appeared in non-coding regions, and four intergenic regions were identified as mutation spots. By contrast, protein-coding genes showed low variations under purifying selection. The phylogenetic and molecular-dating analysis showed that Sorbus was resolved into two major clades, in which S. americana forms one clade originating at 51.78 Ma, and the rest of Sorbus formed another clade, splitting at 36.77 Ma into two sister groups with high support values. These results provide a basis for further studying the phylogenetic relationship and biogeography of Sorbus species.

Paris delavayi Franchet is a perennial herb of the family Melanthiaceae. In this study, the complete chloroplast (cp) genome sequence of P. delavayi was characterized. The cp genome is 164,195 bp in length and contains a pair of inverted repeats (33,415 bp) separated by a large (84,400 bp) and small (12,965 bp) single-copy regions. A total of 112 unique genes were predicted, including 78 protein-coding genes, 30 tRNA genes and 4 rRNA genes. The phylogenetic analysis suggested that P. delavayi is sister to P. mairei but with low support.

The first complete chloroplast (cp) genome sequences of an endemic and endangered species in China, Calanthe henryi, were reported in this study. The cp genome of C. henryi was 158,256 bp long, with two inverted repeat (IR) regions of 26,348 bp, a large single copy (LSC) region of 87,137 bp, and a small single copy (SSC) region of 18,423 bp. The cp genome of this species contained 113 genes, including 79 protein-coding genes, 4 ribosomal RNA genes, and 30 transfer RNA genes. The overall GC content was 36.7%. Phylogenetic analysis of 60 cp genomes within the subfamily of Epidendroideae suggests that C. henryi is closely related to C. bicolor.

Abstract. Background:. Radical nephrectomy with thrombectomy is one of the most difficult and complicated urological operations. But the roles of renal tumor volume and thrombus level in surgical complexity and prognostic outcome are not clear. This study aimed to evaluate the surgical complexity and prognostic outcome between the volume of renal cell carcinoma (RCC) and the level of venous tumor thrombus. Methods:. The clinical data of 67 RCC cases with renal vein or inferior vena cava (IVC) tumor thrombus from January 2015 to May 2018 were retrospectively analyzed. Among these 67 cases, 21 (31.3%) were small tumors with high-level thrombus (tumor ≤7 cm in diameter and thrombus Neves Level II–IV), while 46 (68.7%) were large tumors with low-level thrombus group (tumor >7 cm in diameter and thrombus Level 0–I). Clinical features, operation details, and pathology data were collected. Univariable and multivariable logistic regression analyses were applied to evaluate the risk factors for small tumor with high-level thrombus. Results:. Patients with small tumors and high-level thrombus were more likely to have longer operative time (421.9 ± 135.1 min vs. 282.2 ± 101.9 min, t = 4.685, P

Abstract Objective To define preoperative clinical and radiographic risk factors for the need of inferior vena cava (IVC) resection in patients with renal cell carcinoma (RCC) and IVC tumor thrombus. Methods We reviewed data of 121 patients with renal cell carcinoma and venous tumor thrombus receiving radical nephrectomy and thrombectomy at our institution between 2015 and 2017, and 86 patients with Mayo I–IV level tumor thrombus were included in the final analysis. Clinical features, operation details, and pathology data were collected. Preoperative images were reviewed separately by two radiologists. Univariable and multivariable logistic regression analyses were applied to evaluate clinical and radiographic risk factors of IVC resection. Results Of the 86 patients, 44 (51.2%) received IVC resection during thrombectomy. In univariate analysis, we found that body mass index (BMI) (odds ratio [OR] = 1.22, P = 0.003), primary tumor diameter (OR = 0.84, P = 0.022), tumor thrombus width (OR = 1.08, P = 0.037), tumor thrombus level (OR = 1.57, P = 0.030), and IVC occlusion (OR = 2.67, P = 0.038) were associated with the need for resection of the IVC. After adjusting for the other factors, BMI (OR = 1.18, P = 0.019) was the only significant risk factor for IVC resection. Multivariable analysis in Mayo II–IV subgroups confirmed BMI as an independent risk factor (OR = 1.26, P = 0.024). A correlation between BMI and the width (Pearson’s correlation coefficient [PCC] = 0.27, P = 0.014) and length (PCC = 0.23, P = 0.037) of the tumor thrombus was noticed. Conclusion We identified BMI as an independent risk factor for IVC resection during thrombectomy of RCC with tumor thrombus in a Chinese population. More careful preoperative preparation for the IVC resection and/or reconstruction is warranted in patients with higher BMI.

[This corrects the article DOI: 10.1371/journal.pone.0054211.].

Abstract Background Nearly 50% of breast cancer patients suffer from depression or anxiety. Selective serotonin reuptake inhibitors (SSRIs), the first-line pharmacological treatment for depression, have been implicated in breast cancer development through increased prolactin levels and tamoxifen metabolism inhibition. Previous studies of breast cancer progression have focused on tamoxifen users, or have been limited by their small sample size and methodology. Therefore, we used UK population-based data to more robustly investigate the association between SSRI use and cancer-specific mortality. Methods A cohort of patients with newly-diagnosed breast cancer between 1998 and 2012 was selected from English cancer registries and linked to prescription records from the Clinical Practice Research Datalink, and to death records from the Office for National Statistics. We used Cox regression models to calculate hazard ratios (HRs) comparing mortality between post-diagnostic SSRI users and non-users (using time-dependant covariates), after adjusting for demographics, comorbidities and pre-diagnosis use of hormone replacement therapy or oral contraceptives. We conducted several additional analyses to assess causality. Results Our cohort included 23,669 breast cancer patients, of which 2672 used SSRIs and 3053 died due to their breast cancer during follow-up. After adjustment, SSRI users had higher breast cancer-specific mortality than non-users (HR = 1.27; 95% confidence interval (CI) 1.16, 1.40). However, this association was attenuated when restricting to patients with a prior history of depression (HR = 1.14; 95% CI 0.98, 1.33), and when comparing to users of other antidepressant medications (HR = 1.06; 95% CI 0.93, 1.20). There was some evidence of higher mortality among long-term SSRI users, even when restricting to patients with prior depression (HR = 1.54; 95% CI 1.03, 2.29). Conclusions In this large breast cancer cohort, SSRI use was associated with a 27% increase in breast cancer mortality. The cause of this is unknown; however, confounding by indication seems likely as it was largely attenuated when restricting to patients with prior depression, or when comparing SSRIs to other antidepressant medications. Clinicians should not be unduly concerned when prescribing SSRIs to breast cancer patients, but the increase in mortality among long-term SSRI users warrants further investigation.

Abstract Background Gene expression connectivity mapping has gained much popularity in recent years with a number of successful applications in biomedical research testifying its utility and promise. A major application of connectivity mapping is the identification of small molecule compounds capable of inhibiting a disease state. In this study, we are additionally interested in small molecule compounds that may enhance a disease state or increase the risk of developing that disease. Using breast cancer as a case study, we aim to develop and test a methodology for identifying commonly prescribed drugs that may have a suppressing or inducing effect on the target disease (breast cancer). Results We obtained from public data repositories a collection of breast cancer gene expression datasets with over 7000 patients. An integrated meta-analysis approach to gene expression connectivity mapping was developed, which involved unified processing and normalization of raw gene expression data, systematic removal of batch effects, and multiple runs of balanced sampling for differential expression analysis. Differentially expressed genes stringently selected were used to construct multiple non-joint gene signatures representing the same biological state. Remarkably these non-joint gene signatures retrieved from connectivity mapping separate lists of candidate drugs with significant overlaps, providing high confidence in their predicted effects on breast cancers. Of particular note, among the top 26 compounds identified as inversely connected to the breast cancer gene signatures, 14 of them are known anti-cancer drugs. Conclusions A few candidate drugs with potential to enhance breast cancer or increase the risk of the disease were also identified; further investigation on a large population is required to firmly establish their effects on breast cancer risks. This work thus provides a novel approach and an applicable example for identifying medications with potential to alter cancer risks through gene expression connectivity mapping.

Abstract β-defensin family plays a role in host defense against viral infection, however its role in HCV infection is still unknown. In this study, we demonstrated that β-defensin 1 was significantly reduced in HCV-infected liver specimens. Treatment with interferon and ribavirin upregulated β-defensin-1, but not other β-defensin tested, with the extent and duration of upregulation associated with treatment response. We investigated β-defensin family expression in liver cancer in publicly available datasets and found that among all the β-defensins tested, only β-defensin 1 was significantly downregulated, suggesting β-defensin 1 plays a crucial role in liver cancer development. Further analysis identified E-cadherin as the top positive correlated gene, while hepatocyte growth factor-regulated tyrosine kinase substrate as the top negative correlated gene. Expression of two proteoglycans were also positively correlated with that of β-defensin 1. We have also identified small molecules as potential therapeutic agents to reverse β-defensin 1-associated gene signature. Furthermore, the downregulation of β-defensin 1 and E-cadherin, and upregulation of hepatocyte growth factor-regulated tyrosine kinase substrate, were further confirmed in liver cancer and adjacent normal tissue collected from in-house Chinese liver cancer patients. Together, our results suggest β-defensin 1 plays an important role in protecting HCV progression and liver cancer development.

The complete chloroplast (cp) genome of Eurya loquaiana Dunn. has been reported in this study. The cp genome has a total length of 157,218 bp with the typical quadripartite structure, containing two inverted repeats (IRs) of 25,883 bp separated by a large single-copy (LSC) region of 87,248 bp and a small single-copy (SSC) region of 18,204 bp. The whole cp genome of E. loquaiana contains 128 genes, including 83 protein-coding genes, 37 tRNAs genes, and 8 rRNAs. The phylogenetic result showed that E. loquaiana is sister to E. alate.

Myricaria laxiflora (Tamaricaceae) is an endangered species distributed only along the river beach of Yangtze River. Here, the complete chloroplast (cp) genome of M. laxiflora was assembled and characterized. The cp genome is in a total length of 154,971 bp with the typical quadripartite structure of angiosperms, containing 2 inverted repeats (IRs) of 26,004 bp separated by a large single-copy (LSC) region of 84,702 bp and a small single-copy (SSC) region of 18,261 bp. The whole cp genome of M. laxiflora contains 130 genes, including 85 protein-coding genes, 37 tRNAs genes, and 8 rRNAs. Phylogenetic analysis based on the complete cp genomes within the Tamaricaceae family suggests that M. laxiflora is closer to M. paniculata.

The first complete chloroplast (cp) genome sequences of Pittosporum tobira were reported in this study. The cp genome of P. tobira was 153,754 bp long, which included a large single copy (LSC) region of 85,010 bp and a small single copy (SSC) region of 18,740 bp separated by two inverted repeat (IR) regions of 25,002 bp. The cp genome of this species contained 113 unique genes, including 79 protein-coding genes, 30 transfer RNA genes and 4 ribosomal RNA genes. The overall GC content was 38.3%. Phylogenetic analysis of the complete cp genomes within the order Apiales suggested that P. tobira, the representative of Pittosporaceae, is sister to the families of Apiaceae and Araliaceae.

Achyranthes bidentata (Amarathaceae) has been commonly used as a traditional Chinese medicine in the treatment of osteoporosis and bone nonunion. Here, the complete chloroplast genome of A. bidentata was assembled and characterized. The cp genome is 151,451 bp in length, composed of a pair of 25,150 bp inverted repeat (IR) regions separated by a large single-copy (LSC) region of 83,899 bp and a small single-copy (SSC) region of 17,252 bp. The whole cp genome of A. bidentata contains 130 genes(85 protein-coding genes, 37 tRNAs and eight rRNAs) and the overall GC content is 36.5%. Phylogenetic analysis based on the cp genome data showed that A. bidentata was close to Cyathula capitata.

Acer yangbiense Y.S. Chen & Q.E. Yang is a species of Aceraceae with a very restricted distribution in Yunnan, China. In this study, the complete chloroplast (cp) genome sequence of A. yangbiense was reported and characterized. The cp genome is 155,706 bp in length and contains a pair of inverted repeats (IRs, 25,858 bp) separated by a large (85,859 bp) and small (18,131 bp) single-copy regions. A total of 128 genes were predicted, including 83 protein-coding genes, 37 tRNA genes and 8 rRNA genes. The phylogenetic analysis suggested that A. yangbiense is sister of the clade formed by A. laevigatum, A. palmatum, A. wilsonii, and A. buergerianum.

Engelhardia roxburghiana is a traditional Chinese medicine in the Juglandaceae family. In this study, the complete chloroplast (cp) genome sequence of E. roxburghiana was reported and characterized. The cp genome is 161,550 bp in length and contains a pair of inverted repeats (IRs, 25,862 bp) separated by a large (90,937 bp) and small (18,889 bp) single-copy regions. A total of 113 unique genes were predicted, including 79 protein-coding genes, 30 tRNA genes and 4 rRNA genes. The phylogenetic analysis suggested that E. roxburghiana is resolved as a sister group to the clade of subfam. Juglandoideae.

Uncaria rhynchophylla is a vine plant belonging to the family Rubiaceae and has been used as medicine for a long time in China. In this study, the complete chloroplast (cp) genome sequence of U. rhynchophylla was first reported and characterized. The cp genome was 154,605 bp in length and contains a pair of inverted repeats (IRs, 34,165 bp each) separated by a large (84,327 bp) and small (12,966 bp) single-copy regions. A total of 113 unique genes were predicted, including 79 protein-coding genes, 30 tRNA genes and 4 rRNA genes. The phylogenetic analysis suggested that U. rhynchophylla was closer to Neolamarckia cadamba.

The first complete chloroplast (cp) genome of Indofevillea khasiana was reported in this study. The I. khasiana cp genome was 159,238 bp in size, with two inverted repeat (IR) regions of 26,275 bp separated by a large single copy (LSC) region of 88,538 bp and a small single copy (SSC) region of 18,150 bp. The cp genome of this species contained 113 genes, including 79 protein-coding genes, 4 ribosomal RNA genes, and 30 transfer RNA genes. The overall GC content was 36.9%. Phylogenetic analysis based on the cp genome sequences suggests that I. khasiana is sister to the rest species of subfam. Cucurbitoideae.

The first complete chloroplast (cp) genome of Hovenia dulcis was reported in this study. The H. dulcis cp genome was 161,636 bp long with two inverted repeat (IR) regions of 26,574 bp, the large single-copy (LSC) region of 89,574 bp, and the small single-copy (SSC) region of 18,914 bp. The cp genome of this species contained 113 genes, including 79 protein-coding genes, 4 ribosomal RNA genes, and 30 transfer RNA genes. The overall GC content was 36.6%. Phylogenetic analysis based on the complete cp genomes within the Rhamnaceae family suggests that H. dulcis is closer to the genus of Ziziphus.

The subfamily Cercidoideae is an early-branching legume lineage, which consists of 13 genera distributed in the tropical and warm temperate Northern Hemisphere. A previous study detected two plastid genomic variations in this subfamily, but the limited taxon sampling left the overall plastid genome (plastome) diversification across the subfamily unaddressed, and phylogenetic relationships within this clade remained unresolved. Here, we assembled eight plastomes from seven Cercidoideae genera and conducted phylogenomic-comparative analyses in a broad evolutionary framework across legumes. The plastomes of Cercidoideae all exhibited a typical quadripartite structure with a conserved gene content typical of most angiosperm plastomes. Plastome size ranged from 151,705 to 165,416 bp, mainly due to the expansion and contraction of inverted repeat (IR) regions. The order of genes varied due to the occurrence of several inversions. In Tylosema species, a plastome with a 29-bp IR-mediated inversion was found to coexist with a canonical-type plastome, and the abundance of the two arrangements of isomeric molecules differed between individuals. Complete plastome data were much more efficient at resolving intergeneric relationships of Cercidoideae than the previously used selection of only a few plastid or nuclear loci. In sum, our study revealed novel insights into the structural diversification of plastomes in an early-branching legume lineage, and, thus, into the evolutionary trajectories of legume plastomes in general.

Ruta graveolens L. is a perennial plant belonging to the family Rutaceae and has been used for traditional medicines for a long time. In this study, the complete chloroplast (cp) genome sequence of R. graveolens was first reported and characterized. The cp genome is 157,434 bp in length and contains a pair of inverted repeats (IRs, 26,868 bp) separated by a large (85,387 bp) and small (18,311 bp) single-copy regions. A total of 132 genes were predicted, including 87 protein-coding genes, 37 tRNA genes and 8 rRNA genes. The phylogenetic analysis suggested that R. graveolens is more closely related to the monophyletic subfam. Aurantioideae.

Humulus yunnanensis is an endemic species in Yunnan, China, which is used for beer and pharmacology industry. The phylogenetic position of this species in Humulus remains controversial. The complete chloroplast (cp) genome sequence of H. yunnanensis was reported and characterized in this study. The cp genome is 153,612 bp in length and contains a pair of inverted repeats (IRs, 29,824 bp) separated by a large (87,728 bp) and small (15,390 bp) single-copy regions. A total of 112 unique genes were predicted, including 78 protein-coding genes, 30 tRNA genes, and 4 rRNA genes. The phylogenetic analysis revealed that H. yunnanensis is more closely related to H. scandens than H. lupulus.

The complete chloroplast (cp) genome of Pinus squamata, a critically endangered species in China, was reported in this study. The cp genome is 118,300 bp in length and has four regions: 65,298 bp of large single copy (LSC) region and 52,098 bp of small single copy (SSC) region separated by 452 bp of highly reduced inverted repeat (IR) regions. This cp genome with GC content of 38.8% contains 107 unique genes (73 protein-coding genes, 30 tRNA genes, and four rRNA genes). Phylogenetic analysis based on the complete cp genomes indicates that P. squamata is closer to P. gerardiana than P. bungeana.

The complete chloroplast (cp) genome of Magnolia wilsonii, an endangered and endemic species in China, was first reported in this study. The M. wilsonii cp genome was 157,434 bp in length, including two inverted repeat (IR) regions of 26,868 bp, a large single copy (LSC) region of 85,387 bp, and a small single copy (SSC) region of 18,311 bp. A total of 113 unique genes, including 79 protein-coding genes, 4 ribosomal RNA genes, and 30 transfer RNA genes, were annotated. The overall GC content was 38.8%. Phylogenetic analysis of 34 representative cp genomes within the genus Magnolia suggests that M. wilsonii was sister to M. sieboldii.

Paederia scandens has been used as a traditional medicine in Asian countries to treat jaundice, dysentery, and the pain of rheumatism. The complete chloroplast (cp) genome sequence of P. scandens was reported and characterized in this study. The cp genome is 153,626 bp in length, composed of a pair of 26,513 bp inverted repeat (IR) regions separated by a large single-copy (LSC) region of 83,712 bp and a small single-copy (SSC) region of 16,888 bp. There were 131 predicted genes (86 protein-coding genes, 37 tRNA genes, and 8 rRNA genes) in the genome, and the overall GC content of the genome is 37.7%. Phylogenetic analysis based on the cp genome data showed that P. scandens was sister to the clade formed by Galium mollugo and G. aparine.

Iris domestica has been used as Chinese traditional medicine to treat inflammation and throat disorders for many centuries. In this study, the complete plastid genome of I. domestica was first reported and characterized. The complete plastid genome is a typical quadripartite circular molecule of 153,729 bp in length, including a large single copy (LSC) region of 83,136 bp and a small single copy (SSC) region of 18,165 bp separated by two inverted repeat (IR) regions of 26,214 bp. A total of 132 genes including 86 protein-coding genes, 38 tRNA genes, and eight rRNA genes were identified. The phylogenetic analysis revealed that I. domestica was closer to I. gatesii.

The complete chloroplast (cp) genome of Rosa berberifolia was assembled from high-throughput Illumina sequencing data. The cp genome of R. berberifolia was 156,886 bp in length with a typical quadripartite circular, containing a pair of inverted repeats (26,047 bp) separated by a large (86,045 bp), and small (18,747 bp) single-copy regions. It contains 129 genes, including 84 protein-coding genes, 8 ribosomal RNA genes, 37 transfer RNA genes, and 1 pseudogene (ycf1). The overall GC content of the whole cp genome was 37.2%. Phylogenetic analysis based on the complete chloroplast genomes suggested that R. berberifolia was sister to R. persica.

The first complete chloroplast (cp) genome of the Chinese endemic and endangered species, Magnolia omeiensis, were reported in this study. The M. omeiensis cp genome was 160,091 bp in length, with two inverted repeat (IR) regions of 26,584 bp, one large single-copy (LSC) region of 88,160 bp, and one small single-copy (SSC) region of 18,763 bp. The cp genome of this species contained 113 unique genes, including 79 protein-coding genes, four ribosomal RNA, and 30 transfer RNA genes. The overall GC content was 39.3%. Phylogenetic analysis of 24 representative cp genomes within the genus Magnolia suggested M. omeiensis is closely related to M. yunnanensis.

Bladder cancer is one of the leading causes of cancer-related death in men, however, there was only limited effective treatment for invasive bladder cancer. DAPK1 has been shown to play important role in apoptosis and autophagy to suppress cancer progression. Previous results have shown that DAPK1 promoter was hypermethylated in the majority of bladder cancer specimens, however, the prognostic significance of DAPK1 in bladder cancer has yet to be demonstrated. In the present study, we found that DAPK1 expression was negatively associated with tumor stage and a low level expression of DAPK1 in bladder cancer specimens were associated with shorter survival in bladder cancer patients in 3 independent bladder cancer datasets (n = 462). Further investigation showed that FGFR3 knockdown resulted in downregulation of DAPK1 in bladder cancer cell line, suggesting that FGFR3 may be an upstream factor of DAPK1. Further analysis of the 3 independent bladder cancer datasets have identified ACOX1, UPK2, TRAK1, PLEKHG6 and MT1X genes had their expression significantly correlated with that of DAPK1. Knockdown of DAPK1 in bladder cancer T24 cells resulted in downregulation of ACOX1, UPK2 and TRAK1. Interestingly, TRAK1, by itself, was a favorable prognostic marker in the 3 independent bladder cancer datasets. Importantly, by using connectivity mapping with DAPK1-associated gene signature, we found that vemurafenib and trametinib could possibly reverse DAPK1-associated gene signature, suggesting that inhibition of Raf/MEK pathway may be a potential therapeutic approach for bladder cancer. Indeed, treatment of vemurafenib in T24 bladder cancer cells resulted in upregulation of DAPK1 confirming our connectivity mapping, while knockdown of DAPK1 resulted in reduced sensitivity towards inhibition of Braf signaling by vemurafenib. Together, our results suggest that DAPK1 is an important prognostic marker and therapeutic target for bladder cancer and have identified possible therapeutic agents for future testing in bladder cancer models with low DAPK1 expression.