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The expression of P450 genes is regulated by trans-regulatory factors or cis-regulatory elements and influences how endogenous or xenobiotic substances are metabolized in an organism’s tissues. In this study, we showed that overexpression of the cytochrome P450 gene, CYP6CY22, led to resistance to cyantraniliprole in Aphis gossypii. The expression of CYP6CY22increased in the midgut and remaining carcass of the CyR strain, and after repressing the expression of CYP6CY22, the mortality of cotton aphids increased 2.08-fold after exposure to cyantraniliprole. Drosophilaectopically expressing CYP6CY22exhibited tolerance to cyantraniliprole and cross-tolerance to xanthotoxin, quercetin, 2-tridecanone, tannic acid, and nicotine. Moreover, transcription factor CF2–II(XM_027994540.2) is transcribed only as the splicing variant isoform CF2–II-AS, which was found to be 504 nucleotides shorter than CF2–IIin A. gossypii. RNAi and yeast one-hybrid (Y1H) results indicated that CF2–II-ASpositively regulates CYP6CY22and binds to cis-acting element p (−851/-842) of CYP6CY22to regulate its overexpression. The above results indicated that CYP6CY22was regulated by the splicing isoform CF2-II-AS, which will help us further understand the mechanism of transcriptional adaption of cross-tolerance between synthetic insecticides and plant secondary metabolites mediated by P450s.

Point cloud registration (PCR) is a vital technique in photogrammetry and computer vision. It seeks to identify optimal spatial transformation parameters for adjacent point clouds. In contrast methods based on an initial estimate, PCR based on correspondence operates without the need for an initial guess. However, these correspondences, often established through feature descriptors, can contain a significantly high rate of outliers. Existing methods struggle to balance efficiency and precision effectively. This article, building on matches, constructs an undirected graph and proposes a strategy for preferred correspondences based on the maximum cliques (MC) of reliable edges, thereby selecting potential correspondences based on the reliable edges and MC. The registration challenge is then divided into two separate components: estimating rotation and translation. The rotation matrix is calculated utilizing the adaptive Maxwell–Boltzmann (AMB) algorithm, while the translation vector is derived from the median of the confidence interval (MCI). Comprehensive tests on both simulated and real registration datasets demonstrate that our approach excels in precise PCR, even with outlier rates above 99%. The source code will be available at https://github.com/lixiaoyao0302/RoRO.

To solve point cloud registration, a novel solution to planar feature-based registration of point clouds was proposed in this study according to dual quaternion description based on the constraint of planar feature. The normal vector of the homologous feature plane should be kept parallel according to the registration, and the points on the plane should satisfy the planar equation. Moreover, the modified Levenberg-Marquardt method was adopted to complete the registration model, so as to avoid inappropriate initial values from causing non-convergence of the iteration. Lastly, the robustness and accuracy exhibited by the method were verified using simulated and measured data.

Risks caused by large amounts of distributed photovoltaic (PV) feeding into distribution networks, have an impact on PV planning, which has become a critical consideration for distribution networks’ operation. In this paper, a large-scale PV planning method is proposed which based on risk assessment in distribution networks. Cluster division is used to group large-scale distributed PVs. A risk assessment is performed on the distribution network, considering the correlation between PVs and loads. The effects of load fluctuations, PV quantity, capacity and location on the operational risk of the distribution network are analyzed and discussed. A large-scale PV planning model is established with the goal of maximizing the comprehensive benefits, considering the penalty cost of node voltage over-limit and branch power flow over-limit risk. Finally, the genetic algorithm is used to solve the planning model. The simulation results demonstrate the effectiveness of the proposed method.

Objective There is a lack of research evaluating the effect of tumor markers for prognosis in cervical adenocarcinoma. We aimed to develop and validate a preoperative tumor-marker-based model including clinicopathological factors to clarify the prognostic value of endocervical adenocarcinoma.Methods A total of 572 patients with cervical adenocarcinoma who were staged at the International Federation of Gynecology and Obstetrics (FIGO) IA–IIA were reviewed retrospectively. Preoperative serum carcinoembryonic antigen (CEA), carbohydrate antigen (CA)-125 and CA19-9 levels were measured. The survival and recurrence patterns were analyzed according to the tumor-marker-related stratification. The predictive values of biomarkers and clinical variables were assessed with Cox regression and competing risk models.Results Patients with elevated preoperative tumor markers had evidently poor overall survival and recurrence-free survival. The triple-elevated tumor marker (TETM) subgroup had the worst overall survival and progression-free survival than the triple-negative tumor marker (TNTM) subgroup and the single-elevated tumor marker (SETM) subgroup. The most important predictors for overall survival were elevated tumor markers, FIGO-stage, tumor differentiation, lymphovascular space invasion (LVSI) and lymph nodes metastasis. The most important predictors for recurrence-free survival were elevated tumor markers, FIGO-stage, tumor differentiation, LVSI and deep stromal invasion. Stratified analysis showed that elevated CA-125 and CA19-9 were significantly associated with postoperative distant metastasis. A decision curve analysis confirmed that a combination of tumor markers as predictors significantly outperformed the other common predictors used (FIGO-stage, intermediate and high-risk factors, tumor differentiation, lymph nodes).Conclusions Elevated preoperative serum CEA, CA-125, and CA19-9 levels exhibited poor overall survival and recurrence-free survival in cervical adenocarcinoma patients. Combined preoperative serum CA-125 and CA19-9 independently predicted distant metastasis in patients with endocervical adenocarcinoma.

Alzheimer’s disease (AD) is the most prevalent age-related neurodegenerative disease, which has a high heritability of up to 79%. Exploring the genetic basis is essential for understanding the pathogenic mechanisms underlying AD development. Recent genome-wide association studies (GWASs) reported an AD-associated signal in the Cathepsin H (CTSH)gene in European populations. However, the exact functional/causal variant(s), and the genetic regulating mechanism of CTSHin AD remain to be determined. In this study, we carried out a comprehensive study to characterize the role of CTSHvariants in the pathogenesis of AD. We identified rs2289702 in CTSHas the most significant functional variant that is associated with a protective effect against AD. The genetic association between rs2289702 and AD was validated in independent cohorts of the Han Chinese population. The CTSHmRNA expression level was significantly increased in AD patients and AD animal models, and the protective allele T of rs2289702 was associated with a decreased expression level of CTSHthrough the disruption of the binding affinity of transcription factors. Human microglia cells with CTSHknockout showed a significantly increased phagocytosis of Aβ peptides. Our study identified CTSHas being involved in AD genetic susceptibility and uncovered the genetic regulating mechanism of CTSHin pathogenesis of AD.

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare mesenchymal neoplasm that mainly harbors NCOA1-3rearrangements with partner genes ESR1or GREB1. Here, we explored 23 UTROSCTs by targeted RNA sequencing. The association between molecular diversity and clinicopathologic features was investigated. The mean age of our cohort was 43 years (23–65 y). Only 15 patients (65%) were originally diagnosed with UTROSCTs. Mitotic figures ranged from 1 to 7/10 high power fields, of primary tumors and increased from 1 to 9/10 high power fields in recurrent tumors. Five types of gene fusions were identified in these patients, including GREB1::NCOA2(n=7), GREB1::NCOA1(n=5), ESR1::NCOA2(n=3), ESR1::NCOA3(n=7), and GTF2A1::NCOA2(n=1). To our knowledge, our group included the largest cohort of tumors with GREB1::NCOA2fusions. Recurrences were most common in patients with GREB1::NCOA2fusion (57%), followed by 40% (GREB1::NCOA1), 33% (ESR1::NCOA2), and 14% (ESR1::NCOA3). The recurrent patient who harbored an ESR1::NCOA2fusion was characterized by extensive rhabdoid features. Both of the recurrent patients who harbored GREB1::NCOA1and ESR1::NCOA3had the largest tumor sizes in their own gene alteration groups, and another recurrent GREB1::NCOA1patient had extrauterine involvement. The GREB1-rearranged patients were of older age, larger tumor size, and higher stage than non-GREB1-rearranged patients (P=0.004, 0.028, and 0.016, respectively). In addition, the GREB1-rearranged tumors presented more commonly as intramural masses rather than non-GREB1-rearranged tumors presenting as polypoid/submucosal masses (P=0.021). Microscopically, nested and whorled patterns were frequently seen in GREB1-rearranged patients (P=0.006). Of note, estrogen receptor expression was weaker than progesterone receptor in all 12 GREB1-rearranged tumors, whereas the similar staining intensity of estrogen receptor and progesterone receptor was observed in all 11 non-GREB1-rearranged tumors (P<0.0001). This study demonstrated that UTROSCTs were present at a younger age in the Chinese population. The genetic heterogeneity of UTROSCTs was correlated with variable recurrence rate. Tumors with GREB1::NCOA2fusions are more likely to recur compared with those with other genetic alterations.

Insecticides tolerance in herbivorous arthropods is associated with preadaptation to host plant allelochemicals. However, how plant secondary metabolites activate detoxifying metabolic genes to develop tolerance remains unclear. Herein, the tolerance of Spodoptera lituralarvae to cyantraniliprole was increased after nicotine exposure. An S. lituraα esterase, SlCOE030, was predominantly expressed in the midgut and induced after exposure to cyantraniliprole, nicotine, and cyantraniliprole plus nicotine. Drosophila melanogasterwith ectopically overexpressed SlCOE030enhanced cyantraniliprole and nicotine tolerance by 4.91- and 2.12-fold, respectively. Compared to UAS-SlCOE030and Esg-GAL4 lines, the Esg > SlCOE030line laid more eggs after nicotine exposure. SlCOE030knockdown decreased the sensitivity of nicotine-treated S. lituralarvae to cyantraniliprole. Metabolism assays indicated that recombinant SlCOE030 protein metabolizes cyantraniliprole. Homology modeling and molecular docking analysis demonstrated that SlCOE030 exhibits effective affinities for cyantraniliprole and nicotine. Thus, insect CarEs may result in the development of cross-tolerance between synthetic insecticides and plant secondary metabolites.

With the increasing penetration of distributed photovoltaic in distribution network, it is more difficult to control active distribution network (ADN). A flexible interconnection device (FID) can realize regional interconnection of the ADN through transferring power. However, the influence of installation position and number of FIDs on the ADN varies, it is necessary to analyze its operational planning model. In this study, first, a photovoltaic power and load forecasting model is established, followed by reduction of the typical scenarios. Second, the ADN operational planning model is established according to the line load balance index to analyze the coordination and determine the power transfer value of the FID in different installation positions and numbers for the ADN. Third, the net income index of the distribution network in the entire life cycle is established to analyze the economy of the ADN and determine the optimal FID installation location and quantity. Finally, numerous simulations and comparisons are carried out on the actual example system, and the results show that the FID can effectively transfer the active power, strengthen the ADN power supply level, and solve the problem of power supply imbalance caused by distributed photovoltaic access.

The metastatic or recurrent potential of localized human papillomavirus–associated endocervical adenocarcinoma (HPVA EAC) is difficult to predict, especially based upon biopsy alone. Recent analyses of small cohorts indicate that high tumor nuclear grade (TNG) and the presence of necrotic tumor debris (NTD) from HPVA EACs in cervical biopsy specimens are highly predictive of nodal metastasis (NM). In the present study, we aimed to investigate how reliably tumoral morphologic features from cervical biopsy specimens predict NM or tumor recurrence (TR) and patient outcomes in a large cohort of endocervical adenocarcinoma patients. A cohort comprised of 397 patients with HPVA EAC treated at 18 institutions was identified, and cervical biopsies were paired with their associated complete tumor resections for a total of 794 specimens. A variety of tumoral histologic features were examined for each paired specimen, including TNG (assessed on a 3-tiered scale of increasing abnormalities—TNG1, TNG2, TNG3) and NTD (defined by the presence of necrotic and apoptotic tumor cells within tumor glandular lumens admixed with granular and eosinophilic amorphous material and inflammatory cells), which were correlated with outcomes. The distribution of TNG in biopsies was as follows: 86 (21.7%) TNG1, 223 (56.2%) TNG2, and 88 (22.2%) TNG3. NTD was identified in 176 (44%) of the biopsy specimens. The sensitivity, specificity, positive predictive value, and negative predictive value of a TNG1 assignment in the biopsy being predictive of the same assignment in the full resection were 0.82 (95% confidence interval [CI]: 0.7-0.9), 0.895 (0.86-0.93), 0.593 (0.48-0.696), and 0.96 (0.94-0.98), respectively. Respective values for an NTD-negative status were 0.89 (95% CI: 0.83-0.92), 0.715 (0.64-0.77), 0.72 (0.65-0.77), and 0.89 (0.83-0.93), respectively. Compared with the other cases in each category, both TNG1 and an NTD-negative status were each significantly associated with lower rates of NM (odds ratio for TNG1=0.245, 95% CI: 0.070-0.857, P=0.0277; for NTD=0.199, 95% CI: 0.094-0.421, P<0.0001) and TR (odds ratio for TNG1=0.225, 95% CI: 0.051-0.987, P=0.0479; for NTD=0.367, 95% CI: 0.171-0.786, P=0.0099) independent of depth of stromal invasion, lymphovascular invasion, tumor size, FIGO stage, and Silva pattern. Overall, 73/379 (19%) cases were both TNG1 and NTD-negative on the biopsy, and none of these 73 cases showed NM (0%), but a single case (1.4%) showed TR. In contrast, among the 324 biopsies with TNG2/3 and/or presence of NTD, 62 (19.1%) had NM, and 41 (12.9%) had TR. In summary, 2 variables in combination (ie, TNG1 and NTD-negative) identified a subset of HPVA EAC patients—∼19%—with a 0% frequency of nodal metastases and only 1.4% frequency of recurrence. Biopsies highly but imperfectly predicted these features. Nonetheless, these findings may potentially be of clinical utility in the risk stratification of patients with HPVA EACs. This may allow some patients with a minimal risk of nodal metastases and TR to be identified at the biopsy phase, thereby facilitating more personalized, possibly less aggressive treatment.

•A parameterized P-box model of distributed generations output is demonstrated.•An expansion topology network model for ADN is established.•Structural and operational vulnerability indexes for ADN are defined.•A node vulnerability assessment method with dynamic identification is proposed.•Strengthening the high-vulnerability nodes prevents network cascading failures.

AimsThis study was aimed to investigate the clinicopathological significance of immunohistochemical (IHC) Wilm’s tumour 1 (WT1) expression in invasive breast carcinoma with >90% mucinous components.MethodsOne hundred specimens of invasive breast carcinoma with >90% mucinous component were collected. All H&E-stained slides were reviewed, and the clinicopathological data, including sex, age, tumour size, nuclear grade, histological grade, growth pattern and lymph node (LN) status, were collected. IHC staining of WT1, oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki-67 was performed. Fluorescence in situ hybridisation was used to verify the amplification of the HER2 gene. The relationship between WT1 expression and clinicopathological features was analysed statistically.ResultsWT1 expression was detected in 67% (67/100) of invasive breast carcinoma with >90% mucinous components. WT1 expression was significantly associated with low-to-intermediate nuclear grade/histological grade, ER and PR positivity, HER2 negativity, Ki-67 proliferation index <30% and noLN metastasis (all p<0.001). Micropapillary architecture was observed in 80% of cases. WT1 expression was not significantly correlated with different percentage of micropapillary components (p=0.422). None of the histological grade 3 tumours, tumours with HER2 overexpression/amplification and triple-negative specimens showed WT1 expression.ConclusionsWT1 expression was significantly related with low-intermediate nuclear/histological grade, ER positivity, HER2 negativity, a lower Ki-67 proliferation index and no LN metastasis in invasive breast carcinoma with >90% mucinous component. The micropapillary growth pattern in this type of tumour did not show a specific relationship with WT1 expression.

We developed a deep learning framework to accurately predict the lymph node status of patients with cervical cancer based on hematoxylin and eosin–stained pathological sections of the primary tumor. In total, 1524 hematoxylin and eosin–stained whole slide images (WSIs) of primary cervical tumors from 564 patients were used in this retrospective, proof-of-concept study. Primary tumor sections (1161 WSIs) were obtained from 405 patients who underwent radical cervical cancer surgery at the Fudan University Shanghai Cancer Center (FUSCC) between 2008 and 2014; 165 and 240 patients were negative and positive for lymph node metastasis, respectively (including 166 with positive pelvic lymph nodes alone and 74 with positive pelvic and para-aortic lymph nodes). We constructed and trained a multi-instance deep convolutional neural network based on a multiscale attention mechanism, in which an internal independent test set (100 patients, 228 WSIs) from the FUSCC cohort and an external independent test set (159 patients, 363 WSIs) from the Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma cohort of the Cancer Genome Atlas program database were used to evaluate the predictive performance of the network. In predicting the occurrence of lymph node metastasis, our network achieved areas under the receiver operating characteristic curve of 0.87 in the cross-validation set, 0.84 in the internal independent test set of the FUSCC cohort, and 0.75 in the external test set of the Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma cohort of the Cancer Genome Atlas program. For patients with positive pelvic lymph node metastases, we retrained the network to predict whether they also had para-aortic lymph node metastases. Our network achieved areas under the receiver operating characteristic curve of 0.91 in the cross-validation set and 0.88 in the test set of the FUSCC cohort. Deep learning analysis based on pathological images of primary foci is very likely to provide new ideas for preoperatively assessing cervical cancer lymph node status; its true value must be validated with cervical biopsy specimens and large multicenter datasets.

Pure invasive apocrine carcinoma is a rare type of primary breast cancer, constituting ~1% of all breast cancers. Since most pure invasive apocrine carcinomas are triple negative, the lack of targeted therapies for triple-negative breast cancer has fostered efforts to discover actionable molecular targets in these tumors. In this study, we analyzed the clinicopathologic characteristics and comprehensive genomic profiling of 18 patients with pure triple-negative apocrine carcinomas (TNACs) using a 324-gene panel assay (FoundationOne CDx). The median age of these patients was 55.5 years, and the postmenopausal status rate was 77.8%. In total, 83.3% of patients were diagnosed with histological grade II, and 16.7% were diagnosed with grade III. The majority of patients presented at an early tumor-node-metastasis (TNM) stage (I: 38.9%; II: 50.0%; and III: 11.1%). The mean Ki-67 index was 9.7%, and the percent of PD-L1 positivity was 11.7%. With a median follow-up period of 76.5 months, one patient died, and two experienced distant metastases. There were 61 clinically relevant genomic alterations among all 18 pure TNACs, and the mean tumor mutation burden (TMB) was 3 Mut/Mb. The top ranked altered genes were PIK3CA(72.2%), PTEN(33.3%) and TP53(27.8%). There were four novel mutations found in PTENand an actionable rearrangement involving FGFR2-TACC2that has not been reported in breast cancer before. In total, 88.9%, 50%, 44.4%, and 16.7% of TNACs had at least one clinically relevant genomic alteration in genes involved in the PI3K/mTOR, cell cycle, RAS/RAF/MEK and growth factor receptor-related pathways, respectively. All patients had at least one clinically relevant genomic alteration, and 94.4% had at least one actionable alteration. To the best of our knowledge, this study is the largest genomic sequencing cohort of pure TNACs. Incorporation of comprehensive genomic profiling into TNACs might shed light on potential therapeutic opportunities for both targeted drugs and immune checkpoint inhibitors.

Pure invasive apocrine carcinoma is a rare type of primary breast cancer, constituting ~1% of all breast cancers. Since most pure invasive apocrine carcinomas are triple negative, the lack of targeted therapies for triple-negative breast cancer has fostered efforts to discover actionable molecular targets in these tumors. In this study, we analyzed the clinicopathologic characteristics and comprehensive genomic profiling of 18 patients with pure triple-negative apocrine carcinomas (TNACs) using a 324-gene panel assay (FoundationOne CDx). The median age of these patients was 55.5 years, and the postmenopausal status rate was 77.8%. In total, 83.3% of patients were diagnosed with histological grade II, and 16.7% were diagnosed with grade III. The majority of patients presented at an early tumor-node-metastasis (TNM) stage (I: 38.9%; II: 50.0%; and III: 11.1%). The mean Ki-67 index was 9.7%, and the percent of PD-L1 positivity was 11.7%. With a median follow-up period of 76.5 months, one patient died, and two experienced distant metastases. There were 61 clinically relevant genomic alterations among all 18 pure TNACs, and the mean tumor mutation burden (TMB) was 3 Mut/Mb. The top ranked altered genes were PIK3CA(72.2%), PTEN(33.3%) and TP53(27.8%). There were four novel mutations found in PTENand an actionable rearrangement involving FGFR2-TACC2that has not been reported in breast cancer before. In total, 88.9%, 50%, 44.4%, and 16.7% of TNACs had at least one clinically relevant genomic alteration in genes involved in the PI3K/mTOR, cell cycle, RAS/RAF/MEK and growth factor receptor-related pathways, respectively. All patients had at least one clinically relevant genomic alteration, and 94.4% had at least one actionable alteration. To the best of our knowledge, this study is the largest genomic sequencing cohort of pure TNACs. Incorporation of comprehensive genomic profiling into TNACs might shed light on potential therapeutic opportunities for both targeted drugs and immune checkpoint inhibitors.

Adult-type granulosa cell tumor (aGCT) is a rare malignant ovarian sex cord-stromal tumor, harboring recurrent FOXL2c.C402G/p.C134W hotspot mutations in 97% of cases. These tumors are considered to have a favorable prognosis, however aGCTs have a tendency for local spread and late recurrences, which are associated with poor survival rates. We sought to determine the genetic alterations associated with aGCT disease progression. We subjected primary non-recurrent aGCTs (n= 7), primary aGCTs that subsequently recurred (n= 9) and their matched recurrences (n= 9), and aGCT recurrences without matched primary tumors (n= 10) to targeted massively parallel sequencing of ≥410 cancer-related genes. In addition, three primary non-recurrent aGCTs and nine aGCT recurrences were subjected to FOXL2and TERTpromoter Sanger sequencing analysis. All aGCTs harbored the FOXL2C134W hotspot mutation. TERTpromoter mutations were found to be significantly more frequent in recurrent (18/28, 64%) than primary aGCTs (5/19, 26%, p= 0.017). In addition, mutations affecting TP53, MED12, and TET2were restricted to aGCT recurrences. Pathway annotation of altered genes demonstrated that aGCT recurrences displayed an enrichment for genetic alterations affecting cell cycle pathway-related genes. Analysis of paired primary and recurrent aGCTs revealed that TERTpromoter mutations were either present in both primary tumors and matched recurrences or were restricted to the recurrence and absent in the respective primary aGCT. Clonal composition analysis of these paired samples further revealed that aGCTs display intra-tumor genetic heterogeneity and harbor multiple clones at diagnosis and relapse. We observed that in a subset of cases, recurrences acquired additional genetic alterations not present in primary aGCTs, including TERT, MED12, and TP53mutations and CDKN2A/Bhomozygous deletions. Albeit harboring relatively simple genomes, our data provide evidence to suggest that aGCTs are genetically heterogeneous tumors and that TERTpromoter mutations and/or genetic alterations affecting other cell cycle-related genes may be associated with disease progression and recurrences.

Adult-type granulosa cell tumor (aGCT) is a rare malignant ovarian sex cord-stromal tumor, harboring recurrent FOXL2c.C402G/p.C134W hotspot mutations in 97% of cases. These tumors are considered to have a favorable prognosis, however aGCTs have a tendency for local spread and late recurrences, which are associated with poor survival rates. We sought to determine the genetic alterations associated with aGCT disease progression. We subjected primary non-recurrent aGCTs (n= 7), primary aGCTs that subsequently recurred (n= 9) and their matched recurrences (n= 9), and aGCT recurrences without matched primary tumors (n= 10) to targeted massively parallel sequencing of ≥410 cancer-related genes. In addition, three primary non-recurrent aGCTs and nine aGCT recurrences were subjected to FOXL2and TERTpromoter Sanger sequencing analysis. All aGCTs harbored the FOXL2C134W hotspot mutation. TERTpromoter mutations were found to be significantly more frequent in recurrent (18/28, 64%) than primary aGCTs (5/19, 26%, p= 0.017). In addition, mutations affecting TP53, MED12, and TET2were restricted to aGCT recurrences. Pathway annotation of altered genes demonstrated that aGCT recurrences displayed an enrichment for genetic alterations affecting cell cycle pathway-related genes. Analysis of paired primary and recurrent aGCTs revealed that TERTpromoter mutations were either present in both primary tumors and matched recurrences or were restricted to the recurrence and absent in the respective primary aGCT. Clonal composition analysis of these paired samples further revealed that aGCTs display intra-tumor genetic heterogeneity and harbor multiple clones at diagnosis and relapse. We observed that in a subset of cases, recurrences acquired additional genetic alterations not present in primary aGCTs, including TERT, MED12, and TP53mutations and CDKN2A/Bhomozygous deletions. Albeit harboring relatively simple genomes, our data provide evidence to suggest that aGCTs are genetically heterogeneous tumors and that TERTpromoter mutations and/or genetic alterations affecting other cell cycle-related genes may be associated with disease progression and recurrences.

Invasive micropapillary carcinoma is characterized by the inside-out growth of tumor clusters and displays incomplete membrane immunostaining of HER2. According to the 2018 American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) HER2-testing recommendation, moderate to intense but incomplete staining could be scored as immunohistochemical 2+. Furthermore, the criteria of immunohistochemical 3+ for this staining pattern are not mentioned. One hundred and forty-seven cases of invasive micropapillary carcinoma with moderate-to-intense HER2immunostaining were enrolled. Invasive micropapillary carcinoma components of all cases were scored as immunohistochemical 2+ based on the 2018 ASCO/CAP recommendation. The invasive micropapillary carcinoma component varied from 10% to 100% (mean, 80%). Invasive micropapillary carcinoma components of all 147 tumors exhibited reversed polarity and incomplete basolateral HER2membrane staining. One hundred and seventeen of the tumors (80%, 117/147) had moderate staining, and 38 (32%, 38/117) showed HER2gene amplification by fluorescence in-situ hybridization. HER2gene was amplified in all the remaining 30 tumors (20%, 30/147) that exhibited intense basolateral membrane staining. Besides, average HER2signals per cell and ratio of HER2/CEP17 were significantly higher in the intense-staining tumors compared with the moderate-staining tumors (p< 0.0001). Follow-up data were available for 140 patients. None of the patients were died. The follow-up time ranged from 1 month to 99 months (median, 57 months). Thirteen (9%, 13/140) patients exhibited disease progression (recurrence or metastasis). HER2gene amplification was correlated inversely with estrogen receptor (p= 0.000) and progesterone receptor (p= 0.000) expression, and positively with histological grade (p= 0.003) and disease progression (p= 0.000). Invasive micropapillary carcinoma with intense clear linear basolateral membrane immunostaining indicates HER2positivity, even if the staining is incomplete. They should be classified as immunohistochemical 3+ rather than immunohistochemical 2+, which would avoid further fluorescence in-situ hybridization-testing procedure and greatly save the related time, labor, and financial costs. Ultimately, ensure all patients with HER2gene amplification obtain effective targeted therapy in time.

Invasive micropapillary carcinoma is characterized by the inside-out growth of tumor clusters and displays incomplete membrane immunostaining of HER2. According to the 2018 American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) HER2-testing recommendation, moderate to intense but incomplete staining could be scored as immunohistochemical 2+. Furthermore, the criteria of immunohistochemical 3+ for this staining pattern are not mentioned. One hundred and forty-seven cases of invasive micropapillary carcinoma with moderate-to-intense HER2immunostaining were enrolled. Invasive micropapillary carcinoma components of all cases were scored as immunohistochemical 2+ based on the 2018 ASCO/CAP recommendation. The invasive micropapillary carcinoma component varied from 10% to 100% (mean, 80%). Invasive micropapillary carcinoma components of all 147 tumors exhibited reversed polarity and incomplete basolateral HER2membrane staining. One hundred and seventeen of the tumors (80%, 117/147) had moderate staining, and 38 (32%, 38/117) showed HER2gene amplification by fluorescence in-situ hybridization. HER2gene was amplified in all the remaining 30 tumors (20%, 30/147) that exhibited intense basolateral membrane staining. Besides, average HER2signals per cell and ratio of HER2/CEP17 were significantly higher in the intense-staining tumors compared with the moderate-staining tumors (p< 0.0001). Follow-up data were available for 140 patients. None of the patients were died. The follow-up time ranged from 1 month to 99 months (median, 57 months). Thirteen (9%, 13/140) patients exhibited disease progression (recurrence or metastasis). HER2gene amplification was correlated inversely with estrogen receptor (p= 0.000) and progesterone receptor (p= 0.000) expression, and positively with histological grade (p= 0.003) and disease progression (p= 0.000). Invasive micropapillary carcinoma with intense clear linear basolateral membrane immunostaining indicates HER2positivity, even if the staining is incomplete. They should be classified as immunohistochemical 3+ rather than immunohistochemical 2+, which would avoid further fluorescence in-situ hybridization-testing procedure and greatly save the related time, labor, and financial costs. Ultimately, ensure all patients with HER2gene amplification obtain effective targeted therapy in time.

BackgroundOvarian clear cell carcinoma (OCCC) arises from endometriosis and represents a difficult-to-treat gynaecological malignancy, in part, because its spatial intratumour heterogeneity and temporal evolutionary trajectories have not been explicitly defined.MethodsWe performed whole-genome sequencing on six pathologically confirmed patients with OCCC. An R package named KataegisPortal was developed to identify and annotate loci of localised hypermutations. Immunohistochemical staining was conducted on a tissue microarray containing 143 OCCC specimens.ResultsMultiregion analysis demonstrated considerable degrees of subclonal diversification, ascribable to dynamic mutagenic processes, as well as macroevolutionary events including the acquisition of aneuploidy and chromoplexy. KataegisPortal unveiled APOBEC-mediated kataegis in the early phases of OCCC pathogenesis. We further showed evidence that APOBEC3A and APOBEC3B were frequently expressed in OCCC and possibly regulated by the MAPK pathway. Notably, APOBEC3B-expressing OCCC displayed favourable prognosis and appreciable immunogenicity manifested by marked cytotoxic T-cell infiltration.ConclusionsThese results point to an appealing model of punctuated tumour evolution underlying OCCC neoplastic transformation and progression, which may pose formidable challenges of early detection and intervention, and indicate the intratumour heterogeneity of cancer-driving alterations, yielding important implications for molecular diagnosis and targeted treatment of this lethal disease.

This research explores how top management participation and three types of IT capability enable SMEs' competitive process alignment and flexibility capabilities. Our research hypotheses are tested using data from 310 Australian SMEs. Results show that top management participation and external IT linkage capability positively affect both process alignment and process flexibility. While IT infrastructure capability and IT business spanning capability positively affect process alignment, they are not significantly related to process flexibility. In addition, both process alignment and process flexibility capabilities have significant positive effects on SME performance. Contributions and implications of this study are discussed.

Veratridine is a lipid-soluble neurotoxin derived from plants in the family Liliaceae. It has been broadly investigated for its action as a sodium channel agonist. However, the effects of veratridine on subtypes of sodium channels, especially Nav1.7, remain to be studied. Here, we investigated the effects of veratridine on human Nav1.7 ectopically expressed in HEK293A cells and recorded Nav1.7 currents from the cells using whole-cell patch clamp technique. We found that veratridine exerted a dose-dependent inhibitory effect on the peak current of Nav1.7, with the half-maximal inhibition concentration (IC50) of 18.39 µM. Meanwhile, veratridine also elicited tail current (linearly) and sustained current [half-maximal concentration (EC50): 9.53 µM], also in a dose-dependent manner. Veratridine (75 µM) shifted the half-maximal activation voltage of the Nav1.7 activation curve in the hyperpolarized direction, from −21.64 ± 0.75 mV to −28.14 ± 0.66 mV, and shifted the half-inactivation voltage of the steady-state inactivation curve from −59.39 ± 0.39 mV to −73.78 ± 0.5 mV. An increased frequency of stimulation decreased the peak and tail currents of Nav1.7 for each pulse along with pulse number, and increased the accumulated tail current at the end of train stimulation. These findings reveal the different modulatory effects of veratridine on the Nav1.7 peak current and tail current.

Alzheimer’s disease (AD) is the most common cause of dementia. Mitochondrial dysfunction has been widely reported in AD due to its important role in cellular metabolism and energy production. Complex IV (cytochrome c oxidase, COX) of mitochondrial electron transport chain, is particularly vulnerable in AD. Defects of COX in AD have been well documented, but there is little evidence to support the genetic association of the COX-related genes with AD. In this study, we investigated the genetic association between 17 nuclear-encoded COX-related genes and AD in 1572 Han Chinese. The whole exons of these genes were also screened in 107 unrelated AD patients with a high probability of hereditarily transmitted AD. Variants in COX6B1, NDUFA4, SURF1, and COX10were identified to be associated with AD. An integrative analysis with data of eQTL, expression and pathology revealed that most of the COX-related genes were significantly downregulated in AD patients and mouse models, and the AD-associated variants in COX6B1, SURF1, and COX10were linked to altered mRNA levels in brain tissues. Furthermore, mRNA levels of Ndufa4, Cox5a, Cox10, Cox6b2, Cox7a2, and Lrpprcwere significantly correlated with Aβ plaque burden in hippocampus of AD mice. Convergent functional genomics analysis revealed strong supportive evidence for the roles of COX6B1, COX10, NDUFA4, and SURF1in AD. As the result of our comprehensive analysis of the COX-related genes at the genetic, expression, and pathology levels, we have been able to provide a systematic view for understanding the relationships of the COX-related genes in the pathology of AD.

AimsTo fully elucidate the clinicopathological features of breast carcinoma in sclerosing adenosis (SA-BC).MethodsClinical and histological characteristics of 206 SA-BCs from 180 patients were retrospectively evaluated. Immunohistochemical phenotype was examined. The clinicopathological relevance of the topographical pattern of SA-BCs was analysed.ResultsOverall, up to 46 patients (25.6%) had contralateral cancer, either SA associated or not. Of 99 cases who underwent core needle biopsy (CNB), 36 were underestimated as adenosis or atypical ductal hyperplasia at CNB, 5 invasive cases were misinterpreted as in situ carcinomas, whereas 4 ductal carcinoma in situ (DCIS) cases were overdiagnosed as invasive carcinoma. Microscopically, 163 tumours were in situ, including 136 DCIS, 19 lobular carcinomas in situ (LCIS) and 8 mixed DCIS/LCIS; of these carcinomas in situ (CIS), 37 had microinvasion. The DCIS group exhibited low, intermediate and high grades in 53.7%, 34.6% and 11.8% of cases, respectively, mostly with solid (43.4%) or cribriform (41.9%) pattern. Forty out of 43 invasive cases were invasive ductal carcinoma (IDC), mostly DCIS predominant. Immunophenotypically, luminal A phenotype was identified in 55.1%, 63.2% and 45.0% of DCIS, LCIS and IDC cases, respectively. Topographical type A group (carcinoma being entirely confined to SA, n=176) was characterised by smaller size, less invasiveness, lower grade and more frequency of luminal A immunophenotype compared with type B group (≥ 50% but not all of the carcinomatous lesion being located in SA, n=30) (all P<0.05).ConclusionsCIS, especially non-high-grade DCIS, represents the most common variant of SA-BC, and luminal A is the most predominant immunophenotype. CNB assessment might be challenging in some SA-BCs. The topographical pattern has great clinicopathological relevance. Careful evaluation of the contralateral breast and long-term follow-up for patients with SA-BC is necessary given its high prevalence of bilaterality.

Leiomyomas associated with hereditary leiomyomatosis and renal cell carcinoma syndrome and leiomyomas with bizarre nuclei often show overlapping morphological features, in particular cells with prominent eosinophilic nucleoli, perinucleolar halos, and eosinophilic cytoplasmic inclusions. Although hereditary leiomyomatosis and renal cell carcinoma syndrome is defined by fumarate hydratase (FH) germline mutations, resulting in S-(2-succino)-cysteine (2SC) formation, it is unknown whether leiomyomas with bizarre nuclei show similar alterations. In this study, we evaluated the morphology and FH/2SC immunoprofile of 31 leiomyomas with bizarre nuclei. DNA from tumor and normal tissues from 24 cases was subjected to massively parallel sequencing targeting 410 key cancer genes. Somatic genetic alterations were detected using state-of-the-art bioinformatics algorithms. No patient reported a personal history of renal neoplasia or cutaneous leiomyomas, but one had a family history of renal cell carcinoma while another had a family history of uterine leiomyomas. Aberrant FH/2SC expression was noted in 17 tumors (16 FH-negative/2SC-positive, 1 FH-positive/2SC-positive). On univariate analysis, staghorn vessels, eosinophilic cytoplasmic inclusions, diffuse distribution of prominent eosinophilic nucleoli with perinucleolar halos, and an ‘alveolar pattern of edema’ were associated with an abnormal immunoprofile, but only staghorn vessels remained significant on multivariate analysis. Massively parallel sequencing analysis (n=24) revealed that 13/14 tumors with aberrant FH/2SC immunoprofile harbored somatic FH somatic genetic alterations, including homozygous deletions (n=9), missense mutations coupled with loss of heterozygosity (n=3), and a splice site mutation (n=1), whereas no somatic FH mutations/deletions were found in tumors with normal immunoprofile (n=10; P<0.0001). Leiomyomas with bizarre nuclei with normal FH/2SC staining pattern more frequently harbored TP53 and/or RB1 alterations than those with aberrant FH/2SC immunoprofile (60 vs 14%; P=0.032). These data demonstrate that leiomyomas with bizarre nuclei are morphologically and genetically heterogeneous and that hereditary leiomyomatosis and renal cell carcinoma syndrome-related morphological features, abnormal FH/2SC staining, and somatic FH mutations/deletions can be seen in a subset of sporadic tumors.

Leiomyomas associated with hereditary leiomyomatosis and renal cell carcinoma syndrome and leiomyomas with bizarre nuclei often show overlapping morphological features, in particular cells with prominent eosinophilic nucleoli, perinucleolar halos, and eosinophilic cytoplasmic inclusions. Although hereditary leiomyomatosis and renal cell carcinoma syndrome is defined by fumarate hydratase (FH) germline mutations, resulting in S-(2-succino)-cysteine (2SC) formation, it is unknown whether leiomyomas with bizarre nuclei show similar alterations. In this study, we evaluated the morphology and FH/2SC immunoprofile of 31 leiomyomas with bizarre nuclei. DNA from tumor and normal tissues from 24 cases was subjected to massively parallel sequencing targeting 410 key cancer genes. Somatic genetic alterations were detected using state-of-the-art bioinformatics algorithms. No patient reported a personal history of renal neoplasia or cutaneous leiomyomas, but one had a family history of renal cell carcinoma while another had a family history of uterine leiomyomas. Aberrant FH/2SC expression was noted in 17 tumors (16 FH-negative/2SC-positive, 1 FH-positive/2SC-positive). On univariate analysis, staghorn vessels, eosinophilic cytoplasmic inclusions, diffuse distribution of prominent eosinophilic nucleoli with perinucleolar halos, and an ‘alveolar pattern of edema’ were associated with an abnormal immunoprofile, but only staghorn vessels remained significant on multivariate analysis. Massively parallel sequencing analysis (n=24) revealed that 13/14 tumors with aberrant FH/2SC immunoprofile harbored somatic FHsomatic genetic alterations, including homozygous deletions (n=9), missense mutations coupled with loss of heterozygosity (n=3), and a splice site mutation (n=1), whereas no somatic FHmutations/deletions were found in tumors with normal immunoprofile (n=10; P<0.0001). Leiomyomas with bizarre nuclei with normal FH/2SC staining pattern more frequently harbored TP53and/or RB1alterations than those with aberrant FH/2SC immunoprofile (60 vs14%; P=0.032). These data demonstrate that leiomyomas with bizarre nuclei are morphologically and genetically heterogeneous and that hereditary leiomyomatosis and renal cell carcinoma syndrome-related morphological features, abnormal FH/2SC staining, and somatic FHmutations/deletions can be seen in a subset of sporadic tumors.

Tree shrews have a close relationship to primates and have many advantages over rodents in biomedical research. However, the lack of gene manipulation methods has hindered the wider use of this animal. Spermatogonial stem cells (SSCs) have been successfully expanded in culture to permit sophisticated gene editing in the mouse and rat. Here, we describe a culture system for the long-term expansion of tree shrew SSCs without the loss of stem cell properties. In our study, thymus cell antigen 1 was used to enrich tree shrew SSCs. RNA-sequencing analysis revealed that the Wnt/β-catenin signaling pathway was active in undifferentiated SSCs, but was downregulated upon the initiation of SSC differentiation. Exposure of tree shrew primary SSCs to recombinant Wnt3a protein during the initial passages of culture enhanced the survival of SSCs. Use of tree shrew Sertoli cells, but not mouse embryonic fibroblasts, as feeder was found to be necessary for tree shrew SSC proliferation, leading to a robust cell expansion and long-term culture. The expanded tree shrew SSCs were transfected with enhanced green fluorescent protein (EGFP)-expressing lentiviral vectors. After transplantation into sterilized adult male tree shrew's testes, the EGFP-tagged SSCs were able to restore spermatogenesis and successfully generate transgenic offspring. Moreover, these SSCs were suitable for the CRISPR/Cas9-mediated gene modification. The development of a culture system to expand tree shrew SSCs in combination with a gene editing approach paves the way for precise genome manipulation using the tree shrew.

The aim of this study was to examine the reliability and validity of the Chinese version of the Daily Living Self-Efficacy Scale (DLSES) in stroke patients. In total, 172 participants were recruited from a local hospital in China. The internal consistent reliability and convergent validity of the total scale and activities of daily living (ADL) and psychosocial functioning subscales were examined and factor analysis was carried out. Cronbach’s αs for the Chinese version of the DLSES, ADL subscale, and psychosocial subscale were 0.96, 0.90, and 0.95, respectively. In the factor analysis, two factors (ADL and psychosocial functioning) were extracted, explaining 84.4% of the total variance in self-efficacy (χ2/d.f.=2.19, root mean square error of approximation=0.08, normed fit index=0.95, comparative fit index=0.98, incremental fit index=0.98). Convergent validity was confirmed by positive relationships between the Chinese version of the DLSES and the Modified Fall Efficacy Scale (r=0.87). The ADL subscale was associated positively with the Barthel Index (r=0.74) and the psychosocial functioning subscale was associated negatively with the Functional Activities Questionnaire (r=−0.73) and Center for Epidemiologic Studies Depression Scale (r=−0.44). The Chinese version of the DLSES was shown to be a reliable and valid measure of self-efficacy in stroke patients.

Pathogenic mitochondrial DNA (mtDNA) mutations can cause a variety of human diseases. The recent development of genome-editing technologies to manipulate mtDNA, such as mitochondria-targeted DNA nucleases and base editors, offer a promising way for curing mitochondrial diseases caused by mtDNA mutations. The CRISPR-Cas9 system is a widely used tool for genome editing; however, its application in mtDNA editing is still under debate. In this study, we developed a mito-Cas9 system by adding the mitochondria-targeted sequences and 3′ untranslated region of nuclear-encoded mitochondrial genes upstream and downstream of the Cas9gene, respectively. We confirmed that the mito-Cas9 system was transported into mitochondria and enabled knockin of exogenous single-stranded DNA oligonucleotides (ssODNs) into mtDNA based on proteinase and DNase protection assays. Successful knockin of exogenous ssODNs into mtDNA was further validated using polymerase chain reaction-free third-generation sequencing technology. We also demonstrated that RS-1, an agonist of RAD51, significantly increased knockin efficiency of the mito-Cas9 system. Collectively, we provide direct evidence that mtDNA can be edited using the CRISPR-Cas9 system. The mito-Cas9 system could be optimized as a promising approach for the treatment of mitochondrial diseases caused by pathogenic mtDNA mutations, especially those with homoplasmic mtDNA mutations.

The immune response is highly active in Alzheimer’s disease (AD). Identification of genetic risk contributed by immune genes to AD may provide essential insight for the prognosis, diagnosis, and treatment of this neurodegenerative disease. In this study, we performed a genetic screening for AD-related top immune genes identified in Europeans in a Chinese cohort, followed by a multiple-stage study focusing on Complement Factor H (CFH) gene. Effects of the risk SNPs on AD-related neuroimaging endophenotypes were evaluated through magnetic resonance imaging scan, and the effects on AD cerebrospinal fluid biomarkers (CSF) and CFH expression changes were measured in aged and AD brain tissues and AD cellular models. Our results showed that the AD-associated top immune genes reported in Europeans (CR1, CD33, CLU, and TREML2) have weak effects in Chinese, whereas CFH showed strong effects. In particular, rs1061170 (Pmeta=5.0 × 10−4) and rs800292 (Pmeta=1.3 × 10−5) showed robust associations with AD, which were confirmed in multiple world-wide sample sets (4317 cases and 16 795 controls). Rs1061170 (P=2.5 × 10−3) and rs800292 (P=4.7 × 10−4) risk-allele carriers have an increased entorhinal thickness in their young age and a higher atrophy rate as the disease progresses. Rs800292 risk-allele carriers have higher CSF tau and Aβ levels and severe cognitive decline. CFH expression level, which was affected by the risk-alleles, was increased in AD brains and cellular models. These comprehensive analyses suggested that CFH is an important immune factor in AD and affects multiple pathological changes in early life and during disease progress.

In this paper, we focus on the electroplating technology used for RF micro inductor coil. The technological parameters in DC electroplating are determined by SEM, linear sweep voltammetry and so on. It turns out that a high quality of plating layer is obtained when the PH value of electrochemical solution is 9, temperature is 45°C,current density is 1 A/dm2, additive is added and stirred slowly. Then the research on pulse electroplating is conducted on the basis of DC electroplating, and the result indicates that the pulse plating layer is of better quality compared with DC plating layer. Afterwards, surface structure and resistance of the copper layer are analyzed, demonstrating the obtained coating layer is good enough to be the main structure of micro inductor coil. In the end, this electroplating technology is applied to micro inductor coil. The simulation, fabrication, package and test of micro inductor coil are introduced briefly.

According to the low intensity, good plasticity in soft coal seam, the effect of direct fracturing to increase permeability was not ideal, the new technology of hydraulic fracture soft coal rock was proposed, which increased coal seam permeability. Its technical principles and characteristics were researched. Water injection pressure was analyzed, including injection time, parameters of the technology and so on. Field application experiment and effect of inspection were conducted. The results showed that the concentration of gas extraction increased 4.3 times, and the gas extraction flow increased 6.2times. The technology has a good effect of fracturing and advantages in enlarging the released area and decreasing diffusion seepage resistance of coal seam. Most important, the technology has broad application prospects in soft coal seam.

According to the conventional fracturing could easily lead to the local stress concentration of coal, the effect of pressure relief and permeability improvement is not ideal. The mechanism of directional hydraulic fracturing is analyzed and the parameters such as the layout of directional hole, the fracturing hole sealing, the minimum cracking pressure are discussed, then the field application tests are carried out. The results show that the directional hydraulic fracturing effect is better than that of ordinary fracturing hole and the maximum concentration and the average drainage scalar is respectively 3.75 times and 4 times of the ordinary hole pumping gas fracturing effects. The effect of permeability improvement is remarkable.

This paper discusses the research and implementation of the mid-frequency power (MFP). The paper analyzes the present research situation and the existence question of 400Hz mid-frequency power supply. Then the research of full digital control realization process of mid-frequency power supply with high power factor and multiple closed-loop feedback (MCLF) is given. The principle and characteristic of the closed-loop control system are provided. Finally the experimental prototype taking DSP of TMS320F2812 type as control device is developed. The experimental results verify the rationality .

AbstractThis research investigates the role of market orientation (MO) and supply chain capabilities in Australian fast-growth family SMEs (FGFSMEs). Two research questions are addressed: i) how does MO affect supply chain capabilities (i.e., information exchange, inter-firm activity integration, inter-firm coordination & supply chain responsiveness)?; and ii) how do supply chain capabilities influence sales performance? Statistical analyses involved the use of exploratory and confirmatory factor analytic techniques and structural equation modeling. Results indicate that supply chain capabilities are able to transform a market-based resource into higher value for FGFSMEs. The mediation effect of supply chain capabilities implies that incorporating mediators can help better explain the impact of MO on firm performance. In other words, embedding MO into supply chain systems enables these entities to enhance channel specific assets through activity integration, information exchange and superior coordination with supply chain partners. Family firm management needs to foster organizational cultures that embody MO throughout the organization.

Organizations have increasingly invested money in information technology (IT) in order to improve their agility. It is generally believed that organizations with greater IT investment tend to be more agile to response to environmental changes. However, the issue of whether IT is an enabler or impeder of organizational agility still remains unresolved. Drawing upon resource-based view theory and the literatures of information systems and supply chain management, the authors develop and test a theoretical model that integrates IT capability, supply chain capability and organizational agility. The authors propose that IT capability enables the development of a higher level of supply chain capability which is embedded within inter-firm processes and in turn enhances organizational agility. Structural equation modelling is employed to test their theoretical conceptualization of 310 Australian fast-growth small-to-medium enterprises across different industrial sectors. The results show that IT capability does contribute to firm agility through enhancing inter-firm supply chain processes such as integration, information sharing and coordination. This research highlights the role of IT-enabled intermediated processes and the ways in which IT is used by firms to enhance core business processes.

AbstractSmall-to-medium firms on a fast-growth trajectory experience a variety of pressures from both internal and external sources. The effect business coaching has on entrepreneurs’ self-confidence and ultimately firm growth, has rarely been studied. This study reports on the findings from 200 entrepreneurs, representing two cohorts from fast-growth firms, across different industries. Results suggest that business coaching is a non-direct influencer of entrepreneurial self-efficacy on firm growth. With the establishment and testing of a business coaching model, important implications are demonstrated for firms querying return-on-investment for business coaching. This investigation provides solid evidence-based outcomes, adding substantially to empirical literature on business coaching.

Mitochondrial DNA (mtDNA) somatic mutations have been identified in nearly all kinds of cancer during the past decade. Normally one need to determine the complete mtDNA sequences from both cancerous and normal tissues of the same patient to score the somatic mutation in cancer. In this study, we intended to explore a strategy to quickly identify somatic mutations in the entire mtDNA genome based on its phylogeny. The principal assumption for this strategy is that somatic mutations, as recently accumulated in cancerous tissue, have younger age and will be located in the terminal branches of mtDNA phylogenetic tree. In contrast, the haplogroup-specific variants, which appear as germline variants and have ancient age, will be located in the basal or intermediate-node branches of the tree, depending on their relative age. When the complete mtDNA sequence of the cancerous tissue is determined and is classified relative to the available mtDNA phylogeny, we only need to screen the variants that are located in the terminal branch in the paracancerous tissue or other normal tissue from the same patient to identify somatic mutations in cancer. We validated this strategy by using paired gastric cancer tissue and paracancerous tissue or blood from 10 Chinese patients (including one with gastric stromal tumor). A total of seven somatic mutations were identified in the cancerous tissues from four patients. Our result suggests that employing mtDNA phylogenetic knowledge facilitates rapid identification of mitochondrial genome somatic mutations in cancer.