Integrated cytological and transcriptomic analyses provide new insights into restoration of pollen viability in synthetic allotetraploid Brassica carinata.

KEY MESSAGE: Upregulation of genes involved in DNA damage repair and sperm cell differentiation leads to restoration of pollen viability in synthetic allotetraploid B. carinata after chromosome doubling. Apart from the well-known contribution of polyploidy to crop improvement, polyploids can also be induced for other purposes, such as to restore the viability of sterile hybrids. The mechanism related to viability transition between the sterile allodiploid and the fertile allotetraploid after chromosome doubling are not well understood. Here, we synthesised allodiploid B. carinata (2n = 2x = 17) and allotetraploid B. carinata (2n = 4x = 34) as models to investigate the cytological and transcriptomic differences during pollen development. The results showed that after chromosome doubling, the recovery of pollen viability in allotetraploid was mainly reflected in the stabilisation of microtubule spindle morphology, normal meiotic chromosome behaviour, and normal microspore development. Interestingly, the deposition and degradation of synthetic anther tapetum were not affected by polyploidy. Transcription analysis showed that the expression of genes related to DNA repair (DMC1, RAD51, RAD17, SPO11-2), cell cycle differentiation (CYCA1;2, CYCA2;3) and ubiquitination proteasome pathway (UBC4, PIRH2, CDC53) were positively up-regulated during pollen development of synthetic allotetraploid B. carinata. In summary, these results provide some refreshing updates about the ploidy-related restoration of pollen viability in newly synthesised allotetraploid B. carinata.

Cytological and transcriptomic analyses provide insights into the pollen fertility of synthetic allodiploid Brassica juncea hybrids.

KEY MESSAGE: Imbalanced chromosomes and cell cycle arrest, along with down-regulated genes in DNA damage repair and sperm cell differentiation, caused pollen abortion in synthetic allodiploid Brassica juncea hybrids. Interspecific hybridization is considered to be a major pathway for species formation and evolution in angiosperms, but the occurrence of pollen abortion in the hybrids is common, prompting us to recheck male gamete development in allodiploid hybrids after the initial combination of different genomes. Here, we investigated the several key meiotic and mitotic events during pollen development using the newly synthesised allodiploid B. juncea hybrids (AB, 2n = 2× = 18) as a model system. Our results demonstrated the partial synapsis and pairing of non-homologous chromosomes concurrent with chaotic spindle assembly, affected chromosome assortment and distribution during meiosis, which finally caused difference in genetic constitution amongst the final tetrads. The mitotic cell cycle arrest during microspore development resulted in the production of anucleate pollen cells. Transcription analysis showed that sets of key genes regulating cyclin (CYCA1;2 and CYCA2;3), DNA damage repair (DMC1, NBS1 and MMD1), and ubiquitin-proteasome pathway (SINAT4 and UBC) were largely downregulated at the early pollen meiosis stages, and those genes involved in sperm cell differentiation (DUO1, PIRL1, PIRL9 and LBD27) and pollen wall synthesis (PME48, VGDH11 and COBL10) were mostly repressed at the late pollen mitosis stages in the synthetic allodiploid B. juncea hybrids (AB). In conclusion, this study elucidated the related mechanisms affecting pollen fertility during male gametophyte development at the cytological and transcriptomic levels in the synthetic allodiploid B. juncea hybrids.

Single-Cell Genomics-Based Molecular Algorithm for Early Cancer Detection.

As one of the prime applications of liquid biopsy, the detection of tumor-derived whole cells and molecular markers is enabled in a noninvasive means before symptoms or hints from imaging procedures used for cancer screening. However, liquid biopsy is not a diagnostic test of malignant diseases per se because it fails to establish a definitive cancer diagnosis. Although single-cell genomics provides a genome-wide genetic alternation landscape, it is technologically challenging to confirm cell malignancy of a suspicious cell in body fluids due to unknown technical noise of single-cell sequencing and genomic variation among cancer cells, especially when tumor tissues are unavailable for sequencing as the reference. To address this challenge, we report a molecular algorithm, named scCancerDx, for confirming cell malignancy based on single-cell copy number alternation profiles of suspicious cells from body fluids, leading to a definitive cancer diagnosis. The scCancerDx algorithm has been trained with normal cells and cancer cell lines and validated with single tumor cells disassociated from clinical samples. The established scCancerDx algorithm then validates hexokinase 2 (HK2) as an efficient metabolic function-associated marker of identifying disseminated tumor cells in different body fluids across many cancer types. The HK2-based test, together with scCancerDx, has been investigated for the early detection of bladder cancer (BC) at a preclinical phase by detecting high glycolytic HK2high tumor cells in urine. Early BC detection improves patient prognosis and avoids radical resection for enhancing life quality.

A Multicancer Malignant Pleural Effusion Diagnostic Test Using Hexokinase 2 and Single-Cell Sequencing.

BACKGROUND: Malignant pleural effusion (MPE) represents advanced malignant disease with poor prognosis. To date, pleural effusion cytology remains the best test to diagnose MPE but suffers from limited diagnostic sensitivity and high variation. We report a hexokinase 2-based method (HK2-seq) as a novel diagnostic method for multicancer MPE diagnosis. METHODS: HK2-seq employed HK2 as a new metabolic function-associated marker to detect disseminated tumor cells engaging increased glycolysis in pleural effusion from many cancer types. Single-cell sequencing was used to confirm the malignancy of HK2-derived high glycolytic tumor cells (hgTCs) at the single-cell level via surveying genome-wide copy number alterations (CNAs), leading to establishment of definitive MPE diagnosis. RESULTS: In a prospective cohort study including 111 patients with pleural effusion, the HK2 test showed diagnostic sensitivity, diagnostic specificity, positive predictive value, and negative predictive value of 91% (95% CI: 80%-97%), 84% (95% CI: 68%-93%), 90% (95% CI: 79%-96%), and 86% (95% CI: 70%-95%), respectively, in MPE diagnosis across 12 different cancer types. In contrast, pleural effusion cytology exhibits an overall diagnostic sensitivity of 45%. In addition to confirming the tumor origin of hgTCs, single-cell sequencing allowed identification of prognostic or targetable CNAs in hgTCs, especially CNAs found in liquid biopsies but absent in solid biopsies. CONCLUSIONS: HK2-seq establishes definitive MPE diagnosis across many cancer types with high diagnostic performance. It has the potential to be used for multicancer detection of circulating tumor cells in blood and other types of body fluids, as well as liquid biopsy-based genomic characterization for informative diagnosis.

ATBF1 is a potential diagnostic marker of histological grade and functions via WNT5A in breast cancer.

BACKGROUND: Histological grade has been demonstrated to be an important factor of breast cancer outcome and is associated with cell differentiation and is currently being evaluated via H&E-stained sections. Molecular biomarkers are essential to improve the accuracy of histological grading. ATBF1, a large transcription factor, has been considered a tumor suppressor gene with frequent mutations or deletions in multiple cancers. In breast cancer, ATBF1 was reported to function in cell differentiation and mammary development. However, its role in the clinic has rarely been reported. METHODS: Breast cancer tissues (BCTs) and adjacent noncancerous tissues (ANCTs) were collected to analyze the expression of ATBF1 at the mRNA and protein levels. Three anti-ATBF1 antibodies recognizing independent peptides of ATBF1 (N-terminal end, middle region and C-terminal end) were applied for IHC staining. Small interfering RNA (siRNA) was used to silence ATBF1 expression and to investigate the roles of ATBF1 in MCF7 cells. Microarrays were introduced to analyze the differentially expressed genes, enriched GO terms and KEGG terms regulated by ATBF1 and its potential downstream genes, which were further confirmed in vitro and in clinical samples. RESULTS: The expression of ATBF1 was reduced in BCTs at both the mRNA and protein levels compared with that in ANCTs. ATBF1 protein was predominantly localized in the nucleus of ANCTs but in the cytoplasm of BCTs. Both the mRNA and protein levels of ATBF1 were significantly correlated with histological grade. Consistently, knockdown of ATBF1 increased stemness marker expression and reduced differentiation markers in vitro. Further analysis identified WNT5A as an essential downstream gene of ATBF1 in breast cancer cells. Treatment of WNT5A disrupted cell proliferation induced by ATBF1 silencing. In BCTs, a significant correlation was observed between the expression of WNT5A and ATBF1. CONCLUSION: The results indicated that ATBF1 expression might be a useful diagnostic marker associated with histological grade and breast cancer malignancy. WNT5A and its signaling pathway are novel mechanisms by which ATBF1 contributes to breast cancer tumorigenesis.

Gastrointestinal Langerhans cell histiocytosis with unifocal, single-system involvement in adults: Cases report and literature review.

BACKGROUND: Langerhans cell histiocytosis (LCH) is characterized by unifocal, multifocal single-system, or multi-system disease that occurs in all age groups, while it primarily attacks pediatric patients. Solitary gastrointestinal (GI) LCH in adults is exceedingly rare, so we aimed to investigate GI LCH in adults with unifocal single-system involvement and clarified the clinicopathologic characteristics of this disease. METHODS: Two cases of solitary GI LCH in adults were presented, and the clinicopathologic features of this diagnosis in the literature were reviewed. RESULTS: The main diagnostic feature of LCH is the morphologic identification of the characteristic Langerhans cells with prominent nuclear grooves and abundant eosinophilic cytoplasm, accompanied by a variable number of lymphocytes, eosinophils, and plasma cells. The distinctive cells expressed S100, CD1a, and langerin (CD207) on immunohistochemistry. BRAF V600E mutations were detected in the two patients. CONCLUSIONS: Gastrointestinal Langerhans cell histiocytosis in adults with unifocal, single-system involvement is extremely rare. Most patients were asymptomatic and usually a small solitary polyp in GI tract can be observed under routine endoscopy. Although the overall prognosis of unifocal single-system LCH is favorable, long-term follow-up is still necessary to rule out systemic disease.

Astragaloside IV suppresses transforming growth factor-ß1-induced epithelial-mesenchymal transition through inhibition of Wnt/ß-catenin pathway in glioma U251 cells.

Astragaloside IV (AS#IV) has previously demonstrated antitumoractivity. We investigated the effect and mechanisms of AS#IV in relation to epithelial-mesenchymal transition (EMT), viainterference with the Wnt/ß-catenin signaling pathway in gliomaU251 cells. Induction of glioma U251 cells by transforming growthfactor (TGF)#ß1 activated EMT, including switching E#cadherin toN-cadherin and altering the expression of Wnt/ß-catenin signalingpathway components such as vimentin, ß-catenin, and cyclin-D1.AS-IV inhibited the viability, invasion, and migration of TGF-ß1-induced glioma U251 cells. AS-IV also interfered with the TGF#ß1-induced Wnt/ß-catenin signaling pathway in glioma U251 cells.These findings indicate that AS#IV prohibits TGF#ß1-induced EMTby disrupting the Wnt/ß-catenin pathway in glioma U251 cells. AS#IV may thus be a potential candidate agent for treating glioma andother central nervous system tumors.

Overexpression of gene DEP domain containing 1 and its clinical prognostic significance in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most commonly seen malignancies worldwide, yet its regulatory mechanisms still need to be further illuminated. Abundant evidence revealed that aberrant expression of cancer-related genes contributes to CRC progression. DEP domain containing 1 (DEPDC1) has been found to play a crucial role in the carcinogenesis and development of malignancies. Nevertheless, limited studies have been concerned with the role of DEPDC1 in CRC. This study aimed to investigate the relationship between DEPDC1 expression and CRC clinicopathological parameters. METHODS: Solid CRC tissues and adjacent noncancerous tissues (ANCTs) (n = 150) were chosen randomly to detect the mRNA expression levels of DEPDC1 by real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR). Formalin-fixed, paraffin-embedded (FFPE) blocks of CRC tissues and ANCTs (n = 150) were acquired to examine DEPDC1 protein expression levels by immunohistochemistry (IHC). RESULTS: DEPDC1 was significantly overexpressed in CRC tissues than that in ANCTs (P < .05). High protein expression of DEPDC1 was associated with poorer TNM stage and recurrence (P < .001 and P = .003, respectively). Kaplan-Meier survival analysis showed significantly shorter overall survival (OS) and disease-free survival (DFS) in DEPDC1 protein high-expression group compared with low-expression group (P < .05). Univariate analysis demonstrated that DEPDC1 protein expression was correlated with DFS (P = .005) and OS (P = .006). Multivariate analysis revealed that the combination of DEPDC1 protein expression and TNM stage has statistical significance in CRC prognosis prediction (P = .024 and P = .009, respectively). CONCLUSIONS: DEPDC1 may act as a potential biomarker for CRC detection as well as a prognostic predictor concerning the survival of CRC patients.

Long noncoding RNAs in osteosarcoma via various signaling pathways.

Osteosarcoma is one of the most commonly seen bone malignancies with high incidence rate in both children and adults. Although the regulatory network of osteosarcoma has been greatly concerned for years, the mechanisms regarding its oncogenesis and development are still not clear. Recent discoveries have revealed that long noncoding RNAs (lncRNAs) play a crucial role in the development, progression, and invasion of osteosarcoma. Deregulated expression of lncRNAs has been found to participate in the regulation of various signaling transduction pathways in osteosarcoma. This review summarized roles of lncRNAs in the pathogenesis, development, and potential therapeutic of osteosarcoma via different signaling pathways. For examples, MALAT1, CCAT2, FER1L4, LOXL1-AS1, OIP5-AS1, PVT1, DBH-AS1, and AWPPH regulate PI3K/Akt signaling; AWPPH and BE503655 regulate Wnt/ß-catenin signaling; NKILA and XIST regulate NF-κB signaling; MEG3 and SNHG12 regulate Notch signaling; FOXD2-AS1 and LINK-A regulate HIF-1α signaling; GClnc1 and HOTAIR regulate P53 signaling; ZFAS1, H19, and MALAT1 regulate MAPK, Hedgehog and Rac1/JNK signaling, respectively.

Activation of MET signaling by HDAC6 offers a rationale for a novel ricolinostat and crizotinib combinatorial therapeutic strategy in diffuse large B-cell lymphoma.

Some histone deacetylases (HDACs) promote tumor cell growth and pan- or selective HDAC inhibitors are active in some cancers; however, the pivotal HDAC enzyme and its functions in human diffuse large B-cell lymphoma (DLBCL) remain largely unknown. Using NanoString nCounter assays, we profiled HDAC mRNA expression and identified HDAC6 as an upregulated HDAC family member in DLBCL tissue samples. We then found that HDAC6 plays an oncogenic role in DLBCL, as evidenced by its promotion of cell proliferation in vitro and tumor xenograft growth in vivo. Mechanistically, the interaction between HDAC6 and HR23B downregulated HR23B expression, thereby reducing the levels of casitas B-lineage lymphoma (c-Cbl), an E3 ubiquitin ligase for hepatocyte growth factor receptor (MET), which resulted in the inhibition of MET ubiquitination-dependent degradation. In addition, enhanced HDAC6 expression and decreased HR23B expression were correlated with poor overall survival rates among patients with DLBCL. Taken together, these results establish an HDAC6-HR23B-MET axis and indicate that HDAC6 is a potent promoter of lymphomagenesis in DLBCL. Thus, a therapeutic strategy based on HDAC6 inhibitors in combination with MET inhibitors is promising. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

New optical gating technique for detection of electric field waveforms with subpicosecond resolution.

The new optical gating technique uses a femtosecond optical laser pulses for the photoconductive detection of short pulses of terahertz (THz) radiation. This technique reproduces the shape of the THz pulse and after pulse plasmonic response of the two-dimensional electron gas in a short channel high electron mobility transistor (HEMT). The results are in excellent agreement with the electro-optic effect measurements and with the simulation results obtained in the frame of a two-dimensional hydrodynamic model. The femtosecond optical laser pulse time is delayed with respect to the THz pulse and generates a large concentration of the electron-hole pairs in the AlGaAs/InGaAs HEMT. This drastically increases the channel conductivity on the femtosecond scale and effectively shorts the device quenching the transistor response. The achieved time resolution is better than 250 femtoseconds and could be improved using shorter femtosecond laser pulses. The spatial resolution of this technique is on the order of tens of nanometers or even smaller. It could be applied for studying the electron transport in a variety of electronic devices ranging from silicon MOSFETs to heterostructure bipolar transistors.

Pituitary tumor-transforming gene-1 serves as an independent prognostic biomarker for gastric cancer.

BACKGROUND: Pituitary tumor-transforming gene-1 (PTTG1) is a transcription factor that can affect transcriptional activity, angiogenesis, and cell senescence. We examined PTTG1 mRNA and protein expression in gastric cancer (GC) cell lines and tissues to determine its value as a biomarker for GC diagnosis and therapy. METHODS: PTTG1 mRNA expression from 78 GC cases and paired adjacent normal mucosa (PCR cohort) as well as from five gastric cell lines was assessed using qRT-PCR. Nuclear and cytoplasmic RNA were extracted from two gastric cell lines to determine PTTG1 mRNA localization. PTTG1 protein expression from 98 GC cases, their paired adjacent normal mucosa, and 23 gastric intraepithelial neoplasia (GIN) cases was examined using immunohistochemistry (IHC cohort). The correlation between PTTG1 mRNA and protein expression and GC clinicopathological parameters was analyzed. RESULTS: PTTG1 mRNA expression in GC tissues and cell lines was significantly increased compared with adjacent normal gastric mucosa and normal gastric mucous cell lines (p < 0.05). PTTG1 expression was nuclear and cytoplasmic, with higher cytoplasmic expression. PTTG1 immunostaining significantly differed in GC (95.66 ± 20.65), GIN (84.00 ± 34.16), and normal adjacent mucosa (28 ± 22.25) (p < 0.001). Multivariate Cox regression analysis revealed that PTTG1 mRNA and protein expression are independent prognostic factors for GC patient survival. CONCLUSION: Our results suggest that PTTG1 is a promising target for GC diagnosis and therapy.

A molecular signature for the prediction of recurrence in colorectal cancer.

BACKGROUND: Several clinical and pathological factors have an impact on the prognosis of colorectal cancer (CRC), but they are not yet adequate for risk assessment. We aimed to identify a molecular signature that can reliably identify CRC patients at high risk for recurrence. RESULTS: Two hundred eighty-one CRC samples (stage II/III) were included in this study. A two-step gene expression profiling study was conducted. First, gene expression measurements from 81 fresh frozen CRC samples were obtained using Affymetrix Human Genome U133 Plus 2.0 Arrays. Second, a focused gene expression assay, including prognostic genes and genes of interest from literature reviews, was performed using 200 fresh frozen samples and a Taqman low-density array (TLDA) analysis. An optimal 31-gene expression classifier for the prediction of recurrence among patients with stage II/III CRC was developed using logistic regression analysis. This gene expression signature classified 58.5% of patients as low-risk and 41.5% as high-risk (P < 0.001). The signature was the strongest independent prognostic factor in the multivariate analysis. The five-year relapse-free survival (RFS) rates for the low-risk patients and the high-risk patients were 88.5% and 41.3% (P < 0.001), respectively. CONCLUSION: We identified a 31-gene expression signature that is closely associated with the clinical outcome of stage II/III CRC patients.

Reciprocal repression between TUSC7 and miR-23b in gastric cancer.

Recently, long noncoding RNAs (lncRNAs) were demonstrated to play important regulatory roles in biological processes and cancer biology. However, the overall pathophysiological contribution of lncRNAs to gastric cancer (GC) remains largely unknown. In this study, differentially expressed lncRNAs in GC and paired adjacent normal tissue samples were identified by microarray and were validated using quantitative real-time polymerase chain reaction (qRT-PCR). One particular lncRNA, tumour suppressor candidate 7 (TUSC7), was analyzed in sequential large cohorts, and the Kaplan-Meier method with the log-rank test for comparisons was used to analyse the survival data. The results indicated that TUSC7 was downregulated in GC samples and was an independent prognostic indicator of disease-free survival (DFS) and disease-specific survival (DSS) in GC patients. Applying loss-of-function and gain-of-function approaches, we determined that TUSC7 suppressed tumour cell growth in vitro and in vivo. Furthermore, we showed that TUSC7 was a direct transcriptional target of p53 via interaction of p53 with the putative p53-response element in the upstream region of TUSC7. Finally, we demonstrated reciprocal repression between TUSC7 and miR-23b; in contrast to TUSC7, miR-23b promoted cell growth. The results indicated that TUSC7 is a p53-regulated tumour suppressor that acts in part by repressing miR-23b and that TUSC7 may be a key regulatory hub in GC.

Down-regulation of ncRAN, a long non-coding RNA, contributes to colorectal cancer cell migration and invasion and predicts poor overall survival for colorectal cancer patients.

Accumulating evidence has indicated that long non-coding RNAs (lncRNAs) play critical roles in regulating cellular processes, such as cell growth and apoptosis, as well as cancer progression and metastasis. ncRAN (non-coding RNA expressed in aggressive neuroblastoma) was previously shown to be dramatically up-regulated and associated with poor prognosis in human neuroblastoma. This lncRNA also plays an important role in bladder cancer growth and invasion. Colorectal cancer (CRC) progression typically follows a complex cascade from primary malignancy to distant metastasis, but whether the aberrant expression of ncRAN in CRC is associated with malignancy, metastasis or prognosis remains unknown. In this study, we demonstrated that ncRAN expression is significantly down-regulated in tumor tissue and CRC cell lines compared with adjacent normal tissue and a normal intestinal mucous cell line. Reduced expression of ncRAN was detected in poorly differentiated or undifferentiated tumors and in tumors with liver metastases. Kaplan-Meier analysis indicated that patients with lower ncRAN expression have a worse overall survival. Moreover, multivariate analysis revealed that decreased expression of ncRAN is an independent predictor of overall survival. Our experimental data indicated that ncRAN mediates the in vitro migration and invasion of CRC cells. Together, these results suggest that ncRAN might represent a novel prognostic indicator, a biomarker for the early detection of metastasis and a target for gene therapy in CRC.

Long non-coding RNAs in cancer invasion and metastasis.

Recent large-scale transcriptome analyses have revealed that the human genome contains more than just protein-coding genes. Indeed, a large number of transcripts, including long non-coding RNAs (lncRNAs), lack protein-coding capacity, and increasing evidence suggests that lncRNAs could have a critical role in the regulation of diverse cellular processes, such as stem cell pluripotency, development, cell growth and apoptosis, and cancer invasion and/or metastasis. Furthermore, the aberrant expression of several lncRNAs is closely linked to cancer invasion and/or metastasis. Although the underlying molecular mechanisms by which lncRNAs regulate cancer invasion and/or metastasis are not clearly understood, recent studies have revealed that aberrant lncRNAs expression affects the progression of cancer. In this review, we highlight recent findings regarding the roles of lncRNAs in cancer invasion and/or metastasis.

Single-cell low-pass whole genome sequencing accurately detects circulating tumor cells for liquid biopsy-based multi-cancer diagnosis.

Accurate detection of circulating tumor cells (CTCs) in blood and non-blood body fluids enables generation of deterministic cancer diagnosis and represent a less invasive and safer liquid biopsy approach. Although genomic alternations have been widely used in circulating tumor DNA (ctDNA) analysis, studies on cell-based genomic alternations profiling for CTC detection are rare due to major technical limitations in single-cell whole genome sequencing (WGS) including low throughput, low accuracy and high cost. We report a single-cell low-pass WGS-based protocol (scMet-Seq) for sensitive and accurate CTC detection by combining a metabolic function-associated marker Hexokinase 2 (HK2) and a Tn5 transposome-based WGS method with improved cell fixation strategy. To explore the clinical use, scMet-Seq has been investigated with blood and non-blood body fluids in diagnosing metastatic diseases, including ascites-based diagnosis of malignant ascites (MA) and blood-based diagnosis of metastatic small-cell lung cancer (SCLC). ScMet-Seq shows high diagnostic sensitivity (MA: 79% in >10 cancer types; metastatic SCLC: 90%) and ~100% of diagnostic specificity and positive predictive value, superior to clinical cytology that exhibits diagnostic sensitivity of 52% in MA diagnosis and could not generate blood-based diagnosis. ScMet-Seq represents a liquid biopsy approach for deterministic cancer diagnosis in different types of cancers and body fluids.

Trends and Age-Period-Cohort Effect on Incidence of Male Breast Cancer from 1980 to 2019 in Taiwan and the USA.

Although male breast cancer (MBC) is globally rare, its incidence significantly increased from 1990 to 2017. The aim of this study was to examine variations in the trends of MBC incidence between populations in Taiwan and the USA from 1980 to 2019. The Taiwan Cancer Registry database and the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute of the USA were used. The age-standardized incidence rate was calculated using the world standard population in 2000. The long-term trends of the age, time period, and birth cohort effect on MBC incidence rates were estimated using the SEER Age-Period-Cohort Web Tool. The results revealed that the incidence of MBC in both countries increased from 2010 to 2019 (Taiwan: average annual percentage change (AAPC) = 2.59%; USA: AAPC = 0.64%). The age and period effects on the incidence rates in both countries strengthened, but the cohort effect was only identified in Taiwan (Rate ratio: 4.03). The identified cohort effect in this study bears resemblance to that noted in a previous investigation on female breast cancer in Taiwan. This suggests the possible presence of common environmental factors influencing breast cancer incidence in both genders, such as a high fat diet and xenoestrogen.

Sulfhydryl compound levels are associated with ATO-induced side effects in acute promyelocytic leukemia patients.

OBJECTIVE: The remarkable effect of arsenic trioxide (ATO) was verified, but side effects are generally observed in acute promyelocytic leukemia (APL) patients, especially leukocytosis and hepatotoxicity. Our aims are to study predictors and reduce ATO-induced side effects without inhibiting efficacy. METHODS: Sulfhydryl in ATO-treated APL patients was detected by the Spectra Max M5 microplate reader. And patients were divided into high and low sulfhydryl groups according to median sulfhydryl concentration. The onset time of leukocytosis and the peak value of WBC were compared . Correlations between hepatotoxicity indicators and sulfhydryl concentrations were analysed. RESULTS: The concentration of sulfhydryl before treatment was significantly higher in the high sulfhydryl group. Leukocytosis ((7.0 ± 5.5) vs. (14.6 ± 8.5) day) and the peak value of WBC occurred earlier in the low sulfhydryl group ((10.8 ± 5.9) vs. (19.3 ± 5.5) day) than in the high group, and the peak value was significantly lower in the low sulfhydryl group ((24.04 ± 15.05) × 109/L) than in the high group ((42.95 ± 25.57) × 109/L). The elevated liver enzymes were smaller in the higher sulfhydryl group between time points before treatment and the treatment one week later (ΔALT 66.57 vs. 9.85 U/L, ΔAST 59.52 vs. 17.76 U/L), as between time points before treatment and peak value. There was a negative correlation between sulfhydryl and elevated liver enzymes. CONCLUSIONS: Higher sulfhydryl compounds contribute to ameliorating ATO-induced leukocytosis and hepatotoxicity in APL patients. The low sulfhydryl before treatment can advance the onset of leukocytosis. For patients with higher sulfhydryl in the early stage, close monitoring of liver enzymes is warranted instead of prophylactic applying any hepatoprotective intervention, to maintain ATO efficacy.

Prediction of Rhizoma Drynariae Targets in the Treatment of Osteonecrosis of the Femoral Head based on Network Pharmacology and Experimental Verification.

BACKGROUND: Rhizoma drynariae, a classic prescription in traditional Chinese medicine, has long been used for the treatment of osteonecrosis of the femoral head (ONFH), but its potential targets and molecular mechanisms remain to be further explored. OBJECTIVE: This study aims to explore the mechanism of Rhizoma drynariae in ONFH treatment via network pharmacology and in vitro experiments. METHODS: Targets of Rhizoma drynariae and ONFH were predicted using relevant databases, and intersection analysis was conducted to screen for shared targets. A PPI network of the shared targets was built using STRING to identify the key targets. Functional enrichment analyses of Gene Ontology and KEGG pathway data were carried out using R software. The compound-target-pathway network was constructed for Rhizoma Drynariae in the treatment with ONFH using Cytoscape 3.9.0. Cell proliferation was assessed using CCK8 and apoptosis was detected using (Propidium Iodide) PI staining and western blotting. RESULTS: This study depicts the interrelationship of the bioactive compounds of Rhizoma drynariae with ONFH-associated signaling pathways and target receptors and is a potential reagent for ONFH treatment. CONCLUSION: Based on a network pharmacology analysis and in vitro experiment, we predicted and validated the active compounds and potential targets of Rhizoma drynariae, provide valuable evidence of Rhizoma Drynariae in future ONFH treatment.