Genomic and transcriptomic profiling of inflammatory breast cancer reveals distinct molecular characteristics to non-inflammatory breast cancers.

PURPOSE: Inflammatory breast cancer (IBC), a rare and highly aggressive form of breast cancer, accounts for 10% of breast cancer-related deaths. Previous omics studies of IBC have focused solely on one of genomics or transcriptomics and did not discover common differences that could distinguish IBC from non-IBC. METHODS: Seventeen IBC patients and five non-IBC patients as well as additional thirty-three Asian breast cancer samples from TCGA-BRCA were included for the study. We performed whole-exon sequencing (WES) to investigate different somatic genomic alterations, copy number variants, and large structural variants between IBC and non-IBC. Bulk RNA sequencing (RNA-seq) was performed to examine the differentially expressed genes, pathway enrichment, and gene fusions. WES and RNA-seq data were further investigated in combination to discover genes that were dysregulated in both genomics and transcriptomics. RESULTS: Copy number variation analysis identified 10 cytobands that showed higher frequency in IBC. Structural variation analysis showed more frequent deletions in IBC. Pathway enrichment and immune infiltration analysis indicated increased immune activation in IBC samples. Gene fusions including CTSC-RAB38 were found to be more common in IBC. We demonstrated more commonly dysregulated RAS pathway in IBC according to both WES and RNA-seq. Inhibitors targeting RAS signaling and its downstream pathways were predicted to possess promising effects in IBC treatment. CONCLUSION: We discovered differences unique in Asian women that could potentially explain IBC etiology and presented RAS signaling pathway as a potential therapeutic target in IBC treatment.

A Subpopulation of Luminal Progenitors Secretes Pleiotrophin to Promote Angiogenesis and Metastasis in Inflammatory Breast Cancer.

Inflammatory breast cancer (IBC) is a highly aggressive subtype of breast cancer characterized by rapidly arising diffuse erythema and edema. Genomic studies have not identified consistent alterations and mechanisms that differentiate IBC from non-IBC tumors, suggesting that the microenvironment could be a potential driver of IBC phenotypes. Here, using single-cell RNA sequencing, multiplex staining, and serum analysis in patients with IBC, we identified enrichment of a subgroup of luminal progenitor (LP) cells containing high expression of the neurotropic cytokine pleiotrophin (PTN) in IBC tumors. PTN secreted by the LP cells promoted angiogenesis by directly interacting with the NRP1 receptor on endothelial tip cells located in both IBC tumors and the affected skin. NRP1 activation in tip cells led to recruitment of immature perivascular cells in the affected skin of IBC, which are correlated with increased angiogenesis and IBC metastasis. Together, these findings reveal a role for cross-talk between LPs, endothelial tip cells, and immature perivascular cells via PTN-NRP1 axis in the pathogenesis of IBC, which could lead to improved strategies for treating IBC. SIGNIFICANCE: Nonmalignant luminal progenitor cells expressing pleiotrophin promote angiogenesis by activating NRP1 and induce a prometastatic tumor microenvironment in inflammatory breast cancer, providing potential therapeutic targets for this aggressive breast cancer subtype.

Effect of Lipid Levels on Tumor-Infiltrating Lymphocytes and Prognosis in Patients with Triple-Negative Breast Cancer.

Objective: Dyslipidemia can promote cell proliferation, malignant transformation, metastasis, and cancer recurrence. Moreover, it could also affect immune infiltration in the tumor microenvironment. Therefore, we aimed to explore the effects of lipid levels on tumor-infiltrating lymphocytes (TILs) and prognosis in patients with triple-negative breast cancer (TNBC). Methods: Samples from 222 patients with TNBC from July 2007 to December 2019 were obtained from the tissue specimen banks in 3 hospitals. The blood samples were used to detect the levels of lipid levels such as apolipoprotein B (Apo B), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C). The TILs in the 222 TNBC tissues were detected using hematoxylin and eosin (H&E) staining, and the relationship between the lipid levels, clinical characteristics, and prognosis was analyzed. Results: Among TNBC patients, the overall survival (OS) time and disease-free survival (DFS) time were lower in patients with high LDL-C levels than those with low LDL-C levels (p < 0.01, respectively). The DFS was shorter in patients with low stromal TIL (STIL) levels than those with moderate or high STIL levels (p = 0.023). Multifactor Cox regression analysis showed that LDL-C level, Apo B level, and lymphocyte-predominant breast cancer were independent risk factors for OS in TNBC patients. The number of positive lymph nodes, postoperative staging, and total amount of TILs were independent risk factors for DFS in TNBC patients. Conclusion: The LDL-C and STIL levels were correlated with survival and prognosis in patients with TNBC.

Different Life-Stage Exposure to Hexafluoropropylene Oxide Trimer Acid Induces Reproductive Toxicity in Adult Zebrafish (Danio rerio).

As a novel alternative to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide trimer acid (HFPO-TA) has been widely used and has caused ubiquitous water pollution. However, its adverse effects on aquatic organisms are still not well known. In the present study, zebrafish at different life stages were exposed to 0, 5, 50, and 100 µg/L of HFPO-TA for 21 days to investigate reproductive toxicity in zebrafish. The results showed that HFPO-TA exposure significantly inhibited growth and induced reproductive toxicity in zebrafish, including a decrease of the condition factor, gonadosomatic index, and the average number of eggs. Histological section observation revealed that percentages of mature oocytes and spermatozoa were reduced, while those of primary oocytes and spermatocytes increased. In addition, exposure to HFPO-TA at three stages induced a significant decrease in the hatching rate, while the heart rate and normal growth rate of F1 offspring were only significantly inhibited for the exposure from fertilization to 21 days postfertilization (dpf). Compared with the exposure from 42 to 63 dpf, the reproductive toxicity induced by HFPO-TA was more significant for the exposure from fertilization to 21 dpf and from 21 to 42 dpf. Expression of the genes for cytochrome P450 A1A, vitellogenin 1, estrogen receptor alpha, and estrogen receptor 2b was significantly up-regulated in most cases after exposure to HFPO-TA, suggesting that HFPO-TA exhibited an estrogen effect similar to PFOA. Therefore, HFPO-TA might disturb the balance of sex steroid hormones and consequently induce reproductive toxicity in zebrafish. Taken together, the results demonstrate that exposure to HFPO-TA at different life stages could induce reproductive toxicity in zebrafish. However, the underlying mechanisms deserve further investigation. Environ Toxicol Chem 2023;42:2490-2500. © 2023 SETAC.

Development of a novel prognostic signature derived from enhancer RNA-regulated genes in head neck squamous cell carcinoma.

BACKGROUND: Enhancer RNAs (eRNAs) are increasingly recognized as prognostic biomarkers-across human cancers. Here, we sought to develop a novel eRNA-regulated genes (ERGs)-derived prognostic signature for head neck squamous cell carcinoma (HNSCC). METHODS: Candidate ERGs were identified via co-expression between individual survival-related eRNAs and their putative targets by Spearman's correlation analyses. The ERG signature was developed by univariate Cox regression, Kaplan-Meier survival analysis and maximum AUC in 1000 iterations of LASSO-penalized multivariate Cox regression. An ERG nomogram incorporating ERG signature and selected clinicopathological parameters were constructed by multivariate Cox regression. Biological roles of eRNA of interest were further explored in vitro. RESULTS: The ERG signature successfully stratified patients into subgroups with distinct survival in multiple cohorts. An ERG nomogram was developed with satisfactory performance in prognostication. Inhibition of ENSR00000165816 significantly reduced transcript level of SLC2A9 and impaired cell proliferation and invasion. CONCLUSION: Our results establish ERG signature and nomogram as powerful prognostic predictors for HNSCC.

Development of a novel head and neck squamous cell carcinoma prognostic signature by bulk/single-cell sequencing data integration.

BACKGROUND: Identifying cell subpopulations conferring unfavorable prognosis in cancer holds clinical significance. Here, we sought to identify prognostic cell subsets and develop a novel, prognostic signature for head neck squamous cell carcinoma (HNSCC). METHODS: Highly prognostic cell subpopulations in HNSCC were identified by integrating single-cell and bulk transcriptomic datasets. The prognostic signature and nomogram were developed by least absolute shrinkage and selection operator and multivariate Cox regression analyses based on significantly upregulated genes in this specific cell subpopulation, respectively. The qRT-PCR experiments were utilized for independent validation in our patient cohort. RESULTS: A specific cancer cell subset associated with unfavorable prognoses was identified. Functional dissections revealed that its transcriptional programs were significantly enriched in E2F, epithelial-to-mesenchymal transition, and glycolysis. A novel prognostic signature comprising six genes was developed and further validated. Risk scores based on qRT-PCR data robustly stratified patients into subgroups with distinct prognoses. A nomogram integrated from this signature and clinical stage had superior performance. CONCLUSION: Our model derived from integrative analyses of single-cell and bulk RNA-sequencing is a novel, robust prognostic biomarker for HNSCC.

miR-107 Inhibits the Proliferation of Gastric Cancer Cells In vivo and In vitro by Targeting TRIAP1.

Gastric cancer is a kind of gastrointestinal tumor with high morbidity and mortality. Finding effective methods for early diagnosis and treatment of gastric cancer has important significance and application prospects. MicroRNAs without protein coding potential affect the occurrence and development of gastric cancer. This study aims to explore the biological function and mechanism of microRNA-107 (miR-107) in gastric cancer. The results show that miR-107 is low expressed in gastric cancer, while TRIAP1 is highly expressed; the overexpression of miR-107 can inhibit the progression of gastric cancer in vivo and in vitro, while the overexpression plasmid of TRIAP1 can restore the miR-107 mimic-induced cell proliferation and metastasis inhibition, and the small interfering RNA of TRIAP1 can inhibit the cell proliferation and invasion induced by miR-107 inhibitor. In conclusion, the results of this study show that miR-107 can inhibit the proliferation of gastric cancer in vivo and in vitro by targeting TRIAP1.

DLGAP1-AS2 promotes estrogen receptor signalling and confers tamoxifen resistance in breast cancer.

BACKGROUND: Tamoxifen is a first-line endocrine agent and is often used to treat estrogen receptor-positive (ER+) breast cancer. Unfortunately, approximately 30-40% of patients who received tamoxifen therapy experience recurrence or progression to a fatal advanced stage due to tamoxifen resistance. However, the mechanisms of tamoxifen resistance remain unclear. METHODS: The expression of lncRNA DLGAP1 antisense RNA 2 (DLGAP1-AS2) was detected by qPCR. The effect of DLGAP1-AS2 on tamoxifen resistance was evaluated by MTT, colony formation, TUNEL and flow cytometric assays. The mechanisms by which DLGAP1-AS2 regulates tamoxifen resistance were investigated through qPCR, RNA pull-down assays and RNA immunoprecipitation (RIP) assays. RESULTS: Our results showed that DLGAP1-AS2 is significantly upregulated in breast cancer and that tamoxifen can induce DLGAP1-AS2 expression. Further investigation suggested that upregulation of DLGAP1-AS2 can increase cell viability and inhibit apoptosis, while downregulation of DLGAP1-AS2 results in the opposite effects. Mechanistically, DLGAP1-AS2 can bind to the AFF3 protein to inhibit its degradation, which further promotes ER signalling. CONCLUSIONS: Our research clarified that DLGAP1-AS2 promotes ER signalling to induce tamoxifen resistance and that targeting DLGAP1-AS2 might be a promising strategy to overcome tamoxifen resistance in breast cancer.

Protein phosphatase 1 regulatory inhibitor subunit 14C promotes triple-negative breast cancer progression via sustaining inactive glycogen synthase kinase 3 beta.

Triple-negative breast cancer (TNBC) is fast-growing and highly metastatic with the poorest prognosis among the breast cancer subtypes. Inactivation of glycogen synthase kinase 3 beta (GSK3ß) plays a vital role in the aggressiveness of TNBC; however, the underlying mechanism for sustained GSK3ß inhibition remains largely unknown. Here, we find that protein phosphatase 1 regulatory inhibitor subunit 14C (PPP1R14C) is upregulated in TNBC and relevant to poor prognosis in patients. Overexpression of PPP1R14C facilitates cell proliferation and the aggressive phenotype of TNBC cells, whereas the depletion of PPP1R14C elicits opposite effects. Moreover, PPP1R14C is phosphorylated and activated by protein kinase C iota (PRKCI) at Thr73. p-PPP1R14C then represses Ser/Thr protein phosphatase type 1 (PP1) to retain GSK3ß phosphorylation at high levels. Furthermore, p-PPP1R14C recruits E3 ligase, TRIM25, toward the ubiquitylation and degradation of non-phosphorylated GSK3ß. Importantly, the blockade of PPP1R14C phosphorylation inhibits xenograft tumorigenesis and lung metastasis of TNBC cells. These findings provide a novel mechanism for sustained GSK3ß inactivation in TNBC and suggest that PPP1R14C might be a potential therapeutic target.

Sequential versus concurrent adjuvant chemo-endocrine therapy for HR+ early breast cancer: a systematic review and Bayesian network meta-analysis.

Background: Chemo-endocrine therapy is the standard adjuvant treatment strategy for hormone receptor-positive (HR+) early breast cancer. Our research aimed to compare the efficacy of adjuvant chemo-endocrine therapies, regarding different endocrinal regimens and integration sequences (sequential or concomitant), for HR+ early breast cancer. Methods: PubMed, Embase, the Cochrane Library and web of science were searched for articles published before October 2018 with Clinicaltrials.gov (https://clinicaltrials.gov) for registered clinical trials and ASCO, AACR, ESCO, SABCS meeting abstracts for addition. Randomized clinical trials (RCTs) comparing chemotherapy and/or endocrine therapy in the adjuvant treatment of primary breast cancer patients were included. Hazard ratios (HRs) of disease-free survival (DFS) and overall survival (OS) were extracted and analyzed in Bayesian analysis. Patients were stratified by menopause status. Results: Thirty-three trials with 28,515 patients and 19 treatments were enrolled. Comparisons between regimens has seen better efficacy of ovarian function suppressor (OFS) + aromatase inhibitors (AI) than OFS + tamoxifen, either used concurrently [HR =0.69, 95% credible intervals (CrI): 0.47-1.02] or sequentially with chemotherapy (HR =0.72, 95% CrI: 0.49-1.06) in premenopausal patients. Adding OFS to tamoxifen was marginally better than tamoxifen used alone (DFS: HR =0.85, 95% CrI: 0.65-1.09; OS: HR =0.77, 95% CrI: 0.52-1.08). Comparisons between different sequences of chemo-endocrine therapy proved equal efficacy in premenopausal and postmenopausal patients. Recommendation was given based on ranking of treatments. Sequential and concurrent use of chemotherapy and OFS + AI ranked equally in premenopausal patients and were recommended as the best option. However, tamoxifen ranked higher when used concurrently with chemotherapy in both premenopausal and postmenopausal HR+ early breast cancer. Conclusions: In the adjuvant chemo-endocrine therapy for premenopausal HR+ early breast cancer, concurrent and sequential adjuvant chemo-endocrine therapy was demonstrated of equal efficacy in both postmenopausal and premenopausal HR+ early breast cancer. Trial Registration: PROSPERO CRD42018104889.

Malignant adenomyoepithelioma of the breast: Two case reports and review of the literature.

BACKGROUND: Malignant adenomyoepithelioma (AME) of the breast is a rare tumor in which malignancy can arise from either epithelial or myoepithelial components, or from both cell types. The incidence and prognosis of malignant AME of the breast are difficult to assess due to its rarity. Therefore, the optimal treatment for this disease is still controversial. CASE SUMMARY: We present two middle-aged women (48 and 56 years old) with malignant AME of the breast. Core needle biopsy was performed before surgery. However, breast adenoma and malignant tumors were observed. The preoperative diagnosis of malignant AME of the breast is still challenging for pathologists and clinicians. Both patients underwent mastectomy and sentinel lymph node biopsy, both of which were negative, followed by adjuvant chemotherapy. CONCLUSION: The follow-up duration of the two patients was two years and four months, respectively. No signs of relapse or metastasis have been observed thus far.

LncRNA LGALS8-AS1 Promotes Breast Cancer Metastasis Through miR-125b-5p/SOX12 Feedback Regulatory Network.

BACKGROUND: Metastasis is a major factor weakening the long-term survival of breast cancer patients. Increasing evidence revealed that long non-coding RNAs (lncRNAs) were involved in the occurrence and development of breast cancer. In this study, we aimed to investigate the role of LGALS8-AS1 in the metastatic progression of breast cancer cells and its potential mechanisms. RESULTS: The lncRNA LGALS8-AS1 was highly expressed in breast cancer and associated with poor survival. LGALS8-AS1 functioned as an oncogenic lncRNA that promoted the metastasis of breast cancer both in vitro and in vivo. It upregulated SOX12 via competing as a competing endogenous RNA (ceRNA) for sponging miR-125b-5p and acted on the PI3K/AKT signaling pathway to promote the metastasis of breast cancer. Furthermore, SOX12, in turn, activated LGALS8-AS1 expression via direct recognition of its sequence binding enrichment motif on the LGALS8-AS1 promoter, thereby forming a positive feedback regulatory loop. CONCLUSION: This study manifested a novel mechanism of LGALS8-AS1 facilitating the metastasis of breast cancer. The LGALS8-AS1/miR-125b-5p/SOX12 reciprocal regulatory loop dyscrasia promoted the migration and invasion of breast cancer cells. This signaling axis could be applicable to the design of novel therapeutic strategies against this malignancy.

AHNAK2 promotes thyroid carcinoma progression by activating the NF-κB pathway.

Thyroid carcinoma metastasis is the main reason for treatment failure; therefore, understanding the regulatory mechanisms of thyroid carcinoma metastasis is critical to treat patients with thyroid carcinoma. The present study aimed to investigate the role of AHNAK Nucleoprotein 2 (AHNAK2) in thyroid carcinoma metastasis. AHNAK2 was found to be upregulated in thyroid carcinoma tissues, especially in metastatic thyroid carcinoma tissues. Patients with high AHNAK2 expression had poor prognosis. AHNAK2 knockdown inhibited thyroid carcinoma migration, invasion, and metastasis. Mechanistic analysis showed that AHNAK2 knockdown reduced thyroid carcinoma progression by inhibiting nuclear factor kappa B (NF-κB) pathway activity. The results identified a novel target to treat metastatic thyroid carcinoma.

Glucagon-like peptide-1 attenuates cardiac hypertrophy via the AngII/AT1R/ACE2 and AMPK/mTOR/p70S6K pathways.

Glucagon-like peptide-1 (GLP-1), a novel type of glucose-lowering agent, has been reported to exert cardioprotective effects. However, the cardioprotective mechanism of GLP-1 on spontaneous hypertension-induced cardiac hypertrophy has not been fully elucidated. In this study, we revealed that liraglutide or alogliptin treatment ameliorated spontaneous hypertension-induced cardiac hypertrophy, as evidenced by decreased levels of cardiac hypertrophic markers (atrial natriuretic peptide, brain natriuretic peptide, and ß-myosin heavy chain), as well as systolic blood pressure, diastolic blood pressure, mean arterial pressure, and histological changes. Both drugs significantly reduced the levels of angiotensin II (AngII) and AngII type 1 receptor (AT1R) and upregulated the levels of AngII type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2), as indicated by a reduced AT1R/AT2R ratio. Simultaneously, treatment with liraglutide or alogliptin significantly increased GLP-1 receptor expression and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and downregulated the phosphorylation of mammalian target of rapamycin (mTOR), p70 ribosomal S6 protein kinase, and eukaryotic translation initiation factor 4E binding protein 1 in spontaneous hypertension rats. Furthermore, our data demonstrated that the AMPK inhibitor compound C or mTOR activator MHY1485 inhibited the anti-hypertrophic effect of GLP-1. In summary, our study suggests that liraglutide or alogliptin protects the heart against cardiac hypertrophy by regulating the expression of AngII/AT1R/ACE2 and activating the AMPK/mTOR pathway, and GLP-1 agonist can be used in the treatment of patients with cardiac hypertrophy.

Interleukin-8 Promotes Epithelial-to-Mesenchymal Transition via Downregulation of Mir-200 Family in Breast Cancer Cells.

The microRNA-200 (miR-200) family has been reported to be vital for the inhibition of epithelial-to-mesenchymal transition (EMT) in tumor cells. The miR-200 family represents a complex multi-factorial regulatory network which has not been well described in breast cancer. This study aimed to clarify the underlying regulatory association between IL-8 and miR-200 family in the process of EMT in breast cancer cell. In estrogen-receptor (ER) positive breast cancer cell line MCF-7, IL-8 overexpression cells were performed by lentivirus transfection as endogenous regulation with additional exogenous IL-8 stimulation. Transient overexpressions of miR-200 family were performed after endogenous or exogenous IL-8 overexpression in MCF-7 cells. IL-8 knockdown cells were constructed via siRNA and shRNA transfection in triple negative breast cancer cell line MDA-MB-231. N-cadherin, vimentin and ZEB2 were down-regulated and E-cadherin was up-regulated in IL-8 knockdown group compared with control group. On the other hand, N-cadherin, vimentin and ZEB2 were up-regulated and E-cadherin was down-regulated in IL-8 overexpression group compared with control group. This indicated IL-8 promotes EMT in breast cancer cells. Transwell assay showed that IL-8 increased the migration and invasiveness of tumor cells. Furthermore, we performed transient overexpression of miR-200 family after endogenous or exogenous IL-8 overexpression in MCF-7 cells, which showed that the miR-200 family could inhibit EMT induced by IL-8. IL-8 promoted EMT via downregulation of miR-200 family expression in breast cancer cells and increases tumor cell migration and invasion.

Glucagon-like peptide 1 reverses myocardial hypertrophy through cAMP/PKA/RhoA/ROCK2 signaling.

Myocardial hypertrophy is a major pathological and physiological process during heart failure. Glucagon-like peptide 1 (GLP-1) is a glucagon incretin hormone released from the gut endocrine L-cells that has protective effects on various cardiovascular diseases, including hypertension, atherosclerosis, and myocardial hypertrophy. However, the protective mechanisms of GLP-1 in myocardial hypertrophy remain unclear. Here, we showed that the GLP-1 agonist liraglutide and dipeptidyl peptidase 4 inhibitor alogliptin decreased heart weight and cardiac muscle cell volume in spontaneously hypertensive rats (SHR). In H9C2 cell hypertensive models induced by angiotensin II, GLP-1 treatment reduced myocardial cell volume, inhibited the expressions of atrial natriuretic peptide, brain/B-type natriuretic peptide, ß-myosin heavy chain, RhoA, and ROCK2, and decreased MLC and MYPT1 phosphorylation. When H9C2 cells were treated with H89, a PKA inhibitor, the inhibitory effect of GLP-1 disappeared, while the inhibitory role was enhanced under the treatment of Y-27632, a ROCK2 inhibitor. These results suggested that GLP-1 might reverse myocardial hypertrophy through the PKA/RhoA/ROCK2 signaling pathway.

HePTP promotes migration and invasion in triple-negative breast cancer cells via activation of Wnt/ß-catenin signaling.

AIM: Cancer metastasis remains a major challenge for the clinical management of breast cancer, especially triple-negative breast cancer (TNBC), and the underlying molecular mechanisms remain largely unknown. The aim of this study was to explore the mechanism of TNBC metastasis. MAIN METHODS: The expression of protein tyrosine phosphatase, non-receptor type 7 (HePTP) was detected using real time-PCR, western blot. Wound healing assay and transwell matrix assay were used to evaluate the pro-migration and pro-invasion potential of HePTP in vitro. Luciferase activity assay and nuclear extract analysis were used to evaluate Wnt/ß-catenin signaling activity. KEY FINDINGS: We reported that HePTP was overexpressed in TNBC, where it acted to drive migration and invasion of tumor cells. We showed that knockdown of HePTP significantly suppressed metastatic capacity of TNBC cells. Moreover, HePTP promoted cells migration and invasion by dephosphorylating glycogen synthase kinase 3 beta (GSK3ß), thereby activating Wnt/ß-catenin signaling. Additionally, we demonstrated that overexpression of HePTP in HePTP lowly expressed cells could effectively promote the migration and invasion of breast cancer cells. SIGNIFICANCE: Our results suggest that HePTP plays a key role in the metastasis of TNBC via activating Wnt/ß-catenin signaling. Hence, we propose that HePTP may serve as a novel prognostic marker and a potential therapeutic target for the treatment of TNBC.

LUTI: a double-function inhibitor isolated from naked flax seeds.

Acute glucose fluctuation during the postprandial period causes a risk for type 2 diabetes mellitus (T2DM). α-Glucosidase inhibitors have been approved as therapeutic agents for diabetes. In the present study, a protein with α-glucosidase inhibitory activity from Flax (Linum usitatissimum) seeds was isolated using a one-step purification with Q-Sepharose4B column, followed by Sephacryl S-200 size-exclusion chromatography. It was identified as a trypsin inhibitor, named L. usitatissimum trypsin inhibitor (LUTI). The half maximal inhibitory concentration (IC50) of LUTI was 113.92 µM for α-glucosidase and 6.17 µM for trypsin. Lineweaver-Burk kinetic experiment showed that the protein exhibited two distinct inhibitory modes, a competitive inhibitor type for α-glucosidase and a non-competitive type for trypsin. The interaction between LUTI and α-glucosidase was detected through gel filtration chromatography and dynamic light scattering. Increased glucose consumption and lactic acid production were also observed following LUTI treatment in Caco-2 and HepG2 cells. LUTI inhibits not only the activity of trypsin but also the activity of α-glucosidase. It is expected that LUTI will become an oral hypoglycemic polypeptide drug for T2DM.

Prospect for Application of PARP Inhibitor in Patients with HER2 Negative Breast Cancer.

Human epidermal growth factor receptor (HER2) negative metastatic breast cancer (BC) accounts for 73% of BC. The molecular analysis of this disease is essential for potential options for targeted therapy. Several promising clinical strategies are being evaluated which includes endocrine therapy, modified chemotherapy, angiogenesis inhibitors, immune checkpoint inhibitors, and anti-androgens. New therapeutic approaches are being developed that target BC patients with germline mutations in either BRCA1, BRCA2 as well as BRCAness, a condition in which tumors have molecular similarity to BRCA-mutated tumors. Poly (ADP-ribose) polymerase inhibitors (PARPi) which are effective therapy in germline BRCA1 and BRCA2 mutations, are also observed to be effective in somatic mutations. Germline mutations in the homologous recombination pathway genes could also contribute to PARPi sensitivity. PARPi act as chemo- and radio-sensitizers by limiting the DNA-damage response and potentiating the activity of chemo- and radio-therapy when used alone or in combination with chemotherapy. Apart from PARPi as monotherapy, additional researches are ongoing in combination with cytotoxic chemotherapeutics and targeted agents in HER2 negative BC. This review aims at the most recent developments in the targeted therapy, summarizes the recent clinical trials outcomes, along with the overview of ongoing clinical trials in HER2 negative patients with BRCA1/2 mutations and sporadic tumors with BRCAness.

Comparison of the 7th and 8th edition of American Joint Committee on Cancer (AJCC) staging systems for breast cancer patients: a Surveillance, Epidemiology and End Results (SEER) Analysis.

BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for breast cancer has incorporated tumor grade, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status as staging biologic factors reflecting prognosis. The purpose of this study was to compare the 7th and 8th edition of AJCC staging system for prognostic impact. MATERIALS AND METHODS: Primary breast cancer patients diagnosed from 2010 to 2014 were identified using the Surveillance, Epidemiology and End Results 18 registries research database. Breast cancer-specific survival (BCSS) and overall survival (OS) between stages were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariable analysis was performed using Cox proportional hazards regression analysis to identify factors independently associated with outcome. Akaike's information criterion (AIC) was calculated to estimate how well the staging system fitted the data and the complexity of the model. RESULTS: A total of 184,221 primary breast cancer patients were identified in the 7th AJCC staging system; 16,145 (8.8%) patients could not be categorized according to 8th AJCC prognostic staging system leaving 168,076 patients included for final analyses. The 8th AJCC performed well with the BCSS and OS concordant with stage. A total of 89,494 (53.2%) of patients were restaged to a different stage group in the 8th AJCC; stage IIIA in the 7th AJCC migrated to stage IB with a worse prognosis than IIA and IIB in the 8th AJCC. Nevertheless, the 8th AJCC had a better AIC than the 7th staging system. CONCLUSION: The prognostic accuracy of the 8th AJCC staging system was generally superior to the 7th AJCC, although subtle differences between the two systems should be noted in comparative studies.