circBRAF promotes the progression of triple-negative breast cancer through modulating methylation by recruiting KDM4B to histone H3K9me3 and IGF2BP3 to mRNA.

Understanding the molecular characteristics of triple-negative breast cancer (TNBC) and developing more tailored treatment approaches is crucial. Circular RNAs (circRNAs), as potential therapeutic targets, remain largely unexplored in TNBC. This study utilized circRNA microarray analysis to determine the expression of circRNAs in TNBC, analyzing nine patient specimens. The characteristics of circBRAF were examined using divergent PCR primers, Sanger sequencing, fluorescence in situ hybridization (FISH) analysis, and the application of RNase and actinomycin D. The biological function of circBRAF in TNBC was further investigated through colony formation, tube formation, and transwell assays. Crucially, the mechanisms underlying the effects of circBRAF on TNBC progression were explored via RNA immunoprecipitation sequencing (RIP-seq) data, MS2 pulldown, RNA sequencing (RNA-seq) analysis, circBRAF knockdown, histone H3K9me3 modification, and Chromatin Isolation by RNA Purification (ChIRP) tests followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). We focused particularly on hsa_circ_0007178, produced from exons 4-13 of the oncogene BRAF. Functional experiments revealed that circBRAF is crucial for the development of TNBC, with its knockdown preventing angiogenesis, metastasis, and cell division in vitro. Mechanistically, circBRAF interacts with KDM4B and IGF2BP3, promoting TNBC growth. Interaction of circBRAF with IGF2BP3 increased the expression of VCAN, FN1, CDCA3, or B4GALT3 by controlling mRNA stability through RNA N6-methyladenosine (m6A) modification. Furthermore, circBRAF upregulated the expression of ADAMTS14 and MMP9 through recruitment of KDM4B to enhance respective H3K9me3 modification. Furthermore, overexpression of circBRAF was able to overcome the inhibitory effects of siKDM4B and siIGF2BP3 on cell migration and invasion. Our findings suggest that circBRAF may act as an oncogene in TNBC through its specific interactions with KDM4B and IGF2BP3, implying that circBRAF could serve as a potentially effective novel therapeutic target for TNBC.

An Injectable Puerarin Depot Can Potentiate Chimeric Antigen Receptor Natural Killer Cell Immunotherapy Against Targeted Solid Tumors by Reversing Tumor Immunosuppression.

Chimeric antigen receptor natural killer (CAR-NK) cell therapy represents a potent approach to suppressing tumor growth because it has simultaneously inherited the specificity of CAR and the intrinsic generality of NK cells in recognizing cancer cells. However, its therapeutic potency against solid tumors is still restricted by insufficient tumor infiltration, immunosuppressive tumor microenvironments, and many other biological barriers. Motivated by the high potency of puerarin, a traditional Chinese medicine extract, in dilating tumor blood vessels, an injectable puerarin depot based on a hydrogen peroxide-responsive hydrogel comprising poly(ethylene glycol) dimethacrylate and ferrous chloride is concisely developed. Upon intratumoral fixation, the as-prepared puerarin depot (abbreviated as puerarin@PEGel) can activate nitrogen oxide production inside endothelial cells and thus dilate tumor blood vessels to relieve tumor hypoxia and reverse tumor immunosuppression. Such treatment can thus promote tumor infiltration, survival, and effector functions of customized epidermal growth factor receptor (HER1)-targeted HER1-CAR-NK cells after intravenous administration. Consequently, such puerarin@PEGel-assisted HER1-CAR-NK cell treatment exhibits superior tumor suppression efficacy toward both HER1-overexpressing MDA-MB-468 and NCI-H23 human tumor xenografts in mice without inducing obvious side effects. This study highlights a potent strategy to activate CAR-NK cells for augmented treatment of targeted solid tumors through reprogramming tumor immunosuppression.

Role and function of plakophilin 3 in cancer progression and skin disease.

Plakophilin 3 (PKP3), a component of desmosome, is aberrantly expressed in many kinds of human diseases, especially in cancers. Through direct interaction, PKP3 binds with a series of desmosomal proteins, such as desmoglein, desmocollin, plakoglobin, and desmoplakin, to initiate desmosome aggregation, then promotes its stability. As PKP3 is mostly expressed in the skin, loss of PKP3 promotes the development of several skin diseases, such as paraneoplastic pemphigus, pemphigus vulgaris, and hypertrophic scar. Moreover, accumulated clinical data indicate that PKP3 dysregulates in diverse cancers, including breast, ovarian, colon, and lung cancers. Numerous lines of evidence have shown that PKP3 plays important roles in multiple cellular processes during cancer progression, including metastasis, invasion, tumor formation, autophagy, and proliferation. This review examines the diverse functions of PKP3 in regulating tumor formation and development in various types of cancers and summarizes its detailed mechanisms in the occurrence of skin diseases.

Optimization of tetrastigma hemsleyanum extraction process based on GA-BPNN model and analysis of its antioxidant effect.

Tetrastigma hemsleyanum (Tetrastigma hemsleyanum Diels et Gilg) is a valuable traditional Chinese medicine with various applications. In this study, we aimed to optimize the extraction process for the total extraction yield of five flavonoid components, namely kaempferol, quercetin, rutin, kaempferol-3-O-rutinoside, and astragalin from the Tetrastigma hemsleyanum root (THR), and explore its potential molecular mechanisms in treating oxidative diseases as well as antioxidant activity. To achieve these objectives, we employed the genetic algorithm-back propagation neural network (GA-BPNN), the Box-Behnken design (BBD) with 4-factors and 3-levels to establish the optimal ethanol extraction process for the total extraction yield of the 5 components. Using public databases, the "component core targets-disease core target genes" networks were built, as well as molecular docking. Furthermore, DPPH was used to examine the antioxidant activity of the extracts obtained from THR under the optimal extraction process. The experimental value of the total extraction yield of the 5 components achieved a maximum of 788.12 mg/kg when the ethanol concentration was 73%, the solid-liquid ratio was 26 g/mL, and the ultrasonic duration was 30 min, and the ultrasonic temperature was 76 °C. When docked with protein molecules such as 6Y8I, quercetin, and other components received moderate to high scores. When the total concentration of the 5 components was 3.033 µg/mL, the DPPH radical scavenging rate was 89.81%. Compared with the BBD method, the GA-BPNN method is more efficient and reliable for optimizing the extraction process of active ingredients in THR because of its good data-fitting ability.

Role of ADAM33 short isoform as a tumor suppressor in the pathogenesis of thyroid cancer via oncogenic function disruption of full-length ADAM33.

Thyroid cancer is the most prevalent endocrine malignancy globally; however, its underlying pathogenesis remains unclarified. Reportedly, alternative splicing is involved in processes such as embryonic stem and precursor cell differentiation, cell lineage reprogramming, and epithelial-mesenchymal transitions. ADAM33-n, an alternative splicing isoform of ADAM33, encodes a small protein containing 138 amino acids of the N-terminal of full-length ADAM33, which constructs a chaperone-like domain that was previously reported to bind and block the proteolysis activity of ADAM33. In this study, we reported for the first time that ADAM33-n was downregulated in thyroid cancer. The results of cell counting kit-8 and colony formation assays showed that ectopic ADAM33-n in papillary thyroid cancer cell lines restricted cell proliferation and colony formation. Moreover, we demonstrated that ectopic ADAM33-n reversed the oncogenic function of full-length ADAM33 in cell growth and colony formation in the MDA-T32 and BCPAP cells. These findings indicate the tumor suppressor ability of ADAM33-n. Altogether, our study findings present a potential explanatory model of how the downregulation of the oncogenic gene ADAM33 promotes the pathogenesis of thyroid cancer.

TNFRSF9 Suppressed the Progression of Breast Cancer via the p38MAPK/PAX6 Signaling Pathway.

Worldwide, breast cancer is the most common cancer in females. Endocrine therapy can effectively treat 85% of breast cancer patients, but 15% of patients could only be treated with chemotherapy and surgery, and the prognosis is much worse. Immunotherapy is the novel treatment for breast cancer, where PD-1 and CTLA-4 antibodies have shown evidence of immune modulation in breast cancer drug trials. In this study, we report that TNFRSF9 regulates the cell proliferation, invasion, and apoptosis of breast cancer cells through regulating the phosphorylation of p38, thus further regulating the expression of PAX6. In both breast cancer tissues and cell lines, the levels of TNFRSF9 are significantly decreased, and breast cancer cell development will be promoted with knockdown of TNFRSF9. Moreover, we identify that downregulation of TNFRSF9 can upregulate the phosphorylated p38 (p-p38) and PAX6. We further elucidate that p-p38 is essential for PAX6 expression as p38 phosphorylation inhibitor can reverse the upregulation of PAX6 and suppress cell proliferation and invasion and promote apoptosis in breast cancer cells. In summary, this study proposed a novel TNFRSF9/p38/PAX6 axis that contributes to tumor suppression, which suggests a potential immunotherapy target for breast cancer.

Clinical Effect of the Treatment of Lumbar Intervertebral Disc Protrusion.

Compared with traditional acupuncture, it is urgently needed for more effective method for the disease to serve the clinical treatment. This paper combines acupuncture and massage to treat lumbar intervertebral disc protrusion, uses a controlled trial to study the clinical effects of acupuncture combined with massage for the treatment of lumbar intervertebral disc protrusion, combines mathematical statistics to test the data, and compares and analyzes the statistical object parameters. Through experimental research, it is known that in the treatment of lumbar intervertebral disc protrusion, in order to obtain a faster and better effect, traditional acupuncture treatment should be combined with massage therapy. On the basis of fully eliminating the pathological factors, the intervertebral disc is reset by mechanical treatment, which makes the patient more likely to heal. Therefore, it is a comprehensive treatment plan that is worth adopting.

Molecular profiles and circulating tumor-DNA detected in Chinese early stage breast cancer.

Background: With the development of gene-sequencing technology, genome biomarkers, including Erb-B2 receptor tyrosine kinase 2 (ERBB2), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (pIK3CA), BReast CAncer gene 1 (BRCA1), and BReast CAncer gene 2 (BRCA2), and immunomarkers, including the tumor mutational burden (TMB) and programmed death-ligand 1 (PD-L1), have become important in the selection of treatment. Methods: Twenty patients with early stage breast cancer who underwent surgery were enrolled in this study. Tissue samples and paired postoperative peripheral blood samples were collected and subjected to the targeted-capture sequencing of 1,021 cancer-associated genes. Results: The most frequently altered genes were tumor protein 53 (TP53; 70%), PIK3CA (40%), protooncogene MYC (35%), ERBB2 (30%), and cyclin-dependent kinase 12 (CDK12; 20%). Six (30%) patients presented with ERBB2 amplification of NGS and simultaneously were positive for human epidermal growth factor receptor 2 (HER2) of IHC. ERBB2 amplification and being HER2 positive were common in breast cancer patients without lymph node metastasis (5/6, 83.3%) and those in stages IA-IIA. Most of the somatic mutations clustered in the TP53 pathway, followed by the PI3K pathway. The TMB was lower than metastatic breast cancer in our cohort, and ranged from 0 to 9.6 mut/Mb (median: 1.92 mut/Mb). Interestingly, more patients had the ERBB2 mutation in the non-lymph node metastasis group than the lymph node metastasis group (55.6% vs. 9.1%; P=0.049). Similarly, more patients had the CDK12 mutation in the non-lymph node metastasis group than the lymph node metastasis group (44.4% vs. 0%; P=0.026). Circulating tumor deoxyribonucleic acid (ctDNA) was detected in 7 of the 20 patients (35%). Of these patients, 71.4% (5/7) were in stage I/II. In addition, no correlation was found between ctDNA detection and clinicopathological features or the driver gene mutations (e.g., PIK3CA and ERBB2). However, patients positive for ctDNA had a higher TMB than those negative for ctDNA when grouped according to the median TMB (1.92 mut/Mb; 85.7% vs. 38.5%; P=0.043). Conclusions: This study described that genomic characteristics of Chinese early stage breast cancer, and the results showed that TMB was related to the detection of ctDNA in postoperative blood.

Inhibition Lysosomal Degradation of Clusterin by Protein Kinase D3 Promotes Triple-Negative Breast Cancer Tumor Growth.

Triple negative breast cancer (TNBC), with its lack of targeted therapies, shows the worst mortality rate among all breast cancer subtypes. Clusterin (CLU) is implicated to play important oncogenic roles in cancer via promoting various downstream oncogenic pathways. Here, protein kinase D3 (PRKD3) is defined to be a key regulator of CLU in promoting TNBC tumor growth. Mechanically, PRKD3 with kinase activity binding to CLU is critical for CLU protein stability via inhibiting CLU's lysosomal distribution and degradation. CLU and PRKD3 protein level are significantly elevated and positively correlated in collected TNBC tumor samples. CLU silencer (OGX-011) and PRKDs inhibitor (CRT0066101) can both result in impressive tumor growth suppression in vitro and in vivo, suggesting targeting CLU and its key regulator-PRKD3 are promisingly efficient against TNBC. Finally, secreted CLU (sCLU) is found to be elevated in serums from TNBC patients and reduced in serum from TNBC murine models post OGX-011 and/or CRT0066101 treatment, suggesting serum sCLU is a promising blood-based biomarker for clinical management of TNBC. Taken together, this study provides a thorough molecular basis as well as preclinical evidences for targeting CLU pathway as a new promising strategy against TNBC via revealing PRKD3 as the key regulator of CLU in TNBC.

CircWAC induces chemotherapeutic resistance in triple-negative breast cancer by targeting miR-142, upregulating WWP1 and activating the PI3K/AKT pathway.

BACKGROUND: Chemotherapeutic resistance is the main cause of clinical treatment failure and poor prognosis in triple-negative breast cancer (TNBC). There is no research on chemotherapeutic resistance in TNBC from the perspective of circular RNAs (circRNAs). METHODS: TNBC-related circRNAs were identified based on the GSE101124 dataset. Quantitative reverse transcription PCR was used to detect the expression level of circWAC in TNBC cells and tissues. Then, in vitro and in vivo functional experiments were performed to evaluate the effects of circWAC in TNBC. RESULTS: CircWAC was highly expressed in TNBC and was associated with worse TNBC patient prognosis. Subsequently, it was verified that downregulation of circWAC can increase the sensitivity of TNBC cells to paclitaxel (PTX) in vitro and in vivo. The expression of miR-142 was negatively correlated with circWAC in TNBC. The interaction between circWAC and miR-142 in TNBC cells was confirmed by RNA immunoprecipitation assays, luciferase reporter assays, pulldown assays, and fluorescence in situ hybridization. Mechanistically, circWAC acted as a miR-142 sponge to relieve the repressive effect of miR-142 on its target WWP1. In addition, the overall survival of TNBC patients with high expression of miR-142 was significantly better than that of patients with low expression of miR-142, and these results were verified in public databases. MiR-142 regulated the expression of WWP1 and the activity of the PI3K/AKT pathway. It was confirmed that WWP1 is highly expressed in TNBC and that the prognosis of patients with high WWP1 expression is poor. CONCLUSIONS: CircWAC/miR-142/WWP1 form a competing endogenous RNA (ceRNA) network to regulate PI3K/AKT signaling activity in TNBC cells and affect the chemosensitivity of cells.

The oncogenic role of protein kinase D3 in cancer.

Protein kinase D3 (PRKD3), a serine/threonine kinase, belongs to protein kinase D family, which contains three members: PRKD1, PRKD2, and PRKD3. PRKD3 is activated by many stimuli including phorbol esters, and G-protein-coupled receptor agonists. PRKD3 promotes cancer cell proliferation, growth, migration, and invasion in various tumor types including colorectal, gastric, hepatic, prostate, and breast cancer. Accumulating data supports that PRKD3 is a promising therapeutic target for treatment of cancer. This review discusses the functions and mechanisms of PRKD3 in promoting tumorigenesis and tumor progression of various tumor types as well as the latest developments of small-molecule inhibitors selection for PRKD/PRKD3.

Circular RNA circRPPH1 promotes triple-negative breast cancer progression via the miR-556-5p/YAP1 axis.

Circular RNAs (circRNAs), which are considered to be important functional regulators in cancer, have provided a new perspective regarding our understanding of tumor biology, including that of breast cancer. To investigate the regulatory effect of circRPPH1 on cellular behaviors of breast cancer and the potential mechanism, the expression of circRPPH1 and miR-556-5p in breast cancer tissues and cell lines were examined by quantitative RT-PCR. The regulatory effects of the circRPPH1/miR-556-5p/YAP1 axis on cellular behaviors of breast cancer cells were evaluated through functional experiments in vitro and tumor growth in vivo. The relationship between circRPPH1 and miR-556-5p/YAP1 was assessed using dual-luciferase reporter and RNA immunoprecipitation assays. PCR results showed that circRPPH1 levels were significantly upregulated in tumor tissues and breast cancer cells. Functionally, circRPPH1 promoted the proliferation, migration, invasion, and angiogenesis of breast cancer cell lines and tumor growth in vivo. Regarding the mechanism, dual-luciferase reporter and RNA immunoprecipitation assays showed that circRPPH1 was capable of sponging miR-556-5p to increase expression of the oncogene YAP1. Our data reveal that circRPPH1 plays a vital regulatory role in breast cancer via the miR-556-5p/YAP1 axis and may serve as a promising therapeutic target for breast cancer treatment.

Targeting epidermal growth factor-overexpressing triple-negative breast cancer by natural killer cells expressing a specific chimeric antigen receptor.

OBJECTIVES: Traditional cancer therapy and regular immunotherapy are ineffective for treating triple-negative breast cancer (TNBC) patients. Recently, chimeric antigen receptor-engineered natural killer cells (CAR NK) have been applied to target several hormone receptors on different cancer cells to improve the efficacy of immunotherapy. Furthermore, epidermal growth factor receptor (EGFR) is a potential therapeutic target for TNBC. Here, we demonstrated that EGFR-specific CAR NK cells (EGFR-CAR NK cells) could be potentially used to treat patients with TNBC exhibiting enhanced EGFR expression. MATERIALS AND METHODS: We investigated the cytotoxic effects of EGFR-CAR NK cells against TNBC cells in vitro and in vivo. The two types of EGFR-CAR NK cells were generated by transducing lentiviral vectors containing DNA sequences encoding the single-chain variable fragment (scFv) regions of the two anti-EGFR antibodies. The cytotoxic and anti-tumor effects of the two cell types were examined by performing cytokine release and cytotoxicity assays in vitro, and tumor growth assays in breast cancer cell line-derived xenograft (CLDX) and patient-derived xenograft (PDX) mouse models. RESULTS: Both EGFR-CAR NK cell types were activated by TNBC cells exhibiting upregulated EGFR expression and specifically triggered the lysis of the TNBC cells in vitro. Furthermore, the two EGFR-CAR NK cell types inhibited CLDX and PDX tumors in mice. CONCLUSIONS: This study suggested that treatment with EGFR-CAR NK cells could be a promising strategy for TNBC patients.

Prognostic value of the systemic inflammation response index (SIRI) before and after surgery in operable breast cancer patients.

BACKGROUND: The new systemic inflammation response index (SIRI) constructed based on neutrophil, monocyte and lymphocyte counts in peripheral blood is considered to be related to the prognosis of a variety of tumours. OBJECTIVE: To evaluate the prognostic value of the SIRI in operable breast cancer patients and establish a nomogram to predict the survival of breast cancer patients. METHODS: A total of 949 patients with operable breast cancer were enrolled in the present study. RESULTS: The overall survival (OS) of breast cancer patients with SIRI ⩽ 0.65 was significantly higher than that of breast cancer patients with SIRI > 0.65 (P< 0.001). A nomogram generated based on SIRI, grade and TNM stage and SIRI predicted the 5- and 10-year survival rates of breast cancer patients more accurately than TNM stage alone. In addition, the change in SIRI relative to baseline at 4 weeks after surgery was closely related to the survival of breast cancer patients. Compared with those with no SIRI changes (absolute value of variation < 25%), breast cancer patients with an increase in SIRI > 75% or 25-75% had worse OS (P< 0.001). CONCLUSIONS: The SIRI before and after surgery is closely related to the prognosis of breast cancer patients.

Protein Kinase D3 promotes the cell proliferation by activating the ERK1/c-MYC axis in breast cancer.

Breast cancer is the second leading death cause of cancer death for all women. Previous study suggested that Protein Kinase D3 (PRKD3) was involved in breast cancer progression. In addition, the protein level of PRKD3 in triple-negative breast adenocarcinoma was higher than that in normal breast tissue. However, the oncogenic mechanisms of PRKD3 in breast cancer is not fully investigated. Multi-omic data showed that ERK1/c-MYC axis was identified as a major pivot in PRKD3-mediated downstream pathways. Our study provided the evidence to support that the PRKD3/ERK1/c-MYC pathway play an important role in breast cancer progression. We found that knocking out PRKD3 by performing CRISPR/Cas9 genome engineering technology suppressed phosphorylation of both ERK1 and c-MYC but did not down-regulate ERK1/2 expression or phosphorylation of ERK2. The inhibition of ERK1 and c-MYC phosphorylation further led to the lower protein level of c-MYC and then reduced the expression of the c-MYC target genes in breast cancer cells. We also found that loss of PRKD3 reduced the rate of the cell proliferation in vitro and tumour growth in vivo, whereas ectopic (over)expression of PRKD3, ERK1 or c-MYC in the PRKD3-knockout breast cells reverse the suppression of the cell proliferation and tumour growth. Collectively, our data strongly suggested that PRKD3 likely promote the cell proliferation in the breast cancer cells by activating ERK1-c-MYC axis.

EGFR-specific CAR-T cells trigger cell lysis in EGFR-positive TNBC.

Triple-negative breast cancer (TNBC) is an aggressive cancer subtype for which effective therapies are lacking. Epidermal growth factor receptor (EGFR) is overexpressed in various types of TNBC cells, and several EGFR-specific immunotherapies have been used to treat cancer patients. Chimeric antigen receptor engineered T (CAR-T) cells have also been used as cancer therapies. In this study, we generated two types of EGFR-specific CAR-modified T cells using lentiviral vectors with DNA sequences encoding the scFv regions of two anti-EGFR antibodies. The cytotoxic and antitumor effects of these CAR-modified T cells were examined in cytokine release and cytotoxicity assays in vitro and in tumor growth assays in TNBC cell line- and patient-derived xenograft mouse models. Both types of EGFR-specific CAR-T cells were activated by high-EGFR-expressing TNBC cells and specifically triggered TNBC cell lysis in vitro. Additionally, the CAR-T cells inhibited growth of cell-line- and patient-derived xenograft TNBC tumors in mice. These results suggest that EGFR-specific CAR-T cells might be a promising therapeutic strategy in patients with high-EGFR-expressing TNBC.

The Role and Mechanism of CRT0066101 as an Effective Drug for Treatment of Triple-Negative Breast Cancer.

BACKGROUND/AIMS: Breast cancer is clinically classified into three main subtypes: estrogen receptor-positive (ER+) breast cancer, human epidermal growth factor receptor 2-positive (HER2+) breast cancer, and triple-negative breast cancer (TNBC). Without specific targeted therapies, patients with TNBC have poorer prognosis compared with those with ER+ and HER2+ breast cancer. Protein kinase D (PRKD) family members play crucial roles in cancer progression. CRT0066101, a PRKD inhibitor, has been reported to have anticancer activity in many cancer types. Nevertheless, the role and mechanism of CRT0066101 in TNBC have not been well investigated. METHODS: The expression level of PRKDs was analyzed in breast cancer samples and breast cancer cell lines. The effects of inhibiting PRKD activity with CRT0066101 on TNBC cell proliferation, cell cycle, apoptosis, and tumor growth were studied by Cell Counting Kit8 assay, cell cycle assay, propidium iodide/annexin-V assay, and a xenograft mouse model, respectively. To uncover the molecular mechanism of CRT0066101 in TNBC, comparative phosphoproteomic analysis using iTRAQ was employed. RESULTS: We found that PRKD2 and PRKD3 were preferentially expressed in breast cancers. Immunohistochemistry confirmed the overexpression of PRKD2 and PRKD3 in TNBC. CRT0066101, which inhibited the activity of PRKDs, dramatically inhibited proliferation, increased apoptosis and the G1-phase population of TNBC cells in vitro, and reduced breast tumor volume in vivo. Comparative phosphoproteomic analysis between breast cancer cells with and without CRT0066101 treatment revealed that the anti-breast cancer effects involved regulation of a complex network containing multiple enriched pathways and several hub-nodes contributing to multiple cancer-related processes, thus explaining the described effects of CRT0066101 on TNBC in vitro and in vivo. Finally, we validated several targets of PRKD inhibition by treatment with CRT0066101 and small interfering RNAs against PRKD2 and PRKD3 (siPRKD2 and siPRKD3), including p-MYC(T58/ S62), p-MAPK1/3(T202/Y204), p-AKT(S473), p-YAP(S127), and p-CDC2(T14). CONCLUSION: PRKD inhibitor CRT0066101 exhibits anti-TNBC effects via modulating a phosphor-signaling network and inhibiting the phosphorylation of many cancer-driving factors, including MYC, MAPK1/3, AKT, YAP, and CDC2, providing insight into the important roles as well as the molecular mechanism of CRT0066101 as an effective drug for TNBC.

Oncogenic functions of protein kinase D2 and D3 in regulating multiple cancer-related pathways in breast cancer.

Protein Kinase D (PKD) family contains PKD1, PKD2, and PKD3 in human. Compared to consistent tumor-suppressive functions of PKD1 in breast cancer, how PKD2/3 functions in breast cancer are not fully understood. In the current study, we found that PKD2 and PKD3 but not PKD1 were preferentially overexpressed in breast cancer and involved in regulating cell proliferation and metastasis. Integrated phosphoproteome, transcriptome, and interactome showed that PKD2 was associated with multiple cancer-related pathways, including adherent junction, regulation of actin cytoskeleton, and cell cycle-related pathways. ELAVL1 was identified as a common hub-node in networks of PKD2/3-regulated phosphoproteins and genes. Silencing ELAVL1 inhibited breast cancer growth in vitro and in vivo. Direct interaction between ELAVL1 and PKD2 or PKD3 was demonstrated. Suppression of PKD2 led to ELAVL1 translocation from the cytoplasm to the nucleus without significant affecting ELAVL1 expression. Taken together, we characterized the oncogenic functions of PKD2/3 in breast cancer and their association with cancer-related pathways, which shed lights on the oncogenic roles and mechanisms of PKDs in breast cancer.

Dual drug loaded coaxial electrospun PLGA/PVP fiber for guided tissue regeneration under control of infection.

Electrospinning promisingly fabricate mats for Guided Tissue Regeneration (GTR). Due to a chronic inflammatory pathology in periodontal, it is highly desirable to develop a novel GTR mats to realize tissue regeneration under control of infection. In the study, coaxial electrospinning was firstly conducted to fabricate dual drug loaded fiber mats with core/shell structure. Naringin-loaded polyvinylpyrrolidone was designed as core fiber to enrich tissue regeneration and metronidazole-loaded poly(lactic-co-glycolic acid) as shell fiber to inhibit bacterial. TEM revealed that the fibers with distinct core/shell structure were in an outer diameter of 1.5-1.7 µm with an inner diameter of <1.0 µm. The loading of dual drug decreased the tensile strength and elongation of the coaxial fiber mats. On in vitro assessment, metronidazole had a short-term release while naringin had a long-term release behavior in all the coaxial mats. The colonization of anaerobic bacteria on the mats effectively were inhibited over 21 days. Furthermore, the dual drug loaded coaxial fiber mats were observed to positively supported the adhesion and proliferation of MC3T3-E1 and was conductive to high alkaline phosphatase express. Thus, a simple and effective coaxial electrospinning approach was demonstrated for the fabrication of anti-infective GTR mats with promoting tissue regeneration.

Acute Primary Angle Closure in the Fellow Eye as a Complication of Facedown Position After Vitrectomy Surgery.

PURPOSE: To report a case of acute primary angle closure that developed in the fellow eye rapidly after facedown position after vitrectomy surgery. PATIENTS AND METHODS: A 66-year-old female developed acute primary angle closure in the fellow eye approximately 1.5 hours after facedown position after vitrectomy surgery for macular hole. RESULTS: The intraocular pressure was controlled after treatment that included halting the facedown position, intravenous mannitol injection, and topical pilocarpine instillation. Facedown position was continued after laser peripheral iridotomy was performed. The intraocular pressure was controlled within normal range even after pilocarpine was withdrawn. CONCLUSIONS: Although rare, the potential risk of acute-angle closure should be explicitly explained to patients being considered for facedown position after vitrectomy. Prophylactic intervention, such as laser peripheral iridotomy, could be considered for anatomically predisposed eyes.