Ceritinib is a novel triple negative breast cancer therapeutic agent.

BACKGROUND: Triple-negative breast cancers (TNBCs) are clinically aggressive subtypes of breast cancer. TNBC is difficult to treat with targeted agents due to the lack of commonly targeted therapies within this subtype. Androgen receptor (AR) has been detected in 12-55% of TNBCs. AR stimulates breast tumor growth in the absence of estrogen receptor (ER), and it has become an emerging molecular target in TNBC treatment. METHODS: Ceritinib is a small molecule inhibitor of tyrosine kinase and it is used in the therapy of non-small lung cancer patients. Enzalutamide is a small molecule compound targeting the androgen receptor and it is used to treat prostate cancer. Combination therapy of these drugs were investigated using AR positive breast cancer mouse xenograft models. Also, combination treatment of ceritinib and paclitaxel investigated using AR- and AR low mouse xenograft and patient derived xenograft models. RESULTS: We screened 133 FDA approved drugs that have a therapeutic effect of AR+ TNBC cells. From the screen, we identified two drugs, ceritinib and crizotinib. Since ceritinib has a well- defined role in androgen independent AR signaling pathways, we further investigated the effect of ceritinib. Ceritinib treatment inhibited RTK/ACK/AR pathway and other downstream pathways in AR+ TNBC cells. The combination of ceritinib and enzalutamide showed a robust inhibitory effect on cell growth of AR+ TNBC cells in vitro and in vivo. Interestingly Ceritinib inhibits FAK-YB-1 signaling pathway that leads to paclitaxel resistance in all types of TNBC cells. The combination of paclitaxel and ceritinib showed drastic inhibition of tumor growth compared to a single drug alone. CONCLUSIONS: To improve the response of AR antagonist in AR positive TNBC, we designed a novel combinational strategy comprised of enzalutamide and ceritinib to treat AR+ TNBC tumors through the dual blockade of androgen-dependent and androgen-independent AR signaling pathways. Furthermore, we introduced a novel therapeutic combination of ceritinib and paclitaxel for AR negative or AR-low TNBCs and this combination inhibited tumor growth to a great extent. All agents used in our study are FDA-approved, and thus the proposed combination therapy will likely be useful in the clinic.

Endoscopy-aided retrieval of broken drainage tube after lumbar spine surgery.

BACKGROUND: A ruptured drainage tube which remains in the incision is a rare surgical complication. The usual mode of retrieval is to detach the suture and explore the pre-existing incisional wound. However, spinal endoscopy provides an alternative method for successful removal, avoiding the enlargement of the surgical wound. CASE REPORT: A 53-year-old male patient underwent open lumbar spine surgery for lumbar spondylolisthesis between the 5th lumbar and 1st sacral vertebral bodies. Prior to closure, two negative pressure ball drainage tubes were inserted, one of which broke during removal,beneath the fascia. Use of spinal endoscopy enabled the complete removal of the broken drainage tube. Both the original incisional and endoscopic wounds healed well without any sign of infection. CONCLUSIONS: The use of spinal endoscopy to remove the broken drainage tube is an alternative to open the surgical wound and should be took into account.

Nischarin Deletion Reduces Oxidative Metabolism and Overall ATP: A Study Using a Novel NISCHΔ5-6 Knockout Mouse Model.

Nischarin (Nisch) is a cytosolic scaffolding protein that harbors tumor-suppressor-like characteristics. Previous studies have shown that Nisch functions as a scaffolding protein and regulates multiple biological activities. In the current study, we prepared a complete Nisch knockout model, for the first time, by deletion of exons 5 and 6. This knockout model was confirmed by Qrt-PCR and Western blotting with products from mouse embryonic fibroblast (MEF) cells. Embryos and adult mice of knockouts are significantly smaller than their wild-type counterparts. Deletion of Nisch enhanced cell migration, as demonstrated by wound type and transwell migration assays. Since the animals were small in size, we investigated Nisch's effect on metabolism by conducting several assays using the Seahorse analyzer system. These data indicate that Nisch null cells have lower oxygen consumption rates, lower ATP production, and lower levels of proton leak. We examined the expression of 15 genes involved in lipid and fat metabolism, as well as cell growth, and noted a significant increase in expression for many genes in Nischarin null animals. In summary, our results show that Nischarin plays an important physiological role in metabolic homeostasis.

Knockout model reveals the role of Nischarin in mammary gland development, breast tumorigenesis and response to metformin treatment.

Previously, our lab discovered the protein Nischarin and uncovered its role in regulating cell migration and invasion via its interactions with several proteins. We subsequently described a role for Nischarin in breast cancer, in which it is frequently underexpressed. To characterize Nischarin's role in breast tumorigenesis and mammary gland development more completely, we deleted a critical region of the Nisch gene (exons 7-10) from the mouse genome and observed the effects. Mammary glands in mutant animals showed delayed terminal end bud formation but did not develop breast tumors spontaneously. Therefore, we interbred the animals with transgenic mice expressing the mouse mammary tumor virus-polyoma middle T-antigen (MMTV-PyMT) oncogene. The MMTV-PyMT mammary glands lacking Nischarin showed increased hyperplasia compared to wild-type animal tissues. Furthermore, we observed significantly increased tumor growth and metastasis in Nischarin mutant animals. Surprisingly, Nischarin deletion decreased activity of AMPK and subsequently its downstream effectors. Given this finding, we treated these animals with metformin, which enhances AMPK activity. Here, we show for the first time, metformin activates AMPK signaling and inhibits tumor growth of Nischarin lacking PyMT tumors suggesting a potential use for metformin as a cancer therapeutic, particularly in the case of Nischarin-deficient breast cancers.

Combination treatment of bicalutamide and curcumin has a strong therapeutic effect on androgen receptor-positive triple-negative breast cancers.

Triple-negative breast cancers account for approximately 15-20% of breast cancer patients. Due to lack of expression of estrogen receptor, PR and human epidermal growth factor receptor 2 in triple-negative breast cancers, there are no targeted therapies available for these cancers. Therefore, a major research priority is to find potential therapeutic targets. Androgen receptor is present in 80-90% of all breast cancers, including 55% of estrogen receptor-α-negative cancers and 12%-35% of triple-negative breast cancers. Androgen receptor stimulates growth and survival in triple-negative breast cancer cells. Treatment with bicalutamide, an androgen receptor antagonist, has a good benefit for AR triple-negative breast cancer patients. AR triple-negative breast cancer cells were treated with curcumin or bicalutamide alone or in combination of both together. Cell growth, apoptosis and Wnt signaling pathways were examined. We found that curcumin dramatically suppressed Wnt signaling pathway in AR triple-negative breast cancer cells. Curcumin treatment inhibited androgen receptor protein expression in AR triple-negative breast cancer cells. Combination treatment of curcumin and bicalutamide has a robust increase in apoptosis. Furthermore, the combination treatment suppressed the growth of AR triple-negative breast cancer cells more effectively than with the single drug alone. Our data indicate that androgen receptor inhibition is a potential therapeutic approach for AR triple-negative breast cancers. In summary, our study for the first time shows that the combination treatment of curcumin and bicalutamide is effective in AR triple-negative breast cancer cells.

Development of insulin resistance in Nischarin mutant female mice.

BACKGROUND/OBJECTIVES: NISCH-STAB1 is a newly identified locus correlated to human waist-hip ratio (WHR), which is a risk indicator of developing obesity-associated diabetes. Our previous studies have shown that Nisch mutant male mice increased glucose tolerance in chow-fed conditions. Thus we hypothesized that Nisch mutant mice will have changes in insulin resistance, adipocytes, hepatic steatosis when mice are fed with high-fat diet (HFD). METHODS: Insulin resistance was assessed in Nisch mutant mice and WT mice fed with high-fat diet (60% by kCal) or chow diet. Whole-body energy metabolism was examined using an indirect calorimeter. Adipose depots including inguinal white adipose tissue (WAT), perigonadal WAT, retroperitoneal WAT, and mesenteric WAT were extracted. Area and eqdiameter of each adipocyte were determined, and insulin signaling was examined as well. Paired samples of subcutaneous and omental visceral adipose tissue were obtained from 400 individuals (267 women, 133 men), and examined the expression of Nischarin. RESULTS: We found that insulin signaling was impaired in major insulin-sensitive tissues of Nisch mutant female mice. When mice were fed with HFD for 15 weeks, the Nisch mutant female mice not only developed severe insulin resistance and decreased glucose tolerance compared with wild-type control mice, but also accumulated more white fat, had larger adipocytes and developed severe hepatic steatosis than wild-type control mice. To link our animal studies to human diseases, we further analyzed Nischarin expression in the paired human samples of visceral and subcutaneous adipose tissue from Caucasians. In humans, we found that Nischarin expression is attenuated in adipose tissue with obesity. More importantly, we found that Nischarin mRNA inversely correlated with parameters of obesity, fat distribution, lipid and glucose metabolism. CONCLUSIONS: Taken together, our data revealed sexual dimorphism of Nischarin in body fat distribution, insulin resistance, and glucose tolerance in mice.

Nischarin inhibition alters energy metabolism by activating AMP-activated protein kinase.

Nischarin (Nisch) is a key protein functioning as a molecular scaffold and thereby hosting interactions with several protein partners. To explore the physiological importance of Nisch, here we generated Nisch loss-of-function mutant mice and analyzed their metabolic phenotype. Nisch-mutant embryos exhibited delayed development, characterized by small size and attenuated weight gain. We uncovered the reason for this phenotype by showing that Nisch binds to and inhibits the activity of AMP-activated protein kinase (AMPK), which regulates energy homeostasis by suppressing anabolic and activating catabolic processes. The Nisch mutations enhanced AMPK activation and inhibited mechanistic target of rapamycin signaling in mouse embryonic fibroblasts as well as in muscle and liver tissues of mutant mice. Nisch-mutant mice also exhibited increased rates of glucose oxidation with increased energy expenditure, despite reduced overall food intake. Moreover, the Nisch-mutant mice had reduced expression of liver markers of gluconeogenesis associated with increased glucose tolerance. As a result, these mice displayed decreased growth and body weight. Taken together, our results indicate that Nisch is an important AMPK inhibitor and a critical regulator of energy homeostasis, including lipid and glucose metabolism.

Suppression of PDHX by microRNA-27b deregulates cell metabolism and promotes growth in breast cancer.

BACKGROUND: The disruption of normal gene regulation due to microRNA dysfunction is a common event in cancer pathogenesis. MicroRNA-27b is an example of an oncogenic miRNA, and it is frequently upregulated in breast cancer. MicroRNAs have been found to deregulate tumor metabolism, which typically manifests as heightened cellular glucose uptake in consort with increased flux through glycolysis, followed by the preferential conversion of glycolytic pyruvate into lactate (a phenomenon known as the Warburg Effect). Pyruvate Dehydrogenase, an enzyme complex linking glycolysis with downstream oxidative metabolism, represents a key location where regulation of metabolism occurs; PDHX is a key structural component of this complex and is essential for its function. METHODS: We sought to characterize the role of miR-27b in breast cancer by identifying novel transcripts under its control. We began by utilizing luciferase, RNA, and protein assays to establish PDHX as a novel target of miR-27b. We then tested whether miR-27b could alter metabolism using several metabolite assay kits and performed a seahorse analysis. We also examined how the altered metabolism might affect cell proliferation. Lastly, we confirmed the relevance of our findings in human breast tumor samples. RESULTS: Our data indicate that Pyruvate Dehydrogenase Protein X is a credible target of miR-27b in breast cancer. Mechanistically, by suppressing PDHX, miR-27b altered levels of pyruvate, lactate and citrate, as well as reducing mitochondrial oxidation and promoting extracellular acidification. These changes corresponded with an increased capacity for cell proliferation. In human breast tumor samples, PDHX expression was deficient, and low levels of PDHX were associated with reduced patient survival. CONCLUSIONS: MicroRNA-27b targets PDHX, resulting in an altered metabolic configuration that is better suited to fuel biosynthetic processes and cell proliferation, thereby promoting breast cancer progression.

Nischarin regulates focal adhesion and Invadopodia formation in breast cancer cells.

BACKGROUND: During metastasis, tumor cells move through the tracks of extracellular matrix (ECM). Focal adhesions (FAs) are the protein complexes that link the cell cytoskeleton to the ECM and their presence is necessary for cell attachment. The tumor suppressor Nischarin interacts with a number of signaling proteins such as Integrin α5, PAK1, LIMK1, LKB1, and Rac1 to prevent cancer cell migration. Although previous findings have shown that Nischarin exerts this migratory inhibition by interacting with other proteins, the effects of these interactions on the entire FA machinery are unknown. METHODS: RT-PCR, Western Blotting, invadopodia assays, and immunofluorescence were used to examine FA gene expression and determine whether Nischarin affects cell attachment, as well as the proteins that regulate it. RESULTS: Our data show that Nischarin prevents cell migration and invasion by altering the expression of key focal adhesion proteins. Furthermore, we have found that Nischarin-expressing cells have reduced ability to attach the ECM, which in turn leads to a decrease in invadopodia-mediated matrix degradation. CONCLUSIONS: These experiments demonstrate an important role of Nischarin in regulating cell attachment, which adds to our understanding of the early events of the metastatic process in breast cancer.

Evolutionarily distinct bacteriophage endolysins featuring conserved peptidoglycan cleavage sites protect mice from MRSA infection.

OBJECTIVES: In the light of increasing drug resistance in Staphylococcus aureus, bacteriophage endolysins [peptidoglycan hydrolases (PGHs)] have been suggested as promising antimicrobial agents. The aim of this study was to determine the antimicrobial activity of nine enzymes representing unique homology groups within a diverse class of staphylococcal PGHs. METHODS: PGHs were recombinantly expressed, purified and tested for staphylolytic activity in multiple in vitro assays (zymogram, turbidity reduction assay and plate lysis) and against a comprehensive set of strains (S. aureus and CoNS). PGH cut sites in the staphylococcal peptidoglycan were determined by biochemical assays (Park-Johnson and Ghuysen procedures) and MS analysis. The enzymes were tested for their ability to eradicate static S. aureus biofilms and compared for their efficacy against systemic MRSA infection in a mouse model. RESULTS: Despite similar modular architectures and unexpectedly conserved cleavage sites in the peptidoglycan (conferred by evolutionarily divergent catalytic domains), the enzymes displayed varying degrees of in vitro lytic activity against numerous staphylococcal strains, including cell surface mutants and drug-resistant strains, and proved effective against static biofilms. In a mouse model of systemic MRSA infection, six PGHs provided 100% protection from death, with animals being free of clinical signs at the end of the experiment. CONCLUSIONS: Our results corroborate the high potential of PGHs for treatment of S. aureus infections and reveal unique antimicrobial and biochemical properties of the different enzymes, suggesting a high diversity of potential applications despite highly conserved peptidoglycan target sites.

Integrin-binding protein nischarin interacts with tumor suppressor liver kinase B1 (LKB1) to regulate cell migration of breast epithelial cells.

Biallelic inactivation of LKB1, a serine/threonine kinase, has been detected in 30% of lung adenocarcinomas, and inhibition of breast tumor growth has been demonstrated. We have identified the tumor suppressor, Nischarin, as a novel binding partner of LKB1. Our mapping analysis shows that the N terminus of Nischarin interacts with amino acids 44-436 of LKB1. Time lapse microscopy and Transwell migration data show that the absence of both Nischarin and LKB1 from an invasive breast cancer cell line (MDA-MB-231) enhances migration as measured by increased distance and speed of migrating cells. Our data suggest that this is a result of elevated PAK1 and LIMK1 phosphorylation. Moreover, the absence of Nischarin and LKB1 increased tumor growth in vivo. Consistent with this, the percentage of S phase cells was increased, as demonstrated by flow cytometry and enhanced cyclin D1. The absence of Nischarin and LKB1 also led to a dramatic increase in the formation of lung metastases. Our studies, for the first time, demonstrate functional interaction between LKB1 and Nischarin to inhibit cell migration and breast tumor progression. Mechanistically, we show that these two proteins together regulate PAK-LIMK-Cofilin and cyclin D1/CDK4 pathways.

The effect of preoperative use of anticoagulants on the hemostatic effect of intravenous application of tranexamic acid in PLIF: a case control study.

Intravenous application of tranexamic acid (TXA) in posterior lumbar interbody fusion (PLIF) can effectively reduce blood loss without affecting coagulation function. However, it has not been reported whether preoperative use of anticoagulants may affect the efficacy of TXA in PLIF. The purpose of this study is to observe the effect of preoperative use of anticoagulants on coagulation indicators and blood loss after PLIF receiving intravenous unit dose TXA. A retrospective analysis was conducted on data from 53 patients with PLIF between 2020.11 and 2022.9, who received intravenous application of a unit dose of TXA (1 g/100 mL) 15 min before the skin incision after general anesthesia. Those who used anticoagulants within one week before surgery were recorded as the observation group, while those who did not use anticoagulants were recorded as the control group. The main observation indicators include surgical time, intraoperative blood loss, postoperative drainage volume, blood transfusion, and red blood cell (RBC), hemoglobin (HB), and hematocrit (HCT) measured on the 1st, 4th, 7th, and last-test postoperative days. Secondary observation indicators included postoperative incision healing, deep vein thrombosis of lower limbs, postoperative hospital stay, and activated partial thrombin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen (FIB), and platelets (PLT) on the 1st and 4th days after surgery. The operation was successfully completed in both groups, the incision healed well after operation, and no lower limb deep vein thrombosis occurred. There was no significant difference in surgical time, intraoperative blood loss, postoperative drainage volume, and blood transfusion between the two groups (p > 0.05). There was no significant difference in the RBC, HB, and HCT measured on the 1st, 4th, 7th, and last-test postoperative days between the two groups (p > 0.05). There was no statistically significant difference in APTT, PT, TT, FIB and PLT between the two groups on the 1st and 4th postoperative days (p > 0.05). There was no significant difference in postoperative hospital stay between the two groups (p > 0.05). The use of anticoagulants within one week before surgery does not affect the hemostatic effect of intravenous unit dose TXA in PLIF.

The hemostatic and anti-inflammatory effects of intravenous single-dose of tranexamic acid in double-segment posterior lumbar interbody fusion: a case control study.

This study aims to observe the hemostatic and anti-inflammatory effects of intravenous administration of tranexamic acid (TXA) in dual segment posterior lumbar interbody fusion (PLIF). The data of 53 patients with lumbar disease treated with double-segment PLIF were included in this study. The observation group was received a single-dose intravenous of TXA (1 g/100 mL) 15 min before skin incision after general anesthesia. The control group was not received TXA. The observation indicators included postoperative activated partial prothrombin time (APTT), thrombin time (PT), thrombin time (TT), fibrinogen (FIB), platelets (PLT), and postoperative deep vein thrombosis in the lower limbs, surgical time, intraoperative bleeding volume, postoperative drainage volume, transfusion rate, postoperative hospital stay, red blood cell (RBC), hemoglobin (HB), hematocrit (HCT), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) on the 1st, 4th, 7th, and last tested day after surgery. All patients successfully completed the operation, and there was no deep vein thrombosis after operation. There was no statistically significant difference in postoperative APTT, PT, TT, FIB, PLT, surgical time, and postoperative hospital stay between the two groups (p > 0.05). The intraoperative bleeding volume, postoperative drainage volume, and transfusion rate in the observation group were lower than those in the control group, and the differences were statistically significant (p < 0.05). There was no statistically significant difference in RBC, HB, HCT, CRP, and ESR between the two groups on the 1st, 4th, 7th, and last tested day after surgery (p > 0.05). Intravenous administration of TXA in dual segment PLIF does not affect coagulation function and can reduce bleeding volume, postoperative drainage volume, and transfusion rate. Moreover, it does not affect the postoperative inflammatory response.

Workplace accommodation requests: Experiences of barriers and facilitators among deaf and hard-of-hearing.

BACKGROUND: Despite the protections afforded by the Americans with Disabilities Act (ADA), workers who are deaf and hard-of-hearing (DHH) face workplace challenges that may require the aid of workplace resources and accommodations. Limited research has been conducted to understand the process of accommodation requests among DHH workers. OBJECTIVE: This qualitative study examined barriers and facilitators to requesting accommodations among DHH workers. METHODS: Fifty-nine DHH workers, recruited from organizations serving DHH workers across U.S., participated in the study. Participants' open-ended survey responses were analyzed and coded into themes representing barriers or facilitators to participants' decisions to request or withhold requests for accommodations. RESULTS: Facilitators to accommodation request include an employee's effective use of self-efficacy and self-advocacy; supportive work environments; and the presence of peers with disabilities. Barriers to accommodation requests include the anticipation of negative perception of stigmatization in the workplace; lack of knowledge related to accommodations and ADA; absence of workplace support; ineffectual workplace structure, policies, or procedures; concerns surrounding costs; and physical and access barriers in the workplace. CONCLUSION: To fulfill the workers' rights as guaranteed by the ADA, and to best serve the interests of the workplace, strategies are highlighted on how to assist DHH employees to take advantage of workplace accommodations with aims to promote job retention and success.

Examining psychosocial factors associated with receiving workplace accommodations among people with disabilities.

BACKGROUND: People with disabilities experience challenges in obtaining workplace support including job accommodations. OBJECTIVE: This study examined the impacts of psychosocial factors affecting the likelihood of an employee with disability receiving an accommodation and subsequent effects on job satisfaction and job performance. METHODS: This study recruited 596 participants from multiple national and state agencies serving persons with disabilities in U.S. A mediation model was conducted to examine the impacts of psychosocial factors (i.e., self-efficacy, positive affect, negative affect, workplace support, Americans with Disabilities Act (ADA) knowledge, accommodation knowledge, and work goal) on receiving accommodation, and the impacts of receiving accommodations on job satisfaction and job performance. The indirect effects of the psychosocial factors on job satisfaction and job performance via receiving accommodations were examined using the Delta method. RESULTS: Among all the examined direct effects, only the effect from workplace support to receiving accommodations and the effect from receiving accommodations to job satisfaction were significant. Nevertheless, indirect effects were non-significant, indicating that all the psychosocial factors had no indirect effect (via receiving accommodation) on job satisfaction and job performance. CONCLUSION: The findings reveal the significance of workplace support on employees' likelihood of receiving accommodations, and subsequent association between accommodation receipt and job satisfaction. Rehabilitation professionals need to provide adequate training to employers to facilitate inclusive and supportive workplace environments.

Racial Identity and Mindfulness as Predictors of Posttraumatic Growth in Black Adults Experiencing Race-Based Trauma.

Racial discrimination and race-based trauma (RBT) have led to the development of various negative psychological and physiological effects among Black adults in the USA. There is a lack of understanding in relation to how various psychosocial factors influence posttraumatic growth (PTG) in the context of RBT among Black adults. The authors examined associations of RBT, racial identity, and mindfulness with PTG among Black adults while controlling for gender, household income, and duration of trauma. The sample consisted of 134 self-identified Black adults who met the criteria for RBT from the USA. The hierarchical regression analysis showed the final model with all the predictors accounted for 35% of the total variance of PTG, with racial identity and mindfulness facets accounting for 26% of the variance. The study provides a foundation for future research addressing RBT and promoting PTG in Black adults.

Case report: Shock after percutaneous vertebroplasty of the 5th thoracic vertebra.

Background: Percutaneous vertebroplasty (PVP) is a common treatment for osteoporotic vertebral compression fracture (OVCF). Perioperative bleeding is usually rare, so there are few reports of shock. However, we developed shock after treating a case of OVCF of the 5th thoracic vertebra with PVP. Case presentation: An 80 years old female patient received PVP due to OVCF of the 5th thoracic vertebra. The operation was successfully completed and the patient returned to the ward safely after the operation. At 90 min after operation, she developed shock, which was induced by subcutaneous hemorrhage up to 1500 ml at the puncture site. Before using vascular embolization, transfusion and blood transfusion were used to maintain blood pressure, and local ice bag compression was used to reduce swelling and stop bleeding, which achieved successful hemostasis. She recovered and discharged after 15 days, with the hematoma having absorbed. There was no recurrence during the 17-month follow-up. Conclusion: Although PVP is considered to be a safe and effective method to treat OVCF, the possible hemorrhagic shock still needs to arouse the vigilance of surgeons.

Targeting Mcl-1 by a small molecule NSC260594 for triple-negative breast cancer therapy.

Triple-negative breast cancers (TNBCs) are aggressive forms of breast cancer and tend to grow and spread more quickly than most other types of breast cancer. TNBCs can neither be targeted by hormonal therapies nor the antibody trastuzumab that targets the HER2 protein. There are urgent unmet medical needs to develop targeted drugs for TNBCs. We identified a small molecule NSC260594 from the NCI diversity set IV compound library. NSC260594 exhibited dramatic cytotoxicity in multiple TNBCs in a dose-and time-dependent manner. NSC260594 inhibited the Myeloid cell leukemia-1 (Mcl-1) expression through downregulation of Wnt signaling proteins. Consistent with this, NSC260594 treatment increased apoptosis, which was confirmed by using an Annexin-V/PI assay. Interestingly, NSC260594 treatment reduced the cancer stem cell (CSC) population in TNBCs. To make NSC260594 more clinically relevant, we treated NSC260594 with TNBC cell derived xenograft (CDX) mouse model, and with patient-derived xenograft (PDX) organoids. NSC260594 significantly suppressed MDA-MB-231 tumor growth in vivo, and furthermore, the combination treatment of NSC260594 and everolimus acted synergistically to decrease growth of TNBC PDX organoids. Together, we found that NSC260594 might serve as a lead compound for triple-negative breast cancer therapy through targeting Mcl-1.

The effect of intravenous unit-dose tranexamic acid on visible and hidden blood loss in posterior lumbar interbody fusion: a randomized clinical trial.

There are few reports of intravenous unit-dose tranexamic acid (TXA) on the relationship between visible blood loss (VBL) and hidden blood loss (HBL) in posterior lumbar interbody fusion (PLIF). Therefore, the objective of this randomized, prospective, double-blind, single center study was to investigate the effect of intravenous unit-dose TXA on VBL and HBL in patients who underwent PLIF. Among 100 patients, 11 were excluded due to failue to comply with the study, 1 was excluded due to non-conpliance with the study, and 88 were eligible for inclusion in the study. 46 patients who treated with PLIF received unit-dose of TXA (1 g/100 mL) intravenously 15 min before skin incision after general anesthesia (observation group) and 42 patients were given 100 mL of normal saline (control group). The operation time, intraoperative blood loss, postoperative drainage, VBL, HBL, blood transfusion rate, and adverse events were recorded in the two groups. Besides, activated partial prothrombin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen (FIB), platelets (PLT), red blood cells (RBC), hemoglobin (HB), hematocrit (HCT), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) on the 1st postoperative day; and RBC, HB, HCT, CRP, ESR on the 4th postoperative day were recorded. All 88 patients successfully completed the operation, the incision healed well, and there was no deep vein thrombosis of the lower extremity after operation. The intraoperative blood loss, postoperative drainage, VBL, HBL, and blood transfusion rate in the observation group were lower than those in the control group, and the differences were statistically significant (p < 0.05). There was no significant difference in operation time between the two groups (p > 0.05). There was no significant difference in postoperative APTT, PT, TT, FIB, PLT, RBC, HB, HCT, CRP and ESR between the two groups (p > 0.05). Intravenous unit-dose TXA is safe and feasible in PLIF, and it can effectively reduce perioperative VBL and HBL.

Antitumoural hydroxyapatite nanoparticles-mediated hepatoma-targeted trans-arterial embolization gene therapy: in vitro and in vivo studies.

BACKGROUND/AIMS: Absence of curative treatment creates urgent need for new strategies for unresectable hepatoma. Based on former discoveries of good liver cell compatibility, safety and tumour-specific inhibition of hydroxyapatite nanoparticles (nHAP), this work tries to make nHAP serve as gene vector in the hepatoma-targeted trans-arterial embolization (TAE) gene therapy to elevate and synergize the therapeutic efficacy of TAE and target gene therapy. METHOD: Following dosage and ratio optimization, polypolex formed by surface modified nHAP and p53 expressing plasmid was applied in vitro for human hepatoma HePG2 cell, and then in vivo for rabbit hepatic VX2 tumour by injection of polypolex/lipodoil emulsion to the hepatic artery in a tumour-target manner. RESULTS: In vitro, the polypolex transfected only about 5% HepG2 cells, but can elevate the inhibition of its growth and apoptosis in a much more degree while keeping safe to the normal hepatocyte line, L02. In vivo, the emulsion, with better dispersion than the polypolex and more specific tumour-target than lipiodol, mediated specific 4% p53 expression and antitumoural nanoparticle retention in the target tumour site, also significantly reduced tumour growth and prolonged the animal survival times more than the lipiodol (P < 0.05). CONCLUSIONS: In all, this new treatment based on nHAP can enhance therapeutic effect of HCC safely both in vitro and in vivo.