True brachial artery aneurysm: A systematic review.

Objective: To identify and critically appraise literature on true brachial artery aneurysm, exploring its demographic characteristics, aetiologies, clinical manifestations and different methods of repair along with complication rates to determine future treatment strategies. METHODS: The systematic review was conducted at Liaquat National Hospital, Karachi, from September 30, 2021, to November 30, 2022, in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Literature was searched on MEDLINE, EMBASE and Cochrane databases for relevant studies in English language or with English translation published till May 31, 2022. The key words used for the search were "brachial artery aneurysm". Data was noted on a proforma and was subjected to descriptive analysis. RESULTS: Of 113 articles, 6 (5.3%) were retrospective studies, 7 (6.1%) were case series and 100 (88.4%) were case reports. The total number of patients involved was 157 with mean age 43.1±23.4 years (range: 2 months to 84 years). The gender was mentioned for 152(96.8%) patients; 111(73%) males and 41(27%) females. The mean diameter of true brachial artery aneurysm was 36.2 ±17.5mm and 106(67.5%) patients presented with localised swelling, 65(41.4%) with pain, 41(26.1%) with distal ischaemic symptoms, and 28(17.8%) with median nerve compression. True brachial artery aneurysms were more common in renal failure patients having a history of arteriovenous fistula creation in the affected limb and were on immunosuppressant drugs due to renal transplant 81(51.5%). Less common causes included primary/idiopathic 27(17.1%), trauma 13(8.2%), connective tissue disorders 8(5%) and vasculitis 7(4.5%). The treatment of choice was aneurysmectomy in 142(90.4%) cases, with revascularisation of limb primarily with reversed great saphenous vein graft 79(50.3 %), followed by end-to-end anastomosis of brachial artery 17(10.8%) and synthetic grafting 17(10.8%). Endovascular intervention was performed in 6(3.8%) cases to exclude true brachial artery aneurysm, and to re-establish adequate blood flow to the associated limb. Conclusion: True brachial artery aneurysm, although a rarity, may lead to significant neurological and vascular problems if ignored. Arteriovenous fistula and immunosuppression are identified as two significant risk factors in the development of true brachial artery aneurysm. Therefore, an effective long-term follow up in renal failure patients is recommended to prevent its complications. Open surgical repair has been the most preferred mode of treatment, but further significant studies are needed to explore and compare different modes of surgical intervention, like open versus endovascular, to plan future treatment strategies.

Treatment of superior mesenteric artery mycotic aneurysm by synthetic vascular graft: A case report.

Superior mesenteric artery (SMA) aneurysm is a rare disease, especially if it is mycotic (infective) in origin. It is difficult to detect the problem during its initial natural course and usually presents in late phase due to its complications such as rupture, dissection, haemorrhage, and mesenteric ischaemia. Initially, the patient present with non-specific symptoms like vague colicky abdominal pain, nausea, vomiting, discomfort, malaise, and low-grade fever but prompt workup and intervention can lead to definitive diagnosis and uneventful outcome. This report describes the case of a 60-year-old male patient who presented with non-specific abdominal symptoms and, on workup, was diagnosed with superior mesenteric artery mycotic aneurysm. It was successfully treated surgically by resection of aneurysm and reconstruction of superior mesenteric artery by inter-positional Polytetrafluoroethylene (PTFE) synthetic vascular graft.

Synergistic inhibition of aggressive breast cancer cell migration and invasion by cytoplasmic delivery of anti-RhoC silencing RNA and presentation of EPPT1 peptide on "smart" particles.

Overexpression of RhoC protein in breast cancer patients has been linked to increased cancer cell invasion, migration, and metastases. Suppressing RhoC expression in aggressive breast cancer cells using silencing RNA (siRNA) molecules is a viable strategy to inhibit the metastatic spread of breast cancer. In this report, we describe the synthesis of a series of asymmetric pH-sensitive, membrane-destabilizing polymers engineered to complex anti-RhoC siRNA molecules forming "smart" nanoparticles. Using ß-CD as the particle core, polyethylene glycol (PEG) chains were conjugated to the primary face via non-cleavable bonds and amphiphilic polymers incorporating hydrophobic and cationic monomers were grafted to the secondary face via acid-labile linkages. We investigated the effect of PEG molecular weight (2 & 5 kDa) on transfection capacity and serum stability of the formed particles. We evaluated the efficacy of EPPT1 peptides presented on the free tips of the PEG brush to function as a targeting ligand against underglycosylated MUC1 (uMUC1) receptors overexpressed on the surface of metastatic breast cancer cells. Results show that "smart" nanoparticles successfully delivered anti-RhoC siRNA into the cytoplasm of aggressive SUM149 and MDA-MB-231 breast cancer cells, which resulted in a dose-dependent inhibition of cell migration and invasion. Further, EPPT1-targeted nanoparticles demonstrate a synergistic inhibition of cell migration and invasion imparted via RhoC knockdown and EPPT1-mediated signaling via the uMUC1 receptor.

UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer.

PURPOSE: c-Src has been shown to play a pivotal role in breast cancer progression, metastasis, and angiogenesis. In the clinic, however, the limited efficacy and high toxicity of existing c-Src inhibitors have tempered the enthusiasm for targeting c-Src. We developed a novel c-Src inhibitor (UM-164) that specifically binds the DFG-out inactive conformation of its target kinases. We hypothesized that binding the inactive kinase conformation would lead to improved pharmacologic outcomes by altering the noncatalytic functions of the targeted kinases. EXPERIMENTAL DESIGN: We have analyzed the anti-triple-negative breast cancer (TNBC) activity of UM-164 in a comprehensive manner that includes in vitro cell proliferation, migration, and invasion assays (including a novel patient-derived xenograft cell line, VARI-068), along with in vivo TNBC xenografts. RESULTS: We demonstrate that UM-164 binds the inactive kinase conformation of c-Src. Kinome-wide profiling of UM-164 identified that Src and p38 kinase families were potently inhibited by UM-164. We further demonstrate that dual c-Src/p38 inhibition is superior to mono-inhibition of c-Src or p38 alone. We demonstrate that UM-164 alters the cell localization of c-Src in TNBC cells. In xenograft models of TNBC, UM-164 resulted in a significant decrease of tumor growth compared with controls, with limited in vivo toxicity. CONCLUSIONS: In contrast with c-Src kinase inhibitors used in the clinic (1, 2), we demonstrate in vivo efficacy in xenograft models of TNBC. Our results suggest that the dual activity drug UM-164 is a promising lead compound for developing the first targeted therapeutic strategy against TNBC. Clin Cancer Res; 22(20); 5087-96. ©2016 AACR.

Nonhypoxic regulation and role of hypoxia-inducible factor 1 in aromatase inhibitor resistant breast cancer.

INTRODUCTION: Although aromatase inhibitors (AIs; for example, letrozole) are highly effective in treating estrogen receptor positive (ER+) breast cancer, a significant percentage of patients either do not respond to AIs or become resistant to them. Previous studies suggest that acquired resistance to AIs involves a switch from dependence on ER signaling to dependence on growth factor-mediated pathways, such as human epidermal growth factor receptor-2 (HER2). However, the role of HER2, and the identity of other relevant factors that may be used as biomarkers or therapeutic targets remain unknown. This study investigated the potential role of transcription factor hypoxia inducible factor 1 (HIF-1) in acquired AI resistance, and its regulation by HER2. METHODS: In vitro studies using AI (letrozole or exemestane)-resistant and AI-sensitive cells were conducted to investigate the regulation and role of HIF-1 in AI resistance. Western blot and RT-PCR analyses were conducted to compare protein and mRNA expression, respectively, of ERα, HER2, and HIF-1α (inducible HIF-1 subunit) in AI-resistant versus AI-sensitive cells. Similar expression analyses were also done, along with chromatin immunoprecipitation (ChIP), to identify previously known HIF-1 target genes, such as breast cancer resistance protein (BCRP), that may also play a role in AI resistance. Letrozole-resistant cells were treated with inhibitors to HER2, kinase pathways, and ERα to elucidate the regulation of HIF-1 and BCRP. Lastly, cells were treated with inhibitors or inducers of HIF-1α to determine its importance. RESULTS: Basal HIF-1α protein and BCRP mRNA and protein are higher in AI-resistant and HER2-transfected cells than in AI-sensitive, HER2- parental cells under nonhypoxic conditions. HIF-1α expression in AI-resistant cells is likely regulated by HER2 activated-phosphatidylinositide-3-kinase/Akt-protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, as its expression was inhibited by HER2 inhibitors and kinase pathway inhibitors. Inhibition or upregulation of HIF-1α affects breast cancer cell expression of BCRP; AI responsiveness; and expression of cancer stem cell characteristics, partially through BCRP. CONCLUSIONS: One of the mechanisms of AI resistance may be through regulation of nonhypoxic HIF-1 target genes, such as BCRP, implicated in chemoresistance. Thus, HIF-1 should be explored further for its potential as a biomarker of and therapeutic target.

Zoledronic acid reverses the epithelial-mesenchymal transition and inhibits self-renewal of breast cancer cells through inactivation of NF-κB.

Zoledronic acid, a third-generation bisphosphonate, has been shown to reduce cell migration, invasion, and metastasis. However, the effects of zoledronic acid on the epithelial-mesenchymal transition (EMT), a cellular process essential to the metastatic cascade, remain unclear. Therefore, the effects of zoledronic acid on EMT, using triple-negative breast cancer (TNBC) cells as a model system, were examined in more detail. Zoledronic acid treatment decreased the expression of mesenchymal markers, N-cadherin, Twist, and Snail, and subsequently upregulated expression of E-cadherin. Zoledronic acid also inhibited cell viability, induced cell-cycle arrest, and decreased the proliferative capacity of TNBC, suggesting that zoledronic acid inhibits viability through reduction of cell proliferation. As EMT has been linked to acquisition of a self-renewal phenotype, the effects of zoledronic acid on self-renewal in TNBC were also studied. Treatment with zoledronic acid decreased expression of self-renewal proteins, BMI-1 and Oct-4, and both prevented and eliminated mammosphere formation. To understand the mechanism of these results, the effect of zoledronic acid on established EMT regulator NF-κB was investigated. Zoledronic acid inhibited phosphorylation of RelA, the active subunit of NF-κB, at serine 536 and modulated RelA subcellular localization. Treatment with zoledronic acid reduced RelA binding to the Twist promoter, providing a direct link between inactivation of NF-κB signaling and loss of EMT transcription factor gene expression. Binding of Twist to the BMI-1 promoter was also decreased, correlating modulation of EMT to decreased self-renewal. On the basis of these results, it is proposed that through inactivation of NF-κB, zoledronic acid reverses EMT, which leads to a decrease in self-renewal.

The importance of HER2 signaling in the tumor-initiating cell population in aromatase inhibitor-resistant breast cancer.

Aromatase inhibitors (AIs) are an effective therapy in treating estrogen receptor-positive breast cancer. Nonetheless, a significant percentage of patients either do not respond or become resistant to AIs. Decreased dependence on ER-signaling and increased dependence on growth factor receptor signaling pathways, particularly human epidermal growth factor receptor 2 (EGFR2/HER2), have been implicated in AI resistance. However, the role of growth factor signaling remains unclear. This current study investigates the possibility that signaling either through HER2 alone or through interplay between epidermal growth factor receptor 1 (EGFR/HER1) and HER2 mediates AI resistance by increasing the tumor initiating cell (TIC) subpopulation in AI-resistant cells via regulation of stem cell markers, such as breast cancer resistance protein (BCRP). TICs and BCRP are both known to be involved in drug resistance. Results from in vitro analyses of AI-resistant versus AI-sensitive cells and HER2-versus HER2+ cells, as well as from in vivo xenograft tumors, indicate that (1) AI-resistant cells overexpress both HER2 and BCRP and exhibit increased TIC characteristics compared to AI-sensitive cells; (2) inhibition of HER2 and/or BCRP decrease TIC characteristics in letrozole-resistant cells; and (3) HER2 and its dimerization partner EGFR/HER1 are involved in the regulation of BCRP. Overall, these results suggest that reducing or eliminating the TIC subpopulation with agents that target BCRP, HER2, EGFR/HER1, and/or their downstream kinase pathways could be effective in preventing and/or treating acquired AI resistance.

Sensitivity to the aromatase inhibitor letrozole is prolonged after a "break" in treatment.

Using a hormone-dependent xenograft model, we established that loss of response to letrozole was accompanied by upregulation of the Her-2/mitogen-activated protein kinase (MAPK) pathway and downregulation of estrogen receptor alpha (ERalpha) and aromatase activity. In our previous study, we showed that stopping letrozole treatment or adding trastuzumab could reverse acquired resistance. In this study, we compared the effects of intermittent letrozole treatment and switching treatment between letrozole and trastuzumab on tumor growth in an attempt to optimize discontinuous letrozole treatment. The mice were treated with letrozole until the tumors developed resistance and then were divided into three groups: (a) letrozole, (b) trastuzumab, and (c) "off" (Delta(4)A supplement only); tumors were collected every week to examine changes in tumor protein expression and activity. In off group tumors, Her-2/p-MAPK activation gradually decreased and ERalpha and aromatase protein (and activity) increased. Within the first week of trastuzumab treatment, Her-2 and MAPK were downregulated and ERalpha was upregulated. When letrozole-resistant MCF-7Ca tumors were taken off treatment for 4 weeks, the second course of letrozole treatment provided a much longer duration of response (P = 0.02). However, switching treatment to trastuzumab for 4 weeks did not provide any inhibition of tumor growth. Our studies revealed that the adaptation of cells to a low-estrogen environment by upregulation of Her-2/MAPK and downregulation of ERalpha/aromatase was reversed on letrozole withdrawal. The tumors once again became responsive to letrozole for a significant period. These results suggest that response to letrozole can be prolonged by a short "break" in the treatment.

Immobilization stress causes extra-cellular oxidant-antioxidant imbalance in rats: restoration by L-NAME and vitamin E.

Stress has been shown to be associated with altered homeostasis that may lead to oxidant-antioxidant imbalance. Non-enzymatic antioxidants are important regulators of reactive oxygen species produced in extra-cellular milieu and represent the first line of defense against them. Extra-cellular non-enzymatic antioxidants may be disturbed by the production of superoxide and nitric oxide and this has not been studied in stressful situation previously. In the present study, effects of immobilization stress (IS), both acute (IS x 1) and repeated (IS x 7) were assessed on extra-cellular total antioxidant capacity measured as plasma ferric reducing antioxidant power (FRAP) and protein sulfhydryls, and oxidative stress measured as leukocyte superoxide generation, plasma nitric oxide production (total nitrates and nitrites, NOx) and lipid peroxides in rats. Effects of pretreatment with nitric oxide synthase (NOS) inhibitors and vitamin E were also studied on these biochemical parameters. The results showed that both IS x 1 and IS x 7 resulted in extra-cellular oxidant-antioxidant imbalance as oxidant generation was increased and non-enzymatic antioxidants were depleted. Pretreatment either with NOS inhibitors or vitamin E restored stress-induced extracellular oxidant-antioxidant imbalance implying their potential role as antioxidants. Our data suggest that there is extra-cellular oxidant-antioxidant imbalance in the stressed rats, with greater magnitude of severity in repeated stress paradigm. Augmentation of antioxidant defenses might be beneficial in long-term stress.

Cerebroprotective effect of Korean ginseng tea against global and focal models of ischemia in rats.

Korean ginseng tea (KGT), prepared from the roots of Panax ginseng, is widely used by Korean people for antistress, antifatigue, and endurance promoting effects. In the present study we evaluated neuroprotective/cerebroprotective actions of KGT in stroke, using rat global and focal models of ischemia. Varied biochemical/enzymatic alterations, produced subsequent to the application of middle cerebral artery (MCAO) and bilateral carotid artery occlusion (BCAO) followed by reperfusion viz. increase in lipid peroxidation (LPO) and decrease in glutathione (GSH), glutathione reductase (GR), catalase (CAT), glutathione-S-transferase (GST), glutathione peroxidase (GPx) and superoxide dismutase (SOD), were markedly reversed and restored to near normal levels in the groups pre-treated with KGT (350 mg/kg given orally for 10 days). It is concluded that the protective action, exhibited by KGT against hypoperfusion/reperfusion induced brain injury, suggests its therapeutic potential in cerebrovascular diseases (CVD) including stroke. These findings are important because: (a) the present treatment strategies for CVD are far from adequate and (b) KGT with wide usage is known to be a safe natural product.

Attenuation of stress-elicited brain catecholamines, serotonin and plasma corticosterone levels by calcined gold preparations used in Indian system of medicine.

Problems associated with mental health have increased tremendously in modern times. The search for effective and safe alternatives should, therefore, be pursued vigorously. Forced immobilization is one of the best explored models of stress in rats and the role of corticosterone, serotonin (5-HT) and catecholamines, i.e. norepinephrine, epinephrine, dopamine is well documented. We investigated the therapeutic potential of two gold preparations (Ayurvedic Swarna Bhasma and Unani Kushta Tila Kalan) in restraint induced stress at different time points of 1 hr, 2 hr and 4 hr. We pretreated rats with two gold preparations, Ayurvedic Swarna Bhasma and Unani Kushta Tila Kalan (25 mg/kg, orally for 10 days) prior to restraint stress. Brain catecholamine, serotonin and plasma corticosterone levels were determined following 1, 2 and 4 hr restraint stress, using HPLC and also plasma corticosterone using luminescence spectrophotometry. Gold preparations restored restraint stress-induced elevation in levels of brain catecholamines (norepinephrine, epinephrine and dopmine), 5-HT and plasma corticosterone to near normal levels. Gold, widely used in modern medicine for the treatment of rheumatoid arthritis, is highly valued for various medicinal uses in Indian systems of medicine. Traditional gold preparations are attributed with tonic/rejuvenating and antioxidant properties. Our earlier studies revealed interesting analgesic, immunostimulant, adaptogenic and glycogen sparing properties in these preparations, but their effects in stress and depression have not been investigated yet. Significant restoration of altered values to near normal levels suggest potentials for gold preparations in stress and depression.