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  • Article
    Kähler ST, Wendt M, Dühnen IM, Luna-Rodriguez A, Jacobsen T.
    Acta Psychol (Amst). 2024 May;245:104205.
    Attention can be directed to the global or local level of a visual stimulus (i.e., Navon figure). Previous studies yielded reliable trial-to-trial level switch costs (i.e., worse performance when responding to the other level than on a previous trial), even though level cueing effects indicated anticipatory deployment of attention to the upcoming target level. To investigate the interplay of attentional preparation and persistence, we applied a probe trial method assumed to ensure a high degree of preparation for the upcoming target level and minimizing stimulus-specific proactive interference. Mirroring previous findings obtained in the domain of spatial attention, we found evidence for anticipatory attentional focusing on global/local target levels but not for persistence of the attentional set adopted on the previous trial. In a second experiment, we prevented preparation for upcoming attentional demands (in both global-local and spatial attention tasks). This resulted in the modulation of performance (in critical probe trials) by the attentional demands of the predecessor trial. Together, our findings demonstrate sensitivity of the probe trial method for attentional persistence and raise the possibility that such persistence can be completely eliminated by sufficiently strong preparation for the attentional demands of the following trial.
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  • Article
    Chen C, Liu Y, Tian H, Ai L, Yu H.
    Food Microbiol. 2023 May;111:104205.
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  • Article
    He AX, Huang S, Waxman S, Arunachalam S.
    Cognition. 2020 05;198:104205.
    Successful word learning requires establishing an initial representation that is sufficiently robust to be retained in memory. Sleep has profound advantages for memory consolidation, but evidence concerning the effects of sleep in young children's word learning is slim and focuses almost exclusively on learning nouns. Verbs are representationally more complex and are often learned from non-concurrent linguistic and observational information (e.g., hearing "let's pour your milk" before the pouring event takes place). What remains unknown is whether initial representations built this way are robust enough to sustain a delay, and how these representations are affected by sleep. We presented two-year-olds with non-concurrent linguistic and observational information about novel verbs and immediately tested their knowledge of the verbs' meanings by evaluating their eye gaze as they looked at potential referents. Then, after a 4-hour delay during which half of the children napped and half remained awake, we retested them to see if they remembered the verbs' meanings. The results demonstrate differences in two-year-olds' representations of a novel verb before and after the delay; specifically, their verb representations withstood the 4-hour delay if they had napped, but decayed if they had remained awake.
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  • Article
    Bergamino MA, López-Knowles E, Morani G, Tovey H, Kilburn L, Schuster EF, Alataki A, Hills M, Xiao H, Holcombe C, Skene A, Robertson JF, Smith IE, Bliss JM, Dowsett M, Cheang MCU, POETIC investigators.
    EBioMedicine. 2022 Sep;83:104205.
    BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks' presurgical AI treatment in ER+/HER2+ BCs.
    METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering.
    FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14-5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes.
    INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse.
    FUNDING: Cancer Research UK (CRUK/07/015).
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  • Article
    Ozan G, Sancakli HS, Erdemir U, Yaman BC, Yildiz SO, Yildiz E.
    J Dent. 2022 08;123:104205.
    OBJECTIVES: The purpose of the present clinical evaluation was to investigate the effect of a fissure sealant and a flowable composite at fissures of permanent molars in terms of retention and caries-incidence rates over a 36-month period.
    METHODS: Thirty-four patients, ages varied from 16 to 22 years, diagnosed with at least 2 non-cavitated pit-and-fissure caries in the first and second molars were involved in the study. A total of 220 sealants, were placed in 117 upper molars and 103 lower molars. Teeth were sealed with either a flowable resin composite (Tetric Evo Flow) or a sealant material (Helioseal F)(n = 110). Each restoration was evaluated in terms of retention and caries incidence at 6, 12, 24 and 36 months according to their location as well. Data were analyzed using Mann-Whitney U, Friedman and 1-way ANOVA tests at p < 0.05.
    RESULTS: Tetric Evo Flow showed total retention with 95.5%, 93.8%, 88.5% and 80.2% at 6, 12, 24 and 36-month follow-ups respectively, while Helioseal F had retention rates of 95.5%, 94.8%, 85.4% and 80.2% respectively. After 36-months, there were 6 subjects totally lost in Helioseal F group, whereas 7 of the Tetric Evo Flow sunjects were totally lost. Caries development was firstly detected at 12-month evaluation for both of the materials however, no significant differences were observed among materials in retention rates or caries incidence after 36-month follow-ups (p > 0.05).
    SIGNIFICANCE: Using the flowable composite found as effective as the fissure sealant after 36-months regarding retention and caries incidence rates.
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  • Article
    Pamidi V, Trivedi S, Behara S, Fichtner M, Reddy MA.
    iScience. 2022 May 20;25(5):104205.
    Confining the particle-electrolyte interactions to the particle surface in electrode materials is vital to develop sustainable and safe batteries. Micron-sized single-crystal particles offer such opportunities. Owing to the reduced surface area and grain boundary-free core, particle-electrolyte interactions in micron-sized single-crystal particles will be confined to the particle surface. Here, we reveal the potential of such materials in sodium-ion batteries. We synthesized and investigated the chemical, electrochemical, and thermal properties of single-crystalline P2-type Na0.7Mn0.9Mg0.1O2 as a cathode material for sodium-ion batteries. Single-crystalline Na0.7Mn0.9Mg0.1O2 with a mean particle size of 8.1 μm exhibited high cycling and voltage stability. In addition, the exothermic heat released by the charged single-crystal Na0.7Mn0.9Mg0.1O2 cathodes was four times lower than that of the corresponding polycrystalline Na0.7Mn0.9Mg0.1O2. This significantly enhances the thermal stability of electrode materials and possibly mitigates thermal runaways in batteries. Surprisingly, single crystals of Na0.7Mn0.9Mg0.1O2 were relatively stable in water and ambient atmosphere.
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  • Article
    Adelson RP, Palikuqi B, Weiss Z, Checco A, Schreiner R, Rafii S, Rabbany SY.
    Microvasc Res. 2021 11;138:104205.
    The rapid engraftment of vascular networks is critical for functional incorporation of tissue explants. However, existing methods for inducing angiogenesis utilize approaches that yield vasculature with poor temporal stability or inadequate mechanical integrity, which reduce their robustness in vivo. The transcription factor Ets variant 2 (Etv2) specifies embryonic hematopoietic and vascular endothelial cell (EC) development, and is transiently reactivated during postnatal vascular regeneration and tumor angiogenesis. This study investigates the role for Etv2 upregulation in forming stable vascular beds both in vitro and in vivo. Control and Etv2+ prototypical fetal-derived human umbilical vein ECs (HUVECs) and adult ECs were angiogenically grown into vascular beds. These vessel beds were characterized using fractal dimension and lacunarity, to quantify their branching complexity and space-filling homogeneity, respectively. Atomic force microscopy (AFM) was used to explore whether greater complexity and homogeneity lead to more mechanically stable vessels. Additionally, markers of EC integrity were used to probe for mechanistic clues. Etv2+ HUVECs exhibit greater branching, vessel density, and structural homogeneity, and decreased stiffness in vitro and in vivo, indicating a greater propensity for stable vessel formation. When co-cultured with colon tumor organoid tissue, Etv2+ HUVECs had decreased fractal dimension and lacunarity compared to Etv2+ HUVECs cultured alone, indicating that vessel density and homogeneity of vessel spacing increased due to the presence of Etv2. This study sets forth the novel concept that fractal dimension, lacunarity, and AFM are as informative as conventional angiogenic measurements, including vessel branching and density, to assess vascular perfusion and stability.
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  • Article
    Xu B, Lee EM, Medina A, Sun X, Wang D, Tang H, Zhou GC.
    Bioorg Chem. 2020 11;104:104205.
    Zika virus (ZIKV) infection represents a significant threat to the global health system, and the search for efficient antivirals to ZIKV remains necessary and urgent. In this study, we extended the exploration of our previously discovered scaffold of 1H-pyrrolo[1,2-c]imidazol-1-one and revealed that two trans isomers of compounds 2 and 7 and one mixture with major trans isomer of compound 3 as novel tetrahydroquinoline-fused imidazolone derivatives are active against ZIKV infection but they are not virucidal. Western Blot and ELISA analyses of ZIKV NS5 and NS1 further demonstrate that compounds of (±)-2, (±)-3 and (±)-7 act as effective agents against ZIKV infection. We show that the N10's basicity is not the basic requirement for these compounds' antiviral activity in the current work. Importantly, tuning of some pharmacophores including substituents at arene can generate promising candidates for anti-ZIKV agents.
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  • Article
    Kondo A, Tanaka H, Rai S, Shima H, Matsumura I, Watanabe T.
    Exp Hematol. 2024 May;133:104205.
    Protein phosphatase 6 (PP6) is a serine/threonine (Ser/Thr) protein phosphatase, and its catalytic subunit is Ppp6c. PP6 forms the PP2A subfamily with PP2A and PP4. The diverse phenotypes observed following small interfering RNA (siRNA)-based knockdown of Ppp6c in cultured mammalian cells suggest that PP6 plays roles in cell growth and DNA repair. There is also evidence that PP6 regulates nuclear factor kappa B (NF-κB) signaling and mitogen-activated protein kinases and inactivates transforming growth factor-β-activated kinase 1 (TAK1). Loss of Ppp6c causes several abnormalities, including those of T cell and regulatory T cell function, neurogenesis, oogenesis, and spermatogenesis. PP2A has been reported to play an important role in erythropoiesis. However, the roles of PP6 in other hematopoietic cells have not been investigated. We generated Ppp6cfl/fl;Tie2-Cre (Ppp6cTKO) mice, in which Ppp6c was specifically deleted in hematopoietic and vascular endothelial cells. Ppp6cTKO mice displayed embryonic lethality. Ppp6c deficiency increased the number of dead cells and decreased the percentages of erythroid and monocytic cells during fetal hematopoiesis. By contrast, the number of Lin-Sca-1+c-Kit+ cells, which give rise to all hematopoietic cells, was slightly increased, but their colony-forming cell activity was markedly decreased. Ppp6c deficiency also increased phosphorylation of extracellular signal-regulated kinase 1/2 and c-Jun amino (N)-terminal kinase in fetal liver hematopoietic cells.
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  • Article
    Bianca E, Dotti F, Orrico F, Ferri A.
    Appl Ergon. 2024 Apr;116:104205.
    Thermal comfort plays a crucial role in the performance and well-being of mountaineers, especially in extreme environments. The aim of this study was to develop a reliable protocol to assess the thermal comfort of mountaineering boots, with a specific focus on temperature variations in different regions of the foot and their correlation with physiological factors. Two different models of mountaineering boots were tested at two different environmental temperature (-15°C and -30°C). The mean skin temperature, measured according to International Standards BS EN ISO 9886:2004, was used as an indicator of overall thermal comfort. Physiological factors such as heart rate (HR), body mass index (BMI) and body surface area (BSA) were also measured to understand their relationship to thermoregulation. Kruskal-Wallis and Pearson's ProductMoment correlation tests were performed to investigate whether there was a statistically significant relationship. The results showed significant differences in foot temperature among the Testers, indicating variations in the perception of thermal comfort. The correlation analysis showed a strong positive relationship between mean skin temperature and HR, highlighting the influence of physiological factors on thermal comfort. In addition, the analysis showed that the dorsum and hallux areas had the largest temperature variations, suggesting the occurrence of vasoconstriction and potential discomfort. This study represents a preliminary approach to establishing a reliable protocol for assessing the thermal performance of cold protective footwear.
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  • Article
    Delaplace F, Ivanov S.
    Biosystems. 2020 Nov;197:104205.
    Discrete modelling frameworks of Biological networks can be divided in two distinct categories: Boolean and multivalued. Although multivalued networks are more expressive for qualifying the regulatory behaviours modelled by more than two values, the ability to automatically convert them to Boolean network with an equivalent behaviour breaks down the fundamental borders between the two approaches. Theoretically investigating the conversion process provides relevant insights into bridging the gap between them. Basically, the conversion aims at finding a Boolean network bisimulating a multivalued one. In this article, we investigate the bisimilar conversion where the Boolean integer coding is a parameter that can be freely modified. Based on this analysis, we define a computational method automatically inferring a bisimilar Boolean network from a given multivalued one.
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  • Article
    Sánchez-Peralta ES, Ortega-Moreno DA, Velasco-Gallegos G.
    J Fr Ophtalmol. 2024 May 15:104205.
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  • Article
    Muhammad T, Ismail S, Ikhwanuddin M, Abol-Munafi AB.
    Data Brief. 2019 Aug;25:104205.
    The data collected in the present work correspond to the behavioral, Hepatosomatic Index (HSI), Gonadosomatic Index (GSI) and total lipid analysis between male and female mud crabs, Scylla olivacea at different water velocities. A total of 56 immature male and female crabs were used in this data article. The important criteria for estimating the selective habitat facing by S. olivacea is a considerate of (1) the behavioral range in response to abiotic factors (and how it adapt ontogenetically) and (2) the movement of the crab under wild velocities situations. This work purposes to recognize the performance, locomotion rate and escaping capability of S. olivacea under stagnant and flowing water situations and to discuss the significance of horizontal walking to habitat choice. The collective outcomes clearly show that the locomotor activities and escaping capabilities of S. olivacea were influenced by water flow in the mangrove habitats. For the HSI data, velocities of 20 cm/s were the highest increased mean HSI percentage and highest mean HSI percentage in males and females was recorded on the end of the experiment. For GSI percentage of male and female crabs, 20 cm/s dominates the highest increases mean GSI, followed by 60, 40 and 0 cm/s. For total lipid percentage, the results showed that, the mean total lipid of hepatopancrease, muscle and gonad were increased at the beginning and decreased at the final in each water velocities except for 20 cm/s over a culture period of 60 days. Velocities of 20 cm/s were the highest increased mean total lipid percentage followed by 40, 60, and lastly 0 cm/s. The high flow velocities inhibit the production of hepatopancrease and gonad, in terms of nutrients from food used to endeavor the stress condition faced.
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  • Article
    Urayama S, Tanaka A, Kusano K, Sato H, Muranaka M, Mita H, Nagashima T, Matsuda H.
    J Equine Vet Sci. 2023 02;121:104205.
    Flunixin meglumine (FM), a nonselective cyclooxygenase (COX) inhibitor, is most frequently selected for the treatment of equine systemic inflammatory response syndrome (SIRS)/endotoxemia. However, FM has considerable adverse effects on gastrointestinal function. The aims of this study were to compare the effect of meloxicam (MX), a COX-2 selective inhibitor commonly used in equine clinical practice, with FM, and to investigate the potential for clinical application in horses with SIRS/endotoxemia. Fifteen horses were divided into three groups of five and orally administered MX (0.6 mg/kg), FM (1.1 mg/kg), or saline as placebo at 30 minutes after LPS challenge. Clinical parameters, including behavioral pain scores, were recorded and blood for clinical pathological data was collected at various times from 60 minutes before to 420 minutes after LPS infusion. The pain score were significantly lower in both the MX and FM groups than in the placebo group, with no significant difference between them. Body temperature was significantly lower in the MX and FM groups than in the placebo group. Heart rates and respiratory rates, hoof wall surface temperature, and leukocyte counts changed similarly between the MX and FM groups. TNF-α and cortisol were lower in the FM group than in the MX group. The results suggest that MX suppresses the inflammatory response after LPS infusion and has an analgesic effect similar to that of FM. Given the adverse effects of nonselective COX inhibitors, clinical application of MX may be beneficial in horses with SIRS/endotoxemia.
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  • Article
    Amera GM, Khan RJ, Pathak A, Jha RK, Muthukumaran J, Singh AK.
    Microb Pathog. 2020 Oct;147:104205.
    A. baumannii has been considered as Priority-I as suggested by the World Health Organization (WHO) and the most critical pathogenic microorganism for causing nosocomial infection in imunno-compromised hospital-acquired patients due to multi-drug resistance (MDR). In the current study, we utilized "Computer-aided ligand-based virtual screening approach" for identification of promising molecules against Mur family proteins based on the known inhibitor (Naphthyl Tetronic Acids ((5Z)-3-(4-chlorophenyl)-4-hydroxy-5-(1-naphthylmethylene) furan-2(5H)-one)) of MurB from E. coli. The in-house library was prepared using a similarity search of a known inhibitor (Drug Bank ID: DB07296) against several relevant chemical databases. The molecules obtained from virtual screening of Naphthyl Tetronic Acids in-house library were successively subjected to physicochemical and ADMET screening. After this, the molecules which passed all the filters, subsequently subjected into interaction analysis with the drug target proteins (MurB, MurD, MurE and MurG) of A. baumanni and the results explained that four molecules were promising (CHEMBL468144, DB07296, Enamine_T5956969 and 54723243) for further molecular dynamics simulations. The free and ligand bounded proteins that undergone MD simulation are listed as follows: MurB, MurB-CHEMBL468144, MurB-DB07296, MurE, MurE-54723243, MurE-DB07296, MurD, MurD-Enamine_T5956969, MurD-DB07296, MurG, MurG-CHEMBL468144, and MurG-DB07296. Based on global and essential dynamics analysis, the stability order of molecules towards MurB (CHEMBL468144 > DB07296); MurD (Enamine_T5956969 > DB07296); MurE (54723243 > DB07296) and MurG (CHEMBL468144 > DB07296) indicates that the newly identified molecules are more promising one in comparison with the existing inhibitor. Based on all the docking and MD simulation results, the stability order of the free and ligand bounded protein are as follows; MurB and MurB-ligand complexes > MurD and MurD-ligand complexes > MurG and MurG-ligand complexes > MurE and MurE-ligand complexes. Finally, the selected compounds would be recommended for further experimental investigations and used as promising inhibitors of the infection caused by A. baumannii.
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  • Article
    Marshall PW, Morrison NMV, Gibbs M, Schabrun SM.
    Behav Res Ther. 2022 12;159:104205.
    Despite being a first-line treatment recommendation, there is uncertainly for how exercise helps people with chronic low back pain. We designed this study to examine how exercise might help people with chronic low back pain by following a large community sample for 1-year. Qualitative questionnaires and self-report measures were collected every 3-months for 1-year in 400 people with chronic low back pain. People were not provided any specific treatment advice as part of this study but were allowed to engage with any normal physical activity, treatment, or medication as part of their normal life. Exercise engagement was defined from inspection of participant qualitative responses, according to minimum acceptable levels of exercise that elicit symptom reduction. Multiple mediation analysis was performed to examine the effect of exercise engagement on disability through the proposed mediators (pain, fear, catastrophizing, depression, anxiety, self-efficacy). The significant effect of exercise engagement on reductions in disability at 6- and 12-months was explained through pain and catastrophizing. People with chronic low back pain who reported worsening of symptoms over the year had similar reporting of exercise throughout the 12-months to people who had improvements in disability. Exercise can reduce disability through the effect on pain and catastrophizing, but how this effect occurs (i.e., an active or passive component of exercise) is unclear.
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  • Article
    Bhattarai HB, Chhantyal S, Dahal K, Shah S, Yadav SK, Yadav BK, Subedi A, Baniya S, Singh PB, Priya A.
    Ann Med Surg (Lond). 2022 Aug;80:104205.
    Introduction: Atypical spindle cell lipomatous tumor (ASPLT), a separate entity for the group of benign/low grade adipocytic neoplasm that is characterized by adipocyte adequacy and the presence of lipoblast-like cells and spindle cells at varying degrees.
    Case presentation: Here, we report a rare case of 60 years old male with atypical spindle cell lipomatous tumor in the anterior abdominal wall.
    Discussion: Histopathology is the gold standard for establishing the diagnosis and grade of soft tissue tumor and consistent radiology-pathology correlation is essential to avoid any diagnostic pitfalls [1]. Ultrasound is preferred as an initial investigation for superficially located lesions.
    Conclusion: ASPLT show a wide variety of microscopic features, and differential diagnosis is important and difficult. Recognition of morphologic clues and immunohistochemistry/molecular tests to confirm the diagnosis.
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  • Article
    Lu M, Xiao X, Song H, Liu G, Lu H, Kikkawa T.
    Comput Biol Med. 2021 03;130:104205.
    The realistic numerical breast model is an important tool for verifying algorithms, improving design concepts, and exploring new technologies related to microwave breast cancer detection. Recently, several numerical breast models have been developed. However, these models do not include the real breast boundary and the chest region, which causes the electromagnetic wave propagation in the breast models to deviate from the actual situation. The proposed breast models in this paper overcome the significant deficiencies of the recent breast models in terms of structure completeness and authenticity. The model construction based on magnetic resonance imaging (MRI) scans is a multistep approach. Firstly, intensity inhomogeneity in MRI images is corrected by an improved nonparametric nonuniform intensity normalization (N4) algorithm. Then, a dual threshold and morphological transformation (DTMT) method is developed to segment the real breast region. Subsequently, a modified maximum inter-class variance (MICV) method is employed to automatically divide the breast region into the fat and the fibroglandular clusters with desired complexity. Finally, the dielectric properties of breast tissues are calculated by a piecewise weighted mapping method. The applicability and effectiveness of the proposed method are verified by constructing four breast models with varying tissue density, shape, and size. The constructed models in this study are significant to achieve reliable and precise effects for microwave breast cancer detection due to the accurate expression of the breast anatomical information and electromagnetic characteristics.
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  • Article
    Bruthans J.
    Int J Med Inform. 2020 09;141:104205.
    INTRODUCTION: The electronic prescribing system (EPS) is now widely used in the USA and largely also in EU member countries. Nevertheless, comparisons of different EPS are very scarce. Whilst the EU strives for cross-border interoperability in healthcare, the aim of this study is to provide a contemporary account of the state of national EPS in such countries.
    METHODS: For the sake of consistency the state of each of the EPS as of the end of 2018 was researched using an e-mail questionnaire. Respondents were chosen from among authors who have previously published studies on electronic prescriptions.
    RESULTS: Data on EPS was gathered from 23 out of the 28 EU member states. In 2018 EPS was in daily use in 19 EU states, and one further country had a pilot project, whereas the remaining 3 were only at the planning stage. Most of the EPS do not differ significantly in basic design, however authentication procedures vary substantially.
    DISCUSSION: There is a significant increase in EPS usage in EU countries as compared with previous studies. Cross-border interoperability in the EU is still limited, and further advancement might be hampered by differences in authentication procedures.
    CONCLUSION: Although it was not possible to acquire data from all the EU countries, this study shows the present state of electronic prescription in most of them and demonstrates continuous development in this area.
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  • Article
    Chen Y, Wang X, Cao C, Wang X, Liang S, Peng C, Fu L, He G.
    Oncotarget. 2017 Nov 28;8(61):104193-104205.
    Raf and extracellular signal-regulated kinases (ERK) are both important therapeutic targets in the mitogen-activated protein kinase (MAPK) pathway, and play crucial roles in the apoptosis resistance of breast cancer cells. In the present study, cytotoxic and apoptosis-inducing activities of the Raf/ERK dual inhibitor CY-9d were found to be restricted in triple negative breast cancer (TNBC) cells compared with ER/PR-positive cells. Based on the analysis of differentially expressed proteins using a quantitative proteomic iTRAQ method and bioinformatics analysis, HSP90 was found to identify as a potential mediator between Raf and ERK in TNBC cells. Western blotting and RNA interference suggested that down-regulated IQGAP1 can attenuate the routine Raf/MEK/ERK cascade and recruit HSP90 as a bypass pathway. Simultaneous treatment with the HSP90 inhibitor and CY-9d at sub-therapeutic doses was found to produce synergistic therapeutic and apoptosis-inducing effects in TNBC cells. Moreover, CY-9d was also found to suppress breast cancer growth, inhibit the activation of Raf/ERK, and induce mitochondrial apoptosis in vivo without remarkable toxicity. These results support the combination of HSP90 and Raf/ERK inhibitors as a potential target therapeutic strategy with enhanced tumor growth suppression, downstream pathway blockade, and greater induction of apoptosis.
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