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Under conditions of high temperature, humidity, and incidence of solar radiation, dairy cows use behavioral changes as a strategy to decrease the metabolic heat production at pasture. The objective of this study was to evaluate the behavioral and physiological responses of Gyr and Girolando (5/8 Holstein 3/8 Gyr, and ½ Holstein ½ Gyr) dairy cows submitted to environments with and without shade. The experiment was conducted at Embrapa Cerrados (Technology Center for Dairy Zebu breeds—CTZL), Brasilia, Distrito Federal—Brazil, with 48 Gyr and Girolando cows total in the lactation group, with low to medium milk production, in full sun or shade with Eucalyptus urograndis (267 plants/ha−1). The physiological and behavioral characteristics evaluated were panting score, superficial temperature, and time spent grazing, ruminating, and lying down. Other traits included skin and coat thickness, hair diameter, density and length, and predominant coat color. In addition, body measurements, such as body length, the height of withers, chest circumference, and shin circumference, were measured. Shaded cows had 34% longer rumination times than cows in full sun (p = 0.01). With a temperature-humidity index ranging from 79 to 83, the rumination time was 1.7 times higher in cows under shade (p = 0.01) during a 24-h period of observation. There were no significant differences in the grazing time between the environments, but lying time was 23% longer in cows under the sun (p = 0.01). The panting score was not influenced by the environment (p = 0.17). Girolando cows had a 35% higher panting score than Gyr cows (p = 0.01) regardless of the environment. The panting score increased two and a half times during the afternoon compared with the morning (p = 0.01). The surface and rectal core temperatures had significant differences between treatments and time of the day. Body measurements were not different between cows in both environments, but there was a difference between breeds. The use of trees in pastures with a silvopastoral system for dairy zebu cows is indicated to improve grazing behavior, as well as time spent ruminating and lying down.

This work aims to perform a comparative study of two mechanical processes for the recycling of metals from coaxial cables (aluminium and copper-clad steel): Process I – comminution, sieving and electrostatic separation; and Process II – comminution, magnetic separation and electrostatic separation. Characterization techniques were performed on the cables to discover their composition. The parameters evaluated of electrostatic separation were: roll speed (n), electrostatic electrode distance (D2), voltage applied to the electrodes (U) and splitter angle (γ). The best conditions for electrostatic separation were: Process I – n = 30 rpm, D2 = 8 cm, U = 30 kV and γ = 0°; Process II – n = 10 rpm, D2 = 10 cm, U = 25 kV and γ = 2.5°. Process I presented aluminium with purity of 99.51% and recovery efficiency of 94.53%, as well as copper-clad steel with purity of 96.79% and recovery efficiency of 99.68%. Process II presented aluminium with purity of 96.51% and recovery of 70.12%, as well as copper-clad steel with purity of 99.53% and recovery of 99.46%. A simplified economic assessment was performed on both process, and Process I has demonstrated to be the most profitable for coaxial cable recycling. The results showed that Process I is promising for the recovery of metals from cables due to its simplicity and lower cost, being capable of wide application to other processes that contain a mixture of conductive and non-conductive particles. [ABSTRACT FROM AUTHOR]

Identification of specific and therapeutically actionable vulnerabilities, ideally present across multiple mutational backgrounds, is needed to improve acute myeloid leukemia (AML) patients' outcomes. We identify stearoyl-CoA desaturase (SCD), the key enzyme in fatty acid (FA) desaturation, as prognostic of patients' outcomes and, using the clinical-grade inhibitor SSI-4, show that SCD inhibition (SCDi) is a therapeutic vulnerability across multiple AML models in vitro and in vivo. Multiomic analysis demonstrates that SCDi causes lipotoxicity, which induces AML cell death via pleiotropic effects. Sensitivity to SCDi correlates with AML dependency on FA desaturation regardless of mutational profile and is modulated by FA biosynthesis activity. Finally, we show that lipotoxicity increases chemotherapy-induced DNA damage and standard chemotherapy further sensitizes AML cells to SCDi. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their full therapeutic potential., (© 2024. The Author(s).)

The ultimate sensitivity of field-effect-transistor (FET)-based devices for ionic species detection is of great interest, given that such devices are capable of monitoring single-electron-level modulations. It is shown here, from both theoretical and experimental perspectives, that for such ultimate limits to be approached the thermodynamic as well as kinetic characteristics of the (FET surface)-(linker)-(ion-receptor) ensemble must be considered. The sensitivity was probed in terms of optimal packing of the ensemble, through a minimal charge state/capacitance point of view and atomic force microscopy. Through the fine-tuning of the linker and receptor interaction with the sensing surface, a record limit of detection as well as specificity in the femtomolar range, orders of magnitude better than previously obtained and in excellent accord with prediction, was observed.

In prostate cancer (PCa) patients, a proto-oncogene Tumor protein D52 (TPD52) is overexpressed, and it is involved in different cellular functions. In this study, we report that TPD52 expression is positively associated with the emergence of neuroendocrine PCa (NEPC). With overexpression of TPD52 in LNCaP cells, we found neuroendocrine differentiation (NED) of cells in in-vitro and distinct NED features confirmed by NE markers neuron-specific enolase (NSE) and chromogranin A (CHR-A). Further, we investigated the molecular mechanisms involved in TPD52 mediated NED of PCa cells. We found that TPD52 activates the NF- κB - STAT3 axis for the induction of NED in LNCaP cells. Indeed, inhibition of NF-κB - STAT3 attenuated the progression of NED in TPD52 positive LNCaP cells. Importantly, silencing of TPD52 expression or inhibition of NF-κB - STAT3 activity in a neuroendocrine cell line NCI-H660 showed a marked decrease in the expression of NSE and CHR-A, confirming the reversal of the NE properties. Notably, TPD52 overexpression in LNCaP cells induced expression of N-cadherin, Vimentin, ZEB1, and Snail1 indicating that TPD52 positively regulates epithelial to mesenchymal transition (EMT) of PCa cells towards NED. Moreover, silencing of Snail1 in TPD52 positive cells blocked the progression of NED and, in NCI-H660 cells reversed NE properties as expected. Of the few requirements of TPD52, activation of NF-κB - STAT3 is essential for promoting EMT compelling NED of LNCaP cells. Collectively, these results reveal that TPD52 is associated with the progression of NEPC and emphasizes the need for therapeutic targeting of TPD52 in PCa., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest. All the authors reviewed the data, read the manuscript and consented for publication. All the raw data and material is available with the corresponding author., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Guidelines for transcatheter aortic valve replacement (TAVR) antithrombotic prophylaxis are extrapolated predominantly from percutaneous coronary intervention (PCI) data. Here, we examined temporal coagulation changes occurring in the early perioperative period to determine the pathobiologic validity of this supposition. This was a prospective observational study of consecutive patients who underwent transfemoral TAVR (n = 27), PCI (n = 12), or surgical aortic valve replacement (SAVR) requiring cardiopulmonary bypass and cross-clamping (n = 12). Blood samples were taken at 4 time points: T1 (baseline), after general anesthesia or sedation; T2, after heparin administration; T3, at the end of the procedure; and T4, 6 hours after the procedure. The samples were assessed concurrently using standard laboratory coagulation tests and viscoelastic tests of whole blood clotting, including the latest generation thromboelastometry (ROTEM sigma) and thromboelastometry (TEG 6s). Patients in the TAVR cohort were older and a had lower baseline hemoglobin level than patients in the PCI and SAVR cohorts. The baseline platelet function was similar between the TAVR and PCI cohorts and impaired in the SAVR cohort Figure S1. The baseline hemostatic measures were comparable among cohorts. Regarding the per-patient change from baseline, the TAVR cohort showed an overall more prothrombotic state than the other cohorts, with the most marked differences from the SAVR cohort after intraoperative heparin administration and from the PCI cohorts 6 hours after the procedure. In addition, the ROTEM and TEG parameters were well correlated but not interchangeable. In conclusion, patients who underwent TAVR have a more prothrombotic hemostatic profile than PCI and SAVR patients. These findings question the current guidelines that extrapolate antithrombotic regimens from PCI to TAVR settings., Competing Interests: Declaration of Competing Interest Drs. Poon and Incani have significant relations with Edwards LifeSciences and Abbott Vascular, including consulting/proctoring fees and an unrestricted institutional grant. Dr. Fanning received a Research Fellowship from the Health Investment, Innovation and Research Office, Department of Health, Queensland Government, Australia (reference JDRF-02). The remaining authors have no competing interests to declare., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Tumor protein D52 (TPD52) is a proto-oncogene overexpressed in prostate cancer (PCa) due to gene amplification and it is involved in the cancer progression of many cancers including PCa. However, the molecular mechanisms underlying the role of TPD52 in cancer progression are still under investigation. In this study, we report that the activation of AMP-activated protein kinase (AMPK) by AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide) inhibited the LNCaP and VCaP cells growth by silencing TPD52 expression. Activation of AMPK inhibited the proliferation and migration of LNCaP and VCaP cells. Interestingly, AICAR treatment to LNCaP and VCaP cells led to the downregulation of TPD52 via activation of GSK3β by a decrease of inactive phosphorylation at Ser9. Moreover, in AICAR treated LNCaP cells, inhibition of GSK3β by LiCl attenuated downregulation of TPD52 indicating that AICAR acts via GSK3β. Furthermore, we found that TPD52 interacts with serine/threonine kinase 11 or Liver kinase B1 (LKB1) a known tumor suppressor and an upstream kinase for AMPK. The molecular modeling and MD simulations indicates that the interaction between TPD52 and LKB1 leads to inhibition of the kinase activity of LKB1 as its auto-phosphorylation sites were masked in the complex. Consequently, TPD52-LKB1 interaction may lead to inactivation of AMPK. Moreover, overexpression of TPD52 is found to be responsible for the reduction of pLKB1 (Ser428) and pAMPK (Thr172). Therefore, TPD52 may be playing its oncogenic role via suppressing the AMPK activation. Altogether, our results revealed a new mechanism of PCa progression in which TPD52 overexpression inhibits AMPK activation by interacting with LKB1. These results support that the use of AMPK activators and/or small molecules that could disrupt the TPD52-LKB1 interaction might be useful to suppress PCa cell growth. TPD52 interacts LKB1 and interfere with activation of AMPK in PCa cells., (© 2023. The International CCN Society.)

Background: Prostate cancer (PCa) is the leading cause of cancer related deaths in men, often androgen deprivation therapy (ADT) leads to the progression of androgen independent PCa (AIPC) which further leads to Neuroendocrine PCa (NEPC). Identifying the molecular mechanisms which navigate the neuroendocrine differentiation (NED) of PCa cells is clinically relevant. It has been suggested that the micro RNAs (miRNAs) play an important role in the regulation of intrinsic mechanisms relevant to tumor progression, resistance as a result leads to poor prognosis. miR-147b has been transpiring as one of the deregulated miRNAs associated with the occurrence of multiple cancers. The present study has studied the role of miRNA-147b in inducing NEPC., Methods: To investigate the functional role of miR-147b in NEPC, we have expressed miRNA mimics or inhibitors in PCa cells and monitored the progression of NEPC along with PCa cell proliferation and survival. The molecular mechanism miRNA-147b follows was studied using western blot and reverse transcription polymerase chain analysis. miRNA target prediction using bioinformatics tools followed by target validation using luciferase reporter assays was performed., Results: In the present study, we found that miR-147b is highly expressed in AIPC cell lines in particular neuroendocrine cells NCI-H660 and NE-LNCaP derived from LNCaP. Mechanistic studies revealed that overexpression of miR-147b or miRNA mimics induced NED in LNCaP cells in in-vitro while its inhibitor reversed the NE features (increased NE markers and reduced prostate specific antigen) of PC3, NCI-H660 and NE-LNCaP cells. In addition, miR-147b reduced the proliferation rate of LNCaP cells via elevated p27kip1 and lowered cyclin D1 for promoting differentiation. In reporter assays, we have identified ribosomal protein S15A (RPS15A) is a direct target of miRNA-147b and RPS15A expression was negatively regulated by miR-147b in PCa cells. Furthermore, we also report that RPS15A is downregulated in NEPC cells and its expression is inversely correlated with NE markers., Conclusion: Targeting the miR-147b - RPS15A axis may overcome the progression of NEPC and serve as a novel therapeutic target to attenuate NED progression of PCa., (© 2023 Wiley Periodicals LLC.)

We have developed a DNA aptamer-conjugated graphene field-effect transistor (GFET) biosensor platform to detect receptor-binding domain (RBD), nucleocapsid (N), and spike (S) proteins, as well as viral particles of original Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus and its variants in saliva samples. The GFET biosensor is a label-free, rapid (≤20 min), ultrasensitive handheld wireless readout device. The limit of detection (LoD) and the limit of quantitation (LoQ) of the sensor are 1.28 and 3.89 plaque-forming units (PFU)/mL for S protein and 1.45 and 4.39 PFU/mL for N protein, respectively. Cognate spike proteins of major variants of concern (N501Y, D614G, Y453F, Omicron-B1.1.529) showed sensor response ≥40 mV from the control (aptamer alone) for fM to nM concentration range. The sensor response was significantly lower for viral particles and cognate proteins of Middle East Respiratory Syndrome (MERS) compared to SARS-CoV-2, indicating the specificity of the diagnostic platform for SARS-CoV-2 vs. MERS viral proteins. During the early phase of the pandemic, the GFET sensor response agreed with RT-PCR data for oral human samples, as determined by the negative percent agreement (NPA) and positive percent agreement (PPA). During the recent Delta/Omicron wave, the GFET sensor also reliably distinguished positive and negative clinical saliva samples. Although the sensitivity is lower during the later pandemic phase, the GFET-defined positivity rate is in statistically close alignment with the epidemiological population-scale data. Thus, the aptamer-based GFET biosensor has a high level of precision in clinically and epidemiologically significant SARS-CoV-2 variant detection. This universal pathogen-sensing platform is amenable for a broad range of public health applications and real-time environmental monitoring.

Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is overexpressed in prostate cancer (PCa) and promotes PCa progression in in vivo through the ADMA-NO pathway by degrading nitric oxide synthase (NOS) inhibitors such as asymmetric dimethylarginine (ADMA) and monomethylamine arginine (L-NMMA). In this study, we investigated the molecular mechanism involved in the overexpression of DDAH1 in PCa and examined its potential role as a therapeutic target. We observed that DDAH1expression is elevated in PCa (PC3, LNCaP, and DU145) cell lines under hypoxia. ChIP and reporter assay results confirmed that DDAH1 expression is positively regulated by HIF-1α through directly binding to the hypoxia response elements (HRE) located within the promoter region between - 1242/- 1238 upstream of its transcription start site (TSS). Under hypoxia, HIF-1α is translocated into the nucleus and activates its target gene expression in PC3 cells. Interestingly, in the event of HIF-1α inhibition or siRNA-mediated knockdown, an alternative transcription factor Nrf2 promotes DDAH1 expression through antioxidant response elements (AREs) on its promoter. ChIP assay results showed that Nrf2 binds to AREs located between -1016 / -1008 bp from the TSS of DDAH1. Furthermore, knockdown of PCa therapeutic target HSP90, an essential co-factor for both HIF-1α and Nrf2 causes attenuation of hypoxia induced DDAH1 overexpression in PCa cells. These results demonstrate that hypoxia induced upregulation of DDAH1 expression is positively regulated by HIF-1α and Nrf2 in association with HSP90. Therefore, targeting tumor angiogenesis promoting DDAH1 along with standard androgen receptor (AR) targeted therapy may offer an effective strategy to prevent PCa progression., (Copyright © 2022. Published by Elsevier Ltd.)

Neuroendocrine prostate cancer (NEPC) is an aggressive, androgen independent PCa and it is detected in patients undergoing androgen deprivation therapy (ADT). Interleukin-6 (IL-6) is a pleiotropic cytokine elevated in PCa patients promotes neuroendocrine differentiation (NED). In this study, PCa cells were differentiated with IL-6 in in-vitro to identify novel targets or signaling pathways associated with emergence of NEPC on deprivation of androgens. From the results, we observed an activation of TGF-β signaling pathway is altered through multiple proteins in differentiated LNCaP cells. Hence, we investigated the role of TGF-β axis in PCa cells differentiation. LNCaP cells treated with IL-6 in androgens deprived media release excess TGF-β ligand and this as conditioned media added to cells stimulated NED of PCa cells. TGF-β released by IL-6 stimulated cells activate p38MAPK through SMAD2 thereby promote NED. Inhibition of TGF-βRI and TGF-βRII signaling activation in LNCaP cells treated with IL-6 did not reversed the NED of cells, possibly due to the reason that the inhibition of TGF-β axis is further activating p38MAPK through SMAD independent manner in PCa cells. However, siRNA mediated knock down or inhibition p38MAPK inactivated TGF-β - SMAD axis in differentiating cells and attenuated NED of LNCaP cells. This result suggests that p38MAPK is the central node for receiving IL-6 signals and promotes NED of LNCaP cells in androgens free media. Remarkably, downregulation or inhibition of p38MAPK in NCI-H660 reversed NED characteristics as well as markers along with inactivation of SMAD2 whereas no effect observed in WPMY-1 normal prostate cells. Taken together these findings unveil that p38MAPK and its upstream regulators are potential targets to overcome the progression of NED of PCa and develop novel therapeutic measures along ADT for effective treatment of PCa., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Neuroendocrine Prostate Cancer (NEPC) is an aggressive form of androgen independent prostate cancer (AIPC), correlated with therapeutic resistance. Interleukin (IL)-6 promotes proliferation and neuroendocrine differentiation (NED) of androgen dependent LNCaP cells. We treated LNCaP cells with IL-6 and observed for in vitro NED of cells and also expression of NE markers βIII tubulin, neuron-specific enolase (NSE) and chromogranin A (ChA). Here we investigated the proteins and/or pathways involved in NED of LNCaP cells induced by IL-6 and characterized their role in NED of PCa cells. We found that the altered proteins modulated AMPK signaling pathway in NE cells. Remarkably, IL-6 induces NED of LNCaP cells through activation of AMPK and SIRT1 and also both of these are co-regulated while playing a predominant role in NED of LNCaP cells. Of the few requirements of AMPK-SIRT1 activation, increased eNOS is essential for NED by elevating Nitric oxide (NO) levels. Pleiotropic effects of NO ultimately regulate p38MAPK in IL-6 induced NED. Hence, IL-6 induced AMPK-SIRT1 activation eventually transfers its activation signals through p38MAPK for advancing NED of LNCaP cells. Moreover, inactivation of p38MAPK with specific inhibitor (SB203580) attenuated IL-6 induced NED of LNCaP cells. Therefore, IL-6 promotes NED of PCa cells via AMPK/SIRT1/p38MAPK signaling. Finally, targeting AMPK-SIRT1 or p38MAPK in androgen independent PC3 cells with neuroendocrine features reversed their neuroendocrine characteristics. Taken together these novel findings reveal that targeting p38MAPK mitigated NED of PCa cells, and thus it can be a favorable target to overcome progression of NEPC., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Glyoxalase I (GLO I) is a known therapeutic target in cancer. Even though TLSC702, a GLO I inhibitor that we discovered, induces apoptosis in tumor cells, exceptionally higher doses are required compared with those needed to inhibit GLO I activity in vitro. In this work, structure-activity optimization studies were conducted on four sections of the TLSC702 molecule to determine the partial structural features necessary for the inhibition of GLO I. Herein, we found that the carboxy group in TLSC702 was critical for binding with the divalent zinc at the active site of GLO I. In contrast, the side chain substituents in the meta- and para- positions of the benzene ring had little influence on the in vitro inhibition of GLO I. The CLogP values of the TLSC702 derivatives showed a positive correlation with the antiproliferative effects on NCI-H522 cells. Thus, two derivatives of TLSC702, which displayed either high or low lipophilicity due to the types of substituents at the phenyl position, were selected. Even though both derivatives showed comparable inhibitory effects as that of their parent compound, the derivative with the high CLogP value was distinctly more antiproliferative than TLSC702. In contrast, the derivative with the low CLogP value did not decrease cell viability in NCI-H522 and HL-60 cells. These findings suggested that structural improvements, such as the addition of hydrophobic moieties to the phenyl group, enhanced the ability of TLSC702 to induce apoptosis by increasing cell membrane permeability., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Point of care viscoelastic measures with thromboelastography (TEG; Haemonetics Corporation, Switzerland) and thromboelastometry (ROTEM, Tem Innovations GmbH, Germany) now supersede laboratory assays in the perioperative assessment and management of coagulation. To the best of our knowledge, this sophisticated coagulation assessment has not been performed to characterise thrombotic changes in the transcatheter aortic valve implantation (TAVI) setting, nor have the two latest iteration cartridge-based systems been directly compared in the elective perioperative period., Methods: Patients undergoing TAVI were prospectively recruited. Samples (n=44) were obtained at four timepoints (postinduction of anaesthesia, postheparin (100 IU/kg), postprotamine (1 mg/100 IU heparin) and 6 hours postoperatively). Each sample was concurrently assessed with standard laboratory tests (prothrombin time/international normalised ratio, activated partial thromboplastin time, thrombin clotting time, platelet count and direct fibrinogen, ROTEMSigma and TEG6s)., Results: Clot strength showed a statistically significant increase postheparin/TAVI deployment. When considering the subgroup of samples taken following the administration heparin, the heparinase channel of the TEG6s did not yield clotting strength results in 55% of samples and clotting time exceeded the upper limit of normal in 70% of samples. It was retrospectively recognised that the arachidonic acid channel of the TEG6s Platelet Mapping Cartridge had been decommissioned prohibiting assessment of aspirin effect., Conclusions: This study demonstrated a small intraprocedural prothrombotic change of uncertain clinical importance during the transcatheter aortic valve procedure. Further comparison with percutaneous coronary intervention and aortic valve replacement cohorts are needed to assess the merits of current antithrombotic guidelines, which are extrapolated from the PCI setting. The heparin effect was more consistently quantified by ROTEM., Competing Interests: Competing interests: KP and AI have 'significant relationships' with Edwards LifeSciences and Abbott Vascular including consulting/proctoring fees and an unrestricted institutional grant., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Transcatheter aortic valve implantation (TAVI) was first performed in Australia in 2008 with a steady increase in the number of implanting centres from seven in 2008 to 42 in 2018 (24 private and 18 public hospitals). There is limited published data on outcomes from Australian centres and no published data from Australian private hospitals. We describe outcomes of the first 300 cases at Queensland's first TAVI implanting private hospital., Methods: From July 2015 to August 2018, 300 patients with severe, symptomatic aortic stenosis underwent TAVI at our centre. A heart team assessed all patients as suitable. All patients underwent computed tomography (CT) assessment of valve sizing and peripheral access., Results: Median age was 85 years, 58% male, mean Society of Thoracic Surgeons' score 4.0%, 49% had New York Heart Association Class III/IV, 28% previous coronary artery bypass grafts, 14% peripheral vascular disease and 3.7% renal impairment (creatinine >177 μmol/L). At 30 days mortality was 1%, stroke 1.3%, myocardial infarction (MI) 0.3%, major vascular complication 3.0%, no life-threatening or disabling bleeding and new permanent pacemaker (PPM) requirement was 9.0%. Paravalvular leak was none, trace and mild in 27%, 53% and 20% respectively with 0.3%≥moderate paravalvular leak. At 1 year, mortality was 4.2%, stroke 2.1%, MI 0.3%, no life-threatening bleeding and PPM 11.4%. Lower rates of mortality, stroke, and major vascular complications were observed compared to the well-established TAVI centres in USA and Germany., Conclusion: Excellent TAVI clinical outcomes can be achieved in the Australian private hospital setting. Expert heart team assessment and CT guided procedural planning are key to these outcomes., (Copyright © 2020 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). All rights reserved.)

Tumor protein D52 (TPD52) is overexpressed in multiple cancers including prostate cancer due to gene amplification and investigations to understand its role in the pathophysiology of different cancers are continuing. GST pull-down assays and Tandem affinity purification of TPD52 as bait identified novel prey Peroxiredoxin 1 (PRDX1) in prostate cancer (PCa) cells. PRDX1 interaction with TPD52 was confirmed in immunoprecipitation and affinity interaction assays. Mapping of interaction domain indicated that PRDX1 interacts with C-terminal region of TPD52 containing PEST domain between 152 and 179 amino acids, a new binding region of TPD52. Here we show that TPD52 interaction with PRDX1 increased its peroxidase activity and ectopic expression of TPD52 induced dimerization of PRDX1 in PCa cells. Moreover, H 2 O 2 exposure evoked the interaction between TPD52 and PRDX1 while depletion of both proteins led to the accumulation of H 2 O 2 suggesting peroxidase activity is important to maintain oxidative capacity in PCa cells. We also observed that overexpression or downregulation of TPD52 and PRDX1 individually or together affecting PCa cells growth, survival, and migration. Altogether, our results show a novel interaction partner of TPD52 providing new insights of its functions and ascertain the role of TPD52-PRDX1 interaction in PCa progression., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Dimethylarginine dimethylaminohydrolase1 (DDAH1) inhibitors are important therapeutics by virtue of their ability to control nitric oxide (NO) production by elevating asymmetric dimethylarginine (ADMA) levels. In a screening campaign, we identified that DD1E5 (3-amino-6- tert-butyl-N-(1,3-thiazol-2-yl)-4-(trifluoromethyl)thieno[2,3- b]pyridine-2- carboxamide) inhibits the DDAH1 activity both in vitro and in cultured cells. Mechanistic studies found that DD1E5 is a competitive inhibitor (dissociation constant ( K i ) of 2.05 ± 0.15 μM). Enzyme kinetic assays showed time and concentration dependent inhibition of DDAH1 with DD1E5, which shows tight binding with an inactivation rate constant of 0.2756 ± 0.015 M -1 S -1 . Treatment of cancer cells with DDAH1 inhibitors shows inhibition of cell proliferation and a subsequent decrease in NO production with ADMA accumulation. DD1E5 reversed the elevated VEGF, c-Myc, HIF-1α, and iNOS levels induced by exogenous DDAH1 overexpression in PCa cells. Moreover, DD1E5 significantly increased intracellular levels of ADMA and reduced NO production, suggesting its therapeutic potential for cancers in which DDAH1 is upregulated. In in vitro assays, DD1E5 abrogated the secretion of angiogenic factors (bFGF and IL-8) into conditional media, indicating its antiangiogenic potential. DD1E5 inhibited in vivo growth of xenograft tumors derived from PCa cells with DDAH1 overexpression, by reducing tumor endothelial content represented with low CD31 expression. VEGF, HIF-1α, and iNOS expression were reversed in DD1E5 treated tumors compared to respective control tumors. In this work, integrating multiple approaches shows DD1E5 is a promising tool for the study of methylarginine-mediated NO control and a potential therapeutic lead compound against pathological conditions with elevated NO production such as cancers and other diseases.

In patients with a degenerative mitral bioprosthesis and prohibitive surgical risk there is emerging evidence for the feasibility of valve-in-valve procedures via a percutaneous transvenous transseptal approach. This paper describes the first time this procedure has been performed in Australia., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Background: Transesophageal echocardiography operators (TEEOP) provide critical imaging support for percutaneous structural cardiac intervention procedures. They stand close to the patient and the associated scattered radiation., Objectives: This study sought to investigate TEEOP radiation dose during percutaneous structural cardiac intervention., Methods: Key personnel (TEEOP, anesthetist, primary operator [OP1], and secondary operator) wore instantly downloadable personal dosimeters during procedures requiring TEE support. TEEOP effective dose (E) and E per unit Kerma area product (E/KAP) were calculated. E/KAP was compared with C-arm projections. Additional shielding for TEEOP was implemented, and doses were measured for a further 50 procedures. Multivariate linear regression was performed to investigate independent predictors of radiation dose reduction., Results: In the initial 98 procedures, median TEEOP E was 2.62 μSv (interquartile range [IQR]: 0.95 to 4.76 μSv), similar to OP1 E: 1.91 μSv (IQR: 0.48 to 3.81 μSv) (p = 0.101), but significantly higher than secondary operator E: 0.48 μSv (IQR: 0.00 to 1.91 μSv) (p < 0.001) and anesthetist E: 0.48 μSv (IQR: 0.00 to 1.43 μSv) (p < 0.001). Procedures using predominantly right anterior oblique (RAO) and steep RAO projections were associated with high TEEOP E/KAP (p = 0.041). In a further 50 procedures, with additional TEEOP shielding, TEEOP E was reduced by 82% (2.62 μSv [IQR: 0.95 to 4.76] to 0.48 μSv [IQR: 0.00 to 1.43 μSv] [p < 0.001]). Multivariate regression demonstrated shielding, procedure type, and KAP as independent predictors of TEEOP dose., Conclusion: TEE operators are exposed to a radiation dose that is at least as high as that of OP1 during percutaneous cardiac intervention. Doses were higher with procedures using predominantly RAO projections. Radiation doses can be significantly reduced with the use of an additional ceiling-suspended lead shield., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

Background: Transcatheter aortic valve replacement entails profound and unavoidable hemodynamic perturbations that may contribute to the neurological injury associated with the procedure., Methods: Thirty-one patients were monitored with cerebral oximetry as a surrogate marker of perfusion while undergoing transcatheter aortic valve replacement via a transfemoral approach under general anesthesia to detect intraoperative hypoperfusion insult. Serial neurologic, cognitive, and cerebral magnetic resonance imaging assessments were administered to objectively quantify perioperative neurologic injury and ascertain any association with significant cerebral oximetry disturbances., Results: Cerebral oximetry reacted promptly to rapid ventricular pacing with significant cerebral desaturation, relative to baseline, of greater than 12% and greater than 20% in 12 of 31 (68%) and 9 of 31 (29%) patients, respectively; or to an absolute measurement of less than 50% in 10 of 31 (33%) patients. Hyperemia occurred immediately following relief of aortic stenosis exceeding baseline by greater than 10% and greater than 20% in 14 of 31 (45%) and 5 of 31 (16%) patients. Postoperative cognitive dysfunction was evident in 3 of 31 (10%) patients and new magnetic resonance imaging-defined ischemic lesions were seen in 17 of 28 (61%) patients. No patient experienced clinically apparent stroke., Conclusions: Cerebral oximetry reacted promptly to rapid ventricular pacing with significant desaturation and hyperemia a common occurrence. However, no association between this intraoperative insult and objective neurologic injury was detected., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Transthoracic echocardiography (TTE) has established its role for diagnosis and management in cardiology and is used by various other specialities in medicine, but it is not routinely practised by anaesthesiologists in the perioperative period including the pre-admission clinic/outpatient clinic. The last decade has seen the emerging role of anaesthesiologist as a 'Perioperative physician'. This review article highlights the potential role and clinical utility, education, teaching and limitations of point of care (POC) TTE modality in perioperative care. Various echocardiography society guidelines and endorsements, diagnostic protocols and limitations are enumerated. This article also discusses some of the possibilities for future education and development related to clinical ultrasound including POC TTE in anaesthetic training curriculum., Competing Interests: There are no conflicts of interest.