Search results for: check-point blockade

Authors: J. Y. Sun, H. Z. Shen

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We study the photon blockade at exceptional points for a non-Hermitian optomechanical system coupled to the driven whispering-gallery-mode microresonator with two nanoparticles under the weak optomechanical coupling approximation, where exceptional points emerge periodically by controlling the relative angle of the nanoparticles. We find that conventional photon blockade occurs at exceptional points for the eigenenergy resonance of the single-excitation subspace driven by a laser field and discuss the physical origin of conventional photon blockade. Under the weak driving condition, we analyze the influences of the different parameters on conventional photon blockade. We investigate conventional photon blockade at nonexceptional points, which exists at two optimal detunings due to the eigenstates in the single-excitation subspace splitting from one (coalescence) at exceptional points to two at nonexceptional points. Unconventional photon blockade can occur at nonexceptional points, while it does not exist at exceptional points since the destructive quantum interference cannot occur due to the two different quantum pathways to the two-photon state not being formed. The realization of photon blockade in our proposal provides a viable and flexible way for the preparation of single-photon sources in the non-Hermitian optomechanical system.

Keywords: optomechanical systems, photon blockade, non-hermitian, exceptional points

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Authors: Mir Mohammad Reza Hosseini

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In new years immune checkpoint inhibitors have gathered care as being one of the greatest talented kinds of immunotherapy on the prospect. There has been a specific emphasis on the immune checkpoint molecules, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1). In 2011, ipilimumab, the primary antibody obstructive an immune checkpoint (CTLA4) was authorized. It is now documented that recognized tumors have many devices of overpowering the antitumor immune response, counting manufacture of repressive cytokines, staffing of immunosuppressive immune cells, and upregulation of coinhibitory receptors recognized as immune checkpoints. This was fast followed by the growth of monoclonal antibodies directing PD1 (pembrolizumab and nivolumab) and PDL1 (atezolizumab and durvalumab). Anti-PD1/PDL1 antibodies have developed some of the greatest extensively set anticancer therapies. We also compare and difference their present place in cancer therapy and designs of immune-related toxicities and deliberate the role of dual immune checkpoint inhibition and plans for the organization of immune-related opposing proceedings. In this review, the employed code and present growth of numerous immune checkpoint inhibitors are abridged, while the communicating device and new development of Immune checkpoint inhibitors in cancer therapy-based synergistic therapies with additional immunotherapy, chemotherapy, phototherapy, and radiotherapy in important and clinical educations in the historical 5 years are portrayed and tinted. Lastly, we disapprovingly measure these methods and effort to find their fortes and faintness based on pre-clinical and clinical information.

Keywords: checkpoint, cancer therapy, PD-1, PDL-1, CTLA4, immunosuppressive

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Authors: Kriddikorn Kaewwongsri, Nikom Suvonvorn

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In the deep south of Thailand, checkpoints for people verification are necessary for the security management of risk zones, such as official buildings in the conflict area. In this paper, we propose an automatic checkpoint system that verifies persons using information from ID cards and facial features. The methods for a person’s information abstraction and verification are introduced based on useful information such as ID number and name, extracted from official cards, and facial images from videos. The proposed system shows promising results and has a real impact on the local society.

Keywords: face comparison, card recognition, OCR, checkpoint system, authentication

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Authors: Jhabakhar Aryal, Kesh Bahadur Rana, Durga Prasad Neupane

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This research analyzes the nature and impacts of the 2015 unofficial blockade in Nepal, a significant event that triggered an economic and humanitarian crisis. While official channels denied claims of involvement, Nepal perceived the blockade as orchestrated by India due to concerns about the newly adopted constitution and Madheshi infringements. The study adopts a qualitative approach, utilizing semi-structured interviews, document analysis, and content analysis to gather data from various perspectives. Employing a "colonial hangover lens," it investigates if colonial legacies continue to influence postcolonial nation dynamics, focusing on India's potential attempt to exert influence over Nepal. The findings suggest that the 2015 blockade had profound consequences for Nepal, potentially reflecting lingering colonial power dynamics in the region. Despite India's denials, a significant portion of Nepalis perceived the blockade as an act of external pressure. Examining these perceptions offers valuable insights into postcolonial relations and their impact on regional stability. The 2015 unofficial blockade serves as a critical case study in understanding the complex interplay of internal dynamics, external influences, and historical legacies in shaping the geopolitics of the region. This research contributes to a deeper understanding of these factors and their ongoing implications for Nepal and its relationship with India.

Keywords: blockade, unofficial, constitution, Madhesis, India, Nepal, postcolonial, regional stability, geopolitics

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Authors: Zoe Goldberger, Priscilla S. Briquez, Jeffrey A. Hubbell

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Tumor cells have mutations resulting from genetic instability that the immune system can actively recognize. Immune checkpoint immunotherapy (ICI) is commonly used in the clinic to re-activate immune reactions against mutated proteins, called neoantigens, resulting in tumor remission in cancer patients. However, only around 20% of patients show durable response to ICI. While tumor mutational burden (TMB) has been approved by the Food and Drug Administration (FDA) as a criterion for ICI therapy, the relevance of the subcellular localizations of the mutated proteins within the tumor cell has not been investigated. Here, we hypothesized that localization of mutations impacts the effect of immune responsiveness to ICI. We analyzed publicly available tumor mutation sequencing data of ICI treated patients from 3 independent datasets. We extracted the subcellular localization from the UniProtKB/Swiss-Prot database and quantified the proportion of membrane, cytoplasmic, nuclear, or secreted mutations per patient. We analyzed this information in relation to response to ICI treatment and overall survival of patients showing with 1722 ICI-treated patients that high mutational burden localized at the membrane (mTMB), correlate with ICI responsiveness, and improved overall survival in multiple cancer types. We anticipate that our results will ameliorate predictability of cancer patient response to ICI with potential implications in clinical guidelines to tailor ICI treatment. This would not only increase patient survival for those receiving ICI, but also patients’ quality of life by reducing the number of patients enduring non-effective ICI treatments.

Keywords: cancer, immunotherapy, membrane neoantigens, efficacy prediction, biomarkers

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Authors: Sakapas Saengchai

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A Study on Strengthening the Security of the Thai-Myanmar Border Trade Area of the people in the Mae Sot customs checkpoint area, Tak province, was designed as a qualitative research study. Its objectives were to study the principles of strengthening border trade security and enhancing people's participation. To develop a border trade model that enhances the spatial economy and improves people's quality of life by collecting data using a participant observation method. In-depth interview group chats border checkpoint administrators, Mae Sot customs checkpoint, Tak province, private entrepreneurs, community leaders, and the opening of a community forum to exchange opinions with people in the area. The results of the study found that 1. Security development is to promote crime reduction. Reduce drug trafficking problems Smuggling and human trafficking have been reduced. Including planning and preparation to protect people from terrorism, epidemics, and communicable diseases, including cooperation with Burma on border rules for people and workers, 2. Wealth development is to promote investment. Transport links value chain logistics Cross-border goods and services on the Thai-Myanmar border Both amending regulations and laws to promote fair trade. Emphasis on convenient and fast service as well as promoting the Thai border area to be a tourist attraction that can create prosperity and income for the community in the area By using balanced natural resources, with production and consumption that are environmentally friendly, and emphasizes the participation of the public sector, the private sector, and people from all sectors in the sustainable development of the Thai border.

Keywords: security, border trade, customs, participation, people

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Authors: Xian-Peng Jiang, Catherine C. Baucom, Toby Jiang, Robert L. Elliott

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HLA-G binds to the inhibitory receptors of uterine NK cells and plays an important role in protection of fetal cells from maternal NK lysis. HLA-G also mediates tumor escape, but the immunosuppressive role is often neglected. These studies have focused on the examination of HLA-G expression in human breast carcinoma and HLA-G immunosuppressive role in NK cytolysis. We examined HLA-G expression in breast cell lines by real time PCR, ELISA and immunofluorescent staining. We treated the breast cancer cell lines with anti-human HLA-G antibody or progesterone. Then, NK cytolysis was measured by using MTT assay. We find that breast carcinoma cell lines increase the expression of HLA-G mRNA and protein, compared to normal cells. Blocking HLA-G of the breast cancer cells by the antibody increases NK cytolysis. Progesterone upregulates HLA-G mRNA and protein of human breast cancer cell lines. The increased HLA-G expression suppresses NK cytolysis. In summary, human breast carcinoma overexpress HLA-G immunosuppressive molecules. Blocking HLA-G protein by antibody improves NK cytolysis. In contrast, upregulation of HLA-G expression by progesterone impairs NK cytolytic function. Thus, HLA-G is a new immunosuppressive checkpoint and potential cancer immunotherapeutic target.

Keywords: HLA-G, Breast carcinoma, NK cells, Immunosuppressive checkpoint

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Authors: Anshul, Rajni Kalia, Sachin Kumar

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Introduction: The costoclavicular approach, a modification to the infraclavicular approach, has been described for anesthesia for upper limb surgeries. Material And Methods: In this randomized and single-blind study, fourty patients undergoing emergency/elective upper limb surgery were allocated to two groups. Group C and S received ultrasound-guided Costoclavicular block and Supraclavicular block, respectively, with 20 ml 0.5 % ropivacaine with 8 mg dexamethasone under strict asepsis. The primary outcome assessed was the total duration of sensory and motor block in the postoperative period. Secondary outcomes were to compare the time taken to perform the procedure, block characteristics in terms of onset of motor and sensory blockade, the efficacy of analgesia with respect to the time of administration of the first rescue analgesic dose with both the blocks and note the side effects pertaining to either of the blocks. Results: The mean total duration of sensory and motor blockade was longer in group C vs. group S (p=0.002 and 0.024, respectively). The mean duration to perform a block in group S was more than in group C (p=0.012). The mean onset of sensory and motor Blockade Time in group S was more than in group C (p<0.001 and <0.001, respectively). The mean duration to perform a block in group S was more than in group C (p=0.012). Conclusion: The costoclavicular approach is better than supraclavicular in terms of rapid execution, faster onset of sensory-motor blockade, prolonged postoperative analgesia and similar PONV and safety profile.

Keywords: costoclavicular, supraclavicular, ropivacaine, dexamethasone

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Authors: Tianjiao Chu, Carla Rios Luci, Christy Maksoudian, Ara Sargsian, Bella B. Manshian, Stefaan J. Soenen

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Nanomaterials have gained high interest in their use as potent anticancer agents. Apart from delivering chemotherapeutic agents in order to reduce off-target effects, molecular agents have also been widely explored. The advances in our understanding of cell biology and cell death mechanisms1 has generated a broad library of potential therapeutic targets by siRNA, mRNA, or pDNA complexes. In the present study, we explore the ability of pDNA-polyplexes to induce tumor-specific necroptosis. This results in a cascade of effects, where immunogenic cell death potentiates anti-tumor immune responses and results in an influx of dendritic cells and cytotoxic T cells, rendering the tumor more amenable to immune checkpoint inhibition. This study aims to explore whether the induction of necroptosis in a subpopulation of tumor cells can be used to potentiate immune checkpoint inhibition studies.

Keywords: nanoparticle, MLKL, necroptosis, immunotherapy

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Authors: Vishal V. R. Nandigana, Mohammad Heiranian, Narayana R. Aluru

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Graphene material has found tremendous applications in water desalination, DNA sequencing and energy storage. Multiple nanopores are etched to create opening for water desalination and energy storage applications. The nanopores created are of the order of 3-5 nm allowing multiple ions to transport through the pore. In this paper, we present for the first time, molecular dynamics study of single ion transport, where only one ion passes through the graphene nanopore. The diameter of the graphene nanopore is of the same order as the hydration layers formed around each ion. Analogous to single electron transport resulting from ionic transport is observed for the first time. The current-voltage characteristics of such a device are similar to single electron transport in quantum dots. The current is blocked until a critical voltage, as the ions are trapped inside a hydration shell. The trapped ions have a high energy barrier compared to the applied input electrical voltage, preventing the ion to break free from the hydration shell. This region is called “Coulomb blockade region”. In this region, we observe zero transport of ions inside the nanopore. However, when the electrical voltage is beyond the critical voltage, the ion has sufficient energy to break free from the energy barrier created by the hydration shell to enter into the pore. Thus, the input voltage can control the transport of the ion inside the nanopore. The device therefore acts as a binary storage unit, storing 0 when no ion passes through the pore and storing 1 when a single ion passes through the pore. We therefore postulate that the device can be used for fluidic computing applications in chemistry and biology, mimicking a computer. Furthermore, the trapped ion stores a finite charge in the Coulomb blockade region; hence the device also acts a super capacitor.

Keywords: graphene nanomembrane, single ion transport, Coulomb blockade, nanofluidics

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Authors: Francesco Pantano, Marta Fogolari, Michele Iuliani, Sonia Simonetti, Silvia Cavaliere, Marco Russano, Fabrizio Citarella, Bruno Vincenzi, Silvia Angeletti, Giuseppe Tonini

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Background: Although immune checkpoint inhibitors (ICIs) have changed the treatment paradigm of non–small cell lung cancer (NSCLC), these drugs fail to elicit durable responses in the majority of NSCLC patients. The gut microbiota, able to regulate immune responsiveness, is emerging as a promising, modifiable target to improve ICIs response rates. Since the oral microbiome has been demonstrated to be the primary source of bacterial microbiota in the lungs, we investigated its composition as a potential predictive biomarker to identify and select patients who could benefit from immunotherapy. Methods: Thirty-five patients with stage IV squamous and non-squamous cell NSCLC eligible for an anti-PD-1/PD-L1 as monotherapy were enrolled. Saliva samples were collected from patients prior to the start of treatment, bacterial DNA was extracted using the QIAamp® DNA Microbiome Kit (QIAGEN) and the 16S rRNA gene was sequenced on a MiSeq sequencing instrument (Illumina). Results: NSCLC patients were dichotomized as “Responders” (partial or complete response) and “Non-Responders” (progressive disease), after 12 weeks of treatment, based on RECIST criteria. A prevalence of the phylum Candidatus Saccharibacteria was found in the 10 responders compared to non-responders (abundance 5% vs 1% respectively; p-value = 1.46 x 10-7; False Discovery Rate (FDR) = 1.02 x 10-6). Moreover, a higher prevalence of Saccharibacteria Genera Incertae Sedis genus (belonging to the Candidatus Saccharibacteria phylum) was observed in "responders" (p-value = 6.01 x 10-7 and FDR = 2.46 x 10-5). Finally, the patients who benefit from immunotherapy showed a significant abundance of TM7 Phylum Sp Oral Clone FR058 strain, member of Saccharibacteria Genera Incertae Sedis genus (p-value = 6.13 x 10-7 and FDR=7.66 x 10-5). Conclusions: These preliminary results showed a significant association between oral microbiota and ICIs response in NSCLC patients. In particular, the higher prevalence of Candidatus Saccharibacteria phylum and TM7 Phylum Sp Oral Clone FR058 strain in responders suggests their potential immunomodulatory role. The study is still ongoing and updated data will be presented at the congress.

Keywords: oral microbiota, immune checkpoint inhibitors, non-small cell lung cancer, predictive biomarker

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Authors: Mohammaad Afzal Khan, Ghazi Abdulmalik Ashoor , Fatimah Alanazi, Talal Shamma, Abdullah Altuhami, Hala Abdalrahman Ahmed, Abdullah Mohammed Assiri, Dieter Clemens Broering

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Microvascular injuries during inflammation are key causes of transplant malfunctioning and permanent failure, which play a major role in the development of chronic rejection of the transplanted organ. Inflammation-induced microvascular loss is a promising area to investigate the decisive roles of regulatory and effector responses. The present study was designed to investigate the impact of IL-10 on immunotolerance, in particular, the microenvironment of the allograft during rejection. Here, we investigated the effects of IL-10 blockade/ reconstitution and serially monitored regulatory T cells (Tregs), graft microvasculature, and airway epithelium in rejecting airway transplants. We demonstrated that the blocking/reconstitution of IL-10 significantly modulates CD4+FOXP3+ Tregs, microvasculature, and airway epithelium during rejection. Our findings further highlighted that blockade of IL-10 upregulated proinflammatory cytokines, IL-2, IL-1β, IFN-γ, IL-15, and IL-23, but suppressed IL-5 secretion during rejection; however, reconstitution of IL-10 significantly upregulated CD4+FOXP3+ Tregs, tissue oxygenation/blood flow and airway repair. Collectively, these findings demonstrate a potential reparative modulation of IL-10 during microvascular and epithelial repair, which could provide a vital therapeutic window to rejecting transplants in clinical practice.

Keywords: interleukin -10, regulatory T cells, allograft rejection, immunotolerance

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Authors: Shu-Pin Huang, Pai-Chi Teng, Hao-Han Chang, Chia-Hsin Liu, Yung-Lun Lin, Shu-Chi Wang, Hsin-Chih Yeh, Chih-Pin Chuu, Jiun-Hung Geng, Li-Hsin Chang, Wei-Chung Cheng, Chia-Yang Li

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The emergence of immune checkpoint inhibitors (ICIs) targeting proteins like PD-1 and PD-L1 has changed the treatment paradigm of bladder cancer. However, not all patients benefit from ICIs, with some experiencing early death. There's a significant need for biomarkers associated with the PD-1 pathway in bladder cancer. Current biomarkers focus on tumor PD-L1 expression, but a more comprehensive understanding of PD-1-related biology is needed. Our study has developed a seven-gene risk score panel, employing a comprehensive bioinformatics strategy, which could serve as a potential prognostic and predictive biomarker for bladder cancer. This panel incorporates the FYN, GRAP2, TRIB3, MAP3K8, AKT3, CD274, and CD80 genes. Additionally, we examined the relationship between this panel and immune cell function, utilizing validated tools such as ESTIMATE, TIDE, and CIBERSORT. Our seven-genes panel has been found to be significantly associated with bladder cancer survival in two independent cohorts. The panel was also significantly correlated with tumor infiltration lymphocytes, immune scores, and tumor purity. These factors have been previously reported to have clinical implications on ICIs. The findings suggest the potential of a PD-1 pathway-based transcriptomic panel as a prognostic and predictive biomarker in bladder cancer, which could help optimize treatment strategies and improve patient outcomes.

Keywords: bladder cancer, programmed cell death protein 1, prognostic biomarker, immune checkpoint inhibitors, predictive biomarker

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Authors: Rajapaksha Gedara Prasad Tharanga Jayasooriya, Matharage Gayani Dilshara, Yung Hyun Choi, Gi-Young Kim

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Camptothecin (CPT) is a quinolone alkaloid which inhibits DNA topoisomerase I that induces cytotoxicity in a variety of cancer cell lines. We previously showed that CPT effectively inhibited invasion of prostate cancer cells and also combined treatment with subtoxic doses of CPT and TNF-related apoptosis-inducing ligand (TRAIL) potentially enhanced apoptosis in a caspase-dependent manner in hepatoma cancer cells. Here, we found that treatment with CPT caused an irreversible cell cycle arrest in the G2/M phase. CPT-induced cell cycle arrest was associated with a decrease in protein levels of cell division cycle 25C (Cdc25C) and increased the level of cyclin B and p21. The CPT-induced decrease in Cdc25C was blocked in the presence of proteasome inhibitor MG132, thus reversed the cell cycle arrest. In addition to that treatment of CPT-increased phosphorylation of Cdc25C was the resulted of activation of checkpoint kinase 2 (Chk2), which was associated with phosphorylation of ataxia telangiectasia-mutated. Interestingly CPT induced G2/M phase of the cell cycle arrest is reactive oxygen species (ROS) dependent where ROS inhibitors NAC and GSH reversed the CPT-induced cell cycle arrest. These results further confirm by using transient knockdown of nuclear factor-erythroid 2-related factor 2 (Nrf2) since it regulates the production of ROS. Our data reveal that treatment of siNrf2 increased the ROS level as well as further increased the CPT induce G2/M phase cell cycle arrest. Our data also indicate CPT-enhanced cell cycle arrest through the extracellular signal-regulated kinase (ERK) and the c-Jun N-terminal kinase (JNK) pathway. Inhibitors of ERK and JNK more decreased the Cdc25C expression and protein expression of p21 and cyclin B. These findings indicate that Chk2-mediated phosphorylation of Cdc25C plays a major role in G2/M arrest by CPT.

Keywords: camptothecin, cell cycle, checkpoint kinase 2, nuclear factor-erythroid 2-related factor 2, reactive oxygen species

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Authors: Gholamreza Hashemitabr, Reza Valadan, Alireza Rafiei, Mohammad Reza Bassami

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Breast cancer is the most common malignancy among women worldwide. Cancer cells use a complex multilayer network of epidermal growth factor receptors (EGFRs) signaling pathways to support their survival and growth. The overlapping networks of EGFRs signaling pathways account for the failure of most ErbB-targeted therapies. The aim of this study was to enrich a pool of recombinant antibody fragments against common epitopes of ErbB1 and ErbB2 in order to simultaneous blockade of ErbBs signaling pathways. ErbB1 and ErbB2 were expressed stably in VERO cells. Selection of recombinant antibodies was performed on live cells expressing either of ErbB1 and ErbB2 receptors using subtractive phage display approach. The results of PCR and DNA fingerprinting in the last round of panning showed that most clones contained insert (80% and 85% for ErbB1 and ErbB2 respectively) with an identical restriction pattern. The selected clones showed positive reaction to both ErbB1 and ErbB2 receptors in phage-ELISA test. Furthermore, the resulting soluble antibody fragments recognized common epitopes of both immunoprecipitated ErbB1 and ErbB2 in western blot. Additionally, the antibodies directed against the dimerization domain of ErbB1 demonstrated a significant absorbance in EGF-stimulated VERO/ErbB1 cells than non-stimulated cells (1.91 and 1.09 respectively). Moreover, the results of dimerization inhibition test showed that these antibodies blocked ErbB1 and ErbB2 dimerization on the surface of ErbB1 and ErbB2 expressing VERO cells. Regarding the importance of pan-ErbB approach to cancer therapy, the antibodies developed here might provide novel therapeutics for simultaneous blockade of ErbBs signaling pathways.

Keywords: breast cancer, single-chain antibody, ErbB1, ErbB2, epitope

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Authors: Kunal K. S., Shwetashri K. R., Keerthan G., Ajinkya R.

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Background: Normal pressure hydrocephalus is a condition caused by abnormal accumulation of cerebrospinal fluid (CSF) within the brain resulting in enlarged cerebral ventricles due to a disruption of CSF formation, absorption, or flow. Over the course of time, ventriculoperitoneal shunt under general anesthesia has become a standard of care. Yet only a finite number of centers have started the inclusion of regional anesthesia techniques for the such patient cohort. Stem Case: We report a case of a 75-year-old male with underlying aortic sclerosis and cardiomyopathy who presented with complaints of confusion, forgetfulness, and difficulty in walking. Neuro-imaging studies revealed disproportionally enlarged subarachnoid space hydrocephalus (DESH). The baseline blood pressure was 116/67 mmHg with a heart rate of 106 beats/min and SpO2 of 96% on room air. The patient underwent smooth induction followed by sonographically guided superficial cervical plexus block and transverse abdominis plane block. Intraoperative pain indices were monitored with Analgesia nociceptive index monitor (ANI, MdolorisTM) and surgical plethysmographic index (SPI, GE Healthcare, Helsinki, FinlandTM). These remained stable during the application of the block and the entire surgical duration. No significant hemodynamic response was observed during the tunneling of the skin by the surgeon. The patient underwent a smooth recovery and emergence. Conclusion: Our decision to incorporate peripheral nerve blockade in conjunction with general anesthesia resulted in opioid-sparing anesthesia and decreased post-operative analgesic requirement by the patient. This blockade was successful in suppressing intraoperative stress responses. Our patient recovered adequately and underwent an uncomplicated post-operative stay.

Keywords: desh, NPH, VP shunt, cervical plexus block, transversus abdominis plane block

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Authors: Akterono Budiyati, Gita Kusumo, Teguh Putra, Fritzie Rexana, Antonius Kurniawan, Aru Sudoyo, Ahmad Utomo, Andi Utama

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The presence of the programmed death ligand-1 (PD-L1) has been used in multiple clinical trials and approved as biomarker for selecting patients more likely to respond to immune checkpoint inhibitors. However, the expression of PD-L1 is regulated in different ways, which leads to a different significance of its presence. Positive PD-L1 within tumors may result from two mechanisms, induced PD-L1 expression by T-cell presence or genetic mechanism that lead to constitutive PD-L1 expression. Amplification of PD-L1 genes was found as one of genetic mechanism which causes an increase in PD-L1 expression. In case of colorectal cancer (CRC), targeting immune checkpoint inhibitor has been recommended for patients with microsatellite instable (MSI). Although the correlation between PD-L1 expression and MSI status has been widely studied, so far the precise mechanism of PD-L1 gene activation in CRC patients, particularly in MSI population have yet to be clarified. In this present study we have profiled 61 archived formalin fixed paraffin embedded CRC specimens of patients from Medistra Hospital, Jakarta admitted in 2010 - 2016. Immunohistochemistry was performed to measure expression of PD-L1 in tumor cells as well as MSI status using antibodies against PD-L1 and MMR (MLH1, MSH2, PMS2 and MSH6), respectively. PD-L1 expression was measured on tumor cells with cut off of 1% whereas loss of nuclear MMR protein expressions in tumor cells but not in normal or stromal cells indicated presence of MSI. Subset of PD-L1 positive patients was then assessed for copy number variations (CNVs) using single Tube TaqMan Copy Number Assays Gene CD247PD-L1. We also observed KRAS mutation to profile possible genetic mechanism leading to the presence or absence of PD-L1 expression. Analysis of 61 CRC patients revealed 15 patients (24%) expressed PD-L1 on their tumor cell membranes. The prevalence of surface membrane PD-L1 was significantly higher in patients with MSI (87%; 7/8) compared to patients with microsatellite stable (MSS) (15%; 8/53) (P=0.001). Although amplification of PD-L1 gene was not found among PD-L1 positive patients, low-level amplification of PD-L1 gene was commonly observed in MSS patients (75%; 6/8) than in MSI patients (43%; 3/7). Additionally, we found 26% of CRC patients harbored KRAS mutations (16/61), so far the distribution of KRAS status did not correlate with PD-L1 expression. Our data suggest genetic mechanism through amplification of PD-L1 seems not to be the mechanism underlying upregulation of PD-L1 expression in CRC patients. However, further studies are warranted to confirm the results.

Keywords: colorectal cancer, gene amplification, microsatellite instable, programmed death ligand-1

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Authors: Rahma Souli-Jbali, Minyar Sassi Hidri, Rahma Ben Ayed

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Grid of computing nodes has emerged as a representative means of connecting distributed computers or resources scattered all over the world for the purpose of computing and distributed storage. Since fault tolerance becomes complex due to the availability of resources in decentralized grid environment, it can be used in connection with replication in data grids. The objective of our work is to present fault tolerance in data grids with data replication-driven model based on clustering. The performance of the protocol is evaluated with Omnet++ simulator. The computational results show the efficiency of our protocol in terms of recovery time and the number of process in rollbacks.

Keywords: data grids, fault tolerance, clustering, chandy-lamport

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Authors: Agata Migdalska, Joanna Berczynska, Ewa Bieniek, Jacek Sterna

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Muscle relaxation is considered important during general anesthesia for spine stabilization. In a presented case peripherally acting muscle relaxant was applied during general anesthesia for spine stabilization surgery. The patient was a dog, 11-years old, 26 kg, male, mix breed. Spine fracture was situated between Th13-L1-L2, probably due to the car accident. Preanesthetic physical examination revealed no sign underlying health issues. The dog was premedicated with midazolam 0.2 mg IM and butorphanol 2.4 mg IM. General anesthesia was induced with propofol IV. After the induction, the dog was intubated with an endotracheal tube and connected to an open-ended rebreathing system and maintained with the use of inhalation anesthesia with isoflurane in oxygen. 0,5 mg/ kg of rocuronium was given IV. Use of muscle relaxant was accompanied by an assessment of the degree of neuromuscular blockade by peripheral nerve stimulator. Electrodes were attached to the skin overlying at the peroneal nerve at the lateral cranial tibia. Four electrical pulses were applied to the nerve over a 2 second period. When satisfying nerve block was detected dog was prepared for the surgery. No further monitoring of the effectiveness of blockade was performed during surgery. Mechanical ventilation was kept during anesthesia. During surgery dog maintain stable, and no anesthesiological complication occur. Intraoperatively surgeon claimed that neuromuscular blockade results in a better approach to the spine and easier muscle manipulation which was helpful in order to see the fracture and replace bone fragments. Finally, euthanasia was performed intraoperatively as a result of vast myelomalacia process of the spinal cord. This prevented examination of the recovering process. Neuromuscular blocking agents act at the neuromuscular junction to provide profound muscle relaxation throughout the body. Muscle blocking agents are neither anesthetic nor analgesic; therefore inappropriately used may cause paralysis in fully conscious and feeling pain patient. They cause paralysis of all skeletal muscles, also diaphragm and intercostal muscles when given in higher doses. Intraoperative management includes maintaining stable physiological conditions, which involves adjusting hemodynamic parameters, ensuring proper ventilation, avoiding variations in temperature, maintain normal blood flow to promote proper oxygen exchange. Neuromuscular blocking agent can cause many side effects like residual paralysis, anaphylactic or anaphylactoid reactions, delayed recovery from anesthesia, histamine release, recurarization. Therefore reverse drug like neostigmine (with glikopyrolat) or edrofonium (with atropine) should be used in case of a life-threatening situation. Another useful drug is sugammadex, although the cost of this drug strongly limits its use. Muscle relaxant improves surgical conditions during spinal surgery, especially in heavily muscled individuals. They are also used to facilitate the replacement of dislocated joints as they improve conditions during fracture reduction. It is important to emphasize that in a patient with muscle weakness neuromuscular blocking agents may result in intraoperative and early postoperative cardiovascular and respiratory complications, as well as prolonged recovery from anesthesia. This should not appear in patients with recent spine fracture or luxation. Therefore it is believed that neuromuscular blockers could be useful during spine stabilization procedures.

Keywords: anesthesia, dog, neuromuscular block, spine surgery

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Authors: Tosin Osasona

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The Nigeria Police Force bears the constitutional mandate as the primary policing agency for the protection of life and property within Nigeria; however, the police have an historical ill-reputation for corruption, ineptitude and impunity. Using the institutional theory of police as the framework of analysis, the paper argues that the performance of the police in Nigeria mirrors the dominant political, social and economic institutions and the structural environment of the Nigerian state. The article puts in perspective the deliberate political decision to underfund the police, leaving officers of the force the extra task of foraging for funds to undertake the duty that the Nigeria state primarily exists for; the article further explores the nexus between corruption in the police in Nigeria and the issue of funding. The article finds that the Nigerian state, by deliberately under-funding the police, while expecting the agency to perform its duties, has indirectly sanctioned the corruption of the force and approved the cooption of the institution of police and policing for private use in Nigeria.

Keywords: Police Corruption, Funding , Informal Taxation, POlice Checkpoint

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Authors: Serap Pektas

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Ataxia telangiectasia mutated (ATM) is a serine-threonine kinase, which is the major regulator of the DNA damage response. ATM is activated upon the formation of DNA double-strand breaks (DSBs) in the cells. ATM phosphorylates the proteins involved in apoptotic responses, cell cycle checkpoint control, DNA repair, etc. Tumor protein p53, known as p53 is one of these proteins that phosphorylated by ATM. Phosphorylation of p53 at Ser15 residue leads to p53 stabilization in the cells. Often enzymes activity is affected by hydrogen ion concentration (pH). In order to find the optimal pH range for ATM activity, steady-state kinetic assays were performed at acidic and basic pH ranges. Ser15 phosphorylation of p53 is determined by using ELISA. The results indicated that the phosphorylation rate was better at basic pH range compared with the acidic pH range. This could be due to enzyme stability, or enzyme-substrate interaction is pH dependent.

Keywords: ataxia telangiectasia mutated, DNA double strand breaks, DNA repair, tumor protein p53

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Authors: Rahaba Marima, Clement Penny

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The Health-related quality of life (HRQoL) for HIV positive patients has improved since the introduction of the highly active antiretroviral treatment (HAART). However, in the present HAART era, HIV co-morbidities such as lung cancer, a non-AIDS (NAIDS) defining cancer have been documented to be on the rise. Under normal physiological conditions, cells grow, repair and proliferate through the cell-cycle as cellular homeostasis is important in the maintenance and proper regulation of tissues and organs. Contrarily, the deregulation of the cell-cycle is a hallmark of cancer, including lung cancer. The association between lung cancer and the use of HAART components such as Efavirenz (EFV) is poorly understood. This study aimed at elucidating the effects of EFV on the cell-cycle genes’ expression in lung cancer. For this purpose, the human cell-cycle gene array composed of 84 genes was evaluated on both normal lung fibroblasts (MRC-5) cells and adenocarcinoma (A549) lung cells, in response to 13µM EFV or 0.01% vehicle. The ±2 up or down fold change was used as a basis of target selection, with p < 0.05. Additionally, RT-qPCR was done to validate the gene array results. Next, In-silico bio-informatics tools, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), Reactome, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Ingenuity Pathway Analysis (IPA) were used for gene/gene interaction studies as well as to map the molecular and biological pathways influenced by the identified targets. Interestingly, the DNA damage response (DDR) pathway genes such as p53, Ataxia telangiectasia mutated and Rad3 related (ATR), Growth arrest and DNA damage inducible alpha (GADD45A), HUS1 checkpoint homolog (HUS1) and Role of radiation (RAD) genes were shown to be upregulated following EFV treatment, as revealed by STRING analysis. Additionally, functional enrichment analysis by the KEGG pathway revealed that most of the differentially expressed gene targets function at the cell-cycle checkpoint such as p21, Aurora kinase B (AURKB) and Mitotic Arrest Deficient-Like 2 (MAD2L2). Core analysis by IPA revealed that p53 downstream targets such as survivin, Bcl2, and cyclin/cyclin dependent kinases (CDKs) complexes are down-regulated, following exposure to EFV. Furthermore, Reactome analysis showed a significant increase in cellular response to stress genes, DNA repair genes, and apoptosis genes, as observed in both normal and cancerous cells. These findings implicate the genotoxic effects of EFV on lung cells, provoking the DDR pathway. Notably, the constitutive expression of this pathway (DDR) often leads to uncontrolled cell proliferation and eventually tumourigenesis, which could be the attribute of HAART components’ (such as EFV) effect on human cancers. Targeting the cell-cycle and its regulation holds a promising therapeutic intervention to the potential HAART associated carcinogenesis, particularly lung cancer.

Keywords: cell-cycle, DNA damage response, Efavirenz, lung cancer

Procedia PDF Downloads 117

Authors: Minjin Kim, Jihwan Kim, Bongsoo Kim, Junho Suh

Abstract:

We demonstrate nanomechanical resonators constructed with synthetic nanowires (NWs) and study their electro-mechanical properties at millikelvin temperatures. Nanomechanical resonators are fabricated using single-crystalline Au NWs and InAs NWs. The mechanical resonance signals are acquired by either magnetomotive or capacitive detection methods. The Au NWs are synthesized by chemical vapor transport method at 1100 °C, and they exhibit clean surface and single-crystallinity with little defects. Due to pristine surface quality, these Au NW mechanical resonators could provide an ideal model system for studying surface-related effects on the mechanical systems. The InAs NWs are synthesized by molecular beam epitaxy or metal organic chemical vapor deposition method. The InAs NWs show electronic conductance modulation resembling Coulomb blockade, which also manifests in the mechanical resonance signals in the form of damping and resonance frequency shift. Our result provides an evidence of strong electro-mechanical coupling in synthetic NW nanomechanical resonators.

Keywords: Au nanowire, InAs nanowire, nanomechanical resonator, synthetic nanowires

Procedia PDF Downloads 181

Authors: Chunyang Miao, Bingxin Li, Shanglong Ning, Christopher J. B. Ford

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While it is challenging to fabricate electronic devices close to atomic dimensions in conventional top-down lithography, molecular electronics is promising to help maintain the exponential increase in component densities via using molecular building blocks to fabricate electronic components from the bottom up. It offers smaller, faster, and more energy-efficient electronic and photonic systems. A self-assembled monolayer (SAM) of molecules is a layer of molecules that self-assembles on a substrate. They are mechanically flexible, optically transparent, low-cost, and easy to fabricate. A large-area multi-layer structure has been designed and investigated by the team, where a SAM of designed molecules is sandwiched between graphene and gold electrodes. Each molecule can act as a quantum dot, with all molecules conducting in parallel. When a source-drain bias is applied, significant current flows only if a molecular orbital (HOMO or LUMO) lies within the source-drain energy window. If electrons tunnel sequentially on and off the molecule, the charge on the molecule is well-defined and the finite charging energy causes Coulomb blockade of transport until the molecular orbital comes within the energy window. This produces ‘Coulomb diamonds’ in the conductance vs source-drain and gate voltages. For different tunnel barriers at either end of the molecule, it is harder for electrons to tunnel out of the dot than in (or vice versa), resulting in the accumulation of two or more charges and a ‘Coulomb staircase’ in the current vs voltage. This nanostructure exhibits highly reproducible Coulomb-staircase patterns, together with additional oscillations, which are believed to be attributed to molecular vibrations. Molecules are more isolated than semiconductor dots, and so have a discrete phonon spectrum. When tunnelling into or out of a molecule, one or more vibronic states can be excited in the molecule, providing additional transport channels and resulting in additional peaks in the conductance. For useful molecular electronic devices, achieving the optimum orbital alignment of molecules to the Fermi energy in the leads is essential. To explore it, a drop of ionic liquid is employed on top of the graphene to establish an electric field at the graphene, which screens poorly, gating the molecules underneath. Results for various molecules with different alignments of Fermi energy to HOMO have shown highly reproducible Coulomb-diamond patterns, which agree reasonably with DFT calculations. In summary, this large-area SAM molecular junction is a promising candidate for future electronic circuits. (1) The small size (1-10nm) of the molecules and good flexibility of the SAM lead to the scalable assembly of ultra-high densities of functional molecules, with advantages in cost, efficiency, and power dissipation. (2) The contacting technique using graphene enables mass fabrication. (3) Its well-observed Coulomb blockade behaviour, narrow molecular resonances, and well-resolved vibronic states offer good tuneability for various functionalities, such as switches, thermoelectric generators, and memristors, etc.

Keywords: molecular electronics, Coulomb blokade, electron-phonon coupling, self-assembled monolayer

Procedia PDF Downloads 29

Authors: Kun Li, Yuzheng Liu, Xiuqi Fan

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High-security standard and high efficiency of screening seem to be contradictory to each other in the airport security check process. Improving the efficiency as far as possible while maintaining the same security standard is significantly meaningful. This paper utilizes the knowledge of Operation Research and Stochastic Process to establish mathematical models to explore this problem. We analyze the current process of airport security check and use the M/G/1 and M/G/k models in queuing theory to describe the process. Then we find the least efficient part is the pre-check lane, the bottleneck of the queuing system. To improve passenger throughput and reduce the variance of passengers’ waiting time, we adjust our models and use Monte Carlo method, then put forward three modifications: adjust the ratio of Pre-Check lane to regular lane flexibly, determine the optimal number of security check screening lines based on cost analysis and adjust the distribution of arrival and service time based on Monte Carlo simulation results. We also analyze the impact of cultural differences as the sensitivity analysis. Finally, we give the recommendations for the current process of airport security check process.

Keywords: queue theory, security check, stochatic process, Monte Carlo simulation

Procedia PDF Downloads 159

Authors: Anzor Abralava, Ketevan Kokrashvili, Rusudan Kutateladze, Nino Pailodze, Ketevan Kutateladze, Giorgi Sulashvili

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Nowadays when the integration of states is growing fast, it is urgent to study the rules of behavior which they resort to in case of conflicts and disagreements. The reason of disagreement in many ways is the Foreign policy carried out by separate countries, as the market participants define production and export capacity and structure as well as level of international division of labor due to the competition among them. We can say over and over again that outbreak of conflicts in Georgia displays the serious controversy between political and economic powerhouses. However, to tell the truth existence of the unsolved conflicts in Georgia is the result of weakness and inadequacy of Georgian politics. Today the main task of political quarters in Georgia should be a direction to Caucasus, as to the region burdened with the most complicated problems which blockade the settlement of conflicts and farther development of our country (or vice versa). In this situation rehabilitation of our authority, leading role and hegemony; expansion and consolidation of peacekeeping and other missions are considered as the exact activities for accomplishing all Georgian economic and political goals.

Keywords: Awara Group, political centers, administrative services, dynamic process

Procedia PDF Downloads 243

Authors: Suneet Kathuria, Shikha Gupta, Kapil Dev, Sunil Katyal

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Chronic use of opioids in opium abusers can cause poor pain control and increased analgaesic requirement. We compared the duration of spinal anaesthesia in chronic opium abusers and non-abusers. This prospective randomised study included 60 American Society of Anesthesiologists (ASA) Grade I or II adults undergoing surgery under spinal anaesthesia with 10 mg bupivacaine, and 25 μg fentanyl in non-opium abusers (Group A); and chronic opium abusers (Group B), and 40 μg fentanyl in chronic opium abusers (Group C). Patients were assessed for onset and duration of sensory and motor blockade and duration of effective analgesia. Mean time to onset of adequate analgesia in opium abusers was significantly longer in chronic opium abusers than in opium-naive patients. The duration of sensory block and motor block was significantly less in chronic opium abusers than in non-opium abusers. Duration of effective analgesia in groups A, B and C was 255.55 ± 26.84, 217.85 ± 15.15, and 268.20 ± 18.25 minutes, respectively; this difference was statistically significant. In chronic opium abusers, the duration of spinal anaesthesia is significantly shorter than that in opium nonabusers. The duration of spinal anaesthesia with bupivacaine and fentanyl in chronic opium abusers can be improved by increasing the intrathecal fentanyl dose from 25 μg to 40 μg.

Keywords: bupivacaine, chronic opium abusers, fentanyl, intrathecal

Procedia PDF Downloads 262

Authors: Jong Yeop Kim, Jong Bum Choi, Hyun Jeong Kwak, Sook Young Lee

Abstract:

Background: Each supraglottic airway requires different anesthetic depth because it has a specific structure and different compressive force in the oropharyngeal cavity. We designed the study to investigate remifentanil effect-site concentration (Ce) in 50% of patients (EC50) for successful insertion of i- gel, and to compare it with that for laryngeal mask airway (LMA) insertion during propofol target-controlled infusion (TCI). Methods: Forty-one female patients were randomized to the i-gel group (n=20) or the LMA group (n=21). Anesthesia induction was performed using propofol Ce of 5 μg/ml and the predetermined remifentanil Ce, and i-gel or LMA insertion was attempted 5 min later. The remifentanil Ce was estimated by modified Dixon's up-and-down method (initial concentration: 3.0 ng/ml, step size: 0.5 ng/ml). The patient’s response to device insertion was classified as either ‘success (no movement)’ or ‘failure (movement)’. Results: Using the Dixon’s up and down method, EC50 of remifentanil Ce for i-gel (1.58 ± 0.41 ng/ml) was significantly lower than that for LMA (2.25 ± 0.55 ng/ml) (p=0.038). Using isotonic regression, EC50 (83% CI) of remifentanil in the i-gel group [1.50 (1.37-1.80) ng/ml] was statistically lower than that in the LMA group [2.00 (1.82-2.34) ng/ml]. EC95 (95% CI) of remifentanil in the i-gel group [2.38 (1.48-2.50) ng/ml] was statistically lower than that in the LMA group [3.35 (2.58-3.48) ng/ml]. Conclusion: We found that EC50 of remifentanil Ce for i-gel insertion (1.58 ng/ml) was significantly lower than that for LMA insertion (2.25 ng/ml), in female patients during propofol TCI without neuromuscular blockade.

Keywords: i-gel, laryngeal mask airway, propofol, remifentanil

Procedia PDF Downloads 349

Authors: V. Ložar, N. Hadžić, T. Opetuk, R. Keser

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The development of digital twins strongly depends on efficient algorithms and their capability to mirror real-life processes. Nowadays, such efforts are required to establish factories of the future faced with new demands of custom-made production. The ship hull processes face these challenges too. Therefore, it is important to implement design and evaluation approaches based on production system engineering. In this study, the recently developed finite state method is employed to describe the stell hull process as a platform for the implementation of digital twinning technology. The application is justified by comparing the finite state method with the analytical approach. This method is employed to rebuild a model of a real shipyard ship hull process using a combination of serial and splitting lines. The key performance indicators such as the production rate, work in process, probability of starvation, and blockade are calculated and compared to the corresponding results obtained through a simulation approach using the software tool Enterprise dynamics. This study confirms that the finite state method is a suitable tool for digital twinning applications. The conclusion highlights the advantages and disadvantages of methods employed in this context.

Keywords: digital twin, finite state method, production system engineering, shipyard

Procedia PDF Downloads 70

Authors: Lokesh Bhatt, Jayesh Rathod

Abstract:

Hypertension is one of the most prevalent cardiovascular disorder. It is responsible for several other cardiovascular disorders. Although many drugs are available for the treatment of hypertension, still a large population has uncontrolled blood pressure. Thus there is an unmet need for new therapeutic approaches for the same. Fruit juice of Citrus paradise contains several flavonoids with vasodilatory activity. We hypothesized that alcoholic extract of Citrus paradise, which contains flavonoids, might attenuate hypertension. The objective of the present study was to evaluate the antihypertensive activity of alcoholic extract of Citrus paradise fruit juice in rats. Hypertension was induced using one clip one kidney model in rats. The renal artery was occluded for 4 h after removal of one kidney. Once stabilized, the ganglionic blockade was performed followed by removal of the arterial clip from the kidney. Removal of clip resulted in an increase in blood pressure which is due to release of renin from the kidney. Alcoholic extract of Citrus paradise fruit juice was then administered at 50 mg/kg and 100 mg/kg dose by intravenous injection. Blood pressure was monitored continuously. Alcoholic extract of Citrus paradise fruit juice reduced hypertension in dose-dependent manner. Antihypertensive activity was found to be associated with vasodilation. The results of the present study showed antihypertensive potential of alcoholic extract of Citrus paradise fruit juice.

Keywords: citrus paradise, alcoholic extract, one clip one kidney model, vasodilation

Procedia PDF Downloads 253