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  1. Article: Clinal variation as a tool to understand climate change.

    Mayekar, Harshad Vijay / Ramkumar, Durga Kavya / Garg, Divita / Nair, Abhishek / Khandelwal, Ashwin / Joshi, Kavya / Rajpurohit, Subhash

    Frontiers in physiology

    2022  Volume 13, Page(s) 880728

    Abstract: Clines are observable gradients that reflect continuous change in biological traits of species across geographical ranges. Clinal gradients could vary at geographic scales (latitude and altitude). Since clinal variations represent active genomic ... ...

    Abstract Clines are observable gradients that reflect continuous change in biological traits of species across geographical ranges. Clinal gradients could vary at geographic scales (latitude and altitude). Since clinal variations represent active genomic responses at the population level they (clines) provide an immense power to address questions related to climatic change. With the fast pace of climate change i.e. warming, populations are also likely to exhibit rapid responses; at both the phenotypic and genotypic levels. We seek to understand how clinal variation could be used to anticipate climatic responses using
    Language English
    Publishing date 2022-10-11
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2022.880728
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  2. Article: Effect of intravenous dexmedetomidine administered as bolus or as bolus-plus-infusion on subarachnoid anesthesia with hyperbaric bupivacaine.

    Kavya, Upadhya R / Laxmi, Shenoy / Ramkumar, Venkateswaran

    Journal of anaesthesiology, clinical pharmacology

    2018  Volume 34, Issue 1, Page(s) 46–50

    Abstract: Background: Subarachnoid anesthesia is a widely practiced regional anesthetic for infraumbilical surgeries. Intravenous dexmedetomidine is known to prolong both sensory and motor blockade when administered along with subarachnoid anesthesia.: Material ...

    Abstract Background: Subarachnoid anesthesia is a widely practiced regional anesthetic for infraumbilical surgeries. Intravenous dexmedetomidine is known to prolong both sensory and motor blockade when administered along with subarachnoid anesthesia.
    Material and methods: Seventy-five patients scheduled to undergo elective infraumbilical surgeries under subarachnoid anesthesia were randomly allocated to one of the three groups. Group B received intravenous saline over 10 min followed by 12.5 mg intrathecal bupivacaine and then intravenous saline over 60 min. Group bupivacaine + dexmedetomidine bolus (BDexB) received intravenous dexmedetomidine (1 μg/kg) over 10 min followed by 12.5 mg intrathecal bupivacaine and then intravenous saline over 60 min. Group bupivacaine + dexmedetomidine bolus-plus-infusion (BDexBI) received intravenous dexmedetomidine (0.5 μg/kg) over 10 min followed by 12.5 mg intrathecal bupivacaine and then intravenous dexmedetomidine (0.5 μg/kg) over 60 min. Onset of analgesia (at T10), complete motor block (Bromage score 3), and highest level of analgesia were noted. Sensory and motor levels were checked periodically till sensory recovery (at S
    Results: Sensory recovery was significantly longer in Group BDexB (303 min) and Group BdexBI (288 min) as compared to Group B (219.6 min). Motor recovery was also significantly prolonged in Group BDexB (321.6 min) and Group BDexBI (302.4 min) as compared to Group B (233.4 min). Patients receiving dexmedetomidine were sedated but were easily arousable.
    Conclusion: Intravenous dexmedetomidine given as bolus or bolus-plus-infusion with intrathecal hyperbaric bupivacaine prolongs both sensory and motor blockade.
    Language English
    Publishing date 2018-04-10
    Publishing country India
    Document type Journal Article
    ZDB-ID 1401760-x
    ISSN 0970-9185
    ISSN 0970-9185
    DOI 10.4103/joacp.JOACP_132_16
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  3. Article ; Online: Targeting BCL2 Overcomes Resistance and Augments Response to Aurora Kinase B Inhibition by AZD2811 in Small Cell Lung Cancer.

    Ramkumar, Kavya / Tanimoto, Azusa / Della Corte, Carminia M / Stewart, C Allison / Wang, Qi / Shen, Li / Cardnell, Robert J / Wang, Jing / Polanska, Urszula M / Andersen, Courtney / Saeh, Jamal / Pease, J Elizabeth / Travers, Jon / Fabbri, Giulia / Gay, Carl M / Urosevic, Jelena / Byers, Lauren A

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2024  Volume 29, Issue 16, Page(s) 3237–3249

    Abstract: Purpose: Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic ... ...

    Abstract Purpose: Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers of response. Aurora kinase B (AURKB) inhibition exploits an inherent genomic vulnerability in SCLC and is a promising therapeutic approach. Here, we identify biomarkers of response and develop rational combinations with AURKB inhibition to improve treatment efficacy.
    Experimental design: Selective AURKB inhibitor AZD2811 was profiled in a large panel of SCLC cell lines (n = 57) and patient-derived xenograft (PDX) models. Proteomic and transcriptomic profiles were analyzed to identify candidate biomarkers of response and resistance. Effects on polyploidy, DNA damage, and apoptosis were measured by flow cytometry and Western blotting. Rational drug combinations were validated in SCLC cell lines and PDX models.
    Results: AZD2811 showed potent growth inhibitory activity in a subset of SCLC, often characterized by, but not limited to, high cMYC expression. Importantly, high BCL2 expression predicted resistance to AURKB inhibitor response in SCLC, independent of cMYC status. AZD2811-induced DNA damage and apoptosis were suppressed by high BCL2 levels, while combining AZD2811 with a BCL2 inhibitor significantly sensitized resistant models. In vivo, sustained tumor growth reduction and regression was achieved even with intermittent dosing of AZD2811 and venetoclax, an FDA-approved BCL2 inhibitor.
    Conclusions: BCL2 inhibition overcomes intrinsic resistance and enhances sensitivity to AURKB inhibition in SCLC preclinical models.
    MeSH term(s) Humans ; Antineoplastic Agents/therapeutic use ; Apoptosis ; Aurora Kinase B/antagonists & inhibitors ; Cell Line, Tumor ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Proteomics ; Proto-Oncogene Proteins c-bcl-2/drug effects ; Small Cell Lung Carcinoma/drug therapy ; Small Cell Lung Carcinoma/genetics ; Small Cell Lung Carcinoma/pathology ; Xenograft Model Antitumor Assays
    Chemical Substances Antineoplastic Agents ; Aurora Kinase B (EC 2.7.11.1) ; AZD2811 ; BCL2 protein, human ; Proto-Oncogene Proteins c-bcl-2
    Language English
    Publishing date 2024-03-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-23-0375
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    Zs.A 4223: Show issues Location:
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  4. Article ; Online: The Hydroxyquinoline Analogue YUM70 Inhibits GRP78 to Induce ER Stress-Mediated Apoptosis in Pancreatic Cancer.

    Samanta, Soma / Yang, Suhui / Debnath, Bikash / Xue, Ding / Kuang, Yuting / Ramkumar, Kavya / Lee, Amy S / Ljungman, Mats / Neamati, Nouri

    Cancer research

    2021  Volume 81, Issue 7, Page(s) 1883–1895

    Abstract: GRP78 (glucose-regulated protein, 78 kDa) is a key regulator of endoplasmic reticulum (ER) stress signaling. Cancer cells are highly proliferative and have high demand for protein synthesis and folding, which results in significant stress on the ER. To ... ...

    Abstract GRP78 (glucose-regulated protein, 78 kDa) is a key regulator of endoplasmic reticulum (ER) stress signaling. Cancer cells are highly proliferative and have high demand for protein synthesis and folding, which results in significant stress on the ER. To respond to ER stress and maintain cellular homeostasis, cells activate the unfolded protein response (UPR) that promotes either survival or apoptotic death. Cancer cells utilize the UPR to promote survival and growth. In this study, we describe the discovery of a series of novel hydroxyquinoline GRP78 inhibitors. A representative analogue, YUM70, inhibited pancreatic cancer cell growth
    MeSH term(s) A549 Cells ; Animals ; Apoptosis/drug effects ; Cell Line, Tumor ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/drug effects ; Female ; HCT116 Cells ; HT29 Cells ; Heat-Shock Proteins/antagonists & inhibitors ; Humans ; Hydroxyquinolines/pharmacology ; Hydroxyquinolines/therapeutic use ; MCF-7 Cells ; Mice ; Mice, Nude ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Unfolded Protein Response/drug effects ; Xenograft Model Antitumor Assays ; Pancreatic Neoplasms
    Chemical Substances Endoplasmic Reticulum Chaperone BiP ; HSPA5 protein, human ; Heat-Shock Proteins ; Hspa5 protein, mouse ; Hydroxyquinolines
    Language English
    Publishing date 2021-02-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-20-1540
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  5. Article ; Online: A wake-up call for cancer DNA damage: the role of Schlafen 11 (SLFN11) across multiple cancers.

    Zhang, Bingnan / Ramkumar, Kavya / Cardnell, Robert John / Gay, Carl Michael / Stewart, C Allison / Wang, Wei-Lien / Fujimoto, Junya / Wistuba, Ignacio I / Byers, Lauren Averett

    British journal of cancer

    2021  Volume 125, Issue 10, Page(s) 1333–1340

    Abstract: DNA-damaging agents exploit increased genomic instability, a hallmark of cancer. Recently, inhibitors targeting the DNA damage response (DDR) pathways, such as PARP inhibitors, have also shown promising therapeutic potential. However, not all tumors ... ...

    Abstract DNA-damaging agents exploit increased genomic instability, a hallmark of cancer. Recently, inhibitors targeting the DNA damage response (DDR) pathways, such as PARP inhibitors, have also shown promising therapeutic potential. However, not all tumors respond well to these treatments, suggesting additional determinants of response are required. Schlafen 11 (SLFN11), a putative DNA/RNA helicase that induces irreversible replication block, is emerging as an important regulator of cellular response to DNA damage. Preclinical and emerging clinical trial data suggest that SLFN11 is a predictive biomarker of response to a wide range of therapeutics that cause DNA damage including platinum salts and topoisomerase I/II inhibitors, as well as PARP inhibitors, which has raised exciting possibilities for its clinical application. In this article, we review the function, prevalence, and clinical testing of SLFN11 in tumor biopsy samples and circulating tumor cells. We discuss mounting evidence of SLFN11 as a key predictive biomarker for a wide range of cancer therapeutics and as a prognostic marker across several cancer types. Furthermore, we discuss emerging areas of investigation such as epigenetic reactivation of SLFN11 and its role in activating immune response. We then provide perspectives on open questions and future directions in studying this important biomarker.
    MeSH term(s) Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; DNA Damage ; Drug Resistance, Neoplasm ; Epigenesis, Genetic ; Humans ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplastic Cells, Circulating/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Prognosis
    Chemical Substances Biomarkers, Tumor ; Nuclear Proteins ; SLFN11 protein, human
    Language English
    Publishing date 2021-07-22
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 80075-2
    ISSN 1532-1827 ; 0007-0920
    ISSN (online) 1532-1827
    ISSN 0007-0920
    DOI 10.1038/s41416-021-01476-w
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  6. Article: SLFN11 biomarker status predicts response to lurbinectedin as a single agent and in combination with ATR inhibition in small cell lung cancer.

    Kundu, Kiran / Cardnell, Robert J / Zhang, Bingnan / Shen, Li / Stewart, C Allison / Ramkumar, Kavya / Cargill, Kasey R / Wang, Jing / Gay, Carl M / Byers, Lauren A

    Translational lung cancer research

    2021  Volume 10, Issue 11, Page(s) 4095–4105

    Abstract: Background: Lurbinectedin recently received FDA accelerated approval as a second line treatment option for metastatic small cell lung cancer (SCLC). However, there are currently no established biomarkers to predict SCLC sensitivity or resistance to ... ...

    Abstract Background: Lurbinectedin recently received FDA accelerated approval as a second line treatment option for metastatic small cell lung cancer (SCLC). However, there are currently no established biomarkers to predict SCLC sensitivity or resistance to lurbinectedin or preclinical studies to guide rational combinations.
    Methods: Drug sensitivity was assayed in proliferation assays and xenograft models. Baseline proteomic profiling was performed by reverse-phase protein array. Lurbinectedin-induced changes in intracellular signaling pathways were assayed by Western blot.
    Results: Among 21 human SCLC cell lines, cytotoxicity was observed following lurbinectedin treatment at a low dose (median IC50 0.46 nM, range, 0.06-1.83 nM). Notably, cell lines with high expression of Schlafen-11 (SLFN11) protein, a promising biomarker of response to other DNA damaging agents (e.g., chemotherapy, PARP inhibitors), were more sensitive to single-agent lurbinectedin (FC =3.2, P=0.005). SLFN11 was validated as a biomarker of sensitivity to lurbinectedin using siRNA knockdown and in xenografts representing SLFN11 high and low SCLC. Replication stress and DNA damage markers (e.g., γH2AX, phosphorylated CHK1, phosphorylated RPA32) increased in SCLC cell lines following treatment with lurbinectedin. Lurbinectedin also induced PD-L1 expression via cGAS-STING pathway activation. Finally, the combination of lurbinectedin with the ataxia telangiectasia and Rad3-related protein (ATR) inhibitors ceralasertib and berzosertib showed a greater than additive effect in SLFN11-low models.
    Conclusions: Together our data confirm the activity of lurbinectedin across a large cohort of SCLC models and identify SLFN11 as a top candidate biomarker for lurbinectedin sensitivity. In SLFN11-low SCLC cell lines which are relatively resistance to lurbinectedin, the addition of an ATR inhibitor to lurbinectedin re-sensitized otherwise resistant cells, confirming previous observations that SLFN11 is a master regulator of DNA damage response independent of ATR, and the absence of SLFN11 leads to synthetic lethality with ATR inhibition. This study provides a rationale for lurbinectedin in combination with ATR inhibitors to overcome resistance in SCLC with low SLFN11 expression.
    Language English
    Publishing date 2021-12-02
    Publishing country China
    Document type Journal Article
    ZDB-ID 2754335-3
    ISSN 2226-4477 ; 2218-6751
    ISSN (online) 2226-4477
    ISSN 2218-6751
    DOI 10.21037/tlcr-21-437
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  7. Article ; Online: Raltegravir: The evidence of its therapeutic value in HIV-1 infection.

    Ramkumar, Kavya / Neamati, Nouri

    Core evidence

    2010  Volume 4, Page(s) 131–147

    Abstract: Introduction: The antiretroviral treatment paradigm for human immunodeficiency virus-1 (HIV-1) infection has undergone a significant change with the addition of a new class of therapeutic agents targeting HIV-1 integrase (IN). IN inhibitors prevent the ... ...

    Abstract Introduction: The antiretroviral treatment paradigm for human immunodeficiency virus-1 (HIV-1) infection has undergone a significant change with the addition of a new class of therapeutic agents targeting HIV-1 integrase (IN). IN inhibitors prevent the integration of viral DNA into the human genome and terminate the viral life cycle. As the first member of this new class of anti-HIV drugs, raltegravir has shown promising results in the clinic.
    Aims: To review the emerging evidence for the use of the IN inhibitor raltegravir in the treatment of HIV-1 infection.
    Evidence review: Strong evidence shows that raltegravir is effective in reducing the viral load to less than 50 copies/mL and increasing CD4 cell count in treatment-experienced patients with triple-drug class-resistant HIV-1 infection. Substantial evidence also indicates that while raltegravir is able to achieve treatment response in patients with drug-resistant HIV-1, it is susceptible to development of resistance. Raltegravir should be used with at least one other active drug. In addition to its use in salvage therapy upon failure of first-line antiretroviral treatment, a raltegravir-based treatment regimen may also be effective as initial therapy. Substantial evidence also shows that raltegravir-based treatment regimen is well tolerated with minimal clinically severe adverse events and toxicities. Modeling studies suggest a cost-effectiveness of US$21,339 per quality-adjusted life year gained with raltegravir use, though further direct evidence on quality of life and cost-effectiveness is needed.
    Place in therapy: Raltegravir shows significant and sustained virologic and immunologic response in combination with other antiretrovirals in treatment-experienced HIV-1 infected patients who show evidence of viral replication or multidrug-resistant HIV-1 strains, without any significant tolerability issues.
    Language English
    Publishing date 2010-06-15
    Publishing country New Zealand
    Document type Journal Article
    ZDB-ID 2520695-3
    ISSN 1555-175X ; 1555-175X
    ISSN (online) 1555-175X
    ISSN 1555-175X
    DOI 10.2147/ce.s6004
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  8. Article: Targeting MYC-enhanced glycolysis for the treatment of small cell lung cancer.

    Cargill, Kasey R / Stewart, C Allison / Park, Elizabeth M / Ramkumar, Kavya / Gay, Carl M / Cardnell, Robert J / Wang, Qi / Diao, Lixia / Shen, Li / Fan, You-Hong / Chan, Wai Kin / Lorenzi, Philip L / Oliver, Trudy G / Wang, Jing / Byers, Lauren A

    Cancer & metabolism

    2021  Volume 9, Issue 1, Page(s) 33

    Abstract: Introduction: The transcription factor MYC is overexpressed in 30% of small cell lung cancer (SCLC) tumors and is known to modulate the balance between two major pathways of metabolism: glycolysis and mitochondrial respiration. This duality of MYC ... ...

    Abstract Introduction: The transcription factor MYC is overexpressed in 30% of small cell lung cancer (SCLC) tumors and is known to modulate the balance between two major pathways of metabolism: glycolysis and mitochondrial respiration. This duality of MYC underscores the importance of further investigation into its role in SCLC metabolism and could lead to insights into metabolic targeting approaches.
    Methods: We investigated differences in metabolic pathways in transcriptional and metabolomics datasets based on cMYC expression in patient and cell line samples. Metabolic pathway utilization was evaluated by flow cytometry and Seahorse extracellular flux methodology. Glycolysis inhibition was evaluated in vitro and in vivo using PFK158, a small molecular inhibitor of PFKFB3.
    Results: MYC-overexpressing SCLC patient samples and cell lines exhibited increased glycolysis gene expression directly mediated by MYC. Further, MYC-overexpressing cell lines displayed enhanced glycolysis consistent with the Warburg effect, while cell lines with low MYC expression appeared more reliant on oxidative metabolism. Inhibition of glycolysis with PFK158 preferentially attenuated glucose uptake, ATP production, and lactate in MYC-overexpressing cell lines. Treatment with PFK158 in xenografts delayed tumor growth and decreased glycolysis gene expression.
    Conclusions: Our study highlights an in-depth characterization of SCLC metabolic programming and presents glycolysis as a targetable mechanism downstream of MYC that could offer therapeutic benefit in a subset of SCLC patients.
    Language English
    Publishing date 2021-09-23
    Publishing country England
    Document type Journal Article
    ZDB-ID 2700141-6
    ISSN 2049-3002
    ISSN 2049-3002
    DOI 10.1186/s40170-021-00270-9
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  9. Article ; Online: Raltegravir

    Kavya Ramkumar / Nouri Neamati

    Core Evidence, Vol 2009, Iss default, Pp 131-

    The evidence of its therapeutic value in HIV-1 infection

    2009  Volume 147

    Abstract: Kavya Ramkumar, Nouri NeamatiDepartment of Pharmacology and Pharmaceutical Sciences ...

    Abstract Kavya Ramkumar, Nouri NeamatiDepartment of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USAIntroduction: The antiretroviral treatment paradigm for human immunodeficiency virus-1 (HIV-1) infection has undergone a significant change with the addition of a new class of therapeutic agents targeting HIV-1 integrase (IN). IN inhibitors prevent the integration of viral DNA into the human genome and terminate the viral life cycle. As the first member of this new class of anti-HIV drugs, raltegravir has shown promising results in the clinic. Aims: To review the emerging evidence for the use of the IN inhibitor raltegravir in the treatment of HIV-1 infection.Evidence review: Strong evidence shows that raltegravir is effective in reducing the viral load to less than 50 copies/mL and increasing CD4 cell count in treatment-experienced patients with triple-drug class-resistant HIV-1 infection. Substantial evidence also indicates that while raltegravir is able to achieve treatment response in patients with drug-resistant HIV-1, it is susceptible to development of resistance. Raltegravir should be used with at least one other active drug. In addition to its use in salvage therapy upon failure of first-line antiretroviral treatment, a raltegravir-based treatment regimen may also be effective as initial therapy. Substantial evidence also shows that raltegravir-based treatment regimen is well tolerated with minimal clinically severe adverse events and toxicities. Modeling studies suggest a cost-effectiveness of US$21,339 per quality-adjusted life year gained with raltegravir use, though further direct evidence on quality of life and cost-effectiveness is needed. Place in therapy: Raltegravir shows significant and sustained virologic and immunologic response in combination with other antiretrovirals in treatment-experienced HIV-1 infected patients who show evidence of viral replication or multidrug-resistant HIV-1 strains, without any significant tolerability issues.Keywords: raltegravir, isentress, MK-0518, integrase inhibitor, HIV-1, clinical evidence
    Keywords Medicine (General) ; R5-920 ; Medicine ; R ; DOAJ:Medicine (General) ; DOAJ:Health Sciences ; Therapeutics. Pharmacology ; RM1-950 ; DOAJ:Therapeutics
    Subject code 616
    Language English
    Publishing date 2009-07-01T00:00:00Z
    Publisher Dove Medical Press
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Anti-tumor activity of cetuximab plus avelumab in non-small cell lung cancer patients involves innate immunity activation: findings from the CAVE-Lung trial.

    Della Corte, Carminia Maria / Fasano, Morena / Ciaramella, Vincenza / Cimmino, Flora / Cardnell, Robert / Gay, Carl M / Ramkumar, Kavya / Diao, Lixia / Di Liello, Raimondo / Viscardi, Giuseppe / Famiglietti, Vincenzo / Ciardiello, Davide / Martini, Giulia / Napolitano, Stefania / Tuccillo, Concetta / Troiani, Teresa / Martinelli, Erika / Wang, Jing / Byers, Lauren /
    Morgillo, Floriana / Ciardiello, Fortunato

    Journal of experimental & clinical cancer research : CR

    2022  Volume 41, Issue 1, Page(s) 109

    Abstract: Background: We recently conducted Cetuximab-AVElumab-Lung (CAVE-Lung), a proof-of-concept, translational and clinical trial, to evaluate the combination of two IgG1 monoclonal antibodies (mAb): avelumab, an anti-PD-L1 drug, and cetuximab, an anti- ... ...

    Abstract Background: We recently conducted Cetuximab-AVElumab-Lung (CAVE-Lung), a proof-of-concept, translational and clinical trial, to evaluate the combination of two IgG1 monoclonal antibodies (mAb): avelumab, an anti-PD-L1 drug, and cetuximab, an anti-epidermal growth factor receptor (EGFR) drug, as second- or third-line treatment in non-small cell lung cancer (NSCLC) patients. We have reported clinically relevant anti-tumor activity in 6/16 patients. Clinical benefit was accompanied by Natural Killer (NK) cell-mediated antibody-dependent cell cytotoxicity (ADCC). Among the 6 responding patients, 3 had progressed after initial response to a previous treatment with single agent anti-PD-1, nivolumab or pembrolizumab.
    Methods: We report long-term clinical follow-up and additional findings on the anti-tumor activity and on the immune effects of cetuximab plus avelumab treatment for these 3 patients.
    Results: As of November 30, 2021, 2/3 patients were alive. One patient was still on treatment from 34 months, while the other two patients had progression free survival (PFS) of 15 and 19 months, respectively. Analysis of serially collected peripheral blood mononuclear cells (PBMC) revealed long-term activation of NK cell-mediated ADCC. Comprehensive genomic profile analysis found somatic mutations and germline rare variants in DNA damage response (DDR) genes. Furthermore, by transcriptomic analysis of The Cancer Genome Atlas (TCGA) dataset we found that DDR mutant NSCLC displayed high STING pathway gene expression. In NSCLC patient-derived three-dimensional in vitro spheroid cultures, cetuximab plus avelumab treatment induced additive cancer cell growth inhibition as compared to single agent treatment. This effect was partially blocked by treatment with an anti-CD16 mAb, suggesting a direct involvement of NK cell activation. Furthermore, cetuximab plus avelumab treatment induced 10-, 20-, and 20-fold increase, respectively, in the gene expression of CCL5 and CXCL10, two STING downstream effector cytokines, and of interferon β, as compared to untreated control samples.
    Conclusions: DDR mutations may contribute to DDR-induced STING pathway with sustained innate immunity activation following cetuximab plus avelumab combination in previously treated, PD-1 inhibitor responsive NSCLC patients.
    MeSH term(s) Antibodies, Monoclonal, Humanized ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Cetuximab/pharmacology ; Cetuximab/therapeutic use ; Clinical Trials as Topic ; Humans ; Immunity, Innate ; Leukocytes, Mononuclear ; Lung ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics
    Chemical Substances Antibodies, Monoclonal, Humanized ; avelumab (KXG2PJ551I) ; Cetuximab (PQX0D8J21J)
    Language English
    Publishing date 2022-03-26
    Publishing country England
    Document type Journal Article
    ZDB-ID 803138-1
    ISSN 1756-9966 ; 0392-9078
    ISSN (online) 1756-9966
    ISSN 0392-9078
    DOI 10.1186/s13046-022-02332-2
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