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Article: Partial Splenic Embolization in a Patient with Hemophilia A and Severe Thrombocytopenia: A Case Report.

Nakamura, Tomofumi / Uchiba, Mitsuhiro / Nakata, Hirotomo / Mizumoto, Takao / Beppu, Toru / Matsushita, Shuzo

2024 Volume 16, Issue 2, Page(s) 185–192

Abstract: We report a patient with hemophilia A who underwent partial splenic embolization (PSE) for severe thrombocytopenia secondary to portal hypertension-induced splenomegaly, resulting in a stable long-term quality of life. The patient was diagnosed with ... ...

Abstract	We report a patient with hemophilia A who underwent partial splenic embolization (PSE) for severe thrombocytopenia secondary to portal hypertension-induced splenomegaly, resulting in a stable long-term quality of life. The patient was diagnosed with hemophilia A and unfortunately contracted human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) from blood products. He subsequently developed progressive splenomegaly due to portal hypertension from chronic HCV, resulting in severe thrombocytopenia. PSE was performed because he had occasional subcutaneous bleeding and needed to start interferon (IFN) and ribavirin (RBV) treatment for curing his HCV infection at that time. His platelet counts increased, and no serious adverse events were observed. Currently, he continues to receive outpatient treatment, regular factor VIII (FVIII) replacement therapy for hemophilia A, and antiretroviral therapy for HIV infection. Vascular embolization has been reported to be an effective and minimally invasive treatment for bleeding in hemophilia patients. PSE also provided him with a stable quality of life without the side effects of serious infections and thrombocytopenia relapses. We conclude that PSE is a promising therapeutic option for patients with hemophilia A.
Language	English
Publishing date	2024-03-26
Publishing country	Switzerland
Document type	Case Reports
ZDB-ID	2586645-X
ISSN	2038-8330 ; 2038-8322
ISSN (online)	2038-8330
ISSN	2038-8322
DOI	10.3390/hematolrep16020019
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Article ; Online: Conversion of raltegravir carrying a 1,3,4-oxadiazole ring to a hydrolysis product upon pH changes decreases its antiviral activity.

Nakamura, Tomofumi / Okumura, Mayu / Takamune, Nobutoki / Hirotsu, Tatsunori / Sugiura, Masaharu / Yasunaga, Junichiro / Nakata, Hirotomo

PNAS nexus

2023 Volume 3, Issue 1, Page(s) pgad446

Abstract: Raltegravir (RAL), a human immunodeficiency virus (HIV)-1 integrase inhibitor, has been administered as part of antiretroviral therapy. Studies in patients with HIV-1 have shown high variability in the pharmacokinetics of RAL, and in healthy volunteers, ... ...

Abstract	Raltegravir (RAL), a human immunodeficiency virus (HIV)-1 integrase inhibitor, has been administered as part of antiretroviral therapy. Studies in patients with HIV-1 have shown high variability in the pharmacokinetics of RAL, and in healthy volunteers, coadministration of proton-pump inhibitors has been shown to increase the plasma RAL concentrations. Here, we found that RAL containing a 1,3,4-oxadiazole ring is converted to a hydrolysis product (H-RAL) with a cleaved 1,3,4-oxadiazole ring at pH 1.0 and 13.0 conditions in vitro, thereby reducing the anti-HIV activity of the drug. The inclusion of cyclodextrins (beta-cyclodextrin [βCD], random methyl-βCD [RAM-βCD], and hydroxypropyl-βCD [HP-βCD]) can protect RAL from pH-induced changes. The conversion of RAL to H-RAL was detected by using various mass spectrometry analyses. The chromatogram of H-RAL increased in a time-dependent manner similar to another 1,3,4-oxadiazole-containing drug, zibotentan, using high-performance liquid chromatography. Oral bioavailability and target protein interactions of H-RAL were predicted to be lower than those of RAL. Moreover, H-RAL exhibited significantly reduced anti-HIV-1 activity, whereas combinations with βCD, RAM-βCD, and HP-βCD attenuated this effect in cell-based assays. These findings suggest that βCDs can potentially protect against the conversion of RAL to H-RAL under acidic conditions in the stomach, thereby preserving the anti-HIV-1 effect of RAL. Although clinical trials are needed for evaluation, we anticipate that protective devices such as βCDs may improve the pharmacokinetics of RAL, leading to better treatment outcomes, including reduced dosing, long-term anti-HIV-1 activity, and deeper HIV-1 suppression.
Language	English
Publishing date	2023-12-18
Publishing country	England
Document type	Journal Article
ISSN	2752-6542
ISSN (online)	2752-6542
DOI	10.1093/pnasnexus/pgad446
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Article ; Online: Prophylactic effect of tixagevimab-cilgavimab on COVID-19 infection and death in Japanese patients with B cell lymphoma.

Tatetsu, Hiro / Higuchi, Yusuke / Shichijo, Takafumi / Oda, Kazutaka / Nakata, Hirotomo / Yasunaga, Jun-Ichirou / Nosaka, Kisato / Matsuoka, Masao

International journal of hematology

2023 Volume 118, Issue 2, Page(s) 303–305

MeSH term(s)	Humans ; COVID-19/complications ; COVID-19/mortality ; COVID-19/therapy ; East Asian People ; Lymphoma, B-Cell/complications ; Lymphoma, B-Cell/mortality ; COVID-19 Drug Treatment
Chemical Substances	cilgavimab (1KUR4BN70F) ; tixagevimab
Language	English
Publishing date	2023-06-28
Publishing country	Japan
Document type	Letter
ZDB-ID	1076875-0
ISSN	1865-3774 ; 0917-1258 ; 0925-5710
ISSN (online)	1865-3774
ISSN	0917-1258 ; 0925-5710
DOI	10.1007/s12185-023-03629-4
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Article ; Online: Dose Individualization of Cefepime for Febrile Neutropenia in Patients With Lymphoma or Multiple Myeloma: Implications for Therapeutic Drug Monitoring.

Oda, Kazutaka / Yamaguchi, Ayami / Matsumoto, Naoya / Nakata, Hirotomo / Higuchi, Yusuke / Nosaka, Kisato / Jono, Hirofumi / Saito, Hideyuki

Therapeutic drug monitoring

2023 Volume 46, Issue 1, Page(s) 80–88

Abstract: Background: Optimal cefepime dosing is a challenge because of its dose-dependent neurotoxicity. This study aimed to determine individualized cefepime dosing for febrile neutropenia in patients with lymphoma or multiple myeloma.: Methods: This ... ...

Abstract	Background: Optimal cefepime dosing is a challenge because of its dose-dependent neurotoxicity. This study aimed to determine individualized cefepime dosing for febrile neutropenia in patients with lymphoma or multiple myeloma. Methods: This prospective study enrolled 16 patients receiving cefepime at a dose of 2 g every 12 hours. Unbound concentrations were determined at 0.5 hours, 7.2 hours [at the 60% time point of the 12 hours administration interval (C7.2h)], and 11 hours (trough concentration) after the first infusion (rate: 2 g/h). The primary and secondary end points were the predictive performance of the area under the unbound concentration-time curve (AUC unbound ) and the effect of unbound cefepime pharmacokinetic parameters on clinical response, respectively. Results: The mean (SD) AUC unbound was 689.7 (226.6) mcg h/mL, which correlated with C7.2h (R 2 = 0.90), and the Bayesian posterior AUC unbound using only the trough concentration (R 2 = 0.66). Although higher exposure was more likely to show a better clinical response, each parameter did not indicate a statistical significance between positive and negative clinical responses ( P = 0.0907 for creatinine clearance (Ccr), 0.2523 for C7.2h, 0.4079 for trough concentration, and 0.1142 for AUC unbound ). Cutoff values were calculated as 80.2 mL/min for Ccr (sensitivity: 0.889, specificity: 0.714), 18.6 mcg/mL for C7.2h (sensitivity: 0.571, specificity: 1.000), and 9.2 mcg/mL for trough concentration (sensitivity: 0.571, specificity: 1.000). When aiming for a time above 100% the minimum inhibitory concentration, both continuous infusion of 4 g/d and intermittent infusion of 2 g every 8 hours achieved a probability of approximately 100% at a minimum inhibitory concentration of 8 mcg/mL. Conclusions: Therapeutic drug monitoring by sampling at C7.2h or trough can facilitate rapid dose optimization. Continuous infusion of 4 g/d was recommended. Intermittent dosing of 2 g every 8 hours was alternatively suggested for patients with a Ccr of 60-90 mL/min.
MeSH term(s)	Humans ; Cefepime ; Anti-Bacterial Agents/pharmacokinetics ; Multiple Myeloma/complications ; Multiple Myeloma/drug therapy ; Prospective Studies ; Bayes Theorem ; Drug Monitoring ; Microbial Sensitivity Tests ; Lymphoma ; Febrile Neutropenia/drug therapy
Chemical Substances	Cefepime (807PW4VQE3) ; Anti-Bacterial Agents
Language	English
Publishing date	2023-09-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	424443-6
ISSN	1536-3694 ; 0163-4356
ISSN (online)	1536-3694
ISSN	0163-4356
DOI	10.1097/FTD.0000000000001138
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Zs.A 1503: Show issues

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Article ; Online: Lowered Risk of Nephrotoxicity through Intervention against the Combined Use of Vancomycin and Tazobactam/Piperacillin: A Retrospective Cohort Study.

Oda, Kazutaka / Hashiguchi, Yumi / Katanoda, Tomomi / Nakata, Hirotomo / Jono, Hirofumi / Saito, Hideyuki

Microbiology spectrum

2021 Volume 9, Issue 1, Page(s) e0035521

Abstract: The combined use of vancomycin (VCM) and tazobactam/piperacillin (TAZ/PIPC) is a major risk factor for nephrotoxicity. We sought to evaluate interventions against the combined use of VCM and TAZ/PIPC. This retrospective cohort study involved patients who ...

Abstract	The combined use of vancomycin (VCM) and tazobactam/piperacillin (TAZ/PIPC) is a major risk factor for nephrotoxicity. We sought to evaluate interventions against the combined use of VCM and TAZ/PIPC. This retrospective cohort study involved patients who considered the combined use of VCM and TAZ/PIPC as a treatment. Patients that had either or both antimicrobials replaced were assigned to the intervention group, whereas those who were continued on combination therapy were assigned to the comparison group. The primary endpoint was the incidence of acute kidney injury (AKI). The survival rate of patients on day 30 was evaluated as the secondary endpoint. The comparison and intervention groups were composed of 65 and 68 patients, respectively, and the incidence rates of AKI were 44.6% and 17.6%, respectively. Cox proportional hazard analysis identified the intervention as the only independent factor against AKI development, with a hazard ratio of 0.282 (95% confidence interval [CI], 0.141 to 0.565). For the incidence of AKI of grade greater than 1, the hazard ratio was 0.114 (95% CI, 0.025 to 0.497). The survival rates on day 30 in the comparison and intervention groups were 92.3% and 91.2%, respectively, with a relative risk of 0.988 (95% CI, 0.892 to 1.094). The trough VCM concentration was not associated with the incidence of AKI in patients receiving the combination therapy. This study demonstrated that intervention against the combined use of VCM and TAZ/PIPC can lower the risk of nephrotoxicity.
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Anti-Bacterial Agents/administration & dosage ; Anti-Bacterial Agents/adverse effects ; Child ; Child, Preschool ; Drug Therapy, Combination ; Drug-Related Side Effects and Adverse Reactions/drug therapy ; Female ; Humans ; Incidence ; Kidney Diseases/chemically induced ; Kidney Diseases/epidemiology ; Male ; Middle Aged ; Piperacillin, Tazobactam Drug Combination/administration & dosage ; Piperacillin, Tazobactam Drug Combination/adverse effects ; Retrospective Studies ; Risk Factors ; Vancomycin/administration & dosage ; Vancomycin/adverse effects ; Young Adult
Chemical Substances	Anti-Bacterial Agents ; Piperacillin, Tazobactam Drug Combination (157044-21-8) ; Vancomycin (6Q205EH1VU)
Language	English
Publishing date	2021-08-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2807133-5
ISSN	2165-0497 ; 2165-0497
ISSN (online)	2165-0497
ISSN	2165-0497
DOI	10.1128/Spectrum.00355-21
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Article ; Online: A Small Molecule, ACAi-028, with Anti-HIV-1 Activity Targets a Novel Hydrophobic Pocket on HIV-1 Capsid.

Chia, Travis / Nakamura, Tomofumi / Amano, Masayuki / Takamune, Nobutoki / Matsuoka, Masao / Nakata, Hirotomo

Antimicrobial agents and chemotherapy

2021 Volume 65, Issue 10, Page(s) e0103921

Abstract: The human immunodeficiency virus type 1 (HIV-1) capsid (CA) is an essential viral component of HIV-1 infection and an attractive therapeutic target for antivirals. Here, we report that a small molecule, ACAi-028, inhibits HIV-1 replication by targeting a ...

Abstract	The human immunodeficiency virus type 1 (HIV-1) capsid (CA) is an essential viral component of HIV-1 infection and an attractive therapeutic target for antivirals. Here, we report that a small molecule, ACAi-028, inhibits HIV-1 replication by targeting a hydrophobic pocket in the N-terminal domain of CA (CA-NTD). ACAi-028 is 1 of more than 40 candidate anti-HIV-1 compounds identified by
MeSH term(s)	Anti-HIV Agents/pharmacology ; Capsid ; Capsid Proteins/genetics ; HIV-1 ; Humans ; Phenylalanine/pharmacology ; Virus Replication
Chemical Substances	Anti-HIV Agents ; Capsid Proteins ; Phenylalanine (47E5O17Y3R)
Language	English
Publishing date	2021-07-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.01039-21
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Zs.A 809: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: A Conformational Escape Reaction of HIV-1 against an Allosteric Integrase Inhibitor.

Nakamura, Tomofumi / Nakamura, Teruya / Amano, Masayuki / Miyakawa, Toshikazu / Yamagata, Yuriko / Matsuoka, Masao / Nakata, Hirotomo

Journal of virology

2020 Volume 94, Issue 19

Abstract: HIV-1 often acquires drug-resistant mutations in spite of the benefits of antiretroviral therapy (ART). HIV-1 integrase (IN) is essential for the concerted integration of HIV-1 DNA into the host genome. IN further contributes to HIV-1 RNA binding, which ... ...

Abstract	HIV-1 often acquires drug-resistant mutations in spite of the benefits of antiretroviral therapy (ART). HIV-1 integrase (IN) is essential for the concerted integration of HIV-1 DNA into the host genome. IN further contributes to HIV-1 RNA binding, which is required for HIV-1 maturation. Non-catalytic-site integrase inhibitors (NCINIs) have been developed as allosteric IN inhibitors, which perform anti-HIV-1 activity by a multimodal mode of action such as inhibition of the IN-lens epithelium-derived growth factor (LEDGF)/p75 interaction in the early stage and disruption of functional IN multimerization in the late stage of HIV-1 replication. Here, we show that IN undergoes an adaptable conformational change to escape from NCINIs. We observed that NCINI-resistant HIV-1 variants have accumulated 4 amino acid mutations by passage 26 (P26) in the IN-encoding region. We employed high-performance liquid chromatography (HPLC), thermal stability assays, and X-ray crystallographic analysis to show that some amino acid mutations affect the stability and/or dimerization interface of the IN catalytic core domains (CCDs), potentially resulting in the severely decreased multimerization of full-length IN proteins (IN undermultimerization). This undermultimerized IN via NCINI-related mutations was stabilized by HIV-1 RNA and restored to the same level as that of wild-type HIV-1 in viral particles. Recombinant HIV-1 clones with IN undermultimerization propagated similarly to wild-type HIV-1. Our study revealed that HIV-1 can eventually counteract NCINI-induced IN overmultimerization by IN undermultimerization as one of the escape mechanisms. Our findings provide information on the understanding of IN multimerization with or without HIV-1 RNA and may influence the development of anti-HIV-1 strategies.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Allosteric Regulation/drug effects ; Allosteric Regulation/genetics ; Anti-HIV Agents/pharmacology ; Escape Reaction/drug effects ; HEK293 Cells ; HIV Infections/drug therapy ; HIV Integrase/metabolism ; HIV Integrase Inhibitors/chemistry ; HIV Integrase Inhibitors/pharmacology ; HIV-1/drug effects ; HIV-1/genetics ; HIV-1/physiology ; Humans ; Intercellular Signaling Peptides and Proteins ; Mutation ; Protein Multimerization/drug effects ; Recombinant Proteins ; Transcription Factors ; Virion/chemistry ; Virion/genetics ; Virus Replication/drug effects
Chemical Substances	Adaptor Proteins, Signal Transducing ; Anti-HIV Agents ; HIV Integrase Inhibitors ; Intercellular Signaling Peptides and Proteins ; PSIP1 protein, human ; Recombinant Proteins ; Transcription Factors ; lens epithelium-derived growth factor ; HIV Integrase (EC 2.7.7.-) ; p31 integrase protein, Human immunodeficiency virus 1 (YY6481J2FF)
Language	English
Publishing date	2020-09-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00486-20
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Zs.A 609: Show issues

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Article ; Online: Characterization of a Novel CD4 Mimetic Compound YIR-821 against HIV-1 Clinical Isolates.

Matsumoto, Kaho / Kuwata, Takeo / Tolbert, William D / Richard, Jonathan / Ding, Shilei / Prévost, Jérémie / Takahama, Shokichi / Judicate, George P / Ueno, Takamasa / Nakata, Hirotomo / Kobayakawa, Takuya / Tsuji, Kohei / Tamamura, Hirokazu / Smith, Amos B / Pazgier, Marzena / Finzi, Andrés / Matsushita, Shuzo

Journal of virology

2022 Volume 97, Issue 1, Page(s) e0163822

Abstract: Small CD4-mimetic compound (CD4mc), which inhibits the interaction between gp120 with CD4, acts as an entry inhibitor and induces structural changes in the HIV-1 envelope glycoprotein trimer (Env) through its insertion within the Phe43 cavity of gp120. ... ...

Abstract	Small CD4-mimetic compound (CD4mc), which inhibits the interaction between gp120 with CD4, acts as an entry inhibitor and induces structural changes in the HIV-1 envelope glycoprotein trimer (Env) through its insertion within the Phe43 cavity of gp120. We recently developed YIR-821, a novel CD4mc, that has potent antiviral activity and lower toxicity than the prototype NBD-556. To assess the possibility of clinical application of YIR-821, we tested its antiviral activity using a panel of HIV-1 pseudoviruses from different subtypes. YIR-821 displayed entry inhibitor activity against 53.5% (21/40) of the pseudoviruses tested and enhanced neutralization mediated by coreceptor binding site (CoRBS) antibodies in 50% (16/32) of these. Furthermore, when we assessed the antiviral effects using a panel of pseudoviruses and autologous plasma IgG, enhancement of antibody-mediated neutralization activity was observed for 48% (15/31) of subtype B strains and 51% (28/55) of non-B strains. The direct antiviral activity of YIR-821 as an entry inhibitor was observed in 53% of both subtype B (27/51) and non-B subtype (40/75) pseudoviruses. Enhancement of antibody-dependent cellular cytotoxicity was also observed with YIR-821 for all six selected clinical isolates, as well as for the transmitted/founder (T/F) CH58 virus-infected cells. The sequence diversity in the CD4 binding site as well as other regions, such as the gp120 inner domain layers or gp41, may be involved in the multiple mechanisms related to the sensitive/resistant phenotype of the virus to YIR-821. Our findings may facilitate the clinical application of YIR-821.
MeSH term(s)	Animals ; CD4 Antigens/metabolism ; HIV Antibodies/blood ; HIV Envelope Protein gp120 ; HIV Fusion Inhibitors/pharmacology ; HIV Infections/drug therapy ; HIV-1/drug effects ; Immunoglobulin G/blood ; Macaca mulatta
Chemical Substances	CD4 Antigens ; HIV Antibodies ; HIV Envelope Protein gp120 ; HIV Fusion Inhibitors ; Immunoglobulin G
Language	English
Publishing date	2022-12-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.01638-22
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Zs.A 609: Show issues

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Article ; Online: Human retroviral antisense mRNAs are retained in the nuclei of infected cells for viral persistence.

Ma, Guangyong / Yasunaga, Jun-Ichirou / Shimura, Kazuya / Takemoto, Keiko / Watanabe, Miho / Amano, Masayuki / Nakata, Hirotomo / Liu, Benquan / Zuo, Xiaorui / Matsuoka, Masao

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 17

Abstract: Human retroviruses, including human T cell leukemia virus type 1 (HTLV-1) and HIV type 1 (HIV-1), encode an antisense gene in the negative strand of the provirus. Besides coding for proteins, the messenger RNAs (mRNAs) of retroviral antisense genes have ... ...

Abstract	Human retroviruses, including human T cell leukemia virus type 1 (HTLV-1) and HIV type 1 (HIV-1), encode an antisense gene in the negative strand of the provirus. Besides coding for proteins, the messenger RNAs (mRNAs) of retroviral antisense genes have also been found to regulate transcription directly. Thus, it has been proposed that retroviruses likely localize their antisense mRNAs to the nucleus in order to regulate nuclear events; however, this opposes the coding function of retroviral antisense mRNAs that requires a cytoplasmic localization for protein translation. Here, we provide direct evidence that retroviral antisense mRNAs are localized predominantly in the nuclei of infected cells. The retroviral 3' LTR induces inefficient polyadenylation and nuclear retention of antisense mRNA. We further reveal that retroviral antisense RNAs retained in the nucleus associate with chromatin and have transcriptional regulatory function. While HTLV-1 antisense mRNA is recruited to the promoter of C-C chemokine receptor type 4 (
MeSH term(s)	Basic-Leucine Zipper Transcription Factors/genetics ; Basic-Leucine Zipper Transcription Factors/metabolism ; Cell Line ; Cell Nucleus/metabolism ; Gene Expression/genetics ; Gene Expression Regulation, Viral/genetics ; HIV-1/genetics ; Human Immunodeficiency Virus Proteins/genetics ; Human Immunodeficiency Virus Proteins/metabolism ; Human T-lymphotropic virus 1/genetics ; Humans ; Primary Cell Culture ; Promoter Regions, Genetic/genetics ; Proviruses/genetics ; RNA, Antisense/genetics ; RNA, Antisense/metabolism ; RNA, Messenger/metabolism ; RNA, Viral/genetics ; Retroviridae Proteins/genetics ; Retroviridae Proteins/metabolism ; Terminal Repeat Sequences/genetics ; Transcription, Genetic/genetics ; Viral Envelope Proteins/genetics ; Viral Envelope Proteins/metabolism ; Viral Proteins/metabolism ; Virus Latency/genetics ; Virus Replication/genetics
Chemical Substances	ASP protein, HIV-1 ; Basic-Leucine Zipper Transcription Factors ; HBZ protein, human T-cell leukemia virus type I ; Human Immunodeficiency Virus Proteins ; RNA, Antisense ; RNA, Messenger ; RNA, Viral ; Retroviridae Proteins ; Viral Envelope Proteins ; Viral Proteins
Language	English
Publishing date	2021-11-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2014783118
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Zs.A 1148: Show issues

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Article ; Online: CCR5 inhibitors: emergence, success, and challenges.

Maeda, Kenji / Das, Debananda / Nakata, Hirotomo / Mitsuya, Hiroaki

Expert opinion on emerging drugs

2012 Volume 17, Issue 2, Page(s) 135–145

Abstract: Introduction: The discovery of CC-chemokine receptor 5 (CCR5) as a human immunodeficiency virus type 1 (HIV-1) coreceptor opened a new avenue to exploit CCR5 as a potential target for the intervention of HIV-1's cellular entry.: Areas covered: ... ...

Abstract	Introduction: The discovery of CC-chemokine receptor 5 (CCR5) as a human immunodeficiency virus type 1 (HIV-1) coreceptor opened a new avenue to exploit CCR5 as a potential target for the intervention of HIV-1's cellular entry. Areas covered: Various small-molecule CCR5 inhibitors were identified in the last decade; however, maraviroc (MVC) is the only CCR5 inhibitor currently used in the clinic. Concerns and challenges that exist for wider clinical use of CCR5 inhibitors are discussed. Expert opinion: Although MVC-containing regimens have been recommended for treatment-naïve patients, MVC appears to have been used as one of drugs for salvage therapy rather than for treating drug-naïve patients. This is apparently due to MVC's twice-daily dosing schedule. Another significant disadvantage is that a costly tropism assay must be performed prior to MVC treatment. The access to inexpensive, sensitive, and rapid tropism tests should be made easily available. Only a few novel CCR5 inhibitors are presently in the pipeline. Development of potent and metabolically-stable novel CCR5 inhibitors allowing once-daily dosing regimens is needed. Development of CXCR4 inhibitors should greatly improve the treatment options available to patients infected with X4- and/or dual-tropic HIV-1 strains in combination with a CCR5 inhibitor.
MeSH term(s)	Animals ; Anti-HIV Agents/pharmacology ; Anti-HIV Agents/therapeutic use ; CCR5 Receptor Antagonists ; Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; Cyclohexanes/pharmacology ; Cyclohexanes/therapeutic use ; HIV Infections/drug therapy ; Humans ; Receptors, CXCR4/antagonists & inhibitors ; Triazoles/pharmacology ; Triazoles/therapeutic use
Chemical Substances	Anti-HIV Agents ; CCR5 Receptor Antagonists ; Cyclohexanes ; Receptors, CXCR4 ; Triazoles ; maraviroc (MD6P741W8A)
Language	English
Publishing date	2012-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2061369-6
ISSN	1744-7623 ; 1472-8214
ISSN (online)	1744-7623
ISSN	1472-8214
DOI	10.1517/14728214.2012.673584
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