Dual mTORC1/mTORC2 inhibition as a Host-Directed Therapeutic Target in Pathologically Distinct Mouse Models of Tuberculosis [Experimental Therapeutics]

xloma.fota13 shared this article with you from Inoreader Dual mTORC1/mTORC2 inhibition as a Host-Directed Therapeutic Target in Pathologically Distinct Mouse Models of Tuberculosis [Experimental Therapeutics] Via AAC Accepts: Articles Published Ahead of Print Efforts to develop more effective and shorter-course therapies for tuberculosis have included a focus on host-directed therapy (HDT). The goal of HDT is to modulate the host response to infection, thereby improving immune defenses to reduce the duration of antibacterial therapy and/or the amount of lung damage. As a mediator of innate and adaptive immune responses involved in eliminating intracellular pathogens, autophagy is a potential target for HDT in tuberculosis. Because Mycobacterium tuberculosis modulates mammalian target of rapamycin (mTOR) signaling to impede autophagy, pharmacologic mTOR inhibition could provide effective HDT. mTOR exists within two distinct multiprotein complexes, mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2). Rapamycin and its analogs only partially inhibit mTORC1. We hypothesized that novel mTOR kinase inhibitors blocking both complexes would have expanded therapeutic potential. We compared the effects of two mTOR inhibitors: rapamycin and the orally available mTOR kinase domain inhibitor CC214-2, which blocks both mTORC1 and mTORC2, as adjunctive therapies against murine TB, when added to the first-line regimen (RHZE) or the novel bedaquiline-pretomanid-linezolid (BPaL) regimen. Neither mTOR inhibitor affected lung CFU counts after 4-8 weeks of treatment when combined with BPaL or RHZE. However, addition of CC214-2 to BPaL and RHZE was associated with significantly fewer relapses in C3HeB/FeJ compared to addition of rapamycin and, in RHZE-trea ted mice, resulted in fewer relapses compared to RHZE alone. Therefore, CC214-2 and related mTOR kinase inhibitors may be more effective candidates for HDT than rapamycin analogs and may have the potential to shorten the duration of TB treatment. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

In Vitro Activity of Oxazolidinone against Nontuberculous Mycobacteria, Including Macrolide-Resistant Clinical Isolates [Susceptibility]

xloma.fota13 shared this article with you from Inoreader In Vitro Activity of Oxazolidinone against Nontuberculous Mycobacteria, Including Macrolide-Resistant Clinical Isolates [Susceptibility] Via AAC Accepts: Articles Published Ahead of Print We evaluated the in vitro activities of oxazolidinone antibiotics including linezolid, sutezolid, and delpazolid against clinical nontuberculous mycobacteria isolates. Regardless of macrolide resistance, for M. avium, M. intracellulare, and M. kansasii, sutezolid showed the lowest minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) value among oxazolidinone antibiotics. However, for M. abscessus, M. massiliense, the MIC and MBC values fo r all oxazolidinone antibiotics showed similar values. Oxazolidinone antibiotics warrant further investigation as potential antibiotics. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Multidrug Resistance Efflux Pumps in Acinetobacter spp.: An Update [Minireviews]

xloma.fota13 shared this article with you from Inoreader Multidrug Resistance Efflux Pumps in Acinetobacter spp.: An Update [Minireviews] Via AAC Accepts: Articles Published Ahead of Print Acinetobacter spp. have become of increased clinical importance as studies have shown the antimicrobial resistant potential of these species. Efflux pumps can lead to reduced susceptibility to a variety of antibiotics and are present in large number across Acinetobacter spp. There are six families of efflux pumps that have been shown to be of clinical relevance: the Major Facilitator Superfamily (MFS), Small Multidrug Resistance (SMR) family, ATP-binding cassette (ABC) family, Multidrug and Toxi c Compound Extrusion (MATE) family, Proteobacterial Antimicrobial Compound Efflux (PACE) family and Resistance-Nodulation-Division (RND) family. A lot of work has been done on understanding and characterizing the roles that these efflux pumps play in relation to antimicrobial resistance and the physiology of these bacteria. RND efflux pumps, with their expansive substrate profiles, are a major component of Acinetobacter spp. antimicrobial resistance. New discoveries over the last decade have shed a lot of light on to the complex regulation of these efflux pumps leading to greater understanding and potential of slowing the reduced susceptibility seen by these bacterial species. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Luminore CopperTouch™ surface coating effectively inactivates SARS-CoV-2, Ebola and Marburg in vitro [Antiviral Agents]

xloma.fota13 shared this article with you from Inoreader Luminore CopperTouch™ surface coating effectively inactivates SARS-CoV-2, Ebola and Marburg in vitro [Antiviral Agents] Via AAC Accepts: Articles Published Ahead of Print We investigated the ability of Luminore CopperTouchTM copper and copper–nickel surfaces to inactivate filoviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The copper and copper–nickel surfaces inactivated 99.9% of Ebola and Marburg viruses after 30 minutes and the copper surfaces inactivated 99% of SARS-CoV-2 in 2 hours. These data reveal that Ebolavirus, Marburgvirus, and SARS-CoV-2 are inactivated by exposure to copper ions, validating Luminore CopperTouchTM as an efficacious tool for infection control. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Quinolin-(1H)-imines as a new chemotype against leishmaniasis: biological evaluation and mechanistic studies [Mechanisms of Action]

xloma.fota13 shared this article with you from Inoreader Quinolin-(1H)-imines as a new chemotype against leishmaniasis: biological evaluation and mechanistic studies [Mechanisms of Action] Via AAC Accepts: Articles Published Ahead of Print Leishmaniasis is one of the most challenging neglected tropical diseases and remains a global threat to public health. Currently available therapies for leishmaniases present significant drawbacks and are rendered increasingly inefficient due to parasite resistance, urging the need for more effective, safer, and cheaper drugs. In our efforts to identify novel chemical scaffolds for the development of antileishmanial agents, we have screened in house antiplasmodial libraries against axenic and intracellular fo rms of Leishmania infantum, L. amazonensis and L. major. Several of the screened compounds showed IC50 values against intracellular L. infantum parasites in the submicromolar range (1h: IC50 0.9 μM and 1n: IC50 0.7 μM) and selectivity indexes of 11 and 9.7, respectively. Compounds also displayed activity against L. amazonensis and L. major, albeit in the low micromolar range. Mechanistic studies revealed that 1n efficiently inhibits oxygen consumption and significantly decreases the mitochondrial membrane potential in L. infantum axenic amastigotes, suggesting that this chemotype acts, at least in part, by interfering with mitochondrial function. Structure-activity analysis suggests that 1n is a promising antileishmanial lead and emphasize the potential of the quinoline-(1H)-imine chemotype for the future development of new antileishmanial agents. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Melting the Eis: non-detection of kanamycin resistance markers by routine diagnostic tests and identification of new eis-promoter variants [Mechanisms of Resistance]

xloma.fota13 shared this article with you from Inoreader Melting the Eis: non-detection of kanamycin resistance markers by routine diagnostic tests and identification of new eis-promoter variants [Mechanisms of Resistance] Via AAC Accepts: Articles Published Ahead of Print Eis-promoter mutations can confer reduced Mycobacterium tuberculosis kanamycin susceptibility. GenoType MTBDRsl, a widely used assay evaluating this region, wrongly classified 17/410 isolates as eis-promoter wildtype. 6/17 isolates harbored mutations known to confer kanamycin resistance, and the remainder harbored either novel eis-promoter mutations (7/11) or disputed mutations (4/11). GenoType MTBDRsl can miss established and new variants that cause reduced susceptibility. These data highlight the importance of reflex phenotypic kanamycin testing. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Overcoming culture restriction for SARS-CoV-2 in human cells facilitates the screening of compounds inhibiting viral replication [Antiviral Agents]

xloma.fota13 shared this article with you from Inoreader Overcoming culture restriction for SARS-CoV-2 in human cells facilitates the screening of compounds inhibiting viral replication [Antiviral Agents] Via AAC Accepts: Articles Published Ahead of Print Efforts to mitigate the COVID-19 pandemic include screening of existing antiviral molecules that could be re-purposed to treat SARS-CoV-2 infections. Although SARS-CoV-2 replicates and propagates efficiently in African green monkey kidney (Vero) cells, antivirals such as nucleos(t)ide analogs (nucs) often show decreased activity in these cells due to inefficient metabolization. SARS-CoV-2 exhibits low viability in human cells in culture. Here, serial passages of a SARS-CoV-2 isolate (original-SARS2) in the human hepatoma cell clone Huh7.5 led to the selection of a variant (adapted-SARS2) with significantly improved infectivity in human liver (Huh7 and Huh7.5) and lung cancer cells (unmodified Calu-1 and A549). The adapted virus exhibited mutations in the spike protein, including a 9 amino acid deletion and 3 amino acid changes (E484D, P812R, and Q954H). E484D also emerged in Vero E6 cultured viruses that became viable in A549 cells. Original and adapted viru ses were susceptible to SR-B1 receptor blocking and adapted-SARS2 exhibited significantly less dependency of ACE2. Both variants were similarly neutralized by COVID-19 convalescent plasma but adapted-SARS2 exhibited increased susceptibility to exogenous type I interferon. Remdesivir inhibited original- and adapted-SARS2 similarly, demonstrating the utility of the system for the screening of nucs. Among the tested nucs, only remdesivir, molnupiravir and to a limited extent galidesivir, showed antiviral effect across human cell lines, whereas sofosbuvir, ribavirin, and favipiravir had no apparent activity. Analogously to the emergence of spike mutations in vivo, the spike protein is under intense adaptive selection pressure in cell culture. Our results indicate that the emergence of spike mutations will most likely not affect the activity of remdesivir. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

External Evaluation of Two Pediatric Population Pharmacokinetics Models of Oral Trimethoprim and Sulfamethoxazole [Pharmacology]

xloma.fota13 shared this article with you from Inoreader External Evaluation of Two Pediatric Population Pharmacokinetics Models of Oral Trimethoprim and Sulfamethoxazole [Pharmacology] Via AAC Accepts: Articles Published Ahead of Print The antibiotic combination trimethoprim (TMP)-sulfamethoxazole (SMX) has a broad spectrum of activity and it is used for the treatment of numerous infections, but pediatric pharmacokinetic (PK) data are limited. We previously published population PK (popPK) models of oral TMP-SMX in pediatric patients based on sparse opportunistically collected data (POPS study, Antimicrob Agents Chemother 62:e01813-17, 2017, https://doi.org/10.1128/AAC.01813-17). We performed a separate PK study of oral TMP-SMX in infants and children with more traditional PK sample collection, and independently developed new popPK models of TMP-SMX using this external dataset. The POPS dataset and the External dataset were each used to evaluate both popPK models. The External TMP model had identical model and error structure as the POPS TMP model with typical values for PK parameters within 20%. The External SMX model did not identify the covariates in the POPS SMX model as significant. The External popPK models predicted higher exposures of TMP (median overprediction of 0.13 mg/L for the POPS dataset and 0.061 mg/L for the External dataset) and SMX (median overprediction of 1.7 mg/L and 0.90 mg/L) than the POPS TMP (median underprediction of 0.016 mg/L and 0.39 mg/L) and SMX (median underprediction of 1.2 mg/L and 14 mg/L) models. Nonetheless, both models supported TMP-SMX dose increases in infan ts and young children for more resistant pathogens with a minimum inhibitory concentration of 1 mg/L, although the required dose increase based on the External model is lower. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Traumatic ischemic injury in a top of the basilar distribution: a case report

xloma.fota13 shared this article with you from Inoreader Traumatic ischemic injury in a top of the basilar distribution: a case report Via Latest Results for BMC Neurology Abstract Background Top of the basilar syndrome is a rare, heterogeneous disorder that has previously only been described in the setting of acute ischemic stroke in predominantly elderly patients. We present the first reported case of traumatic brain injury (TBI) causing ischemia in a top of the basilar distribution. Case presentation A 19-year-old woman suffered an acute subdural hematoma and sustained hypoxemia after being struck by a motor vehicle. Neurosurgical evacuation of the hematoma was undertaken. Magnetic resonance imaging revealed ischemic injury in the midbrain and diencephalic structures fitting a top of the basilar distribution. No associated vascular injury was identified. The patient was eventually discharged in a state of persistent unresponsive wakefulness. Conclusions Ischemia in a top of the basilar distribution may occur in the setting of TBI. A high degree of clinical suspicion is required to identify this disorder. Further study of the complex inflammatory microenvironment and associated tissue perfusion dynamics in TBI are needed in order to elucidate the mechanisms underlying ischemic injury patterns, develop management paradigms and predict prognosis. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The frequency of cytomegalovirus non-ELR UL146 genotypes in neonates with congenital CMV disease is comparable to strains in the background population

xloma.fota13 shared this article with you from Inoreader The frequency of cytomegalovirus non-ELR UL146 genotypes in neonates with congenital CMV disease is comparable to strains in the background population Via BMC Infectious Diseases - Latest Articles Congenital cytomegalovirus disease (cCMV) is common and can be fatal or cause severe sequelae. Circulating strains of cytomegalovirus carry a high number of variable or disrupted genes. One of these is UL146, ... View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Episodic headache with spontaneous hypothermia reveal Shapiro’s syndrome variant with effectiveness of clonidine therapy

xloma.fota13 shared this article with you from Inoreader Episodic headache with spontaneous hypothermia reveal Shapiro's syndrome variant with effectiveness of clonidine therapy Via The Journal of Headache and Pain - Latest Articles Episodic headache with spontaneous hypothermia constitute an uncommon association and is not well recognized in the International Classification of Headache Disorders (ICHD-3). Spontaneous periodic hypothermia... View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Cancers, Vol. 13, Pages 2100: BLBP Is Both a Marker for Poor Prognosis and a Potential Therapeutic Target in Paediatric Ependymoma

xloma.fota13 shared this article with you from Inoreader Cancers, Vol. 13, Pages 2100: BLBP Is Both a Marker for Poor Prognosis and a Potential Therapeutic Target in Paediatric Ependymoma Via Cancers Cancers, Vol. 13, Pages 2100: BLBP Is Both a Marker for Poor Prognosis and a Potential Therapeutic Target in Paediatric Ependymoma Cancers doi: 10.3390/cancers13092100 Authors: Durgagauri H. Sabnis Jo-Fen Liu Lucy Simmonds Sophie Blackburn Richard G. Grundy Ian D. Kerr Beth Coyle Paediatric ependymomas are aggressive, treatment-resistant tumours with a tendency towards relapse, consistent with a sub-population of therapy-resistant cancer stem cells. These cells are believed to derive from brain lipid binding protein (BLBP)-expressing radial glia, hence we proposed that BLBP may be a marker for ependymoma therapy resistance. BLBP protein expression correlated with reduced overall survival (OS) in patients from two trials (CNS9204, a chemotherapy-led infant trial—5 y OS 45% vs. 80%, p = 0.011—and CNS9904, a radiotherapy-led trial—OS 38% vs. 85%, p = 0.002). All ependymoma cell lines examined by qRT-PCR expressed BLBP, with expression elevated in stem cell-enriched neurospheres. Modulation of BLBP function in 2D and 3D assays, using either peroxisome proliferator activated receptor (PPAR) antagonists or BLBP's fatty acid substrate docosahexaneoic acid (DHA), potentiated chemotherapy response and reduced cell migration and invasion in ependymoma cell lines. BLBP is therefore an independent predictor of poor survival in paediatric ependymoma, and treatment with PPAR antagonists or DHA may represent effective novel therapies, preventing chemotherapy resistance and invasion in paediatric ependymoma patients. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.