Explore the vast range of titles available.

Introduction. RG7128 (prodrug of PSI-6130) shows potent antiviral efficacy in patients infected with hepatitis C virus (HCV) genotypes 1, 2, or 3, with mean viral load decreases of 2.7 and 5 log10 IU/mL, respectively, associated with 1500-mg doses twice daily after monotherapy for 2 weeks and with 1000-mg and 1500-mg doses twice daily after treatment in combination with the standard of care (SOC) for 4 weeks. Results. From 32 patients treated with RG7128 monotherapy for 2 weeks, marginal viral load rebound was observed in 3 HCV genotype 1-infected patients, whereas partial response was observed in 2 genotype 1-infected patients. From 85 patients receiving RG7128 in combination with SOC, 1 HCV genotype 1-infected patient experienced a viral rebound, and 2 genotype 3-infected patients experienced a transient rebound. Five genotype 1-infected patients had an HCV load of >1000 IU/mL at the end of 4-week treatment. No viral resistance was observed, per NS5B sequencing and phenotypic studies. PSI-6130 resistance substitution S282T needs to be present at levels of ⩾90% within a patient's quasispecies to confer low-level resistance. No evidence of S282T was found by population or clonal sequence analyses. Conclusions. The requirement for a predominant S282T mutant quasispecies, its low replication capacity, and the low-level resistance it confers probably contribute to the lack of RG7128 resistance observed in HCV-infected patients.

The role of sexual or intrafamilial transmission of hepatitis C is controversial. A phylogenetic analysis was performed on the non-structural region 5B of the hepatitis C virus (NS5B-HCV). High percentages of homology (mean of 98.3%) were shown between the couples. Twenty (83.3%) of the 24 men but only two of the women (8.3%) reported having had sexually transmitted diseases during their lives. The risk factors for HCV acquisition were blood transfusion (10 couples), use of illegal injected drugs (17), use of inhalants (15), acupuncture (5) and tattoos (5). The shared use of personal hygiene items included toothbrushes between six couples (25%), razor blades between 16 (66.7%), nail clippers between 21 (87.5%) and manicure pliers between 14 (58.3%). The high degree of similarity of the hepatitis C virus genome supports the hypothesis of hepatitis C virus transmission between these couples. The shared use of personal hygiene items suggests the possibility of intrafamilial transmission of infection. O papel da transmissão sexual ou intrafamiliar da hepatite C é controverso. Foi feita análise filogenética, região não estrutural 5B do vírus da hepatite C (NS5B-HCV). Altas percentagens de homologia com média de 98,3% foi revelada entre os casais. Vinte (83,3%) de 24 homens, contra apenas duas (8,3%) mulheres reportaram doença sexualmente transmisível durante suas vidas. Os fatores de risco para aquisição da doença foram: transfusão de sangue para 10 casais, uso de drogas ilícitas injetáveis para 17, inalatórias para 15, acupuntura em 5 e tatuagens para 5. O compartilhamento de utensílios de higiene pessoal incluem: escova de dente para seis (25%) dos casais, lâmina de barbear para 16 (66,7%), cortador de unhas para 21 (87,5%) e alicate de manicure para 14 (58,3%). O alto grau de similaridade genômica entre os vírus da hepatite C suporta a hipótese de transmissão entre os casais. O uso compartilhado de utensílios de higiene pessoal sugere a possibilidade de transmissão intrafamiliar.

The unprecedented magnitude of the 2013-2016 Ebola virus (EBOV) epidemic in West Africa resulted in over 11,000 deaths and spurred an international public health emergency. A second outbreak in 2018-2020 in DRC resulted in an additional >3400 cases and nearly 2300 deaths (WHO Disease Outbreak News: Update 26 June, 2020). These large outbreaks across geographically diverse regions highlight the need for the development of effective oral therapeutic agents that can be easily distributed for self-administration to populations with active disease or at risk of infection. Herein, we report the in vivo efficacy of N4-hydroxycytidine (EIDD-1931), a broadly active ribonucleoside analog and the active metabolite of the prodrug EIDD-2801 (molnupiravir), in murine models of lethal EBOV infection. Twice daily oral dosing with EIDD-1931 at 200 mg/kg for 7 days, initiated either with a prophylactic dose 2 hours before infection, or as therapeutic treatment starting 6 hours post-infection, resulted in 92-100% survival of mice challenged with lethal doses of EBOV, reduced clinical signs of Ebola virus disease (EVD), reduced serum virus titers, and facilitated weight loss recovery. These results support further investigation of molnupiravir as a potential therapeutic or prophylactic treatment for EVD. Competing Interest Statement GRB, MGN and GRP are listed as inventors on the EIDD-2801 patent; SM is listed as inventor on the patent application for mAb 114 (Ebanga (ansuvimab-zykl); GRP and WP are listed on a patent application covering various embodiments relating to molnupiravir; WP and SM are employees at Ridgeback Biotherapeutics; GRB, MGN, AAK and GRP are employees of Emory University and have a financial interest in molnupiravir (EIDD-2801)

Introduction. RG7128 (prodrug of PSI-6130) shows potent antiviral efficacy in patients infected with hepatitis C virus (HCV) genotypes 1, 2, or 3, with mean viral load decreases of 2.7 and 5 log sub(10) IU/mL, respectively, associated with 1500-mg doses twice daily after monotherapy for 2 weeks and with 1000-mg and 1500-mg doses twice daily after treatment in combination with the standard of care (SOC) for 4 weeks. Results. From 32 patients treated with RG7128 monotherapy for 2 weeks, marginal viral load rebound was observed in 3 HCV genotype 1-infected patients, whereas partial response was observed in 2 genotype 1-infected patients. From 85 patients receiving RG7128 in combination with SOC, 1 HCV genotype 1-infected patient experienced a viral rebound, and 2 genotype 3-infected patients experienced a transient rebound. Five genotype 1-infected patients had an HCV load of >1000 IU/mL at the end of 4-week treatment. No viral resistance was observed, per NS5B sequencing and phenotypic studies. PSI-6130 resistance substitution S282T needs to be present at levels of 90% within a patient's quasispecies to confer low-level resistance. No evidence of S282T was found by population or clonal sequence analyses. Conclusions. The requirement for a predominant S282T mutant quasispecies, its low replication capacity, and the low-level resistance it confers probably contribute to the lack of RG7128 resistance observed in HCV-infected patients.

The role of sexual or intrafamilial transmission of hepatitis C is controversial. A phylogenetic analysis was performed on the non-structural region 5B of the hepatitis C virus (NS5B-HCV). High percentages of homology (mean of 98.3%) were shown between the couples. Twenty (83.3%) of the 24 men but only two of the women (8.3%) reported having had sexually transmitted diseases during their lives. The risk factors for HCV acquisition were blood transfusion (10 couples), use of illegal injected drugs (17), use of inhalants (15), acupuncture (5) and tattoos (5). The shared use of personal hygiene items included toothbrushes between six couples (25%), razor blades between 16 (66.7%), nail clippers between 21 (87.5%) and manicure pliers between 14 (58.3%). The high degree of similarity of the hepatitis C virus genome supports the hypothesis of hepatitis C virus transmission between these couples. The shared use of personal hygiene items suggests the possibility of intrafamilial transmission of infection.O papel da transmissão sexual ou intrafamiliar da hepatite C é controverso. Foi feita análise filogenética, região não estrutural 5B do vírus da hepatite C (NS5B-HCV). Altas percentagens de homologia com média de 98,3% foi revelada entre os casais. Vinte (83,3%) de 24 homens, contra apenas duas (8,3%) mulheres reportaram doença sexualmente transmisível durante suas vidas. Os fatores de risco para aquisição da doença foram: transfusão de sangue para 10 casais, uso de drogas ilícitas injetáveis para 17, inalatórias para 15, acupuntura em 5 e tatuagens para 5. O compartilhamento de utensílios de higiene pessoal incluem: escova de dente para seis (25%) dos casais, lâmina de barbear para 16 (66,7%), cortador de unhas para 21 (87,5%) e alicate de manicure para 14 (58,3%). O alto grau de similaridade genômica entre os vírus da hepatite C suporta a hipótese de transmissão entre os casais. O uso compartilhado de utensílios de higiene pessoal sugere a possibilidade de transmissão intrafamiliar.

We hypothesize that elevation of nm23-HI metastasis suppressor gene expression in micrometastatic tumor cells may reduce their subsequent colonization and invasion, and induce differentiation, with a clinical benefit. This report presents the first analysis of the nm23-HI promoter to identify sites which can increase its transcription. Deletion mapping of a 2.1 kb nm23-H1 promoter fragment tethered to a reporter gene identified three regions involved in its differential expression levels among a panel of human breast carcinoma cell lines: a 195 bp NheI-XbaI fragment responsible for basal expression levels, a 248 bp AvrII-Nhel fragment which contributed to the elevated nm23-H1 expression observed in the high expressing cell lines, and a 544 bp AvrII fragment containing an inhibitory element. Examination of the 248 bp AvrII-NheI fragment revealed the unexpected presence of three transcription factor binding sites (MAF/Ets, CTF/NF1 half site and ACAAAG enhancer) previously identified in the MMTV-LTR, and in WAP and milk gene promoters, proposed to mediate mammary-specific gene expression. Mutation of the three sites, individually or together, resulted in two-fold reductions in reporter gene expression. As controls, the same panel of mutations caused a different pattern of reporter gene expression in a non-mammary cell line, and mutation of another nearby site was without effect on nm23-HI. Our data identify a complex regulatory pattern for nm23-H1 transcription, and suggest that a mammary-specific cassette of transcription factors contribute to its elevated expression

We have used the COMPARE computer algorithm and Nm23 expression as a marker of tumor metastatic potential to examine the in vitro antiproliferative activity of chemotherapeutic drugs on human breast carcinoma and melanoma cell lines. None of 171 compounds in clinical use or under development and only 40 of 30,000 repository compounds exhibited preferential growth inhibition of low-Nm23-expressing, metastatically aggressive cell lines with a Pearson correlation coefficient of ≤0.64. Characterization of one compound, NSC 645306, is presented including in vivo activity in a hollow fiber assay. The data demonstrate a novel approach to drug identification for aggressive human tumors.

The metF operator, which consists of five imperfect repeats of the met box (AGACGTCT), has been identified as a nucleotide sequence partially overlapping the metF promoter region. Understanding the mechanisms involved in regulation of metF gene expression by the MetJ repressor protein requires precise identification of the MetJ protein DNA binding site. Plasmids, with and without deletions in the metF promoter/operator region, were constructed and provided material which was employed to test for MetJ/MetK-mediated regulation of metF and/or bla (reporter) gene expression from the metF promoter/operator. Gene expression by plasmids with an intact metF promoter, but with less than three intact met box operator sequences, show no MetJ/MetK regulatory control on bla gene expression when only one chromosomal copy of the metJ gene was present. In the presence of two chromosomal copies of the metJ gene, gene expression by plasmids with an intact metF promoter, but with less than three intact met boxes, show a significant response to MetJ/MetK regulatory control on bla gene expression. Deletion of components of the $-$35 sequence of the metF promoter dramatically reduce the level of metF expression. The data indicates that the $-$35 sequence region of the metF promoter is essential for promoter strength but can be replaced with a poorer sequence. This alteration has a profound impact upon the level of metF expression and upon the efficiency of MetJ-mediated repression of the mutant-metF allele. The results also indicate that the metF promoter is stronger than what is predicted by Hawley-McClure homology scores. Collectively, these results demonstrate that the essential components of the metF promoter/operator sequences can be physically localized to separate, discrete regions of DNA sequence immediately upstream of the metF gene. Also as a result of these investigations a rapid, highly sensitive, and relatively inexpensive spectrophotometric assay was developed to quantify beta-lactamase enzyme activity. This assay provides the means for using beta-lactamase as a reporter gene to study bacterial promoters.

In this study, a screen-printed electrode for nitrate ions was evaluated with a selective membrane based on tetradecyl ammonium nitrate as the ionophore, o-nitrophenyl octyl ether as the plasticizer, and polyvinyl chloride as the polymeric matrix. The electrodes were printed on polyethylene terephthalate sheets using a screen-printing frame with the electrode template. Then, the selective membrane was deposited by drop casting. The principal analytical parameters were determined by the method of additions recommended by IUPAC. The membrane showed a good linear response range of 5.38 × 10−6 to 1 × 10−2 mol/L, being Nernstian according to the slope of −57.13 mV/dec (theoretical slope: −59.16 mV/dec), with a practical detection limit of 2.96 × 10−6 mol/L and a lower limit of linear response of 5.38 × 10−6 mol/L. The potentiometric selectivity coefficients for Cl−, Br−, I−, SO42−, and IO3− ions were determined using the mixed solutions method. The Br− ion was found to be the most relevant interferent. The electrode showed a fast stable response (20 s), as well as the possibility of use in a wide pH range (3–12) without compromising the potentiometric response.

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS) with the immune system attacking myelin sheaths leading to neuronal death. While several disease-modifying therapies are available to treat MS, these therapies are not universally effective and do not stop disease progression. More personalized long-term treatment options that target specific aspects of the disease, such as reducing relapse frequency, delaying disability accumulation, and addressing symptoms that impact daily functioning, as well as therapies that can promote neuroprotection and repair are needed. Chimeric Antigen Receptor (CAR) Tcell therapies have revolutionized cancer treatment by intravenously (IV) administering a defined dose of T cells with high specificity provided by the CAR. An autologous CAR T cell therapy using suppressive regulatory T cells (Tregs) inducing long-lasting tolerance would be the ideal treatment for patients. Hence, we expanded the application of CAR-T cells by introducing a CAR into Tregs to treat MS patients. We developed a myelin oligodendrocyte glycoprotein (MOG)-specific CAR Treg cell therapy for patients with MS. MOG is expressed on the outer membrane of the myelin sheath, the insulating layer the forms around nerves, making it an ideal target for CAR Treg therapy. Our lead candidate is a 2nd generation CAR, composed of an anti-MOG scFv screened from a large human library. In vitro, we demonstrated CAR-dependent functionality and showed efficacy in vivo using a passive EAE mouse model. Additionally, the MOG-CAR Tregs have very low tonic signaling with a desirable signal-to-noise ratio resulting in a highly potent CAR. In summary our data suggest that MOG-CAR Tregs are a promising MS treatment option with the potential to induce long-lasting tolerance in patients.