CD30 + OX40 + Treg is associated with improved overall survival in colorectal cancer

Cancer shared this article with you from Inoreader CD30 + OX40 + Treg is associated with improved overall survival in colorectal cancer Via Latest Results for Cancer Immunology, Immunotherapy Abstract Regulatory T cells (Tregs) are often enriched in tumors, where their immunosuppressive function has a key role in tumor persistence and progression. In colorectal cancer (CRC), however, Tregs are frequently associated with an improved clinical outcome. Tumor-infiltrating Tregs have been shown to exhibit a distinct signature comprising the co-stimulatory molecules (OX40, 4-1BB), cytokine receptors (IL1R2, IL21R, CCR8, CD30), and co-inhibitory molecules (PD-L1, TIGIT). Here, we showed by flow cytometry that circulating CD45RO+ Tregs from patients with CRC (n = 25) have elevated CD30 and OX40 expression compared to healthy subjects (n = 14). We identified co-expression of CD30 and OX40 on circulating CD45RO+ Tregs using single-cell images captured by the DEPArray™ system. The frequency of CD30+OX40+CD45RO+ Tregs was significantly higher in CRC patients than in healthy subje cts (P < 0.001). Importantly, receiver operating characteristic analysis confirmed that this CD30+OX40+ Treg subset could strongly discriminate between CRC patients and healthy subjects with the highest accuracy of 92.3%, an AUC of 0.92, a sensitivity of 88%, a specificity of 100%, a positive predictive value of 100%, a negative predictive value of 82.35%, and a trade-off value of 3.44%, compared to other Treg subsets. Consistently, multiplex-IHC/IF of tumor-infiltrating Tregs revealed a significant association between high densities of CD30+OX40+ Tregs and improved overall survival; no such association was found for other subsets. These data suggest a potential role for CD30+OX40+ Tregs as a diagnostic or prognostic biomarker in CRC. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Mohs Micrographic Surgery in Dermatofibrosarcoma Protuberans

xlomafota13 shared this article with you from Inoreader Mohs Micrographic Surgery in Dermatofibrosarcoma Protuberans: rate and risk factors for recurrence in a prospective cohort study from the Spanish Registry of Mohs Surgery (REGESMOHS) and review of the literature Via Experimental Dermatology Abstract Characterization of patients, surgery procedures and the risk factors for Dermatofibrosarcoma Protuberans (DFSP) recurrences are poorly defined. In this study, we aimed to describe the demographics, tumor characteristics and interventions of DFSP treated with Micrographic Mohs Surgery (MSS) to determine the rate and risk factors for recurrence. Data were collected from REGESMOHS, a nationwide prospective cohort study of patients treated with MMS in Spain. From July 2013 to February 2020, 163 patients with DFSP that underwent MMS were included. DFSP were mostly located on trunk and extremities. Recurrent tumors had deeper tumor invasion and required higher number of MMS stages. Paraffin MMS was the most frequently used technique. Overall recurrence rate was 0.97 cases/100 person‐years (95% IC=0.36‐2.57). No differences were found in epidemiological, tumor, surgery characteristics or surgical technique (frozen or paraffin MMS (p=0.6641)) in terms of recurrence. Median follow‐u p time was 28.6 months with 414 patient‐years of follow‐up. In conclusion, we found an overall low recurrence rate of DFSP treated with MMS. None of the studied risk factors, including MMS techniques, was associated with higher risk for recurrence. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Hemodynamic Changes Associated With Transcervical Laryngeal Injection of Botulinum Toxin

xlomafota13 shared this article with you from Inoreader Hemodynamic Changes Associated With Transcervical Laryngeal Injection of Botulinum Toxin Via Journal of Voice Laryngeal dystonia is a chronic neurologic disorder characterized by intention-induced spasms of the vocal folds driven by aberrant central motor processing. The use of in-office transcervical botulinum toxin injection for the treatment of laryngeal disorders, such as laryngeal dystonia, has been deemed safe and efficacious. There is, however, no available data outlining the hemodynamic changes experienced by patients undergoing this frequently performed procedure. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Evaluation of Voice and Vocal Fold Vibration after Thyroidectomy Using Two-Dimensional Scanning Digital Kymography and High-Speed Videolaryngoscopy

xlomafota13 shared this article with you from Inoreader Evaluation of Voice and Vocal Fold Vibration after Thyroidectomy Using Two-Dimensional Scanning Digital Kymography and High-Speed Videolaryngoscopy Via Journal of Voice Vocal dysfunction is one of the major factors that affect the health-related quality of life of patients after thyroidectomy. Conventionally, voice changes after thyroidectomy have been evaluated by videostroboscopy and acoustic analysis. Recently, two-dimensional scanning digital kymography (2D DKG) and high-speed videolaryngoscopy (HSV) have been developed and have shown usefulness in accurately evaluating vocal fold vibration. This study aimed to evaluate changes of vocal fold vibration and voice after thyroidectomy using 2D DKG and HSV. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Hydration State and Hyaluronidase Treatment Significantly Affect Porcine Vocal Fold Biomechanics

xlomafota13 shared this article with you from Inoreader Hydration State and Hyaluronidase Treatment Significantly Affect Porcine Vocal Fold Biomechanics Via Journal of Voice The understanding of vocal fold hydration state, including dehydrated, euhydrated, rehydrated tissue, and how hydration affects vocal fold biomechanical properties is still evolving. Although clinical observations support the benefits of increasing vocal fold hydration after dehydrating events, more mechanistic information on the effects of vocal fold dehydration and the beneficial effects of rehydration are needed. Alterations to hyaluronic acid (HA), an important component of the vocal fold extracellular matrix, are likely to influence the biomechanical properties of vocal folds. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Temporal bone primary inverted papilloma – Case Report and review of the literatureInvertiertes Papillom des Felsenbeins – Fallbericht und Literaturübersicht

xlomafota13 shared this article with you from Inoreader Temporal bone primary inverted papilloma – Case Report and review of the literatureInvertiertes Papillom des Felsenbeins – Fallbericht und Literaturübersicht Via Laryngo-Rhino-Otologie Laryngorhinootologie 2021; 100: 99-103 DOI: 10.1055/a-1286-5059 Inverted papilloma of middle ear is an extremely rare lesion of the respiratory epithelium that normally occurs in the nasal cavity and paranasal sinuses. So far less than 17 cases were described in literature. A 45-year-old patient was admitted in our Department with hearing loss, otorrhea and pulsing tinnitus on the right ear. The clinical examination showed a granulation tissue on the right eardrum. No tumor formation was seen in the nasal cavity. The MRI showed a tissue formation in the tympanic cavity with an extension in the middle cranial fossa. A mastoidectomy with antrotomy and duraplasty was performed. The histological diagnosis was inverted papilloma of the middle ear. In a second step occurred an eradication of the tumor with a subtotal petrosectomy. The etiology of the inverted papilloma of the middle ear is unknown. Our case is so far the 18nd case described.Our experience has shown that the eradication of the tumor with a subtotal petrosectomy resulted as reasonable procedure. A long-term follow-up is suggested in order to detect possible recurrence or malignant transformation.Das invertierte Papillom des Mittelohrs ist eine äußerst seltene Läsion des respiratorischen Epithels, die normalerweise in der Nasenhöhle und den Nasennebenhöhlen auftritt. Bisher wurden weniger als 17 Fälle in der Literatur beschrieben. Ein 45-jähriger Patient wurde mit Hörverlust, Otorrhö und pulsierendem Tinnitus am rechten Ohr in unsere Abteilung aufgenommen. Die klinische Untersuchung ergab ein Granulationsgewebe am rechten Trommelfell. In der Nasenhöhle wurde keine Tumorbildung gefunden. Die MRT zeigte eine Gewebebildung in der Paukenhöhle mit einer Verlängerung in der mittleren Schädelgrube. Eine Mastoidektomie mit Antrotomie und Duraplastik wurde durchgeführt. Die histologische Diagnose lautete invertiertes Papillom des Mittelohrs. In einem zweiten Schri tt erfolgte eine komplette Exstirpation des Tumors mit einer subtotalen Petrosektomie. Die Ätiologie des invertierten Papilloms des Mittelohrs ist nicht bekannt. Unser Fall ist bisher der 18. beschriebene Fall.Unsere Erfahrung hat gezeigt, dass die Ausrottung des Tumors mit einer subtotalen Petrosektomie als sinnvollem Eingriff resultierte. Eine langfristige Nachsorge wird empfohlen, um ein mögliches Wiederauftreten oder eine maligne Transformation festzustellen. [...] Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany Article in Thieme eJournals: Table of contents  |  Abstract  |  Full text View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Synergistic quinolone sensitization by targeting recA SOS response gene and oxidative stress [Mechanisms of Action]

xloma.fota13 shared this article with you from Inoreader Synergistic quinolone sensitization by targeting recA SOS response gene and oxidative stress [Mechanisms of Action] Via AAC Accepts: Articles Published Ahead of Print Suppression of recA SOS response gene and reactive oxygen species (ROS) overproduction have been shown, separately, to enhance fluoroquinolone activity and lethality. Their putative synergistic impact as a strategy to potentiate the efficacy of bactericidal antimicrobial agents like fluoroquinolones is unknown. We generated Escherichia coli mutants that exhibited suppressed recA gene in combination with inactivated ROS detoxification system genes (sodA, sodB, katG, katE, ahpC) or inactivated oxidative stress regulator genes (oxyR, rpoS) to evaluate the interplay of both DNA repair and detoxification systems in drug response. Synergistic sensitization effects, ranging from 7.5- to 30-fold relative to the wild-type, were observed with ciprofloxacin in double knockouts of recA and inactivated detoxification system genes. Compared to recA knockout, inactivation of an additional detoxification system gene reduced MIC values up to 8-fold. In growth curves, no growth was evident in mutants doubly-deficient for recA gene and oxidative detoxification systems at subinhibitory concentrations of ciprofloxacin, in contrast to the recA-deficient strain. There was a marked reduction of viable bacteria in a short period of time when recA gene and other detoxification system genes (katG, sodA or ahpC) were inactivated (using absolute ciprofloxacin concentrations). At 4 hours, a bactericidal e ffect of ciprofloxacin was observed for katG/recA and ahpC/recA double mutants compared to the single recA mutant (3.4 Log10 CFU/mL). Synergistic quinolone sensitization, by targeting the recA gene and oxidative detoxification stress systems, reinforces the role of both DNA repair systems and ROS in antibiotic-induced bacterial cell death, opening up a new pathway for antimicrobial sensitization. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Cefazolin in the Serum and Hip Joint Capsule of Patients Undergoing Total Hip Arthroplasty [Pharmacology]

xloma.fota13 shared this article with you from Inoreader Population Pharmacokinetic and Pharmacodynamic Target Attainment Analysis of Cefazolin in the Serum and Hip Joint Capsule of Patients Undergoing Total Hip Arthroplasty [Pharmacology] Via AAC Accepts: Articles Published Ahead of Print The objectives of this study were to evaluate the population pharmacokinetics of prophylactic cefazolin (CFZ) from its serum and hip joint capsule concentrations in patients undergoing total hip arthroplasty, and to establish pharmacodynamic target concentration exceeding the MIC for designing an effective dosing regimen for serum and the hip joint capsule. We analyzed 249 serum samples and 125 hip joint capsule samples from 125 individuals using a nonlinear mixed-effects model. The pharmacodynamic index target value obtained from our results indicates the probability of maintaining CFZ trough and hip joint capsule concentrations exceeding the MIC of 1 mg/L, to account for methicillin-susceptible S. aureus (MSSA). We estimated the population pharmacokinetics using a two-compartment model. The estimated population pharmacokinetic parameters were as follows: CL (L/h) = 1.46 x (CLcr (mL/min)/77)0.891, Vc (L) = 7.5, Q (L/h ) = 3.38, and VJC (L) = 36.1. The probability of achieving concentrations exceeding the MIC90 for MSSA was approximately 100% for serum and 100% for the hip joint capsule at 3 h after the initial dose. Our findings suggest that population-based parameters are useful for evaluating CFZ pharmacokinetics and that individual dosages should be determined based on the dosage regimen that achieves and maintains adequate tissue CFZ concentration. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Epidemic territorial spread of IncP-2-type VIM-2 carbapenemase-encoding megaplasmids in nosocomial Pseudomonas aeruginosa populations [Epidemiology and Surveillance]

xloma.fota13 shared this article with you from Inoreader Epidemic territorial spread of IncP-2-type VIM-2 carbapenemase-encoding megaplasmids in nosocomial Pseudomonas aeruginosa populations [Epidemiology and Surveillance] Via AAC Accepts: Articles Published Ahead of Print In 2003-04 first five VIM-2 metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa (MPPA) isolates with an In4-like integron In461 (aadB–blaVIM-2–aadA6) on conjugative plasmids were identified in three hospitals in Poland. In 2005-15 MPPA much expanded in the country, and as many as 80 isolates in a collection of 454 MPPA (~18%) had In461, being one of two most common MBL-encoding integrons. The organisms occurred in 49 hospitals in 33 cities of 11/16 main administrative regions. PFGE and MLST classified them into 55 pulsotypes and 35 STs, respectively, revealing their remarkable genetic diversity overall, with only a few small clonal clusters. The S1 nuclease/hybridization assays and mating of 63 representative isolates showed that ~85% of these had large In461-carrying plasmids of ~350-550 kb, usually self-transmitting with high efficiency (~10–1-10–2 per donor cell). The plasmids fr om 19 isolates were sequenced, and subjected to structural and SNP-based phylogenetic analysis. These formed a subgroup within a family of IncP-2-type megaplasmids, observed worldwide in pseudomonads from various environments and conferring resistance/tolerance to multiple stress factors, including antibiotics. Their microdiversity in Poland arose mainly from acquisition of different accessory fragments, as well as new resistance genes and multiplication of these. Short-read sequence and/or PCR mapping confirmed the In461-carrying plasmids in the remaining isolates to be the IncP-2 types. The study demonstrated a large-scale epidemic spread of multi-drug resistance plasmids in P. aeruginosa populations, creating an epidemiological threat. It contributes to the knowledge on IncP-2 types, which are interesting research objects in resistance epidemiology, environmental microbiology and biotechnology. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Parasite-host dynamics throughout antimalarial drug development stages complicate the translation of parasite clearance [Pharmacology]

xloma.fota13 shared this article with you from Inoreader Parasite-host dynamics throughout antimalarial drug development stages complicate the translation of parasite clearance [Pharmacology] Via AAC Accepts: Articles Published Ahead of Print Ensuring continued success against malaria depends on a pipeline of new antimalarials. Antimalarial drug development utilizes pre-clinical murine and experimental human malaria infection studies to evaluate drug efficacy. A sequential approach is typically adapted, with results from each stage, informing the design of the next stage of development. The validity of this approach depends on confidence that results from murine malarial studies predict the outcome of clinical trials in humans. Parasite clearance rates following treatment are key parameters of drug efficacy. To investigate the validity of forward predictions, we developed a suite of mathematical models to capture parasite growth and drug clearance along the drug development pathway and estimated parasite clearance rates. When comparing the three infection experiments, we identified different relationships of parasite clearance with dose, and different maximum parasite clearance rates: in P. be rghei-NMRI mouse infections we estimated a maximum parasite clearance rate of 0.2 [1/h]; in P. falciparum-SCID mouse infections 0.05 [1/h]; while in human volunteer infection studies with P. falciparum, we found a maximum parasite clearance rate of 0.12 [1/h] and 0.18 [1/h] after treatment with OZ439 and MMV048, respectively. Sensitivity analysis revealed that host-parasite driven processes account for up to 25% of variance in parasite clearance for medium-high doses of antimalarials. Although there are limitations in translating parasite clearance rates across these experiments, they provide insight into characterising key parameters of drug action and dose response, and assist in decision-making regarding dosage for further drug development. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Pharmacokinetic study of rectal artesunate in children with severe malaria in Africa [Pharmacology]

xloma.fota13 shared this article with you from Inoreader Pharmacokinetic study of rectal artesunate in children with severe malaria in Africa [Pharmacology] Via AAC Accepts: Articles Published Ahead of Print When severe malaria is suspected in children, WHO recommends pre-treatment with a single rectal dose of artesunate before referral to an appropriate facility. This was an individually randomized, open-label, 2-arm, cross-over clinical trial in 83 Congolese children with severe falciparum malaria, to characterize the pharmacokinetics of rectal artesunate. At admission, children received a single dose of rectal artesunate (10 mg/kg) followed 12 hours later by intravenous artesunate (2.4 mg/kg) or the reverse order. All children also received standard doses of intravenous quinine. Artesunate and dihydroartemisinin were measured at eleven fixed intervals, following 0- and 12-hour drug administrations. Clinical, laboratory and parasitological parameters were measured. After rectal artesunate, artesunate and dihydroartemisinin showed large inter-individual variability (peak concentrations of dihydroartemisinin ranged from 5.63 to 8,090 nM). The majority of patients however, reached previously suggested in vivo IC50 (98.7%) and IC90 (92.5%) values of combined concentrations of artesunate and dihydroartemisinin between 15 to 30 minutes after drug administration. The median (IQR) time above IC50 and IC90 was 5.68 hours (2.90-6.08) and 2.74 hours (1.52-3.75), respectively. The absolute rectal bioavailability (IQR) was 25.6% (11.7-54.5) for artesunate and 19.8% (10.3-35.3) for dihydroartemisinin. The initial 12-hour parasite reduction ratio was comparable between rectal and intravenous artesunate: median (IQR) 84.3% (50.0-95.4) vs. 69.2% (45.7-93.6), respectively (p=0.49). Despite large inter-individual variability, rectal artesunate can initiate and sustain rapid parasiticidal activity in most children with severe falciparum malaria, while they are transferred to a facility where parenteral artesunate is available. (www.clinicalTrials.gov : NCT02492178) View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Comparative efficacy of the novel diarylquinoline TBAJ-587 and bedaquiline against a resistant Rv0678 mutant in a mouse model of tuberculosis [Experimental Therapeutics]

xloma.fota13 shared this article with you from Inoreader Comparative efficacy of the novel diarylquinoline TBAJ-587 and bedaquiline against a resistant Rv0678 mutant in a mouse model of tuberculosis [Experimental Therapeutics] Via AAC Accepts: Articles Published Ahead of Print Since its conditional approval in 2012, bedaquiline (BDQ) has been a valuable tool for treatment of drug-resistant tuberculosis. More recently, a novel short-course regimen combining BDQ with pretomanid and linezolid won approval to treat highly drug-resistant tuberculosis. Clinical reports of emerging BDQ resistance have identified mutations in Rv0678 that de-repress the expression of the MmpL5/MmpS5 efflux transporter as the most common cause. Because the effect of these mutations on bacterial susceptibility to BDQ is relatively small (e.g., 2-8x MIC shift), increasing the BDQ dose would increase antibacterial activity but also pose potential safety concerns, including QTc prolongation. Substitution of BDQ with another diarylquinoline with superior potency and/or safety has the potential to overcome these limitations. TBAJ-587 has greater in vitro potency than BDQ, including against Rv0678 mutants, and may offer a larger safety margin. Using a mouse model of tuberculosis and different doses of BDQ and TBAJ-587, we found that against wild-type M. tuberculosis H37Rv and an isogenic Rv0678 mutant, TBAJ-587 has greater efficacy against both strains than BDQ, whether alone or in combination with pretomanid and either linezolid or moxifloxacin and pyrazinamide. TBAJ-587 also reduced the emergence of resistance to diarylquinolines and pretomanid. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.