Systematic analysis of disease-specific immunological signatures in patients with febrile illness from Saudi Arabia

10.1002/cti2.1163Clinical and Translational Immunology98e116

Efficacy and Tolerability of 6-Month Treatment with Tamsulosin Plus the Hexanic Extract of Serenoa repens versus Tamsulosin Plus 5-Alpha-Reductase Inhibitors for Moderate-to-Severe LUTS-BPH Patients: Results of a Paired Matched Clinical Study

The objective of this subset analysis was to evaluate and compare the efficacy and tolerability of two combination treatments for men with moderate-to-severe lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). Data were from a real-world, open-label, prospective, and multicenter study performed in outpatient urology clinics. Men with moderate-to-severe LUTS/BPH received 6-month treatment with tamsulosin (TAM) in combination with either the hexanic extract of S. repens (HESr) or a 5-alpha-reductase inhibitor (5ARI). Changes in urinary symptoms and quality of life were measured using the IPSS and BII questionnaires, respectively. Treatment tolerability was assessed by recording adverse effects (AEs). Patients in the two study groups were matched using iterative and propensity score matching approaches. After iterative matching, data were available from 136 patients (n = 68 treated with TAM + 5ARI, n = 68 with TAM + HESr). After 6 months of treatment, mean (SD) IPSS total score improved by 7.7 (6.3) and 6.7 (5.0) points in the TAM + 5ARI and TAM + HESr groups, respectively (p = 0.272); mean BII total scores improved by 3.1 (2.9) and 2.9 (2.4) points (p = 0.751), respectively. AEs were reported by 26.5% and 10.3% of patients in the same groups, mostly affecting sexual function (p < 0.027). When used in a real-world setting to treat patients with moderate-severe LUTS/BPH, 6-month treatment with TAM + HESr was as effective as TAM + 5ARI, but with better tolerability. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

Clinical utility of serum HER2/neu in monitoring and prediction of progression-free survival in metastatic breast cancer patients treated with trastuzumab-based therapies

INTRODUCTION: The purpose of this retrospective study was to determine the clinical utility of serum HER2/neu in monitoring metastatic breast cancer patients undergoing trastuzumab-based therapy and to compare these results with those obtained using cancer antigen (CA) 15-3. We also sought to determine whether early changes in serum HER2/neu concentrations could be a predictor of progression-free survival. METHODS: Sera were obtained retrospectively from 103 women at four medical institutions. Patients eligible for participation were women with metastatic breast cancer who had HER2/neu tissue overexpression and were scheduled to be treated with trastuzumab with or without additional therapies as per the established practices of the treating physicians. A baseline serum sample for each patient was taken before trastuzumab-based therapy was started. Patients were subsequently monitored over 12 to 20 months and serum samples were taken at the time of clinical assessment and tested with Bayer's HER2/neu and CA15-3 assays. RESULTS: Concordance between clinical status in patients undergoing trastuzumab-based treatment and HER2/neu and CA15-3 used as single tests was 0.793 and 0.627, respectively, and increased to 0.829 when the tests were used in combination. Progression-free survival times did not differ significantly in patients with elevated baseline HER2/neu concentrations (≥ 15 ng/mL) and those with normal concentrations (<15 ng/mL). However, progression-free survival differed significantly (P = 0.043) according to whether the patient's HER2/neu concentration at 2 to 4 weeks after the start of therapy was >77% or ≤ 77% of her baseline concentration. The median progression-free survival times for these two groups were 217 and 587 days, respectively. A similar trend was observed for a subcohort of patients treated specifically with a combination of trastuzumab and taxane. CONCLUSION: These findings indicate that serum HER2/neu testing is clinically valuable in monitoring metastatic breast cancer patients undergoing trastuzumab-based treatment and provides additional value over the commonly used CA15-3 test. The percentage of baseline HER2/neu concentrations in the early weeks after the start of therapy may be an early predictor of progression-free-survival

Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.

BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. METHOD AND FINDINGS: The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose-efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. CONCLUSION: The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study

Methicillin Resistant Staphylococcus aureus ST398 in Veal Calf Farming: Human MRSA Carriage Related with Animal Antimicrobial Usage and Farm Hygiene

Introduction Recently a specific MRSA sequence type, ST398, emerged in food production animals and farmers. Risk factors for carrying MRSA ST398 in both animals and humans have not been fully evaluated. In this cross-sectional study, we investigated factors associated with MRSA colonization in veal calves and humans working and living on these farms. Methods A sample of 102 veal calf farms were randomly selected and visited from March 2007–February 2008. Participating farmers were asked to fill in a questionnaire (n = 390) to identify potential risk factors. A nasal swab was taken from each participant. Furthermore, nasal swabs were taken from calves (n = 2151). Swabs were analysed for MRSA by selective enrichment and suspected colonies were confirmed as MRSA by using slide coagulase test and PCR for presence of the mecA-gene. Spa types were identified and a random selection of each spa type was tested with ST398 specific PCR. The Sequence Type of non ST398 strains was determined. Data were analyzed using logistic regression analysis. Results Human MRSA carriage was strongly associated with intensity of animal contact and with the number of MRSA positive animals on the farm. Calves were more often carrier when treated with antibiotics, while farm hygiene was associated with a lower prevalence of MRSA. Conclusion This is the first study showing direct associations between animal and human carriage of ST398. The direct associations between animal and human MRSA carriage and the association between MRSA and antimicrobial use in calves implicate prudent use of antibiotics in farm animals

The unique resistance and resilience of the Nigerian West African Dwarf goat to gastrointestinal nematode infections

<p>Abstract</p> <p>Background</p> <p>West African Dwarf (WAD) goats serve an important role in the rural village economy of West Africa, especially among small-holder livestock owners. They have been shown to be trypanotolerant and to resist infections with <it>Haemonchus contortus </it>more effectively than any other known breed of goat.</p> <p>Methods</p> <p>In this paper we review what is known about the origins of this goat breed, explain its economic importance in rural West Africa and review the current status of our knowledge about its ability to resist parasitic infections.</p> <p>Conclusions</p> <p>We suggest that its unique capacity to show both trypanotolerance and resistance to gastrointestinal (GI) nematode infections is immunologically based and genetically endowed, and that knowledge of the underlying genes could be exploited to improve the capacity of more productive wool and milk producing, but GI nematode susceptible, breeds of goats to resist infection, without recourse to anthelmintics. Either conventional breeding allowing introgression of resistance alleles into susceptible breeds, or transgenesis could be exploited for this purpose. Appropriate legal protection of the resistance alleles of WAD goats might provide a much needed source of revenue for the countries in West Africa where the WAD goats exist and where currently living standards among rural populations are among the lowest in the world.</p

Prognostic impact of clinicopathologic parameters in stage II/III breast cancer treated with neoadjuvant docetaxel and doxorubicin chemotherapy: paradoxical features of the triple negative breast cancer

<p>Abstract</p> <p>Background</p> <p>Prognostic factors in locally advanced breast cancer treated with neoadjuvant chemotherapy differ from those of early breast cancer. The purpose of this study was to identify the clinical significance of potential predictive and prognostic factors in breast cancer patients treated by neoadjuvant chemotherapy.</p> <p>Methods</p> <p>A total of 145 stage II and III breast cancer patients received neoadjuvant docetaxel/doxorubicin chemotherapy were enrolled in this study. We examined the clinical and biological factors (ER, PR, p53, c-erbB2, bcl-2, and Ki-67) by immunohistochemistry. We analyzed clinical outcome and their correlation with clinicopathologic parameters.</p> <p>Results</p> <p>Among the clinicopathologic parameters investigated, none of the marker was correlated with response rate (RR) except triple negative phenotype. Patients with triple negative phenotype showed higher RR (83.0% in triple negative <it>vs</it>. 62.2% in non-triple negative, <it>p </it>= 0.012) and pathologic complete RR (17.0% in triple negative <it>vs</it>. 3.1% in non-triple negative, <it>p </it>= 0.005). However, relapse free survival (RFS) and overall survival (OS) were significantly shorter in triple negative breast cancer patients (<it>p </it>< 0.001, <it>p </it>= 0.021, respectively). Low histologic grade, positive hormone receptors, positive bcl-2 and low level of Ki-67 were associated with prolonged RFS. In addition, positive ER and positive bcl-2 were associated with prolonged OS. In our homogeneous patient population, initial clinical stage reflects RFS and OS more precisely than pathologic stage. In multivariate analysis, initial clinical stage was the only significant independent prognostic factor to impact on OS (hazard ratio 3.597, <it>p </it>= 0.044).</p> <p>Conclusion</p> <p>Several molecular markers provided useful predictive and prognostic information in stage II and III breast cancer patients treated with neoadjuvant docetaxel/doxorubicin chemotherapy. Triple negative phenotype was associated with shorter survival, even though it was associated with a higher response rate to neoadjuvant chemotherapy.</p