Bioaccessible metals in dust materials from non-sulfide Zn deposit and related hydrometallurgical operation.

Mining and processing of ores in arid (desert) areas generates high amounts of dust, which might be enriched in potentially harmful elements. We studied dust fractions of ores, soils, and technological materials from mining and related hydrometallurgical operation at former Skorpion Zinc non-sulfide Zn deposit in southern Namibia (closed and placed under maintenance in 2020). Chemical and mineralogical investigation was combined with oral bioaccessibility testing of fine dust fractions (<48 µm and <10 µm) in simulated gastric fluid (SGF) to assess potential risk of intake of metallic contaminants (Cd, Cu, Pb, Zn) for staff operating in the area. The bulk metals concentrations were largely variable and ranked as follows: soils < tailings â‰ª Skorpion ores < imported ores and dross used for feed ore blending. Maximum contaminant concentrations in the original granular materials were 927 mg Cd/kg, 9150 mg Cu/kg, 50 g Pb/kg and 706 g Zn/kg, respectively, and generally increased as a function of decreasing grain size. The highest bioaccessible concentrations of Cd and Pb yielded imported ores from Taiwan and Turkey and, together with the milled dross, these samples also exhibited the highest Zn bioaccessibilities. The exposure estimates calculated for a worker (weighing 70 kg) in this mining/ore processing operation at a dust ingestion rate of 100 mg/day indicated that most dust samples (soils, tailings, Skorpion ores) exhibited metals intake values far below tolerable daily intake limits. The overall health risk was limited in all mining and ore processing areas except for the ore blending area, where imported ores and recycled dross enriched in bioaccessible Cd, Pb and/or Zn were used for the ore blending. Safety measures required by the mine operator (wearing of masks by the operating staff) helped to prevent the staff's exposure to potentially contaminated dust even in this blending ore area.

Ideal marker for targeted axillary dissection (IMTAD): a prospective multicentre trial.

BACKGROUND: Targeted axillary dissection (TAD) is an established method for axillary staging in patients with breast cancer after neoadjuvant chemotherapy (NAC). TAD consists of sentinel lymph node biopsy and initially pathological lymph node excision, which must be marked by a reliable marker before NAC. METHODS: The IMTAD study is a prospective multicentre trial comparing three localisation markers for lymph node localisation (clip + iodine seed, magnetic seed, carbon suspension) facilitating subsequent surgical excision in the form of TAD. The primary outcome was to prospectively compare the reliability, accuracy, and safety according to complication rate during marker implantation and detection and marker dislodgement. RESULTS: One hundred eighty-nine patients were included in the study-in 135 patients clip + iodine seed was used, in 30 patients magnetic seed and in 24 patients carbon suspension. The complication rate during the marker implantation and detection were not statistically significant between individual markers (p = 0.263; p = 0.117). Marker dislodgement was reported in 4 patients with clip + iodine seed localisation (3.0%), dislodgement did not occur in other localisation methods (p = 0.999). The false-negativity of sentinel lymph node (SLN) was observed in 8 patients, the false-negativity of targeted lymph nodes (TLN) wasn´t observed at all, the false-negativity rate (FNR) from the subcohort of ypN + patients for SLN is 9.6% and for TLN 0.0%. CONCLUSION: The IMTAD study indicated, that clip + iodine seed, magnetic seed and carbon suspension are statistically comparable in terms of complications during marker implantation and detection and marker dislodgement proving their safety, accuracy, and reliability in TAD. The study confirmed, that the FNR of the TLN was lower than the FNR of the SLN proving that the TLN is a better marker for axillary lymph node status after NAC. TRIAL REGISTRATION: NCT04580251. Name of registry: Clinicaltrials.gov. Date of registration: 8.10.2020.

Magnetic Seed (Magseed) Localisation in Breast Cancer Surgery: A Multicentre Clinical Trial.

INTRODUCTION: The aim of this study was to evaluate the accuracy and reliability of the Magseed magnetic marker in breast cancer surgery. METHODS: Thirty-nine patients with 41 implanted Magseeds undergoing surgical treatment in 3 surgical oncology departments were included in the retrospective trial to study pilot use of the Magseed magnetic marker in the Czech Republic for localisation of breast tumours or pathological axillary nodes in breast cancer patients. RESULTS: Thirty-four breast cancer and 7 pathological lymph node localisations were performed by Magseed implantation. No placement failures, or perioperative detection failures of Magseeds were observed (0/41, 0.0%), but one case of Magseed migration was present (1/41, 2.4%). All magnetic seeds were successfully retrieved (41/41, 100.0%). Negative margins were achieved in 29 of 34 (85.3%) breast tumour localisations by Magseed. CONCLUSION: Magseed is a reliable marker for breast tumour and pathological axillary node localisation in breast cancer patients. Magseed is comparable to conventional localisation methods in terms of oncosurgical radicality and safety.

SLC46A1 Haplotype with Predicted Functional Impact has Prognostic Value in Breast Carcinoma.

BACKGROUND AND OBJECTIVE: Membrane solute carrier transporters play an important role in the transport of a wide spectrum of substrates including anticancer drugs and cancer-related physiological substrates. This study aimed to assess the prognostic relevance of gene expression and genetic variability of selected solute carrier transporters in breast cancer. METHODS: Gene expression was determined by quantitative real-time polymerase chain reaction. All SLC46A1 and SLCO1A2 exons and surrounding non-coding sequences in DNA extracted from the blood of patients with breast cancer (exploratory phase) were analyzed by next-generation sequencing technology. Common variants (minor allele frequency ≥ 5%) with in silico-predicted functional relevance were further analyzed in a large cohort of patients with breast cancer (n = 815) and their prognostic and predictive potential was estimated (validation phase). RESULTS: A gene expression and bioinformatics analysis suggested SLC46A1 and SLCO1A2 to play a putative role in the prognosis of patients with breast cancer. In total, 135 genetic variants (20 novel) were identified in both genes in the exploratory phase. Of these variants, 130 were non-coding, three missense, and two synonymous. One common variant in SLCO1A2 and four variants in SLC46A1 were predicted to be pathogenic by in silico programs and subsequently validated. A SLC46A1 haplotype block composed of rs2239911-rs2239910-rs8079943 was significantly associated with ERBB2/HER2 status and disease-free survival of hormonally treated patients. CONCLUSIONS: This study revealed the prognostic value of a SLC46A1 haplotype block for breast cancer that should be further studied.

Use of Germline Genetic Variability for Prediction of Chemoresistance and Prognosis of Breast Cancer Patients.

The aim of our study was to set up a panel for targeted sequencing of chemoresistance genes and the main transcription factors driving their expression and to evaluate their predictive and prognostic value in breast cancer patients. Coding and regulatory regions of 509 genes, selected from PharmGKB and Phenopedia, were sequenced using massive parallel sequencing in blood DNA from 105 breast cancer patients in the testing phase. In total, 18,245 variants were identified of which 2565 were novel variants (without rs number in dbSNP build 150) in the testing phase. Variants with major allele frequency over 0.05 were further prioritized for validation phase based on a newly developed decision tree. Using emerging in silico tools and pharmacogenomic databases for functional predictions and associations with response to cytotoxic therapy or disease-free survival of patients, 55 putative variants were identified and used for validation in 805 patients with clinical follow up using KASPTM technology. In conclusion, associations of rs2227291, rs2293194, and rs4376673 (located in ATP7A, KCNAB1, and DFFB genes, respectively) with response to neoadjuvant cytotoxic therapy and rs1801160 in DPYD with disease-free survival of patients treated with cytotoxic drugs were validated and should be further functionally characterized.

Bioaccessibility of As, Cu, Pb, and Zn in mine waste, urban soil, and road dust in the historical mining village of Kank, Czech Republic.

Historical mining activities in the village of Kank (in the northern part of the Kutná Hora ore district, Czech Republic) produced large amounts of mine wastes which contain significant amounts of metal(loid) contaminants such as As, Cu, Pb, and Zn. Given the proximity of residential communities to these mining residues, we investigated samples of mine waste (n = 5), urban soil (n = 6), and road dust (n = 5) with a special focus on the solid speciation of As, Cu, Pb, and Zn using a combination of methods (XRD, SEM/EDS, oxalate extractions), as well as on in vitro bioaccessibility in simulated gastric and lung fluids to assess the potential exposure risks for humans. Bulk chemical analyses indicated that As is the most important contaminant in the mine wastes (~1.15 wt%), urban soils (~2900 mg/kg) and road dusts (~440 mg/kg). Bioaccessible fractions of As were quite low (4-13%) in both the simulated gastric and lung fluids, while the bioaccessibility of metals ranged between <0.01% (Pb) and 68% (Zn). The bioaccessibilities of the metal(loid)s were dependent on the mineralogy and different adsorption properties of the metal(loid)s. Based on our results, a potential health risk, especially for children, was recognized from the ingestion of mine waste materials and highly contaminated urban soil. Based on the risk assessment, arsenic was found to be the element posing the greatest risk.

Effect of an Echinacea-Based Hot Drink Versus Oseltamivir in Influenza Treatment: A Randomized, Double-Blind, Double-Dummy, Multicenter, Noninferiority Clinical Trial.

BACKGROUND: Echinacea has antiviral activity against influenza viruses in vitro and has traditionally been used for treatment of colds and flu. OBJECTIVES: This randomized, double-blind, double-dummy, multicenter, controlled clinical trial compared a new echinacea formulation with the neuraminidase inhibitor oseltamivir, the gold standard treatment for influenza. METHODS: Following informed consent, 473 patients with early influenza symptoms (≤48 hours) were recruited in primary care in the Czech Republic and randomized to either 5 days of oseltamivir followed by 5 days of placebo, or 10 days of an Echinacea purpurea-based formulation called Echinaforce Hotdrink (A. Vogel Bioforce AG, Roggwil, Switzerland). The proportion of recovered patients (influenza symptoms rated as absent or mild in the evening) was analyzed for noninferiority between treatment groups using a generalized Wilcoxon test with significance level α = 0.05 (2-sided) and using a CI approach in the per-protocol sample. RESULTS: Recovery from illness was comparable in the 2 treatment groups at 1.5% versus 4.1% after 1 day, 50.2% versus 48.8% after 5 days, and 90.1% versus 84.8% after 10 days of treatment with Echinaforce Hotdrink and oseltamivir, respectively. Noninferiority was demonstrated for each day and overall (95% CI, 0.487-0.5265 by generalized Wilcoxon test). Very similar results were obtained in the group with virologically confirmed influenza virus infections and in a retrospective analysis during the peak influenza period. The incidence of complications was lower with Echinaforce Hotdrink than with oseltamivir (2.46% vs 6.45%; P = 0.076) and fewer adverse events (particularly nausea and vomiting) were observed with Echinaforce Hotdrink. CONCLUSIONS: Echinaforce Hotdrink is as effective as oseltamivir in the early treatment of clinically diagnosed and virologically confirmed influenza virus infections with a reduced risk of complications and adverse events. It appears to be an attractive treatment option, particularly suitable for self-care. Clinical trial identifier: Eudra-CT: 2010-021571-88. (Curr Ther Res Clin Exp. 2015; 77:66-72).

Non-coding polymorphisms in nucleotide binding domain 1 in ABCC1 gene associate with transcript level and survival of patients with breast cancer.

OBJECTIVES: ATP-Binding Cassette (ABC) transporters may cause treatment failure by transporting of anticancer drugs outside of the tumor cells. Multidrug resistance-associated protein 1 coded by the ABCC1 gene has recently been suggested as a potential prognostic marker in breast cancer patients. This study aimed to explore tagged haplotype covering nucleotide binding domain 1 of ABCC1 in relation with corresponding transcript levels in tissues and clinical phenotype of breast cancer patients. METHODS: The distribution of twelve ABCC1 polymorphisms was assessed by direct sequencing in peripheral blood DNA (n = 540). RESULTS: Tumors from carriers of the wild type genotype in rs35623 or rs35628 exhibited significantly lower levels of ABCC1 transcript than those from carriers of the minor allele (p = 0.003 and p = 0.004, respectively). The ABCC1 transcript levels significantly increased in the order CT-GT>CC-GT>CC-GG for the predicted rs35626-rs4148351 diplotype. Chemotherapy-treated patients carrying the T allele in rs4148353 had longer disease-free survival than those with the GG genotype (p = 0.043). On the other hand, hormonal therapy-treated patients with the AA genotype in rs35628 had significantly longer disease-free survival than carriers of the G allele (p = 0.012). CONCLUSIONS: Taken together, our study shows that genetic variability in the nucleotide binding domain 1 has a significant impact on the ABCC1 transcript level in the target tissue and may modify survival of breast cancer patients.

First-time proof of endometrial safety of the special black cohosh extract (Actaea or Cimicifuga racemosa extract) CR BNO 1055.

OBJECTIVE: To investigate endometrial safety by assessment of endometrial biopsy samples and the tolerability and efficacy of the special Actaea or Cimicifuga racemosa extract (CR BNO 1055). DESIGN: Four hundred postmenopausal women with symptoms related to estrogen deficiency were enrolled into a prospective, open-label, multinational, multicenter study. Treatment duration (daily dose corresponds to 40 mg of herbal drug) was 52 weeks. To determine the probability of endometrial hyperplasia and more serious adverse endometrial outcome, the point estimator and upper limit of 95% CI were calculated. Descriptive statistics was used to assess the secondary endpoints. RESULTS: Endometrial safety has been proven because no case of hyperplasia or more serious adverse endometrial outcome occurred (point estimate: 0.0; upper limit of 95% CI: 0.011). Endometrial thickness, which was measured by endovaginal ultrasonography, did not show an increase. The number and intensity of hot flushes were markedly decreased. The dropout rate was less than 10%. The overall tolerability was good. CONCLUSIONS: The lack of endometrial proliferation and improvement of climacteric complaints as well as only few gynecologic organ-related adverse events are reported for the first time after a treatment period of 1 year. Due to the improved benefit:risk ratio, it must be assumed that the Cimicifuga racemosa special extract BNO 1055 is a safe alternative for treatment of climacteric complaints.