A Retrospective Analysis of Metronomic Cyclophosphamide, Methotrexate, and Fluorouracil (CMF) Versus Docetaxel and Cyclophosphamide (TC) as Adjuvant Treatment in Early Stage, Hormone Receptor Positive, HER2 Negative Breast Cancer.

BACKGROUND: Anthracycline and taxane-based doublets have largely replaced cyclophosphamide, methotrexate, and fluorouracil (CMF) as preferred regimens in the adjuvant treatment of breast cancer. Metronomic CMF is associated with improved tolerability over anthracycline or taxane-based regimens. Previously, there have been no direct comparisons between taxane-based regimens and CMF. MATERIALS AND METHODS: We performed a retrospective review of 98 breast cancer patients treated at the Seattle Cancer Care Alliance from February 2015 through December 2018 that received either metronomic CMF or docetaxel and cyclophosphamide (TC) as adjuvant therapy for early-stage, hormone receptor-positive/human epidermal growth factor receptor-2 negative (HR+/HER2-) breast cancer. The primary outcome assessed was disease-free survival (DFS). Secondary outcomes included overall survival (OS), dose intensity, and adverse effects. RESULTS: With an average follow-up of 35.9 and 28.2 months for CMF and TC, respectively, there was no significant difference in DFS or OS between the chemotherapy regimens. DFS at 3 years was 96.7% vs. 94.3% and OS 96.7% vs. 100% for CMF and TC, respectively. There were more dose delays in the CMF group, but on average, patients receiving either regimen achieved a dose intensity ≥85%. There was a trend towards increased hospitalization or emergency department utilization (23.1% vs. 10.6%) and Grade 4 toxicities (9.6% vs. 4.3%) with TC vs. CMF. CONCLUSION: Metronomic CMF offers equivalent survival outcomes to TC and remains a viable option in the adjuvant treatment of HR+/HER2- breast cancer. There was a trend towards increased Grade 4 toxicities and hospitalizations with TC, suggesting that metronomic CMF may offer a more tolerable treatment option while maintaining excellent disease outcomes.

American Civil War plant medicines inhibit growth, biofilm formation, and quorum sensing by multidrug-resistant bacteria.

A shortage of conventional medicine during the American Civil War (1861-1865) spurred Confederate physicians to use preparations of native plants as medicines. In 1863, botanist Francis Porcher compiled a book of medicinal plants native to the southern United States, including plants used in Native American traditional medicine. In this study, we consulted Porcher's book and collected samples from three species that were indicated for the formulation of antiseptics: Liriodendron tulipifera, Aralia spinosa, and Quercus alba. Extracts of these species were tested for the ability to inhibit growth in three species of multidrug-resistant pathogenic bacteria associated with wound infections: Staphylococcus aureus, Klebsiella pneumoniae, and Acinetobacter baumannii. Extracts were also tested for biofilm and quorum sensing inhibition against S. aureus. Q. alba extracts inhibited growth in all three species of bacteria (IC50 64, 32, and 32 µg/mL, respectively), and inhibited biofilm formation (IC50 1 µg/mL) in S. aureus. L. tulipifera extracts inhibited biofilm formation (IC50 32 µg/mL) in S. aureus. A. spinosa extracts inhibited biofilm formation (IC50 2 µg/mL) and quorum sensing (IC50 8 µg/mL) in S. aureus. These results support that this selection of plants exhibited some antiseptic properties in the prevention and management of wound infections during the conflict.

The Chemical and Antibacterial Evaluation of St. John's Wort Oil Macerates Used in Kosovar Traditional Medicine.

Hypericum perforatum L. (Hypericaceae), or St. John's Wort, is a well-known medicinal herb often associated with the treatment of anxiety and depression. Additionally, an oil macerate (Oleum Hyperici) of its flowering aerial parts is widely used in traditional medicine across the Balkans as a topical wound and ulcer salve. Other studies have shown that Oleum Hyperici reduces both wound size and healing time. Of its active constituents, the naphthodianthrone hypericin and phloroglucinol hyperforin are effective antibacterial compounds against various Gram-positive bacteria. However, hyperforin is unstable with light and heat, and thus should not be present in the light-aged oil macerate. Additionally, hypericin can cause phototoxic skin reactions if ingested or absorbed into the skin. Therefore, the established chemistry presents a paradox for this H. perforatum oil macerate: the hyperforin responsible for the antibacterial bioactivity should degrade in the sunlight as the traditional oil is prepared; alternately, if hypericin is present in established bioactive levels, then the oil macerate should cause photosensitivity, yet none is reported. In this research, various extracts of H. perforatum were compared to traditional oil macerates with regards to chemical composition and antibacterial activity (inhibition of growth, biofilm formation, and quorum sensing) vs. several strains of Staphylococcus aureus in order to better understand this traditional medicine. It was found that four Kosovar-crafted oil macerates were effective at inhibiting biofilm formation (MBIC50 active range of 0.004-0.016% v/v), exhibited moderate inhibition of quorum sensing (QSIC50 active range of 0.064-0.512% v/v), and contained detectable amounts of hyperforin, but not hypericin. Overall, levels of hypericin were much higher in the organic extracts, and these also exhibited more potent growth inhibitory activity. In conclusion, these data confirm that oil macerates employed in traditional treatments of skin infection lack the compound credited with phototoxic reactions in H. perforatum use and exhibit anti-biofilm and modest quorum quenching effects, rather than growth inhibitory properties against S. aureus.

Comparative Phytochemical Analysis of Chinese and Bay Starvine (Schisandra spp.): Potential for Development as a New Dietary Supplement Ingredient.

Schisandra chinensis (Chinese starvine) is a popular dietary supplement with a rich history of use in traditional Chinese medicine. Schisandra glabra (bay starvine) is the only North American representative of the genus, and little is known about its history of traditional use, chemistry, and potential biological activity. In this study, we conducted comparative high-performance liquid chromatography-diode array detector (HPLC-DAD) analysis on S. glabra and S. chinensis fruits. Additional characterization of S. glabra was performed by liquid chromatography-Fourier transform mass spectrometry (LC-FTMS). Quantitative analysis of four bioactive marker compounds revealed that S. glabra does not have statistically higher levels of schisandrin A or schisandrol B than S. chinensis. S. glabra has lower levels of schisandrol A and γ-schisandrin. Total phenolic contents of the two species' fruits were not statistically different. S. glabra had higher total tannin content than S. chinensis. We discuss the relevance of this analytical analysis to the study of S. glabra as a potential dietary supplement ingredient and give specific consideration to the conservation challenges involved in commercially developing a regionally threatened species, even in semicultivated conditions.

Virulence Inhibitors from Brazilian Peppertree Block Quorum Sensing and Abate Dermonecrosis in Skin Infection Models.

Widespread antibiotic resistance is on the rise and current therapies are becoming increasingly limited in both scope and efficacy. Methicillin-resistant Staphylococcus aureus (MRSA) represents a major contributor to this trend. Quorum sensing controlled virulence factors include secreted toxins responsible for extensive damage to host tissues and evasion of the immune system response; they are major contributors to morbidity and mortality. Investigation of botanical folk medicines for wounds and infections led us to study Schinus terebinthifolia (Brazilian Peppertree) as a potential source of virulence inhibitors. Here, we report the inhibitory activity of a flavone rich extract "430D-F5" against all S. aureus accessory gene regulator (agr) alleles in the absence of growth inhibition. Evidence for this activity is supported by its agr-quenching activity (IC50 2-32 µg mL-1) in transcriptional reporters, direct protein outputs (α-hemolysin and δ-toxin), and an in vivo skin challenge model. Importantly, 430D-F5 was well tolerated by human keratinocytes in cell culture and mouse skin in vivo; it also demonstrated significant reduction in dermonecrosis following skin challenge with a virulent strain of MRSA. This study provides an explanation for the anti-infective activity of peppertree remedies and yields insight into the potential utility of non-biocide virulence inhibitors in treating skin infections.

Anti-Acne Activity of Italian Medicinal Plants Used for Skin Infection.

Propionibacterium acnes is implicated in the pathogenesis of acne vulgaris, which impacts >85% of teenagers. Novel therapies are in high demand and an ethnopharmacological approach to discovering new plant sources of anti-acne therapeutics could contribute to filling this void in effective therapies. The aims of our study were two-fold: (1) To determine if species identified in ethnopharmacological field studies as having traditional uses for skin and soft tissue infection (SSTI) exhibit significantly more activity against P. acnes than species with no such reported use; and (2) Chemically characterize active extracts and assess their suitability for future investigation. Extracts of Italian medicinal (for acne and other skin infection) and randomly collected plants and fungi were screened for growth-inhibitory and anti-biofilm activity in P. acnes using broth microdilution methods. Bioactive extracts were chemically characterized by HPLC and examined for cytotoxicity against human keratinocytes (HaCaTs). Following evaluation of 157 extracts from 10 fungi and 58 plants, we identified crude extracts from seven species exhibiting growth inhibitory activity (MICs 64-256 µg mL-1). All active extracts were examined for cytotoxicity against HaCaTs; extracts from one fungal and one plant species were toxic (IC50 256 µg mL-1). HPLC analysis with chemical standards revealed many of these extracts contained chlorogenic acid, p-coumaric acid, ellagic acid, gallic acid, and tannic acid. In conclusion, species used in traditional medicine for the skin exhibited significantly greater (p < 0.05) growth inhibitory and biofilm eradication activity than random species, supporting the validity of an ethnobotanical approach to identifying new therapeutics. The anti-acne activity of three extracts is reported for the first time: Vitis vinifera leaves, Asphodelus microcarpus leaves, and Vicia sativa aerial parts.

Chemical composition and in vitro antibacterial activity of Pistacia terebinthus essential oils derived from wild populations in Kosovo.

BACKGROUND: Plant material from different organs of Pistacia terebinthus L., (Anacardiaceae) were collected in Kosovo with aim to analyze the chemical variability of the essential oils among native populations and to test them for potential antibacterial activity against Staphylococcus aureus. METHODS: Essential oils obtained from leaves, pedicels, fruits and galls were analyzed by GC-FID and GC/MS. Minimum inhibitory concentration (MIC) against three clinically relevant strains of S. aureus (NRS385, LAC and UAMS-1) were used to evaluate the antibacterial activity of essential oils. RESULTS: In total, 33 different compounds were identified. The main constituents were α-pinene (12.58-66.29 %), D-limonene (13.95-46.29 %), ß-ocimene (0.03-40.49 %), ß-pinene (2.63-20.47 %), sabinene (0.00-5.61 %) and (Z)-ß-ocimene (0.00-44.85 %). Antibacterial testing of the essential oils against three clinical isolates of S. aureus revealed that seven of the eight samples had some activity at the concentration range tested (0.04-0.512 % v/v). The gall tissues from both sites produced the highest yield of essential oil (3.24 and 6 %), and both exhibited growth inhibitory activity against S. aureus. The most bioactive essential oils, which exhibited MIC90 values ranging from 0.032-0.128 % v/v, obtained from the fruits of the Ura e Shejtë collection site. Likewise, the leaf and pedicel essential oil from the same site was highly active with MIC90 values of 0.064-0.128 and 0.032-0.256 % v/v, respectively. CONCLUSIONS: Principle Component Analyses demonstrated that there is a variation in the chemical composition of essential oil depending on the plant organs from which essential oil are obtained and the geographical origin of the plant populations. The highest variability regarding the chemical composition of essential oil was found between oils obtained from different organs originating from the Prizren site. The MIC90 activity of Pistacia terebinthus was on par or superior compared with Tea Tree Oil control (0.128 % v/v), suggesting that essential oils from this species may have some potential for development as an antibacterial agent for S. aureus infections.

Castanea sativa (European Chestnut) Leaf Extracts Rich in Ursene and Oleanene Derivatives Block Staphylococcus aureus Virulence and Pathogenesis without Detectable Resistance.

The Mediterranean is home to a rich history of medical traditions that have developed under the influence of diverse cultures over millennia. Today, many such traditions are still alive in the folk medical practices of local people. Investigation of botanical folk medicines used in the treatment of skin and soft tissue infections led us to study Castanea sativa (European Chestnut) for its potential antibacterial activity. Here, we report the quorum sensing inhibitory activity of refined and chemically characterized European Chestnut leaf extracts, rich in oleanene and ursene derivatives (pentacyclic triterpenes), against all Staphylococcus aureus accessory gene regulator (agr) alleles. We present layers of evidence of agr blocking activity (IC50 1.56-25 µg mL-1), as measured in toxin outputs, reporter assays hemolytic activity, cytotoxicity studies, and an in vivo abscess model. We demonstrate the extract's lack of cytotoxicity to human keratinocytes and murine skin, as well as lack of growth inhibitory activity against S. aureus and a panel of skin commensals. Lastly, we demonstrate that serial passaging of the extract does not result in acquisition of resistance to the quorum quenching composition. In conclusion, through disruption of quorum sensing in the absence of growth inhibition, this study provides insight into the role that non-biocide inhibitors of virulence may play in future antibiotic therapies.