Project description:Complementary treatment possibilities for the therapy of cancer are increasing in demand due to the severe side effects of the standard cytostatics used in the first-line therapy. A common approach as a complementary treatment is the use of aqueous extracts of Viscum album L. (Santalaceace). The therapeutic activity of these extracts is attributed to Mistletoe lectins which are Ribosome-inactivating proteins type II. Besides these main constituents the extract of Viscum album L. comprises also a mixture of lipophilic ingredients like triterpene acids of the oleanane, lupane and ursane type. However, these constituents are not contained in commercially available aqueous extracts due to their high lipophilicity and insolubility in aqueous extraction media. To understand the impact of the extract ingredients in cancer therapy, the intracellular uptake of the mistletoe lectin I (ML) by cultured tumor cells was investigated in relation to the mistletoe triterpene acids, mainly oleanolic acid. Firstly, these hydrophobic triterpene acids were solubilized using cyclodextrins ("TT" extract). Afterwards, the uptake of either single compounds (isolated ML and the aqueous "viscum" extract) or in combination with the TT extract (ML+TT, viscumTT), was analyzed. The uptake of ML was studied inTHP-1-, HL-60-, 143B- and Ewing TC-71-cells and determined after 30, 60 and 120 minutes by an enzyme linked immunosorbent assay which quantifies the A-chain of the hololectin. It could be shown that the intracellular uptake after 120 minutes amounted to 20% in all cell lines after incubation with viscumTT. The studies further revealed that the uptake in THP-1-, HL-60- and Ewing TC-71-cells was independent of the addition of TT extract. Interestingly, the uptake of ML by 143B-cells could only be measured after addition of triterpenes pointing to resistance to mistletoe lectin.
Project description:BackgroundCancer-related fatigue (CRF) affects a majority of patients (pts) with symptoms lasting up to several years after finishing therapy. These symptoms lead to decreased health related quality of life. Fatigue during treatment for colorectal cancer is common, but poorly understood and can affect compliance with post-surgical cancer therapy. We examined the fatigue levels during first-line chemo- or radio-chemotherapy protocols, which were supported by a pharmaceutical mistletoe preparation (Iscador(®)Qu) (181patients). We compared the outcome to a parallel control group (143 patients), which did not receive this supportive care treatment.MethodsThe medical records of 324 patients with non-metastasized colorectal cancer (UICC stage I-III), which were obtained from hospitals and resident physicians, were assessed. The documented treatment decision by chemo- or radio-chemotherapy supported by mistletoe interventions was followed for a median treatment period of 8.6 months. During the post-surgical treatment period the patients were diagnosed twice for the presence of fatigue symptoms by structural interviews carried out by physicians.ResultsAt the end of the median treatment period, 16/181 patients (8.8%) were diagnosed with CRF in the supportive care group and 86/143 (60.1%) in the chemo- or radio-chemotherapy group without supportive mistletoe medication. Multivariable-adjusted ORs provided evidence for a chance to improve CRF by supportive mistletoe medication compared to chemo- or radio-chemotherapy alone over the time of treatment. The OR = 10.651 (95% CI 5.09-22.28; p < 0.001) declined from the first visit to OR = 0.054 (95 CI 0.02-0.13; p < 0.001) at the end of therapy. Furthermore, 14 confounding factors for risk assessment of CRF were compared by means of forest plots. It turned out that the hospital versus office-based treatment and the co-morbidity/inflammation represent independent but important determinants for fatigue levels.ConclusionThe clinically used mistletoe medication (Iscador(®)Qu) is the first candidate to be included in a supportive care modus into chemo- or chemo-radiotherapy protocols for colorectal patients to improve CRF without discernable toxicities.
Project description:Technological advances in high-throughput next-generation sequencing (NGS) along with advances in computational processes have brought about the dawn of the genomic medicine era. NGS has enabled molecular characterization of malignancies, and facilitated the development and approval of gene- and immune-targeted therapies, both of which impact the mutanome. Clinical implementation of this technology, approval of novel targeted agents, and establishment of molecular tumor boards has enabled precision oncology to become a reality.
Project description:Lodgepole pine dwarf mistletoe (DM), Arceuthobium americanum, is a parasitic flowering plant and forest pathogen in North America. Seed dispersal in DM occurs by explosive discharge. Notably, slight warming of ripe DM fruit in the laboratory can trigger explosions. Previously, we showed that alternative oxidase, a protein involved in endogenous heat production (thermogenesis) in plants, is present in DM fruit. These observations have led us to investigate if thermogenesis induces discharge. Here, infrared thermographs reveal that ripe DM fruits display an anomalous increase in surface temperature by an average of 2.1±0.8 °C over an average time of 103±29 s (n=9, 95% confidence interval) before dehiscence. Furthermore, both non-isothermal and isothermal modulated differential scanning calorimetry consistently show an exothermic event (~1 J g(-1)) in the non-reversible heat flow just prior to discharge. These results support thermogenesis-triggered seed discharge, never before observed in any plant.
Project description:Parasitism is a successful survival strategy across all kingdoms and has evolved repeatedly in angiosperms. Parasitic plants obtain nutrients from other plants and some are agricultural pests. Obligate parasites, which cannot complete their lifecycle without a host, may lack functional photosystems (holoparasites), or have retained photosynthesis (hemiparasites). Plastid genomes are often reduced in parasites, but complete mitochondrial genomes have not been sequenced and their mitochondrial respiratory capacities are largely unknown. The hemiparasitic European mistletoe (Viscum album), known from folklore and postulated therapeutic properties, is a pest in plantations and forestry. We compare the mitochondrial genomes of three Viscum species based on the complete mitochondrial genome of V. album, the first from a parasitic plant. We show that mitochondrial genes encoding proteins of all respiratory complexes are lacking or pseudogenized raising several questions relevant to all parasitic plants: Are any mitochondrial gene functions essential? Do any genes need to be located in the mitochondrial genome or can they all be transferred to the nucleus? Can parasitic plants survive without oxidative phosphorylation by using alternative respiratory pathways? More generally, our study is a step towards understanding how host- and self-perception, host integration and nucleic acid transfer has modified ancestral mitochondrial genomes.
Project description:Mistletoe (Viscum album L.) is used in German-speaking European countries in the field of integrative oncology linking conventional and complementary medicine therapies to improve quality of life. Various companies sell extracts, fermented or not, for injection by subcutaneous or intra-tumoral route with a regulatory status of anthroposophic medicinal products (European Medicinal Agency (EMA) assessment status). These companies as well as anthroposophical physicians argue that complex matrices composed of many molecules in mixture are necessary for activity and that the host tree of the mistletoe parasitic plant is the main determining factor for this matrix composition. The critical point is that parenteral devices of European mistletoe extracts do not have a standard chemical composition regulated by EMA quality guidelines, because they are not drugs, regulatory speaking. However, the mechanism of mistletoe's anticancer activity and its effectiveness in treating and supporting cancer patients are not fully understood. Because of this lack of transparency and knowledge regarding the matrix chemical composition, we undertook an untargeted metabolomics study of several mistletoe extracts to explore and compare their fingerprints by LC-(HR)MS(/MS) and 1H-NMR. Unexpectedly, we showed that the composition was primarily driven by the manufacturer/preparation method rather than the different host trees. This differential composition may cause differences in immunostimulating and anti-cancer activities of the different commercially available mistletoe extracts as illustrated by structure-activity relationships based on LC-MS/MS and 1H-NMR identifications completed by docking experiments. In conclusion, in order to move towards an evidence-based medicine use of mistletoe, it is a priority to bring rigor and quality, chemically speaking.
Project description:Mistletoes are a widespread group of plants often considered to be hemiparasitic, having detrimental effects on growth and survival of their hosts. We studied the effects of the Pacific mistletoe, Phoradendron villosum, a member of a largely autotrophic genus, on three species of deciduous California oaks. We found no effects of mistletoe presence on radial growth or survivorship and detected a significant positive relationship between mistletoe and acorn production. This latter result is potentially explained by the tendency of P. villosum to be present on larger trees growing in nitrogen-rich soils or, alternatively, by a preference for healthy, acorn-producing trees by birds that potentially disperse mistletoe. Our results indicate that the negative consequences of Phoradendron presence on their hosts are negligible-this species resembles an epiphyte more than a parasite-and outweighed by the important ecosystem services mistletoe provides.
Project description:Photodynamic therapy (PDT) is a modern, non-invasive therapeutic method used for the destruction of various cells and tissues. It requires the simultaneous presence of three components: a photosensitizer (PS), a light source and oxygen. Precancerous skin lesions are conditions associated with a high likelihood of malignant transformation to squamous cell carcinoma. Data available so far indicate that PDT is a promising treatment method which can be successfully employed in several medical fields including dermatology, urology, ophthalmology, pneumology, cardiology, dentistry and immunology. Numerous authors therefore have studied this technique in order to improve its efficacy. As a result, significant advancement has been achieved with regard to PSs and drug delivery systems. Substantial progress was also obtained with respect to PDT for the treatment of precancerous skin lesions, several authors focusing their efforts on the study of daylight-PDT and on identifying methods of decreasing technique-related pain. This review reports on the most recent findings in PDT, with emphasis on cutaneous precancerous lesions.
Project description:In July 2012, Congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA). The Advancing Breakthrough Therapies for Patients Act was incorporated into a Title of FDASIA to expedite clinical development of new, potential "breakthrough" drugs or treatments that show dramatic responses in early-phase studies. Using this regulatory pathway, once a promising new drug candidate is designated as a "Breakthrough Therapy", the U.S. Food and Drug Administration (FDA) and sponsor would collaborate to determine the best path forward to abbreviate the traditional three-phase approach to drug development. The breakthrough legislation requires that an FDA guidance be drafted that details specific requirements of the bill to aid FDA in implementing requirements of the Act. In this article, we have proposed criteria to define a product as a Breakthrough Therapy, and discussed critical components of the development process that would require flexibility in order to enable expedited development of a Breakthrough Therapy.
Project description:Thoracic malignancies comprise some of the most common and deadly cancers. Immunotherapies have been proven to improve survival outcomes for patients with advanced non-small cell lung cancer (NSCLC) and show great potential for patients with other thoracic malignancies. Radiation therapy (RT), an established and effective treatment for thoracic cancers, has acted synergistically with immunotherapies in preclinical studies. Ongoing clinical trials are exploring the clinical benefits of combining RT with immunotherapies and the optimal manner in which to deliver these complementary treatments.