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  • 1
    Language: English
    In: Science (American Association for the Advancement of Science), 2015-07-17, Vol.349 (6245), p.309-312
    Description: Morphinan alkaloids from the opium poppy are used for pain relief. The direction of metabolites to morphinan biosynthesis requires isomerization of (S)- to (R)-reticuline. Characterization of high-reticuline poppy mutants revealed a genetic locus, designated STORR [(S)- to (R)-reticuline] that encodes both cytochrome P450 and oxidoreductase modules, the latter belonging to the aldo-keto reductase family. Metabolite analysis of mutant alleles and heterologous expression demonstrate that the P450 module is responsible for the conversion of (S)-reticuline to 1,2-dehydroreticuline, whereas the oxidoreductase module converts 1,2-dehydroreticuline to (R)-reticuline rather than functioning as a P450 redox partner. Proteomic analysis confirmed that these two modules are contained on a single polypeptide in vivo. This modular assembly implies a selection pressure favoring substrate channeling. The fusion protein STORR may enable microbial-based morphinan production.
    Subject(s): Biosynthesis ; Enzymes ; Metabolites ; Modules ; Morphine ; Narcotics ; Pathways ; Poppies ; Proteins ; REPORTS
    ISSN: 0036-8075
    E-ISSN: 1095-9203
    Source: JSTOR Life Sciences
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
    Source: Get It Now
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  • 2
    Language: English
    In: Science (American Association for the Advancement of Science), 2015-07-17, Vol.349 (6245), p.309-312
    Description: Morphinan alkaloids from the opium poppy are used for pain relief. The direction of metabolites to morphinan biosynthesis requires isomerization of (S)- to (R)-reticuline. Characterization of high-reticuline poppy mutants revealed a genetic locus, designated STORR [(S)- to (R)-reticuline] that encodes both cytochrome P450 and oxidoreductase modules, the latter belonging to the aldo-keto reductase family. Metabolite analysis of mutant alleles and heterologous expression demonstrate that the P450 module is responsible for the conversion of (S)-reticuline to 1,2-dehydroreticuline, whereas the oxidoreductase module converts 1,2-dehydroreticuline to (R)-reticuline rather than functioning as a P450 redox partner. Proteomic analysis confirmed that these two modules are contained on a single polypeptide in vivo. This modular assembly implies a selection pressure favoring substrate channeling. The fusion protein STORR may enable microbial-based morphinan production.
    Subject(s): Base Sequence ; Benzylisoquinolines - chemistry ; Benzylisoquinolines - metabolism ; Cytochrome P-450 Enzyme System - genetics ; Cytochrome P-450 Enzyme System - metabolism ; Genetic Loci ; Isoquinolines - chemistry ; Isoquinolines - metabolism ; Molecular Sequence Data ; Morphinans - chemistry ; Morphinans - metabolism ; Mutation ; Oxidation-Reduction ; Papaver - enzymology ; Papaver - genetics ; Plant Proteins - genetics ; Plant Proteins - metabolism ; Quaternary Ammonium Compounds - chemistry ; Quaternary Ammonium Compounds - metabolism
    E-ISSN: 1095-9203
    Source: JSTOR Life Sciences
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
    Source: Get It Now
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  • 3
    Language: English
    In: Medicina (Kaunas, Lithuania), 2020-12-23, Vol.57 (1), p.6
    Description: The combination of immune checkpoint inhibitors and definitive radiotherapy is investigated for the multimodal treatment of cisplatin non-eligible locally advanced head and neck cancers (HNC). In the case of recurrent and metastatic HNC, immunotherapy has shown benefit over the EXTREME protocol, being already considered the standard treatment. One of the biggest challenges of multimodal treatment is to establish the optimal therapy sequence so that the synergistic effect is maximal. Thus, superior results were obtained for the administration of anti-CTLA4 immunotherapy followed by hypofractionated radiotherapy, but the anti-PD-L1 therapy demonstrates the maximum potential of radio-sensitization of the tumor in case of concurrent administration. The synergistic effect of radiotherapy-immunotherapy (RT-IT) has been demonstrated in clinical practice, with an overall response rate of about 18% for HNC. Given the demonstrated potential of radiotherapy to activate the immune system through already known mechanisms, it is necessary to identify biomarkers that direct the "nonresponders" of immunotherapy towards a synergistic RT-IT stimulation strategy. Stimulation of the immune system by irradiation can convert "nonresponder" to "responder". With the development of modern techniques, re-irradiation is becoming an increasingly common option for patients who have previously been treated with higher doses of radiation. In this context, radiotherapy in combination with immunotherapy, both in the advanced local stage and in recurrent/metastatic of HNC radiotherapy, could evolve from the "first level" of knowledge (i.e., ballistic precision, dose conformity and homogeneity) to "level two" of "biological dose painting" (in which the concept of tumor heterogeneity and radio-resistance supports the need for doses escalation based on biological criteria), and finally to the "third level" ofthe new concept of "immunological dose painting". The peculiarity of this concept is that the radiotherapy target volumes and tumoricidal dose can be completely reevaluated, taking into account the immune-modulatory effect of irradiation. In this case, the tumor target volume can include even the tumor microenvironment or a partial volume of the primary tumor or metastasis, not all the gross and microscopic disease. Tumoricidal biologically equivalent dose (BED) may be completely different from the currently estimated values, radiotherapy treating the tumor in this case indirectly by boosting the immune response. Thus, the clinical target volume (CTV) can be replaced with a new immunological-clinical target volume (ICTV) for patients who benefit from the RT-IT association (Image 1).
    Subject(s): ab-scopal ; Cisplatin ; head and neck cancers ; Head and Neck Neoplasms - radiotherapy ; Humans ; Immunotherapy ; Opinion ; radiotherapy ; Re-Irradiation ; Tumor Burden ; Tumor Microenvironment
    ISSN: 1648-9144
    ISSN: 1010-660X
    E-ISSN: 1648-9144
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    Source: ProQuest Central
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  • 4
    Language: English
    In: Experimental and therapeutic medicine, 2021-01, Vol.21 (1), p.81-81
    Description: Gestational diabetes mellitus is an important healthcare problem with serious implications both to the mother and to the foetus. The necessity of clear screening criteria for the pregnant woman and also identifying from an early stage the risk groups can be beneficial instruments for better management of gestational diabetes. The present report identify the main screening criteria for patients at risk for gestational diabetes and the therapeutic-nutritional therapy for women that have gestational diabetes. The different diagnostic criteria, as well as the new instruments through which these criteria can be applied, are still heterogeneous, and it is necessary to unify and promote them. The prevalence of gestational diabetes has significantly increased in recent years, and this has led to an increase in the direct and indirect costs of healthcare. Establishing the optimal time and initiating the correct treatment is critical to achieving glycemic control and to minimize the impact on fetal development and perinatal complications.
    Subject(s): Birth weight ; Body fat ; Care and treatment ; Children & youth ; Congenital diseases ; Diabetes in pregnancy ; Diabetes therapy ; Fasting ; Fetus ; Gestational diabetes ; gestational diabetes mellitus ; Glucose ; Growth ; Insulin resistance ; management of gestational diabetes ; Medical screening ; Mortality ; Obstetrics ; Peptides ; Pregnancy ; Pregnant women ; Reports ; Review ; Risk factors ; screening ; treatment of gestational diabetes ; Type 2 diabetes ; Womens health
    ISSN: 1792-0981
    E-ISSN: 1792-1015
    Source: Academic Search Ultimate
    Source: PubMed Central
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  • 5
    Language: English
    In: Science (American Association for the Advancement of Science), 2018-10-19, Vol.362 (6412), p.343-347
    Description: Morphinan-based painkillers are derived from opium poppy ( L.). We report a draft of the opium poppy genome, with 2.72 gigabases assembled into 11 chromosomes with contig N50 and scaffold N50 of 1.77 and 204 megabases, respectively. Synteny analysis suggests a whole-genome duplication at ~7.8 million years ago and ancient segmental or whole-genome duplication(s) that occurred before the Papaveraceae-Ranunculaceae divergence 110 million years ago. Syntenic blocks representative of phthalideisoquinoline and morphinan components of a benzylisoquinoline alkaloid cluster of 15 genes provide insight into how this cluster evolved. Paralog analysis identified P450 and oxidoreductase genes that combined to form the gene fusion essential for morphinan biosynthesis in opium poppy. Thus, gene duplication, rearrangement, and fusion events have led to evolution of specialized metabolic products in opium poppy.
    Subject(s): Addiction ; Analgesics ; Benzylisoquinolines - metabolism ; Biological evolution ; Biosynthesis ; Chemical properties ; Chromosomes ; Clusters ; Divergence ; Drug abuse ; Drug trafficking ; Evolution, Molecular ; Gene Duplication ; Gene Fusion ; Gene Order ; Gene rearrangement ; Genes ; Genetic aspects ; Genome, Plant ; Genomes ; Metabolism ; Morphinans - metabolism ; Multigene Family ; NADPH-Ferrihemoprotein Reductase - genetics ; Narcotics ; Opiates ; Opioids ; Opium poppy ; Oxidoreductase ; Papaver - genetics ; Papaver - metabolism ; Papaver somniferum ; Phthalideisoquinoline ; Plant Proteins - genetics ; Production processes ; Proteins ; Reproduction (copying) ; Synteny
    ISSN: 0036-8075
    E-ISSN: 1095-9203
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
    Source: Get It Now
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  • 6
    Language: English
    In: International journal of environmental research and public health, 2022-03-22, Vol.19 (7), p.3772
    Description: The evolution and development of radiotherapy in the last two decades has meant that postgraduate medical training has not kept up with this rapid progress both in terms of multidisciplinary clinical approaches and especially in terms of technological advances. Education in radiation oncology is a major priority in the context of the rapid development of radiotherapy, including advanced knowledge of radiobiology, radiation physics and clinical oncology, anatomy, tumor biology and advanced medical imaging. In this context, the lack of training in radiation oncology in the curricula of medical faculties may have detrimental consequences for the training of residents in radiotherapy but also in their choice of specialty after completing their university studies. There is a clear gap between resident physicians' actual and required knowledge of radiotherapy, and this requires urgent remediation. In the context of technical advances in imaging-guided radiotherapy (IGRT) and new radiobiology data, a balanced approach divided equally between general oncology, clinical radiation oncology, radiation oncology technology, medical physics and radiobiology, anatomy and multimodal imaging, including mentorship could bring educational and career choice benefits for students of radiation oncology.
    Subject(s): Anatomy ; Breast cancer ; Cancer therapies ; Career Choice ; Careers ; Chemotherapy ; Colleges & universities ; Conformity ; Context ; Curricula ; Curriculum ; Dosimetry ; Education ; Health physics ; Humans ; Immunotherapy ; Internship and Residency ; Knowledge ; Magnetic resonance imaging ; Medical imaging ; Medical prognosis ; Medical research ; Medical students ; mentorship ; Oncology ; Physicians ; Physics ; Quality of life ; Radiation ; radiation oncology ; Radiation Oncology - education ; Radiation therapy ; Radiobiology ; radiotherapy ; students ; Tomography ; Toxicity ; Training ; Tumors
    ISSN: 1661-7827
    E-ISSN: 1660-4601
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 7
    Language: English
    In: Journal of clinical medicine, 2021-02-04, Vol.10 (4), p.587
    Description: Locally advanced head and neck cancer is a unique challenge for cancer management in the Covid-19 situation. The negative consequences of delaying radio-chemotherapy treatment make it necessary to prioritize these patients, the continuation of radiotherapy being indicated even if SARS-CoV-2 infection is confirmed in the case of patients with moderate and mild symptoms. For an early scenario, the standard chemo-radiotherapy using simultaneous integrated boost (SIB) technique is the preferred option, because it reduces the overall treatment time. For a late scenario with limited resources, hypo-fractionated treatment, with possible omission of chemotherapy for elderly patients and for those who have comorbidities, is recommended. Concurrent chemotherapy is controversial for dose values 〉2.4 Gy per fraction. The implementation of hypo-fractionated regimens should be based on a careful assessment of dose-volume constraints for organs at risks (OARs), using recommendations from clinical trials or dose conversion based on the linear-quadratic (LQ) model. Induction chemotherapy is not considered the optimal solution in this situation because of the risk of immunosuppression even though in selected groups of patients TPF regimen may bring benefits. Although the MACH-NC meta-analysis of chemotherapy in head and neck cancers did not demonstrate the superiority of induction chemotherapy over concurrent chemoradiotherapy, an induction regimen could be considered for cases with an increased risk of metastasis even in the case of a possible Covid-19 pandemic scenario.
    Subject(s): chemotherapy ; Coronaviruses ; COVID-19 ; Fatalities ; Head & neck cancer ; head and neck cancer ; Mortality ; non-surgical ; radiotherapy ; Review
    ISSN: 2077-0383
    E-ISSN: 2077-0383
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    Source: ProQuest Central
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  • 8
    Language: English
    In: Frontiers in oncology, 2022, Vol.12, p.862819-862819
    Description: Breast cancer is the most common cancer among women worldwide, which is often treated with radiotherapy. Whole breast irradiation (WBI) is one of the most common types of irradiation. Hypo-fractionated WBI (HF-WBI) reduces the treatment time from 5 to 3 weeks. Recent radiobiological and clinical evidence recommended the use of HF-WBI regardless of the age or stage of disease, and it is proven that hypo-fractionation is non-inferior to conventional fractionation regimen irradiation. However, some studies report an increased incidence of heart-related deaths in the case of breast irradiation by hypo-fractionation, especially in patients with pre-existing cardiac risk factors at the time of treatment. Due to the new technical possibilities of radiotherapy techniques, HF-WBI can reduce the risk of cardiac toxicity by controlling the doses received both by the heart and by the anatomical structures of the heart. The radiobiological "double trouble", in particular "treble trouble", for hypo-fractionated regimen scan be avoided by improving the methods of heart sparing based on image-guided irradiation (IGRT) and by using respiration control techniques so that late cardiac toxicity is expected to be limited. However, long-term follow-up of patients treated with HF-WBI with modern radiotherapy techniques is necessary considering the progress of systemic therapy, which is associated with long-term survival, and also the cardiac toxicity of new oncological treatments. The still unknown effects of small doses spread in large volumes on lung tissue may increase the risk of second malignancy, but they can also be indirectly involved in the later development of a heart disease. It is also necessary to develop multivariable radiobiological models that include histological, molecular, clinical, and therapeutic parameters to identify risk groups and dosimetric tolerance in order to limit the incidence of late cardiac events. MR-LINAC will be able to offer a new standard for reducing cardiac toxicity in the future, especially in neoadjuvant settings for small tumors.
    Subject(s): breast ; cardiac toxicity ; chemotherapy ; coronary arteries ; HF-WBI ; hypo-fractionated radiotherapy
    ISSN: 2234-943X
    E-ISSN: 2234-943X
    Source: PubMed Central
    Source: Alma/SFX Local Collection
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 9
    Language: English
    In: Science (American Association for the Advancement of Science), 2012-06-29, Vol.336 (6089), p.1704-1708
    Description: Noscapine is an antitumor alkaloid from opium poppy that binds tubulin, arrests metaphase, and induces apoptosis in dividing human cells. Elucidation of the biosynthetic pathway will enable improvement in the commercial production of noscapine and related bioactive molecules. Transcriptomic analysis revealed the exclusive expression of 10 genes encoding five distinct enzyme classes in a high noscapine-producing poppy variety, HN1. Analysis of an F₂ mapping population indicated that these genes are tightly linked in HN1, and bacterial artificial chromosome sequencing confirmed that they exist as a complex gene cluster for plant alkaloids. Virus-induced gene silencing resulted in accumulation of pathway intermediates, allowing gene function to be linked to noscapine synthesis and a novel biosynthetic pathway to be proposed.
    Subject(s): Alkaloids ; Anticancer properties ; Antineoplastic Agents, Phytogenic - biosynthesis ; Biological and medical sciences ; Biosynthesis ; Capsules ; Classical genetics, quantitative genetics, hybrids ; Clusters ; Cough ; Enzymes ; Flowers & plants ; Fundamental and applied biological sciences. Psychology ; Gene silencing ; Genes ; Genes, Plant ; Genetic aspects ; Genetics of eukaryotes. Biological and molecular evolution ; Genomes ; Latex ; Libraries ; Low level ; Molecular Sequence Data ; Morphinans ; Multigene Family ; Narcotics ; Noscapine - metabolism ; Open reading frames ; Papaver - enzymology ; Papaver - genetics ; Papaver - metabolism ; Papaver somniferum ; Pharmaceutical sciences ; Physiological aspects ; Plant biology ; Poppies ; Pteridophyta, spermatophyta ; REPORTS ; Synthesis ; Vegetals
    ISSN: 0036-8075
    E-ISSN: 1095-9203
    Source: JSTOR Life Sciences
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
    Source: Get It Now
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  • 10
    Language: English
    In: Current oncology (Toronto), 2022-02-02, Vol.29 (2), p.816-833
    Description: Even though it is only the 6th most common malignancy at the modal level, head and neck cancers are distinguished by a considerable treatment failure rate, especially by locoregional recurrences, the intrinsic tumor radioresistance being one of the causes of this phenomenon. The efforts of radiobiological research of these cancers are oriented towards the identification of biomarkers associated with radioresistance and radiosensitivity in order to modulate the treatment so that the therapeutic benefit is maximum. Micro-RNAs (miRNAs, miRs), small single-stranded non-coding RNA molecules are currently being extensively evaluated as potential biomarkers in numerous diseases, including cancer. The evaluation of the potential of miRNAs to modulate or predict radiosensitivity or radioresistance, to anticipate the risk of recurrence and metastasis, and to differentiate different tumor subtypes is based on multiple mechanisms by which mRNAs control proliferation and apoptosis and interact with cell cycle phases or act as oncogenes with the potential to influence invasion promotion or tumor suppression. A refinement of radiosensitivity based on miRNAs with clinical and radiobiological application in head and neck cancers can lead to a personalization of radiotherapy. Thus, a miRNA signature can anticipate the risk of toxicity associated with chemoradiation, the possibility of obtaining locoregional control after treatment, and the recurrence and distant metastasis risk. The potential of miRNAs as an intrinsic predictor of sensitivity to chemotherapy may also guide the therapeutic decision toward choosing an escalation or de-escalation of concurrent or sequential systemic treatment. The choice of the irradiated dose, the fractional dose, the fractionation scheme, and the refining of the dose-volume constraints depending on the radiosensitivity of each tissue type estimated on a case-by-case basis by miRNAs profile are possible concepts for the future radiotherapy and radiobiology of head and neck cancers.
    Subject(s): chemotherapy ; head and neck cancers ; Head and Neck Neoplasms - genetics ; Head and Neck Neoplasms - radiotherapy ; Humans ; microRNAs ; MicroRNAs - genetics ; Neoplasm Recurrence, Local ; Radiation Tolerance - genetics ; Radiobiology ; radioresistance ; radiosensitivity
    ISSN: 1198-0052
    E-ISSN: 1718-7729
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: Alma/SFX Local Collection
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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