Changes in DNA repair during aging

DNA is a precious molecule. It encodes vital information about cellular content and function. There are only two copies of each chromosome in the cell, and once the sequence is lost no replacement is possible. The irreplaceable nature of the DNA sets it apart from other cellular molecules, and makes it a critical target for age-related deterioration. To prevent DNA damage cells have evolved elaborate DNA repair machinery. Paradoxically, DNA repair can itself be subject to age-related changes and deterioration. In this review we will discuss the changes in efficiency of mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER) and double-strand break (DSB) repair systems during aging, and potential changes in DSB repair pathway usage that occur with age. Mutations in DNA repair genes and premature aging phenotypes they cause have been reviewed extensively elsewhere, therefore the focus of this review is on the comparison of DNA repair mechanisms in young versus old

Ethnic Differences in Susceptibility to the Effects of Platinum- Based Chemotherapy

There is substantial interindividual variability in the efficacy and tolerability of anticancer drugs. Such differences can be greater between individuals of different ethnicities. The clinical studies demonstrate that individuals from Asia (East Asia) are more susceptible to the effects of platinum-containing chemotherapies than their Western counterparts. To determine whether population-related genomics (i.e., frequencies of DNA polymorphisms) contribute to differences in patient outcomes, polymorphisms in 109 genes involved mainly in xenobiotic metabolism, DNA repair, the cell cycle, and apoptosis were tested in Russian (Caucasians) and Yakut (North Asians) ovarian cancer patients receiving cisplatin-based chemotherapy. Totally, 232 polymorphisms were genotyped in individual DNA samples using conventional PCR and arrayed primer extension technology. Single nucleotide polymorphisms (SNPs) in more than 30 genes were found to be associated with one or more of clinical end points (i.e., tumor response, progression-free survival, overall survival, and side effects). However, all associations between SNPs and clinical outcomes were specific for each of ethnic group studied. These findings let us to propose the existence of distinctive ethnic-related characteristics in molecular mechanisms determining the sensitivity of patients to platinum drug effects

Naked mole rat TRF1 safeguards glycolytic capacity and telomere replication under low oxygen.

The naked mole rat (NMR), a long-lived and cancer-resistant rodent, is highly resistant to hypoxia. Here, using robust cellular models wherein the mouse telomeric protein TRF1 is substituted by NMR TRF1 or its mutant forms, we show that TRF1 supports maximal glycolytic capacity under low oxygen, shows increased nuclear localization and association with telomeres, and protects telomeres from replicative stress. We pinpoint this evolutionary gain of metabolic function to specific amino acid changes in the homodimerization domain of this protein. We further find that NMR TRF1 accelerates telomere shortening. These findings reveal an evolutionary strategy to adapt telomere biology for metabolic control under an extreme environment

Health-Related Quality of Life in Patients with Advanced Nonsquamous Non–Small-Cell Lung Cancer Receiving Bevacizumab or Bevacizumab-Plus-Pemetrexed Maintenance Therapy in AVAPERL (MO22089)

IntroductionIn the phase III AVAPERL trial, patients with advanced nonsquamous non–small-cell lung cancer receiving bevacizumab-plus-pemetrexed maintenance after first-line induction had a significant progression-free survival benefit relative to those treated with single-agent bevacizumab maintenance but with an increase in grade ≥3 adverse events. Here, we compare health-related quality of life (HRQOL) between AVAPERL maintenance arms.MethodsPatient-reported outcomes were collected at designated intervals from preinduction to final visits. HRQOL was assessed using the self-administered European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and the Quality of Life Lung Cancer–Specific Module 13. Differences in scores of 10 points or more between arms were above the minimum important difference threshold and considered clinically meaningful.ResultsDuring induction, patient-reported coughing symptoms improved slightly, whereas fatigue and appetite loss scores worsened relative to preinduction baseline. During maintenance, changes in mean global health status and the majority of Quality of Life Questionnaire Core 30 and Quality of Life Lung Cancer–Specific Module 13 subscale scores did not differ between trial arms by the minimum important difference defining clinically meaningful (better or worse) patient-reported outcomes. Exceptions were patient-reported role functional status, fatigue symptoms and appetite loss symptoms (favoring bevacizumab), and pain in arm or shoulder symptoms (favoring bevacizumab-plus-pemetrexed maintenance), which differed by clinically meaningful amounts at more than one maintenance assessment.ConclusionsIn AVAPERL, HRQOL remained relatively stable throughout maintenance and was generally similar in both arms. Despite an increase in adverse event rates, the addition of pemetrexed to bevacizumab maintenance resulted in similar stabilization of disease symptoms with improved efficacy outcomes

The Naked Mole Rat Genome Resource: facilitating analyses of cancer and longevity-related adaptations

Motivation: The naked mole rat (Heterocephalus glaber) is an exceptionally long-lived and cancer-resistant rodent native to East Africa. Although its genome was previously sequenced, here we report a new assembly sequenced by us with substantially higher N50 values for scaffolds and contigs. Results: We analyzed the annotation of this new improved assembly and identified candidate genomic adaptations which may have contributed to the evolution of the naked mole rat’s extraordinary traits, including in regions of p53, and the hyaluronan receptors CD44 and HMMR (RHAMM). Furthermore, we developed a freely available web portal, the Naked Mole Rat Genome Resource (http://www.naked-mole-rat.org), featuring the data and results of our analysis, to assist researchers interested in the genome and genes of the naked mole rat, and also to facilitate further studies on this fascinating species. Availability and implementation: The Naked Mole Rat Genome Resource is freely available online at http://www.naked-mole-rat.org. This resource is open source and the source code is available at https://github.com/maglab/naked-mole-rat-portal. Contact: [email protected]

Using ontology in scientific and technological forecasting

The case is made and proposals are drawn for the development of ontologies of scientific and technological forecasting to secure national interests based on the descriptions of expertise in the forecast domain and the methodology of concept maps. Concept maps of scientific and technological advances are visualised and applicability is described for ontological methods in scientific and technological forecasting, as well as the specifics of automation. The novel contribution of the research findings consists in the authors' systemic and comprehensive approach in describing the ontological principles of scientific and technological forecasting to secure national interests. This eliminates the ambiguity in approaches and conceptualisations of the processes of scientific and technological forecasting. The proposed ontological system of scientific and technological forecasting to secure national interests offers a systemic approach to forecast development and uniform interpretations of the concepts involved. All that would doubtlessly contribute to quality forecasting

Клинико-экономический анализ применения препарата Гиотриф® (афатиниб) в первой линии терапии местнораспространённого или метастатического немелкоклеточного рака лёгкого с мутацией Del19 рецептора эпидермального фактора роста (EGFR)

Purpose of the analysis is to assess the cost-effectiveness and cost-utility of Giotrif® (afatinib) as first line treatment for metastatic non-small cell lung cancer NSCLC with Del 19 mutation of EGFR gene in comparison with erlotinib, gefitinib and combination cisplatin/ pemetrexed. Markov modeling was implemented to simulate clinical and economical outcomes of different strategies in treatment of na ve patients based on randomized clinical trial results. Direct medical costs were considered. Afatinib used as first line treatment in patients with NSCLC with Del 19 gene mutation increased quality-adjusted life years (QALY) by 0,354, 0,665 and 0,670 QALY in comparison with erlotinib, gefitinib and combination cisplatin/ pemetrexed respectively. The ICERs were 1 052 934, 1 067 116 и 1 064 708 rubles in comparison with erlotinib, gefitinib and combination cisplatin/ pemetrexed respectively per QALY. Afatinib was shown to be the cost-effective strategy in first line treatment of metastatic NSCLC with Del 19 gene mutation as willingness to pay threshold (1 455 741,77 rubles) was not exceeded.Целью данного исследования является анализ клинико- экономической эффективности и полезности применения препарата афатиниб у больных немелкоклеточным раком лёгкого (НМРЛ) с мутацией Del19 гена EGFR в 1-й линии терапии в сравнении с эрлотинибом, гефитинибом и комбинацией цисплатин/ пеметрексед. Использовано моделирование на основе результатов клинических исследований. Учитывались только прямые медицинские затраты: стоимость медикаментозного лечения НМРЛ в первой и второй линиях терапии; затраты на коррекцию нежелательных явлений, затраты на госпитализации и амбулаторное лечение пациентов. Анализ показал, что афатиниб увеличивает продолжительность жизни с учётом качества по сравнению с эрлотинибом на 0,354 QALY, по сравнению с гефитинибом на 0,665 QALY, по сравнению с комбинацией цисплатин/пеметрексед на 0,670 QALY у пациентов с мутацией Del19 рецептора EGFR. Значение коэффициента эффективности дополнительных затрат ICER для афатиниба, в сравнении с альтернативными режимами терапии 1-й линии эрлотинибом, гефитинибом и комбинацией цисплатин/пеметрексед составляет 1 052 934, 1 067 116 и 1 064 708 руб. соответственно и не превышает порог готовности общества платить (1 455 741,77 руб.). Таким образом, терапия препаратом Гиотриф® (афатиниб) больных НМРЛ с мутацией Del19 рецептора EGFR в 1-й линии терапии в условиях российского здравоохранения является максимально клинически эффективной и экономически целесообразной

The Insulin-Like Growth Factor System in the Long-Lived Naked Mole-Rat.

Naked mole-rats (Heterocephalus glaber) (NMRs) are the longest living rodents known. They show negligible senescence, and are resistant to cancers and certain damaging effects associated with aging. The insulin-like growth factors (IGFs) have pluripotent actions, influencing growth processes in virtually every system of the body. They are established contributors to the aging process, confirmed by the demonstration that decreased IGF signaling results in life-extending effects in a variety of species. The IGFs are likewise involved in progression of cancers by mediating survival signals in malignant cells. This report presents a full characterization of the IGF system in the NMR: ligands, receptors, IGF binding proteins (IGFBPs), and IGFBP proteases. A particular emphasis was placed on the IGFBP protease, pregnancy-associated plasma protein-A (PAPP-A), shown to be an important lifespan modulator in mice. Comparisons of IGF-related genes in the NMR with human and murine sequences indicated no major differences in essential parts of the IGF system, including PAPP-A. The protease was shown to possess an intact active site despite the report of a contradictory genome sequence. Furthermore, PAPP-A was expressed and translated in NMRs cells and retained IGF-dependent proteolytic activity towards IGFBP-4 and IGF-independent activity towards IGFBP-5. However, experimental data suggest differential regulatory mechanisms for PAPP-A expression in NMRs than those described in humans and mice. This overall description of the IGF system in the NMR represents an initial step towards elucidating the complex molecular mechanisms underlying longevity, and how these animals have evolved to ensure a delayed and healthy aging process