A
bstract
One of the important goals at the future
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colliders is to measure the top-quark mass and width in a scan of the pair production threshold. However, the shape of the pair-production ...cross section at the threshold depends also on other model parameters, as the top Yukawa coupling, and the measurement is a subject to many systematic uncertainties. Presented in this work is the study of the top-quark mass determination from the threshold scan at CLIC. The most general approach is used with all relevant model parameters and selected systematic uncertainties included in the fit procedure. Expected constraints from other measurements are also taken into account. It is demonstrated that the top-quark mass can be extracted with precision of the order of 30 to 40 MeV, including considered systematic uncertainties, already for 100 fb
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of data collected at the threshold. Additional improvement is possible, if the running scenario is optimised. With the optimisation procedure based on the genetic algorithm the statistical uncertainty of the mass measurement can be reduced by about 20%. Influence of the collider luminosity spectra on the expected precision of the measurement is also studied.
Malignant pleural mesothelioma poses unique difficulties in tumor measurement and response assessment; however, robust and reproducible assessment of response is critically important in the conduct, ...interpretation, and reporting of clinical trials.
The current de facto standard for the assessment of mesothelioma tumor response, “modified RECIST” (Response Evaluation Criteria in Solid Tumors), was published in 2004 as a research paper. Practical application of the modified RECIST guidelines has suffered from varied interpretations, resulting in inaccuracies and inconsistencies in tumor response assessment across and within mesothelioma clinical trials. The presented “modified RECIST 1.1 for mesothelioma” response assessment guidelines provide a much-needed update that incorporates recommendations from RECIST 1.1 and approaches to other practical issues, including: (1) definition of minimally measurable disease; (2) definition of measurable lesions; (3) acceptable measurement location; (4) non-pleural disease considerations; (5) characterization of non-measurable pleural disease; (6) assessment of pathological lymph nodes; (7) establishing progressive disease; and (8) accommodations for bilateral pleural disease.
These modified RECIST 1.1 guidelines for mesothelioma tumor response collate and apply research published since the development of modified RECIST, align modified RECIST with RECIST 1.1, address those aspects of tumor measurement that were neglected or not well characterized in the modified RECIST paper, and clarify ambiguous or difficult measurement issues that have been highlighted through the subsequent decade of clinical trials research.
Adoption of the modified RECIST 1.1 guidelines for mesothelioma is recommended to harmonize the application of tumor measurement and response assessment across the next generation of clinical trials in this disease.
Cytotoxic chemotherapeutics form the cornerstone of systemic treatment of many cancers. Patients are dosed at maximum tolerated dose (MTD), which is carefully determined in phase I studies. In ...contrast, in murine studies, dosages are often based on customary practice or small pilot studies, which often are not well documented. Consequently, research groups need to replicate experiments, resulting in an excess use of animals and highly variable dosages across the literature. In addition, while patients often receive supportive treatments in order to allow dose escalation, mice do not. These issues could affect experimental results and hence clinical translation.
To address this, we determined the single-dose MTD in BALB/c and C57BL/6 mice for a range of chemotherapeutics covering the canonical classes, with clinical score and weight as endpoints.
We found that there was some variation in MTDs between strains and the tolerability of repeated cycles of chemotherapy at MTD was drug-dependent. We also demonstrate that dexamethasone reduces chemotherapy-induced weight loss in mice.
These data form a resource for future studies using chemotherapy in mice, increasing comparability between studies, reducing the number of mice needed for dose optimisation experiments and potentially improving translation to the clinic.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights • Essential constituents of immunogenic cell death. • Chemotherapy-induced modulation of antigen-presenting and immunosuppressive cells. • Clinical trials of checkpoint blockade and ...chemotherapy combinations.
Several chemotherapeutics exert immunomodulatory effects. One of these is the nucleoside analogue gemcitabine, which is widely used in patients with lung cancer, ovarian cancer, breast cancer, ...mesothelioma and several other types of cancer, but with limited efficacy. We hypothesized that the immunopotentiating effects of this drug are partly restrained by the inhibitory T cell molecule CTLA-4 and thus could be augmented by combining it with a blocking antibody against CTLA-4, which on its own has recently shown beneficial clinical effects in the treatment of patients with metastatic melanoma. Here we show, using two non-immunogenic murine tumor models, that treatment with gemcitabine chemotherapy in combination with CTLA-4 blockade results in the induction of a potent anti-tumor immune response. Depletion experiments demonstrated that both CD4(+) and CD8(+) T cells are required for optimal therapeutic effect. Mice treated with the combination exhibited tumor regression and long-term protective immunity. In addition, we show that the efficacy of the combination is moderated by the timing of administration of the two agents. Our results show that immune checkpoint blockade and cytotoxic chemotherapy can have a synergistic effect in the treatment of cancer. These results provide a basis to pursue combination therapies with anti-CTLA-4 and immunopotentiating chemotherapy and have important implications for future studies in cancer patients. Since both drugs are approved for use in patients our data can be immediately translated into clinical trials.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: The growth pattern of malignant pleural mesothelioma makes the use of RECIST (response evaluation criteria in solid tumours) response criteria difficult. We have developed and validated ...Modified RECIST criteria adapted to the growth pattern of malignant pleural mesothelioma. Patients and methods: We evaluated 73 patients from two clinical trials of cisplatin/gemcitabine chemotherapy in malignant pleural mesothelioma. Tumour thickness perpendicular to the chest wall or mediastinum was measured in two positions at three separate levels on thoracic CT scans. The sum of the six measurements defined a pleural unidimensional measure. Bidimensionally measureable lesions were measured unidimensionally as for RECIST. All measurements were added to obtain the total tumour measurement. A reduction of at least 30% on two occasions 4 weeks apart defined a partial response; an increase of 20% over the nadir measurement, progressive disease. The validity of the modified criteria was gauged by evaluating survival and pulmonary function. Results: Response according to these criteria predicted for superior survival (15.1 versus 8.9 months; P = 0.03) and forced vital capacity (FVC) increase during treatment (P <0.0001). A significant correlation between change in linear tumour measurement and FVC was seen (R = 0.63; P = 0.0001). Conclusion: These Modified RECIST criteria for tumour response correlate with survival and lung function and can be used to measure outcome in pleural mesothelioma.
Trends in the probabilities of days with liquid, solid, and mixed precipitation are discussed on annual and intra-annual scales along with their relationship to air temperature in the Atlantic sector ...of the Arctic. Data on weather phenomena were used to identify precipitation phases. The data cover various periods but all series extend to 2017. Trends in the annual air temperature and probability of precipitation phases for various long-term periods are discussed and differences in the mean air temperature and probability of precipitation phases between 1979–97 (insignificant warming) and 1999–2017 (significant warming) on an intra-annual scale. In the studied region, the precipitation phases were sensitive to warming and atmospheric circulation to various degrees, depending on the phase, mean climate, month, and local conditions. The probability of days with rainfall increased (by + 1% to +3% per decade), whereas the probability of days with snowfall decreased (by −1.5% to −2.4% per decade). The increasing trends in the probability of rainy days at all stations and decreasing trends in the probability of snowy days in the southern part of the region were warming induced. The most significant and widespread trends in snowy and rainy days were found in September. The probability of days with mixed precipitation exhibited no trends due to an inverse reaction to warming in the warmer and colder parts of the year. Temporal variability in the probability of precipitation phases was significantly linked to three teleconnection patterns playing a role in various parts of the year.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Immunotherapies have revolutionized cancer treatment. In particular, immune checkpoint therapy (ICT) leads to durable responses in some patients with some cancers. However, the majority of treated ...patients do not respond. Understanding immune mechanisms that underlie responsiveness to ICT will help identify predictive biomarkers of response and develop treatments to convert non-responding patients to responding ones. ICT primarily acts at the level of adaptive immunity. The specificity of adaptive immune cells, such as T and B cells, is determined by antigen-specific receptors. T cell repertoires can be comprehensively profiled by high-throughput sequencing at the bulk and single-cell level. T cell receptor (TCR) sequencing allows for sensitive tracking of dynamic changes in antigen-specific T cells at the clonal level, giving unprecedented insight into the mechanisms by which ICT alters T cell responses. Here, we review how the repertoire influences response to ICT and conversely how ICT affects repertoire diversity. We will also explore how changes to the repertoire in different anatomical locations can better correlate and perhaps predict treatment outcome. We discuss the advantages and limitations of current metrics used to characterize and represent TCR repertoire diversity. Discovery of predictive biomarkers could lie in novel analysis approaches, such as network analysis of amino acids similarities between TCR sequences. Single-cell sequencing is a breakthrough technology that can link phenotype with specificity, identifying T cell clones that are crucial for successful ICT. The field of immuno-sequencing is rapidly developing and cross-disciplinary efforts are required to maximize the analysis, application, and validation of sequencing data. Unravelling the dynamic behavior of the TCR repertoire during ICT will be highly valuable for tracking and understanding anti-tumor immunity, biomarker discovery, and ultimately for the development of novel strategies to improve patient outcomes.
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