Ovarian cancer is the fifth cause of cancer-related deaths in women with high grade serous carcinoma (HGSOC) representing the most common histological subtype. Approximately 50 % of HGSOC are ...characterized by deficiency in homologous recombination (HR), one of the main cellular pathways to repair DNA double strand breaks and one of the well-described mechanisms is the loss of function of the BRCA1 or BRCA2 genes. Inhibition of the poly-ADP-ribose polymerase (PARP) is synthetic lethal with HR deficiency and the use of PARP inhibitors (PARPi) has significantly improved the outcome of patients with HGSOC with a greater benefit in patients with BRCA1/2 deficient tumors. However, intrinsic or acquired resistance to PARPi inevitably occurs in most HGSOC patients. Distinct heterogeneous mechanisms underlying the resistance to PARPi have been described, including a decrease in intracellular drug levels due to upregulation of multidrug efflux pumps, loss of expression/inactivating mutations in the PARP1 protein, restoration of HR and the protection of the replicative fork. Deciphering the molecular mechanisms of resistance to PARPi is of paramount importance towards the development of new treatment strategies and/or novel pharmacological agents to overcome this chemoresistance and optimize the treatment regimen for individual HGSOC patients.
The current review summarizes the mechanisms underlying the resistance to PARPi, the available preclinical and clinical data on new combination treatment strategies (with chemotherapy, anti-angiogenic agents and immune checkpoint inhibitors) as well as agents under investigation which target the DNA damage response.
The value of streamflow forecasts to inform water infrastructure operations has been extensively studied. Yet, their value in informing infrastructure design is still unexplored. In this work, we ...investigate how dam design is shaped by information feedbacks supporting the implementation of flexible operating policies informed by streamflow forecasts to enable the design of less costly reservoirs relative to alternatives that do not rely on forecast information. Our approach initially explores the maximum potential gain attainable by searching and using the most valuable forecast information and lead time. We then analyze the results? sensitivities relative to existing and synthetic biased forecasts. We demonstrate our approach through an ex post analysis of the Kariba Dam in the Zambezi River Basin. Results show that informing dam design with perfect forecasts enables attaining the same hydropower production of the existing dam, while reducing infrastructure size and associated capital costs by 20%. A forecast‐informed operation of the existing system can instead facilitate an annual average increase of 60 GWh in hydropower production. This finding, extrapolated to the new planned dams in the basin, suggests that forecast informed policies could yield power production benefits equal to 75% of the current annual electricity consumption of the Zambian agricultural sector. The use of biased forecasts substantially reduces this gain, showing that the ESP forecasts value is marginal and that informed infrastructure designs are particularly vulnerable to forecast overestimation. Advancing information feedbacks may therefore become a valuable asset for the ongoing hydropower expansion in the basin.
Key Points
The value of using streamflow forecasts in informing joint dam design and operation is explored for the first time
The use of perfect seasonal streamflow forecasts could enable a 20% reduction in capital costs for large reservoirs
The value of forecast information changes remarkably with dam size and operational trade‐offs
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults, accounting for 35%–40% of all cases. The combination of the anti-CD20 monoclonal antibody rituximab with ...anthracycline-based combination chemotherapy (R-CHOP, rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone) lead to complete remission in most and can cure more than half of patients with DLBCL. The diversity in clinical presentation, as well as the pathologic and biologic heterogeneity, suggests that DLBCL comprises several disease entities that might ultimately benefit from different therapeutic approaches. In this review, we summarize the current literature focusing on the genetic lesions identified in DLBCL.
Histologic transformation in marginal zone lymphomas Conconi, A.; Franceschetti, S.; Aprile von Hohenstaufen, K. ...
Annals of oncology,
November 2015, 2015-Nov, 2015-11-00, 20151101, Letnik:
26, Številka:
11
Journal Article
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Histologic transformation (HT) is a poorly understood event in patients with marginal zone lymphoma (MZL). The aim of this study was to analyze incidence and risk factors for HT in a large series of ...MZL patients.
The studied cohort included 340 MZL patients diagnosed and treated between 1995 and 2012: 157 extranodal MZLs mucosa-associated lymphoid tissue (MALT) lymphoma, 46%, 85 splenic MZLs (SMZLs, 25%) and 37 nodal MZLs (NMZLs, 11%). Sixty-one patients (18%) had bone marrow infiltration at presentation, with or without detectable involvement of peripheral blood, but without other involved sites; they were considered clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ).
With a median follow-up of 4.8 years, the median overall survival and progression-free survival of the whole population were 14.5 and 5 years, respectively. HT was observed in 13 cases 3.8%, 95% confidence interval (95% CI) 2%–6.5%. Elevated lactate dehydrogenase (LDH) at diagnosis was associated with the risk of HT (P = 0.019). HT occurred in 5% of SMZLs, 4% of MALT lymphomas, 3% of NMZLs and 3% of CBL-MZ (P = 0.974). The risk of HT was 5% (95% CI 3–9%) at 5 and 10 years after diagnosis and 10% (95% CI 5%–20%) at 12 years. At the time of HT, most patients had high LDH and B symptoms. At a median follow-up of 12 months after HT, 4 of 13 patients died, all for lymphoma-related causes, with a 2-year post-transformation survival rate of 57% (95% CI 13%–86%).
In this large retrospective series, the risk of HT across all MZL types appeared lower than the one reported for follicular lymphoma.
The acquisition of a complete neoplastic phenotype requires cancer cells to develop escape mechanisms from the host immune system. This phenomenon, commonly referred to as 'immune evasion,' ...represents a hallmark of cancers and results from a Darwinian selection of the fittest tumor clones. First reported in solid tumors, cancer immunoescape characterizes several hematological malignancies. The biological bases of cancer immunoescape have recently been disclosed and include: (i) impaired human leukocyte antigen-mediated cancer cell recognition (B2M, CD58, CTIIA, CD80/CD86, CD28 and CTLA-4 mutations); (ii) deranged apoptotic mechanisms (reduced pro-apoptotic signals and/or increased expression of anti-apoptotic molecules); and (iii) changes in the tumor microenvironment involving regulatory T cells and tumor-associated macrophages. These immune-escape mechanisms characterize both Hodgkin and non-Hodgkin (B and T cell) lymphomas and represent a promising target for new anti-tumor therapies. In the present review, the principles of cancer immunoescape and their role in human lymphomagenesis are illustrated. Current therapies targeting these pathways and possible applications for lymphoma treatment are also addressed.
Globally, many countries are actively seeking to maximize the hydropower potential of major river basins, yielding proposals for constructing approximately 3,700 major dams in the near future. At ...present, economic cost‐benefit analyses are the dominant approach for evaluating candidate dam designs. Yet they typically fail to explore the interdependence of dam design and operation by (i) monetizing and aggregating potentially conflicting and heterogeneous objectives into a single metric and (ii) using predefined operating rules aimed at maximizing specific performance objectives for the dams to be designed. Careful consideration of alternative reservoir operating schemes can help to avoid biases in how optimal dam sizes are identified while also clarifying their capacity to adapt to changing hydroclimatic conditions and human demands. This paper presents an integrated framework to solve coupled dam sizing and operation design problems. The framework combines Multiobjective Robust Decision Making and Evolutionary Multiobjective Direct Policy Search into a novel approach to dam sizing, which internalizes the operation design problem and explicitly considers uncertainty in external drivers. We demonstrate the potential of this integrated dam design framework through an ex‐post design analysis of the Kariba dam in the Zambezi river basin. Our results show that careful exploration of the coupled planning/operation search space yields designs that significantly outperform the existing Kariba system. Moreover, we demonstrate that our framework leads to a significant reduction in capital costs (i.e., smaller reservoir sizes) while simultaneously improving system robustness with respect to changing hydroclimatology and human irrigation demands.
Key Points
Dependencies across dam design and operations strongly influence attainable robustness
Ex‐post analysis of the Kariba dam directly maps how operations can reshape capital investments
The contributed framework aids in reducing the capital costs required to improve robustness to changing drivers
We performed a systematic review of phase I trials specifically designed for lymphoma patients. PubMed and Cochrane Library databases were searched using (lymphoma*) AND (phase 1) and publication ...date 2015–2020 to identify phase I dose-finding trials including a majority of lymphoma patients. Eighty-two trials (n = 3289 lymphoma patients) were included: 46 (55%) enrolled only lymphoma patients, 34 (41%) included also other hematologic malignancies, 2 (2%) solid tumors. Forty-six trials (56%) evaluated a combination (in 25 addition of experimental drug to standard therapy). Seven trials (9%) enrolled untreated patients. Among trials reporting activity in lymphoma patients, 74% (n = 57) reported an overall response rate ≥ 30%. All trials reported grade ≥ 3 adverse events; however, rates were not comparable across trials. Thirty-one treatment-related deaths in lymphoma patients were reported (overall treatment-related grade 5 adverse events rate 0.94%). Phase I trials designed for lymphoma patients were generally safe and the majority reported overall response rate ≥ 30%.
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•Phase I trials represent the first clinical evaluation of a new drug or combination.•Several phase I trials have been designed specifically for lymphoma patients.•We identified 82 trials (2015–2020) including a majority of lymphoma patients.•These trials were overall safe, the majority reported an overall response rate≥ 30%.•A greater degree of standardization in reporting safety results should be encouraged.
The study of the global atmospheric electric circuit is important to understand the climate system and this can be done by monitoring the atmospheric electric field worldwide. In this way, continuous ...measurements of atmospheric electric field are being recorded by the Atmospheric electric FIeld Network in South America (AFINSA). The main objective of this network is to obtain the daily curve of atmospheric electric field variations under fair weather conditions for each station, through monthly, seasonal and annual averages. These curves are called ‘standard curves’. In this paper, we compare and analyze the monthly, seasonal and annual standard curves for each sensor location. The results indicate significant similarities and differences between the annual standard curve and the Carnegie curve. The similarities, with correlation r ≥ 0.9 for most stations, are associated with a global representation of the global electrical circuit and the differences due to local effects, such as ‘Austausch’ effect and pollution.
•A new network to monitor the atmospheric electric field on the ground.•Global and local contribution are found in the electric field standard curves.•Annual standard curves have a high correlation with the ‘universal’ Carnegie curve.
Delving deeper into MALT lymphoma biology Bertoni, Francesco; Zucca, Emanuele
The Journal of clinical investigation,
01/2006, Letnik:
116, Številka:
1
Journal Article
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Mucosa-associated lymphoid tissue (MALT) lymphomas can arise in a variety of extranodal sites. Interestingly, at least 3 different, apparently site-specific, chromosomal translocations, all affecting ...the NF-kappaB pathway, have been implicated in the development and progression of MALT lymphoma. The most common is the translocation t(11;18)(q21;q21), which results in a fusion of the cIAP2 region on chromosome 11q21 with the MALT1 gene on chromosome 18q21 and is present in more than one-third of cases. The frequency of this translocation is site-related: common in the gastrointestinal tract and lung, rare in conjunctiva and orbit, and almost absent in salivary glands, thyroid, liver, and skin. In this issue of the JCI, Hu et al. add to our understanding of the molecular consequences of this translocation, showing that its fusion product, cIAP2-MALT1, may concomitantly contribute to lymphomagenesis both as a tumor suppressor gene and as an oncogene.
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