Hazard reduction policies include seismic hazard maps based on probabilistic evaluations and the evaluation of geophysical parameters continuously recorded by instrumental networks. Over the past 25 ...centuries, a large amount of information about earthquake precursory phenomena has been recorded by scholars, scientific institutions, and civil defense agencies. In particular, hydrogeologic measurements and geochemical analyses have been performed in geofluids in search of possible and reliable earthquake precursors. Controlled experimental areas have been set up to investigate physical and chemical mechanisms originating possible preseismic precursory signals. The main test sites for such research are located in China, Iceland, Japan, the Russian Federation, Taiwan, and the USA. The present state of the art about the most relevant scientific achievements has been described. Future research trends and possible development paths have been identified and allow for possible improvements in policies oriented to seismic hazard reduction by geofluid monitoring.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Targeting the interaction between tumor suppressor p53 and the E3 ligase MDM2 represents an attractive treatment approach for cancers with wild-type or functional TP53. Indeed, several small ...molecules have been developed and evaluated in various malignancies. We provide an overview of MDM2 inhibitors under preclinical and clinical investigation, with a focus on molecules with ongoing clinical trials, as indicated by (
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Oral use of the selective FLT3 kinase inhibitor gilteritinib in patients who had relapsed or refractory acute myeloid leukemia with
FLT3
mutations led to a median overall survival of 9.3 months (vs. ...5.6 months with standard chemotherapy) and complete remission with full or partial hematologic recovery in 34.0% of patients (vs. 15.3%).
TARGETED THERAPY IN AML TREATMENT Martinelli, Giovanni
Hematology, Transfusion and Cell Therapy,
November 2021, 2021-11-00, 2021-11-01, Volume:
43
Journal Article
Peer reviewed
Open access
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Among adults with relapsed acute lymphoblastic leukemia, treatment with the anti-CD22 drug conjugate inotuzumab ozogamicin produced a higher rate of complete remission, as well as a higher rate of ...veno-occlusive disease, than did standard chemotherapy.
An estimated 2650 adults in the United States received a new diagnosis of acute lymphocytic leukemia (ALL) in 2015; the prognosis for these patients remains poor.
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Current therapies for adults with newly diagnosed B-cell ALL are associated with rates of complete remission of 60 to 90%.
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However, many of the patients with complete remission will have a relapse, and only approximately 30 to 50% will have disease-free survival lasting 3 years or longer.
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Current standard chemotherapy regimens for adults with relapsed or refractory B-cell ALL are associated with rates of complete remission of 31 to 44% when they . . .
The inhibition of the DNA damage response (DDR) pathway in the treatment of cancer has recently gained interest, and different DDR inhibitors have been developed. Among them, the most promising ones ...target the WEE1 kinase family, which has a crucial role in cell cycle regulation and DNA damage identification and repair in both nonmalignant and cancer cells. This review recapitulates and discusses the most recent findings on the biological function of WEE1/PKMYT1 during the cell cycle and in the DNA damage repair, with a focus on their dual role as tumor suppressors in nonmalignant cells and pseudo-oncogenes in cancer cells. We here report the available data on the molecular and functional alterations of WEE1/PKMYT1 kinases in both hematological and solid tumors. Moreover, we summarize the preclinical information on 36 chemo/radiotherapy agents, and in particular their effect on cell cycle checkpoints and on the cellular WEE1/PKMYT1-dependent response. Finally, this review outlines the most important pre-clinical and clinical data available on the efficacy of WEE1/PKMYT1 inhibitors in monotherapy and in combination with chemo/radiotherapy agents or with other selective inhibitors currently used or under evaluation for the treatment of cancer patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Aneuploidy: Cancer strength or vulnerability? Simonetti, Giorgia; Bruno, Samantha; Padella, Antonella ...
International journal of cancer,
1 January 2019, Volume:
144, Issue:
1
Journal Article
Peer reviewed
Open access
Aneuploidy is a very rare and tissue‐specific event in normal conditions, occurring in a low number of brain and liver cells. Its frequency increases in age‐related disorders and is one of the ...hallmarks of cancer. Aneuploidy has been associated with defects in the spindle assembly checkpoint (SAC). However, the relationship between chromosome number alterations, SAC genes and tumor susceptibility remains unclear. Here, we provide a comprehensive review of SAC gene alterations at genomic and transcriptional level across human cancers and discuss the oncogenic and tumor suppressor functions of aneuploidy. SAC genes are rarely mutated but frequently overexpressed, with a negative prognostic impact on different tumor types. Both increased and decreased SAC gene expression show oncogenic potential in mice. SAC gene upregulation may drive aneuploidization and tumorigenesis through mitotic delay, coupled with additional oncogenic functions outside mitosis. The genomic background and environmental conditions influence the fate of aneuploid cells. Aneuploidy reduces cellular fitness. It induces growth and contact inhibition, mitotic and proteotoxic stress, cell senescence and production of reactive oxygen species. However, aneuploidy confers an evolutionary flexibility by favoring genome and chromosome instability (CIN), cellular adaptation, stem cell‐like properties and immune escape. These properties represent the driving force of aneuploid cancers, especially under conditions of stress and pharmacological pressure, and are currently under investigation as potential therapeutic targets. Indeed, promising results have been obtained from synthetic lethal combinations exploiting CIN, mitotic defects, and aneuploidy‐tolerating mechanisms as cancer vulnerability.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Deregulated activity of BCR-ABL1, a nonreceptor tyrosine kinase encoded by the fusion gene resulting from the t(9;22)(q34;q11) chromosomal translocation, is thought to be the driver event responsible ...for initiation and maintenance of chronic myeloid leukemia (CML). BCR-ABL1 was one of the first tyrosine kinases to be implicated in a human malignancy and the first to be successfully targeted. Imatinib mesylate, the first tyrosine kinase inhibitor (TKI) to be approved for therapeutic use, was hailed as a magic bullet against cancer and remains one of the safest and most effective anticancer agents ever developed. Second- and third-generation TKIs were later introduced to prevent or counteract the problem of drug resistance, that may arise in a small proportion of patients. They are more potent molecules, but have been associated to more serious side effects and complications. Patients achieving stable optimal responses to TKI therapy are predicted to have the same life expectancy of the general population. However, TKIs do not 'cure' CML. Only a small proportion of cases may attempt therapy discontinuation without experiencing subsequent relapse. The great majority of patients will have to assume TKIs indefinitely - which raises serious pharmacoeconomic concerns and is now shifting the focus from efficacy to compliance and quality of life issues. Here we retrace the steps that have led from the biological acquisitions regarding BCR-ABL1 structure and function to the development of inhibitory strategies and we discuss drug resistance mechanism and how they can be addressed.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Earthquake precursors are elusive, and this elusiveness has hampered earthquake prediction. In this paper, the available catalogues of historical and contemporary geochemical and fluid-related ...precursors of earthquakes are considered.
The locations of recording sites are mapped and compared with data concerning volcanic locations, heat flows, crustal velocities and the depth of seismic events. Possible relations among the considered geophysical parameters and the occurrence of fluid-related earthquake precursors are discussed. Only some geological and geophysical conditions may allow for the occurrence of fluid-related earthquake precursory phenomena. As a consequence, the geophysical models utilized to explain the occurrence of earthquake precursors should be updated. Furthermore, only some areas of the world are deemed suitable for earthquake fluid-related precursor monitoring.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Chronic myeloid leukemia (CML) is caused by BCRABL1 in a cell with the biological potential, intrinsic or acquired, to cause leukemia. This cell is commonly termed the CML leukemia stem cell (LSC). ...In humans a CML LSC is operationally-defined by ≥1 in vitro or in vivo assays of human leukemia cells transferred to immune-deficient mice. Results of these assays are sometimes discordant. There is also the unproved assumption that biological features of a CML LSC are stable. These considerations make accurate and precise identification of a CML LSC difficult or impossible. In this review, we consider biological features of CML LSCs defined by these assays. We also consider whether CML LSCs are susceptible to targeting by tyrosine kinase inhibitors (TKIs) and other drugs, and whether elimination of CML LSCs is needed to achieve therapy-free remission or cure CML.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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