Parkinson's disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal pathway, where patients do not manifest motor symptoms until >50% of neurons are lost. Thus, it is of ...great importance to determine early neuronal changes that may contribute to disease progression. Recent attention has focused on lipids and their role in pro- and anti-apoptotic processes. However, information regarding the lipid alterations in animal models of PD is lacking. In this study, we utilized high performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) and novel HPLC solvent methodology to profile phosphatidylcholines and sphingolipids within the substantia nigra. The ipsilateral substantia nigra pars compacta was collected from rats 21 days after an infusion of 6-hydroxydopamine (6-OHDA), or vehicle into the anterior dorsal striatum. We identified 115 lipid species from their mass/charge ratio using the LMAPS Lipid MS Predict Database. Of these, 19 lipid species (from phosphatidylcholine and lysophosphotidylcholine lipid classes) were significantly altered by 6-OHDA, with most being down-regulated. The two lipid species that were up-regulated were LPC (16:0) and LPC (18:1), which are important for neuroinflammatory signalling. These findings provide a first step in the characterization of lipid changes in early stages of PD-like pathology and could provide novel targets for early interventions in PD.
Midostaurin and gilteritinib are FLT3 inhibitors that have been recently approved for use in FLT3-mutant acute myeloid leukemia (AML). These approved drugs represent a new standard of care for ...patients with FLT3 mutations in both the first-line and salvage settings. The success of midostaurin used in combination with induction chemotherapy has prompted exploration of newer, more potent and targeted inhibitors (including gilteritinib) in the first-line setting in combination with chemotherapy. At the same time, the success of gilteritinib and other newer FLT3 inhibitors as monotherapy in the salvage setting has been tempered by the development of resistance because of diverse mechanisms. Investigational strategies that incorporate FLT3 inhibitors in combination with hypomethylating agents and as maintenance therapy after allogeneic stem cell transplantation have shown promise. Other novel combination strategies are also undergoing clinical investigation. In this article, we review the current landscape of approved and investigational FLT3 inhibitors in AML, including the current standard of care and investigational strategies.
The FLT3 receptor is overexpressed on the majority of acute myeloid leukemia (AML) blasts. Mutations in
are the most common genetic alteration in AML, identified in approximately one third of newly ...diagnosed patients.
internal tandem duplication mutations (
ITD) are associated with increased relapse and inferior overall survival. Multiple small molecule inhibitors of FLT3 signaling have been identified, two of which (midostaurin and gilteritinib) are currently approved in the United States, and many more of which are in clinical trials. Despite significant advances, resistance to FLT3 inhibitors through secondary
mutations, upregulation of parallel pathways, and extracellular signaling remains an ongoing challenge. Novel therapeutic strategies to overcome resistance, including combining FLT3 inhibitors with other antileukemic agents, development of new FLT3 inhibitors, and FLT3-directed immunotherapy are in active clinical development. Multiple questions regarding
mutated AML remain. In this review, we highlight several of the current most intriguing controversies in the field including the role of FLT3 inhibitors in maintenance therapy, the role of hematopoietic cell transplantation in
mutated AML, use of FLT3 inhibitors in
wild-type disease, significance of non-canonical
mutations, and finally, emerging concerns regarding clonal evolution.
DNA mismatch repair (MMR) increases replication fidelity by eliminating mispaired bases resulting from replication errors. In Saccharomyces cerevisiae, mispairs are primarily detected by the ...Msh2-Msh6 complex and corrected following recruitment of the Mlh1-Pms1 complex. Here, we visualized functional fluorescent versions of Msh2-Msh6 and Mlh1-Pms1 in living cells. We found that the Msh2-Msh6 complex is an S phase component of replication centers independent of mispaired bases; this localized pool accounted for 10%–15% of MMR in wild-type cells but was essential for MMR in the absence of Exo1. Unexpectedly, Mlh1-Pms1 formed nuclear foci that, although dependent on Msh2-Msh6 for formation, rarely colocalized with Msh2-Msh6 replication-associated foci. Mlh1-Pms1 foci increased when the number of mispaired bases was increased; in contrast, Msh2-Msh6 foci were unaffected. These findings suggest the presence of replication machinery-coupled and -independent pathways for mispair recognition by Msh2-Msh6, which direct formation of superstoichiometric Mlh1-Pms1 foci that represent sites of active MMR.
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► S. cerevisiae Msh2-Msh6 is present in DNA replication factory foci ► Lagging-strand DNA mismatch repair (MMR) preferentially requires Exo1 ► Msh2-Msh6 foci-independent MMR is preferentially dependent on Exo1 ► Pms1 foci are active in MMR and contain substoichiometric amounts of Msh2-Msh6
In vivo imaging reveals that two mismatch repair protein complexes involved in mismatch repair have distinct functions, as one recognizes mispaired bases and one mediates active repair. The recognition complex is coupled to the DNA replication machinery, facilitating the detection of mismatches occurring during DNA synthesis.
The Pacific Decadal Oscillation, Revisited Newman, Matthew; Alexander, Michael A.; Ault, Toby R. ...
Journal of climate,
06/2016, Letnik:
29, Številka:
12
Journal Article
Recenzirano
The Pacific decadal oscillation (PDO), the dominant year-round pattern of monthly North Pacific sea surface temperature (SST) variability, is an important target of ongoing research within ...themeteorological and climate dynamics communities and is central to the work of many geologists, ecologists, natural resource managers, and social scientists. Research over the last 15 years has led to an emerging consensus: the PDO is not a single phenomenon, but is instead the result of a combination of different physical processes, including both remote tropical forcing and local North Pacific atmosphere–ocean interactions, which operate on different time scales to drive similar PDO-like SST anomaly patterns. How these processes combine to generate the observed PDO evolution, including apparent regime shifts, is shown using simple autoregressive models of increasing spatial complexity. Simulations of recent climate in coupled GCMs are able to capture many aspects of the PDO, but do so based on a balance of processes often more independent of the tropics than is observed. Finally, it is suggested that the assessment of PDO-related regional climate impacts, reconstruction of PDO-related variability into the past with proxy records, and diagnosis of Pacific variability within coupled GCMs should all account for the effects of these different processes, which only partly represent the direct forcing of the atmosphere by North Pacific Ocean SSTs.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Background We report a prospective randomized study comparing early clinical results between the direct anterior (DAA) and posterior approaches (PA) in primary hip arthroplasty. Methods ...Surgeries were performed by two senior hip arthroplasty surgeons. 72 patients with complete data were assessed pre-operatively, 2, 6 and 12 weeks post-operatively. The primary outcomes were the WOMAC and Oxford Hip Scores. Secondary outcome measures included the EuroQoL, 10 meter walk test, clinical and radiographic parameters. Results Data analyses showed no difference between DAA (n=35) and PA (n=37) groups when comparing total scores for primary outcomes. No significant differences were observed for 10 meter walk test, EuroQoL and radiographic analyses. Subgroup analysis for surgeon 1 identified that the DAA group had shorter acute hospital stay, less post-operative opiate requirements and smaller wounds. However, this was offset by increased operative time, higher intra-operative blood loss and weaker hip flexion at 2 and 6 weeks. Subgroup analysis of items on the WOMAC and OHS identified that hip flexion activity favoured the DAA group up to 6 weeks post-operatively. There was an 83% incidence of lateral cutaneous nerve of thigh neuropraxia at the 12 week mark in the DAA group. No neuropraxias occurred in the PA group. One dislocation occurred in each group. A single patient from the DAA group required reoperation for leg length discrepancy. Conclusion DAA THA has comparable results with PA THA. Choice of surgical approach for THA should be based on patient factors, surgeon preference and experience.
Old age and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukaemia are associated with early relapse and poor survival. Quizartinib is an ...oral, highly potent, and selective next-generation FLT3 inhibitor with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. We aimed to assess the efficacy and safety of single-agent quizartinib in patients with relapsed or refractory acute myeloid leukaemia.
We did an open-label, multicentre, single-arm, phase 2 trial at 76 hospitals and cancer centres in the USA, Europe, and Canada. We enrolled patients with morphologically documented primary acute myeloid leukaemia or acute myeloid leukaemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 into two predefined, independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukaemia within 1 year after first-line therapy (cohort 1), and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or haemopoietic stem cell transplantation (cohort 2). Patients with an FLT3-ITD allelic frequency of more than 10% were considered as FLT3-ITD positive, whereas all other patients were considered as FLT3-ITD negative. Patients received quizartinib once daily as an oral solution; the initial 17 patients received 200 mg per day but the QTcF interval was prolonged for more than 60 ms above baseline in some of these patients. Subsequently, doses were amended for all patients to 135 mg per day for men and 90 mg per day for women. The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete haematological recovery) and the proportion of patients who achieved a complete remission. Efficacy and safety analyses included all patients who received at least one dose of quizartinib (ie, the intention-to-treat population). Patients with a locally assessed post-treatment bone marrow aspirate or biopsy were included in efficacy analyses by response; all other patients were considered to have an unknown response. This study is registered with ClinicalTrials.gov, number NCT00989261, and with the European Clinical Trials Database, EudraCT 2009-013093-41, and is completed.
Between Nov 19, 2009, and Oct 31, 2011, a total of 333 patients were enrolled (157 in cohort 1 and 176 in cohort 2). In cohort 1, 63 (56%) of 112 FLT3-ITD-positive patients and 16 (36%) of 44 FLT3-ITD-negative patients achieved composite complete remission, with three (3%) FLT3-ITD-positive patients and two (5%) FLT3-ITD-negative patients achieving complete remission. In cohort 2, 62 (46%) of 136 FLT3-ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 12 (30%) of 40 FLT3-ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. Across both cohorts (ie, the intention-to-treat population of 333 patients), grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients were febrile neutropenia (76 23% of 333), anaemia (75 23%), thrombocytopenia (39 12%), QT interval corrected using Fridericia's formula (QTcF) prolongation (33 10%), neutropenia (31 9%), leucopenia (22 7%), decreased platelet count (20 6%), and pneumonia (17 5%). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (126 38% of 333; 76 treatment related), acute myeloid leukaemia progression (73 22%), pneumonia (40 12%; 14 treatment related), QTcF prolongation (33 10%; 32 treatment related), sepsis (25 8%; eight treatment related), and pyrexia (18 5%; nine treatment related). Notable serious adverse events occurring in less than 5% of patients were torsades de pointes (one <1%) and hepatic failure (two 1%). In total, 125 (38%) of 333 patients died within the study treatment period, including the 30-day follow-up. 18 (5%) patients died because of an adverse event considered by the investigator to be treatment related (ten 6% of 157 patients in cohort 1 and eight 5% of 176 in cohort 2.
Single-agent quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3-ITD mutations. These findings confirm that targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor is a promising clinical strategy to help improve clinical outcomes in patients with very few options. Phase 3 studies (NCT02039726; NCT02668653) will examine quizartinib at lower starting doses.
Ambit Biosciences/Daiichi Sankyo.
Innate lymphoid cells (ILCs) are increasingly appreciated as key regulators of tissue immunity. However, their role in human tissue homeostasis and disease remains to be fully elucidated. Here we ...characterize the ILCs in human skin from healthy individuals and from the inflammatory skin disease psoriasis. We show that a substantial proportion of IL-17A and IL-22 producing cells in the skin and blood of normal individuals and psoriasis patients are CD3-negative innate lymphocytes. Deep immunophenotyping of human ILC subsets showed a statistically significant increase in the frequency of circulating NKp44+ ILC3 in the blood of psoriasis patients compared with healthy individuals or atopic dermatitis patients. More than 50% of circulating NKp44+ ILC3 expressed cutaneous lymphocyte–associated antigen, indicating their potential for skin homing. Analysis of skin tissue revealed a significantly increased frequency of total ILCs in the skin compared with blood. Moreover, the frequency of NKp44+ ILC3 was significantly increased in non-lesional psoriatic skin compared with normal skin. A detailed time course of a psoriasis patient treated with anti–tumor necrosis factor showed a close association between therapeutic response, decrease in inflammatory skin lesions, and decrease of circulating NKp44+ ILC3. Overall, data from this initial observational study suggest a potential role for NKp44+ ILC3 in psoriasis pathogenesis.
The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory
-mutated (
) acute myeloid leukemia (AML) but seldom reduces
burden or induces sustained ...efficacy. Gilteritinib combines synergistically with the BCL-2 inhibitor venetoclax in preclinical models of
AML.
This phase Ib open-label, dose-escalation/dose-expansion study (ClinicalTrials.gov identifier: NCT03625505) enrolled patients with
wild-type and
(escalation) or
(expansion) relapsed/refractory AML. Patients received 400 mg oral venetoclax once daily and 80 mg or 120 mg oral gilteritinib once daily. The primary objectives were safety, identification of the recommended phase II dose, and the modified composite complete response (mCRc) rate (complete response CR + CR with incomplete blood count recovery + CR with incomplete platelet recovery + morphologic leukemia-free state) using ADMIRAL phase III-defined response criteria.
Sixty-one patients were enrolled (n = 56
); 64% (n = 36 of 56) of
patients had received prior FLT3 inhibitor therapy. The recommended phase II dose was 400 mg venetoclax once daily and 120 mg gilteritinib once daily. The most common grade 3/4 adverse events were cytopenias (n = 49; 80%). Adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively. The mCRc rate for
patients was 75% (CR, 18%; CR with incomplete blood count recovery, 4%; CR with incomplete platelet recovery, 18%; and morphologic leukemia-free state, 36%) and was similar among patients with or without prior FLT3 inhibitor therapy (80%
67%, respectively). The median follow-up was 17.5 months. The median time to response was 0.9 months, and the median remission duration was 4.9 months (95% CI, 3.4 to 6.6).
molecular response (< 10
) was achieved in 60% of evaluable mCRc patients (n = 15 of 25). The median overall survival for
patients was 10.0 months.
The combination of venetoclax and gilteritinib was associated with high mCRc and
molecular response rates regardless of prior FLT3 inhibitor exposure. Dose interruptions were needed to mitigate myelosuppression.
Critical evaluation of online health information has always been central to consumer health informatics. However, with the emergence of new Web media platforms and the ubiquity of social media, the ...issue has taken on a new dimension and urgency. At the same time, many established existing information quality evaluation guidelines address information characteristics other than the content (eg, authority and currency), target information creators rather than users as their main audience, or do not address information presented via novel Web technologies.
The aim of this formative study was to (1) develop a methodological approach for analyzing health-related Web pages and (2) apply it to a set of relevant Web pages.
This qualitative study analyzed 25 type 2 diabetes pages, which were derived from the results of a Google search with the keywords "diabetes," "reversal," and "natural." The coding scheme, developed via a combination of theory- and data-driven approaches, includes 5 categories from existing guidelines (resource type, information authority, validity of background information sources, objectivity, and currency) and 7 novel categories (treatment or reversal method, promises and certainty, criticisms of establishment, emotional appeal, vocabulary, rhetoric and presentation, and use of science in argumentation). The coding involves both categorical judgment and in-depth narrative characterization. On establishing satisfactory level of agreement on the narrative coding, the team coded the complete dataset of 25 pages.
The results set included "traditional" static pages, videos, and digitized versions of printed newspapers or magazine articles. Treatments proposed by the pages included a mixture of conventional evidence-based treatments (eg, healthy balanced diet exercise) and unconventional treatments (eg, dietary supplements, optimizing gut flora). Most pages either promised or strongly implied high likelihood of complete recovery. Pages varied greatly with respect to the authors' stated background and credentials as well as the information sources they referenced or mentioned. The majority included criticisms of the traditional health care establishment. Many sold commercial products ranging from dietary supplements to books. The pages frequently used colloquial language. A significant number included emotional personal anecdotes, made positive mentions of the word cure, and included references to nature as a positive healing force. Most pages presented some biological explanations of their proposed treatments. Some of the explanations involved the level of complexity well beyond the level of an educated layperson.
Both traditional and data-driven categories of codes used in this work yielded insights about the resources and highlighted challenges faced by their users. This exploratory study underscores the challenges of consumer health information seeking and the importance of developing support tools that would help users seek, evaluate, and analyze information in the changing digital ecosystem.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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