bluuebunny/crossref_metadata_2025_split huggingface dataset:
A sex difference in the composition of the rodent postsynaptic density
Authors: Mastro Tara L. , Preza Anthony , Basu Shinjini , Chattarji Shona , Till Sally M. , Kind Peter , Kennedy Mary B. 
Published: October 2019

AbstractSynGAP is a postsynaptic density (PSD) protein that binds to PDZ domains of the scaffold protein PSD-95. We previously reported that heterozygous deletion of synGAP in mice is correlated with increased steady-state levels of other key PSD proteins that bind PSD-95, although the level of PSD-95 remains constant (Walkup et al., 2016). For example, the ratio to PSD-95 of Transmembrane AMPA-Receptor-associated Proteins (TARPs), which mediate binding of AMPA-type glutamate receptors to PSD-95, was increased in young synGAP+/- mice. Here we show that a highly significant increase in TARP in the PSDs of young synGAP+/- rodents is present only in females and not in males. The data reveal a sex difference in the adaptation of the PSD scaffold to synGAP heterozygosity.
Development of a calcified odontogenic hamartoma following avulsion of a permanent central incisor
Authors: Procópio Stefânia Werneck , Matos Hiorran Coelho de Almeida , de Oliveira Pedro Lima Emmerich , de Andrade Bruno Augusto Benevenuto , Agostini Michelle , Esteves Jonatas Caldeira , de Campos Paulo Ricardo Barros , de Souza Margareth Maria Gomes , Maia Lucianne Cople 
Published: October 2019

AbstractThe avulsion of a permanent immature tooth is a serious condition and a real emergency in dentistry. The management of a traumatized avulsed tooth is always a challenge to the clinician. This case report concerns the development of a calcified odontogenic hamartoma after the avulsion of an immature central incisor in an eight‐year‐old female. The patient presented for the treatment four months after the avulsion. Her intraoral examination showed complete healing of the area but an atypical appearance of the alveolar area of the missing tooth was observed in the periapical radiograph. A new radiographic scan performed six months later revealed the formation of a radiopaque irregular structure at the cervical level of the alveolar ridge at the site of the missing tooth. Surgical removal was performed, and the histopathological examination revealed a hamartomatous proliferation of odontogenic tissue with calcification. After healing, the lateral incisor was orthodontically moved mesially and restored to resemble the central incisor. An orthodontic device was installed to improve function and aesthetics of the patient.
Outcomes of treatment with dose‐adjusted EPOCH‐R or R‐CHOP in primary mediastinal large B‐cell lymphoma
Authors: Malenda Agata , Kołkowska‐Leśniak Agnieszka , Puła Bartosz , Długosz‐Danecka Monika , Chełstowska Monika , Końska Agnieszka , Giza Agnieszka , Lech‐Marańda Ewa , Jurczak Wojciech , Warzocha Krzysztof 
Published: October 2019

AbstractBackgroundThe standard first‐line treatment for primary mediastinal B‐cell lymphoma (PMBCL) patients is rituximab‐based immunochemotherapy; however, this is not due to the result of randomized clinical trials.AimsWe retrospectively investigated 53 PMBCL patient outcomes treated either with R‐CHOP‐21 or DA‐EPOCH‐R‐28. The primary endpoint was overall survival (OS). Secondary endpoints were complete remission (CR), overall response rate (ORR), progression‐free survival (PFS), and treatment‐related complications.ResultsTreatment with R‐CHOP‐21 resulted in a 92.0% ORR (60% CR), while DA‐EPOCH‐R yielded a 92.6% ORR (70.4% CR). There were no differences in the occurrence of grade 3‐4 hematological adverse events, but grade 1‐2 cardiologic complications (P = .003) were observed more frequently in the DA‐EPOCH‐R arm. Median PFS and OS were not achieved. The differences in estimated 12‐month PFS in R‐CHOP and DA‐EPOCH‐R group (87% vs 73.9%) and OS (100% vs 92%) were insignificant. Patients treated with R‐CHOP‐21 and autologous hematopoietic stem cell transplantation (auto‐HSCT) had an improved OS (P = .03) but not PFS (P = .43) compared to those treated solely with R‐CHOP‐21. No differences in PFS or OS were observed between patients treated with R‐CHOP‐21/auto‐HSCT and DA‐EPOCH‐R.ConclusionThe results of this study suggest that R‐CHOP‐21 may be an alternative to DA‐EPOCH‐R treatment for PMBCL patients.
Experiences from Southeast Asia on nursing education, practice, mobility and influencing policy
Authors: Kunaviktikul W. , Turale S. , Petrini M.A. , Tungpunkom P. , Avant K.C. 
Published: October 2019

In this report from the field, we describe the challenges and opportunities for nursing practice and education, and ways to improve nurse mobility across Asia. We also explain the collaboration within the Southeast and East Asian Nursing Education and Research Network to influence policy development and review.The collaborative process was supported by evidence drawn from discussions at Network meetings, and with nursing and other leaders, an examination of literature and policy documents, and member surveys. We reviewed the region’s regulatory statutes which all support diversity in the nursing workforce.The Southeast Asian Nursing Education and Research Network was established in 2015 to support policy development around the upgrading of nurse education, clinical competencies and research capacity, in hospital and primary health care; and facilitating the movement of nurses across national boundaries. Most countries have tried to address policy gaps and their efforts to implement changes are seen in policy expansion and development at the national level.We focus on two policies from the Association of Southeast Asian Nations from 2006 and 2012, that cover nurse mobility, information exchange, nurse capacity building and education and mutual professional recognition of nurses’ credentials. However, we found significant variances in education, regulatory policies and clinical competencies that have restricted, and continue to restrict policy implementation.Nursing in South‐East Asia has made significant progress in upgrading standards for education by increasing bachelor degree bridging programs, master and doctoral degrees. Participating countries have passed legislation on licensure, competencies and credentialing of internationally qualified nurses wishing to practice in various contexts. However, much work remains to be done.Implications for nursing policy, education and practiceGoverning bodies determine entry into practice law which requires dialogue to enhance policies for domestic and international practitioners for mutual exchange and recognition. Nursing practice and education are under government regulatory bodies but require new policies and laws to ensure adequate educational requirements for safe quality practice.
Archives of a small planet: The significance of museum collections and museum-based research in invertebrate taxonomy*
Authors: WINSTON JUDITH E. 
Published: October 2019

Museum natural science collections are valuable, in many cases irreplaceable, and vital to research in many disciplines including taxonomy. Since 96% of known multicellular animals belong to one or another of the 34 invertebrate phyla, the value of those collections for invertebrate taxonomy (of both living and fossil taxa) is even higher. Systematic work that does not rely on museum specimens to verify or falsify the identities of the taxa studied is not science. Whether the techniques used are molecular or morphological, high tech analysis, or careful observation, systematics is the primary and most essential use of museum invertebrate collections. Their value and the case for their support for this primary and many other compelling reasons has been argued eloquently time after time, yet support still lags far behind needs.
Pre-Transplant Variables Affecting the Outcome of Submyeloablative Allogeneic HSCT in Uniformly Treated Patients with Hematologic Malignancies.
Authors: Mehta Jayesh , Singhal S. , Tallman M. , Williams S. , Winter J. , Evens A. , Grinblatt D. , Kaminer L. , Gordon L. 
Published: October 2019

Abstract
The outcome of 63 consecutive submyeloablative allografts (27–66 y, median 52) performed for hematologic malignancies after 100 mg/m2 melphalan without (n=21; prior autograft) or with (n=42; no prior autograft) 50 mg/kg cyclophosphamide was analyzed to study the effect of pre-transplant characteristics. GVHD prophylaxis comprised cyclosporine-mycophenolate (n=37; HLA-identical sibling donors) or tacrolimus-mycophenolate (n=26, 1-locus mismatched sibling or 9–10/10 allele-matched unrelated). No growth factors were administered routinely post-transplant and supportive care was uniform. 14 patients experienced transplant-related mortality (TRM), and 32 relapsed. 24 relapsing patients died, and 7 of the other 8 are alive in CR or with declining disease. The following factors were analyzed in a Cox model for their effect on TRM and relapse: chemosensitive (n=25) vs refractory disease (n=38), age ≤55 (n=44) vs >55 (n=19), normal (n=32) vs abnormal (n=31) LDH, HLA match (n=56) vs mismatch (n=7), prior autograft or not, performance status 0–1 (n=47) vs 2–3 (n=16).
Outcome Favorable factor RR (95% CI) P TRM Age ≤55 0.20 (0.04–0.86) 0.03 HLA matched 0.21 (0.05–0.89) 0.04 Performance status 0-1 0.25 (0.06–0.99) 0.05 Relape Chemosensitive disease 0.28 (0.11–0.73) 0.01 Fig 1 shows TRM for patients with 0, 1 or 2 high-risk factors for TRM. Fig 1 shows TRM for patients with 0, 1 or 2 high-risk factors for TRM. Fig 2 shows overall survival (OS) for patients with 0 or 1 high-risk factors for TRM by disease chemosensitivity. Fig 2 shows overall survival (OS) for patients with 0 or 1 high-risk factors for TRM by disease chemosensitivity.
Table 2 shows the causes of death by risk factors for TRM and disease chemosensitivity.
Group (n) Alive TRM Death from disease A: 2 risk factors for TRM (7) 1 (14%) 5 (71%) 1 (14%) B: 1 risk factor for TRM + Refractory (19) 2 (11%) 6 (32%) 11 (58%) C: 1 risk factor for TRM + Sensitive (9) 5 (56%) 1 (11%) 3 (33%) D: 0 risk factor for TRM + Refractory (12) 3 (25%) 1 (8%) 8 (67%) E: 0 risk factor for TRM + Sensitive (16) 13 (81%) 1 (6%) 2 (13%)
These data suggest that while the current treatment approach is optimal for patients falling in Group E, modified approaches are needed for other patients. Based on the causes of failure, the following modifications appear to be warranted. Group A: A completely non-ablative regimen to reduce toxicity. Group B: A completely non-ablative regimen to reduce toxicity with augmentation of graft-vs-tumor effects by elective donor leukocyte infusions and/or abbreviated immunosuppression. Group C: Augmentation of graft-vs-tumor effects by elective donor leukocyte infusions and/or abbreviated immunosuppression. Group D: Conventional-intensity rather than reduced-intensity allogeneic HSCT.
Thalidomide and Dexamethasone Is an Effective Salvage Regimen for Myeloma Patients Relapsing after Autologous Transplant.
Authors: Palumbo Antonio , Falco Patrizia , Ambrosini Maria Teresa , Caravita Tommaso , Musto Pellegrino , Petrucci Maria Teresa , Pregno Patrizia , Avonto Ilaria , Bertola Alessandra , Bringhen Sara , Cavallo Federica , Ciccone Giovannino , Boccadoro Mario 
Published: October 2019

Abstract
PURPOSE: High-dose therapy followed by autologous stem cell transplantation (AT) is the standard treatment for newly diagnosed multiple myeloma patients. Which is the best treatment option for patients relapsing after AT has not been defined. To address this issues the efficacy of Thalidomide and Dexamethasone (TD), AT and Conventional Chemotherapy (CC) was evaluated.
MATERIALS AND METHODS: We retrospective analysed the outcome of 90 multiple myeloma patients, median age 61, range 34–77, who received a first salvage treatment between January 1999 and September 2003. All patients received AT at diagnosis. Relapse was defined as introduction of therapeutic modality that was different from maintenance treatment.
After a median time from diagnosis of 32 months, 43 patients were treated with TD (Thalidomide 100 mg/day associated with DEX 40 mg on days 1-4 each month), after a median time from diagnosis of 29 months, 28 patients were treated at first relapse with AT (86% single MEL100, 11% double MEL100, 4% single MEL200), and after a median time from diagnosis of 32 months, 19 patients were treated with CC (32% Doxorubicin, Cyclophosphamide, Etoposide, Cisplatinum combination chemotherapy, 26% Doxorubicin containing regimens, 26% Cyclophosphamide containing regimens, 11% other therapies).
Data were analysed when the median follow-up from the start of salvage TD was 30 months (range 4.5–45), from the start of salvage AT was 18 months (range 3.5–24) and from the start of salvage CC was 21 months (range 2–19.5).
End points of the study were response, progression free survival (PFS) from first relapse and overall survival (OS) from first relapse and from diagnosis.
RESULTS: Patients characteristics were similar among different groups. At relapse the response rate after TD was: 19% near complete remission (nCR) (absence of M-Protein detected by electrophoresis), 28% partial response (PR) (M-Protein reduction 50–99%), 35% stable disease (SD) (M-Protein reduction 0–49%) and 19% progressive disease (PD). After AT was: 11% nCR, 71% PR, 11% SD, 7% PD; and after CC was: 16% PR, 32% SD and 53% PD. Response rate was significantly lower for patients receiving salvage CC in comparison with AT and TD (p<0.001).
The median PFS from relapse was 20.3 months for TD, 9 months for AT and 4.5 months for CC (p<0.001). The OS from relapse at 50 months was 58% for TD, 13% for AT and 21% for CC (p = 0.008). The median OS from diagnosis was 116.34 months for TD, 41.3 months for AT and 59.5 months for CC (p<0.001).
The multivariate analysis indicates that TD, β2 microglobulin and age were the only independent risk factors associated with improved outcome.
CONCLUSION: In conclusion, TD improved PFS and OS in myeloma patients relapsing after autologous transplant.
A Novel Orally Available Proteasome Inhibitor NPI-0052 Induces Killing in Multiple Myeloma (MM) Cells Resistant to Conventional and Bortezomib Therapies.
Authors: Chauhan Dharminder , Li Guilan , Podar Klaus , Hideshima Teru , Shrigarpure Reshma , Catley Laurence , Mitsiades Constantine , Munshi Nikhil , Sclossman Robert , Bahjat Rena , Neuteboom Saskia , Richardson Paul , Palladino Michael , Anderson Kenneth C. 
Published: October 2019

Abstract
The recent success of bortezomib/proteasome inhibitor PS-341 (VelcadeTm) provides evidence that proteasome inhibitors can be safely utilized clinically. Specifically, bortezomib is currently being used to treat MM patients (pts) who have relapsed after initial therapy and refractory to current therapy and is under evaluation for treatment of newly diagnosed pts. Although bortezomib kills MM cells, prolonged exposure is associated with attendant toxicity and development of bortezomib-resistance. Here we show that a novel non-peptide proteasome inhibitor NPI-0052 triggers apoptosis even in bortezomib-resistant patient MM cells, without affecting the viability of normal cells. NPI-0052 overcomes MM cell-resistance to conventional therapies including melphalan (LR5), doxorubicin (Dox-40), dexamethasone (MM.1R, U266, RPMI-8226) and retains its anti-tumor activity in cells harboring two major mechanisms of drug-resistance: overexpression of P-glycoprotein and altered topoisomerase-II activity. Importantly, NPI-0052, like bortezomib, blocks MM cell growth induced by both adhesion to bone marrow stromal cells (BMSCs) and related cytokine secretion, thereby depriving MM cells of the growth and survival advantage conferred by the BM microenvironment. Moreover, NPI-0052-triggers MM cells apoptosis despite the presence of interleukin-6 or insulin-like growth factor-1 (IGF-1), two major growth and anti-apoptotic factors for MM cells. NPI-0052 also overcomes the cytoprotective effects of anti-apoptotic proteins Bcl2 and Hsp27, as well as NF-kB-mediated growth/survival, and drug-resistance in MM cells. Initial in vivo studies in animal models using either oral or intravenous administration have established the maximum tolerated dose (MTD) based on the whole blood proteasome activity. NPI-0052 decreased proteasome activity in packed whole blood lysates in a dose dependent fashion, and these data also suggest that NPI-0052 is orally active. The mechanisms whereby NPI-0052-trigger MM cell death includes: loss of mitochondrial membrane potential; Superoxide generation; release of mitochondrial proteins cytochrome-c/Smac; and activation of caspase-8/9/3. Conversely, the pan caspase inhibitor Z-VAD-fmk abrogates NPI-0052-induced apoptosis. Finally, combining NPI-0052 and bortezomib triggers synergistic apoptosis. Together, these findings provide the framework for clinical evaluation of NPI-0052, either alone or in combination with bortezomib, to inhibit tumor cell growth, reduce bortezomib-related toxicity, overcome bortezomib-resistance, and improve patient outcome in MM.
Cell Proliferation Induced by the NPM-ALK Fusion Tyrosine Kinase of Anaplastic Large Cell Lymphoma Is Mediated by mTOR/S6K1 and MEK/ERK Signaling.
Authors: Amaravadi Ravi K. , Haq Naznin , Morris Stephan W. , Gilliland D. Gary , Sternberg David W. 
Published: October 2019

Abstract
The nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion is the product of the t(2;5)(p23;q35) chromosomal translocation found in approximately half of anaplastic large cell lymphomas (ALCL). Moreover, this fusion kinase, as well as other ALK fusion proteins, have been found in large B-cell lymphomas. This fusion kinase has been shown to regulate multiple signal transduction pathways and to induce hematopoietic malignancy in murine models. Nonetheless, the functional role of signaling events caused by NPM-ALK expression is incompletely understood. Here we report that NPM-ALK activates the kinase S6K1 (p70/p85) and the extracellular regulated kinase (ERK1/2). In Ba/F3 murine hematopoietic cells that express NPM-ALK, S6K1 activition by NPM-ALK was sensitive to mTOR inhibition by rapamycin. However, treatment of NPM-ALK-Ba/F3 cells with the MEK inhibitor UO126 did not attenuate the activation of S6K1 by NPM-ALK. Pharmacological inhibition of either mTOR or MEK in Ba/F3 cells expressing NPM-ALK resulted in impaired cytokine-independent outgrowth of these cells. For either inhibitor, suppression of cytokine-independent outgrowth was due to impairment of cell proliferation. In contrast, cell survival signaling was not compromised by either inhibitor alone or in combination. Combined inhibition of both the mTOR/S6K1 and MEK/ERK signaling modules resulted in an additive impairment of cytokine-independent outgrowth. Moreover, rapamycin attenuated the proliferation of the human NPM-ALK-expressing ALCL cell line Karpas299. The mTOR/S6K1 and MEK/ERK signaling modules may serve as effective chemotherapeutic targets in the treatment of ALCL and other malignancies that express the activated ALK protein tyrosine kinase.
Functional Analysis of Leukemia-Associated PTPN11 Mutations in Primary Hematopoietic Cells.
Authors: Schubbert Suzanne , Lieuw Kenneth , Rowe Sara L. , Lee Connie M. , Li XiaXin , Loh Mignon , Clapp D. Wade , Shannon Kevin 
Published: October 2019

Abstract
The PTPN11 gene encodes SHP-2, a non-receptor protein tyrosine phosphatase (PTPase) that relays signals from activated growth factor receptors to p21ras (Ras), Src family kinases, and other signaling molecules. Germ-line, missense mutations in PTPN11 account for approximately 50% of cases of the human developmental disorder Noonan Syndrome (NS). More recently, PTPN11 mutations have been identified in approximately 35% of children with juvenile myelomonocytic leukemia (JMML) without NS and have also been detected in other lymphoid and myeloid malignancies. Interestingly, almost all of these leukemia-associated mutations introduce amino acid substitutions within the N-SH2 domain of SHP-2 that are largely distinct from those found in NS. We have assessed the functional consequences of leukemia-associated PTPN11 mutations in primary hematopoietic cells. Expression of an E76K mutant SHP-2 in murine fetal liver and bone marrow cells confers a hypersensitive pattern of colony-forming unit granulocyte-macrophage (CFU-GM) colony growth in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3). Specifically, cells expressing E76K mutant SHP-2 display enhanced colony growth at low concentrations of growth factor compared to cells expressing wild-type (WT) SHP-2 protein. Mutant colonies are significantly larger with an abnormal, spreading morphology. E76K-expressing cells also form CFU-GM colonies in the absence of growth factor. The catalytic activity of the E76K mutant is required for aberrant colony growth as expressing the E76K mutation in the context of defective phosphatase activity (C463S) abolishes hypersensitive CFU-GM growth. Mutant E76K expression also enhances the growth of immature progenitor cells with high repopulating potential (HPP-CFC and LPP-CFC) in response to GM-CSF and IL-3 and perturbs erythroid progenitor colony growth. In addition, expressing the E76K mutation results in more pronounced growth factor hypersensitivity than another leukemia-associated SHP-2 mutation (D61Y), and both of these mutations confer a stronger hematopoietic phenotype than the common N308S substitution found in patients with NS.
Selective Rapid B-Cell Depletion In Vivo by Pharmacologic IKK2 Inhibition.
Authors: Fraser Christopher C. , Nagashima Kumiko , Sasseville Vito , Deeds Jim , McDonald Alice , Simpson Chris , Xu Yajun 
Published: October 2019

Abstract
Studies using genetically deficient mice have revealed that members of the NF-kB family play key roles in B-cell development. IKK2 which activates NF-kB by targeting degradation of IkB, is also required for B-cell development. We have studied the role of IKK2 in hematopoiesis using a chemical specific inhibitor (ML120B). Mice given daily oral dosing of ML120B for 4 days had severe B-cell depletion in spleen and bone marrow. B-cells at all stages (pro-B, pre-B, immature and mature B) were depleted 10 fold in the bone marrow while granulocyte numbers were largely unaffected. IKK2 inhibition in vivo showed selective sensitivity of B-cell progenitors (4 fold decrease) in the marrow compared to myeloid progenitors which were unaffected at an equivalent dose. Foci of cells with an apoptotic morphology were visible in bone marrow and spleen within 6 hours of a single oral dose. Apoptotic cells detected by labeling fragmented DNA were increased within splenic follicles (6 fold) and bone marrow. Also an increase in B220+ / annexin V+ cells and a decrease in pre-B (B220+/IgM−) cells in the marrow were observed. RNA expression studies in the marrow 6 hours after a single oral dose revealed a decrease in IL-7 and increased GM-CSF expression. Image analysis of B220 in spleens within 18 hours of a single dose of an IKK inhibitor revealed decreased follicle size. In order to evaluate hematopoietic progenitor sensitivity to NF-kB inhibition, dose responses to ML120B, panepoxydone (PPD) and proteasome inhibitor Lactacystin (Lcyst) were evaluated in B-cell and myeloid bone marrow colony assays. Inhibitors PPD and Lcyst were more effective at inhibiting B-cell colony growth than myeloid colony growth. In summary, pharmacologic inhibition of IKK2 results in a rapid induction of apoptosis with preferential depletion of B-cells and retention of myeloid cells and progenitors within the bone marrow.