bluuebunny/crossref_metadata_2025 huggingface dataset:
Fracture, Dissolution, and Cementation Events in Ordovician Carbonate Reservoirs, Tarim Basin, NW China
Authors: Baqués Vinyet , Ukar Estibalitz , Laubach Stephen E. , Forstner Stephanie R. , Fall András
Published: April 2020

Ordovician carbonate rocks of the Yijianfang Formation in the Tabei Uplift, Tarim Basin, contain deeply buried (>6000 m), highly productive oil and gas reservoirs associated with large cavities (>10 m). Previous workers inferred that large cavities are paleocaves (paleokarst) formed near the surface and subsequently buried. Alternately, caves may have formed by dissolution at depth along faults. Using 227 samples from 16 cores, we document textures and cement compositions bearing on cavity histories with petrographic, high-resolution scanning electron microscopy (SEM), isotopic, and fluid inclusion microthermometric observations. Results show that dissolution occurred at depth and was caused by (1) acidic fluids derived from Middle-Late Silurian and/or Devonian-Permian hydrocarbon generation and maturation, (2) high-temperature fluids, of which some were associated with Late Permian igneous activity, and (3) Mg-rich fluids that accompanied Jurassic-Cretaceous deformation and the formation of partially open fractures and stylobreccias (fault breccias). The relative paragenetic sequence of the structure-related diagenesis suggests seven stages of fracturing, dissolution, and cementation. Mottle fabrics in the Yijianfang Formation contain argillaceous carbonate-rich silt and are bioturbation features formed within the marine environment. Those mottled fabrics differ from clearly karstic features in the overlying Lianglitage Formation, which formed by near-surface dissolution and subsequent infilling of cavities by allochthonous sediment. Mottle fabrics are crosscut by compacted fractures filled with phreatic-vadose marine cements and followed by subsequent generations of cement-filled fractures and vugs indicating that some fractures and vugs became cement filled prior to later dissolution events. Calcite cements in fractures and vugs show progressively depleted values of δ18O documenting cement precipitation within the shallow (~220 m), intermediate (~625 m), and deep (~2000 m) diagenetic environments. Deep (mesogenetic) dissolution associated with fractures is therefore the principal source of the high porosity-permeability in the reservoir, consistent with other pieces of evidence for cavities localized near faults.
From ʿAlid Treatise to anti-Shiʿi Text: the Riṣāla fī ibṭāl bidaʿ munkarāt of ʿAbdallāh b. ʿUmar Bin Yaḥyā (d. 1265/1849) and its Afterlife in Indonesia
Authors: Alatas Ismail Fajrie
Published: April 2020

This article examines a little-known treatise on the commemoration of ʿĀshūrāʾ (the martyrdom of al-Ḥusayn, the grandson of the Prophet Muḥammad) written by a scholar from the Ḥaḍramawt, ʿAbdallāh b. ʿUmar Bin Yaḥyā (d. 1265/1849). Entitled Risāla fī ibṭāl bidaʿ munkarāt (Treatise on Nullifying Reprehensible Innovations), the text was composed in response to the ʿĀshūrāʾ commemorative processions introduced by South Asian Muslims in early nineteenth century Malay-Indonesian Archipelago and witnessed by the author during his travel there (1832-1835). In this treatise, Ibn Yaḥyā de fines a lawful, regulated, and emotionally restrained way of commemorating al-Ḥusayn’s martyrdom while stressing the imperative of ʿAlid leadership of the umma. I then discuss the recent resurfacing of a redacted summary of the Risāla in Indonesia. I show that in the context of an increasingly intense Sunni-Shiʿi sectarian contestation that characterized contemporary Indonesia, the redacted version of this ʿAlid treatise circulates as an anti-Shiʿi text.
International Investment Agreements and National Governance: The Case of Egypt
Authors: Raslan Reem Anwar Ahmed
Published: April 2020

The current international investment legal regime results from the interplay between international investment norms, embodied mainly in international investment agreements (IIAs), and the legal regime of the host country. This article will outline two major impacts IIAs can exert on national governance in Egypt: first, the domestic reform impact that refers to domestically initiated reform measures taken to compliment IIAs objectives, such as establishment of Economic Courts as well as limitation of third-party challenge of Investor–State contracts; and, second, the Supra-National Impact which involves situations where IIAs constrain the regulatory powers of the host state usually by imposing legal obligations that go beyond international standards, such as alternative dispute resolution (ADR) mechanisms as well as trade-related investment measures-plus (TRIMS-Plus) and trade-related aspects of intellectual property rights-plus (TRIPS-Plus) provisions. Understanding the profound effects of IIAs on national governance will beneficially inform policy makers when concluding IIAs.
Ragnhild’s Images: Migration, Settler Colonialism and Photography
Authors: Lien Sigrid
Published: April 2020

This article address photography’s embeddedness in histories of emigration and relocation. Photographs are integral pieces of life stories that take on new meanings as they circulate in history, while being told and retold. As catalysts of memories and postmemories they have the capacity to bring the hidden or difficult truths to the surface. This capacity is by no means limited to stories on the personal level. The article argues that settler immigrant’s family photographs may also have the potential to question the absence of indigenous peoples in histories of migration and settler colonialism. They may thus be considered as valuable tools in the process of contesting, ‘indigenizing’, and ultimately decolonizing these histories.
Mathematical Analysis of Roll Coating Process by Using Couple Stress Fluid
Authors: Zafar M. , Rana M.A. , Zahid M. , Malik M.A. , Lodhi M.S.
Published: April 2020

In this article, an incompressible isothermal model of a couple stress fluid between two rotating rolls is developed. Lubrication approximation theory is applied to simplify the flow equations. Exact solutions for velocity and pressure profiles are derived. Parameters of an industrial
interest like pressure, separating force, coating thickness, detachment point and power transmitted by the rolls to the fluid are computed numerically. It is observed that the flow parameter is a controlling parameter for an exiting coating thickness. As the problem is symmetric, only one
half of the geometry is considered.
Informal and formal social support during pregnancy and joint maternal and paternal postnatal depression: Data from the French representative ELFE cohort study
Authors: Nakamura Aurélie , Sutter-Dallay Anne-Laure , El-Khoury Lesueur Fabienne , Thierry Xavier , Gressier Florence , Melchior Maria , van der Waerden Judith
Published: April 2020

Background:

Insufficient social support has been intensively studied as a risk factor of postpartum depression (PPD) among mothers. However, to date, no study has examined the role of informal and formal dimensions of social support during pregnancy with regard to joint maternal and paternal depression after birth.

Aim:

Study associations between insufficient informal and formal support during pregnancy and joint parental PPD.

Methods:

Using data from the nationally representative French ELFE ( Etude Longitudinale Française depuis l’Enfance) cohort study ( N = 12,350), we estimated associations between insufficient informal and formal support received by the mother during pregnancy and joint parental PPD in multi-imputed multivariate multinomial regression models.

Results:

In 166 couples (1.3%), both parents were depressed. The likelihood of joint parental PPD was increased in case of insufficient informal support (insufficient partner support: odds ratio (OR) = 1.68 (95% confidence interval (CI): 1.57–1.80); frequent quarrels: OR = 1.38 (95% CI: 1.19–1.60)). We also observed associations between formal support during pregnancy and joint parental PPD (early prenatal psychosocial risk assessment: OR = 1.13 (95% CI: 1.05–1.22); antenatal education: OR = 1.13 (95% CI: 1.05–1.23)), which disappeared when analyses were restricted to women with no psychological difficulties during pregnancy.

Conclusion:

Insufficient informal social support during pregnancy appears to predict risk of joint PPD in mothers and fathers and should be identified early on to limit complications and the impact on children.
Book review: Varinder Sharma. 2019. Agricultural Development in Punjab and Haryana
Authors: Singh Gurpreet
Published: April 2020

Varinder Sharma. 2019. Agricultural Development in Punjab and Haryana. New Delhi, India: LG Publishers Distributors, pp. 200, ₹595 (hardback), ISBN: 978-93-83723-52-2.
Necessary changes, adverse effects? The institutional patterns of adaptation of economics universities to changes prompted by the reform of Poland’s science and higher education system
Authors: Jelonek Magdalena , Mazur Stanisław
Published: April 2020

The currently implemented reform of Poland’s science and higher education system extensively draws on the principles of new public management in both curricula and management. It also replicates, at times uncritically, the changes put into effect in European higher education institutions. As early as 2017, the intentions of the decision makers were made clear by the introduction of a new funding algorithm, which completely altered the existing rules of the game. This algorithm particularly affected public economics universities, which were forced to make some adaptations. In this article, we focus on ways in which economics universities adapted to two specific solutions proposed by the legislator, that is, (1) the new funding algorithm and (2) the new career path called ‘teaching professorship’. Based on an in-depth study and using the theories of new institutionalism, we explore the mechanisms of adaptation to the new provisions as they apply to public economics universities. Finally, we identify and discuss four kinds of risks resulting directly from the new public management–based assumptions adopted by the reformers, namely, (1) the invasiveness of the proposed changes, (2) the fragmentary perception of the science and higher education system, (3) the inconsistency of the actions and (4) the ostensible adaptation measures taken by the institutions.
Perception of family sense of coherence during parental transition: A qualitative study
Authors: Ngai Fei Wan , Chan Pui Sze
Published: April 2020

This study described the perspectives and interplay of factors affecting the family sense of coherence of Chinese couples during the perinatal period. We adopted a grounded theory approach and conducted semi-structured interviews with 36 Chinese couples during pregnancy and at 2–3 months postpartum. Four major themes emerged involving meaningfulness, comprehensibility, and manageability of new parenthood and factors affecting the family sense of coherence. The strong sense of family unity and harmony embedded in the Confucian philosophy and the collective coping, in particular the strong social support network, seemed to contribute to couple’s experience of new parenthood as meaningful, comprehensible, and manageable.
Vernacular architecture in eastern Senegal: Chaînes opératoires and technical choices
Authors: Pelmoine Thomas , Mayor Anne
Published: April 2020

Architecture is an important component of cultural identity, but knowledge regarding construction techniques using local materials is gradually disappearing, and this subject has rarely been studied in sub-Saharan Africa. This ethno-archaeological study of current vernacular architecture and its evolution during the past three centuries in eastern Senegal therefore brings innovative results that are interesting on different levels. In relation to West Africa, the authors aim to provide new knowledge useful for archaeologists lacking references for interpreting past remains, as well as an archive for historical and heritage studies. More widely, the study constitutes a reference for the description of various mud-building techniques and an attempt to understand the mechanisms explaining their transformations, which should concern all scientists interested in vernacular architecture, in Africa and beyond.

More precisely, this article accounts for the variability of techniques used for constructing walls and roofs of dwellings in the Faleme valley among different ethno-linguistic groups, while considering the environmental, cultural and socio-economic factors at play. The authors’ methodology is based on a description of the chaînes opératoires of construction, interviews, mapping and statistical analysis. The patterns observed facilitate a discussion on the evolution of techniques, environmental adaptations, the transfer of knowledge and the role of history in material culture dynamics.
Lifestyle at Time of COVID-19: How Could Quarantine Affect Cardiovascular Risk
Authors: Mattioli Anna Vittoria , Ballerini Puviani Matteo
Published: April 2020

COVID-19 is causing a global pandemic with a high number of deaths and infected people. To contain the diffusion of COVID-19 virus, governments have enforced restrictions on outdoor activities or even collective quarantine on the population. Quarantine carries some long-term effects on cardiovascular disease, mainly related to unhealthy lifestyle and anxiety.
Patient perspectives on research use of residual biospecimens and health information: On the necessity of obtaining societal consent by creating a governance structure based on value-sharing
Authors: Yamanaka Mayumi , Suzuki Mika , Sato Keiko
Published: April 2020

Very few attempts have been made to survey patient opinions, particularly regarding the use of residual biospecimens and health information in research, to clarify their values. We conducted a questionnaire survey that targeted outpatients of a university hospital to gauge their awareness levels and understand patient perspectives on research that uses these items. Few patients felt that obtaining individual consent for each research study was necessary. Most patients expressed the view that researchers should be obligated to inform them about the research use of their items and be subject to self-directed rules (including sanctions). The research community should try to obtain “societal consent regarding an opt-out system” from the public. A salient value-sharing-based governance structure is necessary for obtaining public trust.
Long-Term Incidence and Outcome of BCR-ABL Mutations in Patients (pts) with Chronic Myeloid Leukemia (CML) Treated with Imatinib Mesylate - P-Loop Mutations Are Not Associated with Worse Outcome.
Authors: Jabbour Elias , Kantarjian Hagop , Jones Dan , O’Brien Susan , Luthra Raja , Garcia-Manero Guillermo , Giles Francis , Rios Mary Beth , Verstovsek Srdan , Cortes Jorge
Published: April 2020

Resistance to imatinib in CML may occur through mutations of the BCR-ABL kinase domain. We investigated the occurrence of mutations in 159 pts treated with imatinib by direct sequencing. Pts had been treated with imatinib for a median of 32 months (mo) (range, 4 to 60 mo). 52 mutations were identified in 49 (31%) pts: 3 pts had 2 different mutations; in 2 of them they appeared simultaneously. Mutations mapped to 23 different amino acid residues, with the most frequent locating to the P-loop (n=19; 39%), and the residues in imatinib binding pocket (n=12; 25%). The single most common mutations were G250E (n=8) and F317L (n=7). At the time imatinib was started, 34 pts (70%) were in chronic phase (CP) (13 previously untreated, 21 post-IFN failure), 14 (28%) in accelerated phase (AP), and 1 (2%) in lymphoid blast phase (BP). Three pts (2 AP, 1BP) had clonal evolution. Best response to imatinib for pts in CP was: cytogenetic (CG) response complete (CGCR) in 13 (38%), partial (CGPR) in 8 (24%), minor in 1 (3%), and hematologic response only in 12 (35%) (11 complete, 1 partial). For pts in AP, best response was: CGCR in 5 (36%), CGPR in 3 (21%), minor in 1 (7%), and hematologic only in 5 (36%). The pt in BP had achieved CGCR. At the time mutations occurred, 47 (96%) pts had lost their hematologic or cytogenetic response, and clonal evolution had occurred in 15 (68%) pts. Among pts who were initially treated in CP, 9 had transformed to AP and 3 to BP. Two pts treated in AP had progressed to BP. In 2 (4%) pts (1 CP, 1 AP) the mutation (F317L, F311I) was identified while in CGCR remission; both pts have remained in CG CR 2 and 4 mo, respectively after the mutations was identified. Five patients died (4 AP, 1 CP) after a median of 7 mo (1–20 mo) following the detection of mutations. Their mutations included F317L (n=2), M244V, F359V, H396R (1 each). Thus, after a median follow-up of 6 mo (range, 1–20 mo) from detection, only 1 of 19 pts with P-loop mutations has died versus 4 of 30 with non-P-loop mutations. The estimated 15-months survival rates were 95% and 83%, respectively (p=0.50). We conclude that 1) mutations occur frequently among pts with acquired resistance to imatinib; 2) in few instances they can be identified in pts in CGCR; and 3) P-loop mutations may not be associated with worse outcome compared to other mutations.
Imatinib Alone (IA) Vs. Imatinib + Ara-C (IMAC): A Randomized Phase III Clinical Trial for the Treatment of Early Phase (EP) Chronic Myeloid Leukemia (CML) Ph+. Preliminary Report of Mexican Cooperative Leukemia Group (GRUMELA).
Authors: Monroy Rafael Hurtado , Vargas-Viveros Pablo , Cervera Eduardo , Candelaria Myrna , Aguayo Alvaro , Gallardo Emma , Leon Eucario , Labardini Juan , Sosa Ricardo , Paredes Rogelio , Romero Fernando , Perez Oscar , Coronel-Ayala Omar
Published: April 2020

Imatinib mesylate is the standard treatment for chronic phase CML. Imatinib combinations with interferon alpha or Ara-C has shown synergistic anti-proliferative effects. In an attempt to improve the rate of cytogenetic responses we compare the use of IA vs. IMAC as initial therapy in EP (< 12 months) Ph+ CML patients (pts). The study was conducted in 48 Ph+ CML pts recruited within 12 months from diagnosis with no treatment other than alkylating agents and were randomized to receive IA 400 mg/day (N= 23) or imatinib 400 mg/day plus Ara-C (subcutaneous injection) 10 mg/m2/BSA daily for 10 days monthly (N= 25). Median age for IA group is 44 years (18–75) and 38 years (20–57) for IMAC group. Median time from diagnosis of CML to inclusion was 8 months (1–12). Complete Hematologic Response (CHR) was achieved in 20 pts. (86.9%) for the IA group and in 24 patients (96%) of the IMAC group in a median time of 3 weeks (range: 1–6). With a median follow-up of 9 months (range 3–12 months) Cytogenetic Responses (CgR) in group IA were achieved in 69%: Major Cytogenetic Responses (MCgR) (Bcr/Abl 1–35%) assessed by Bone Marrow Fluorescence in situ Hybridization (FISH) (performed pretreatment and at month 3 and 6) were obtained in 11 pts (47.8%) and minor Cytogenetic Response (mCgR) (Bcr/Abl 36–90%) in 5 pts (21.7%). In the IMAC group Cytogenetic Responses were achieved in 92%: MCgR in 16 (64%) and mCgR in 7(28%). Toxicity grade III neutropenia was present in 2 pts (8.6%) of IA group and in 3 pts (12%) for the IMAC group and grade I –II nausea and edema were the most frequent adverse reactions for both groups in about 30 % of cases. Six pts (26.3%) from the IA group has no response compared with 2 (8%) from the IMAC group. Two patients from the IMAC group and 1 from IA were removed due to Cytogenetic Clonal Evolution and lost of CgR. From these preliminary results we suggest that CHR and Global Cytogenetic Response are higher in the IMAC group, meanwhile there is a lower CgR and high rate of Pts with no cytogenetic response (26.3 vs. 8%) in the IA group. It is too early to conclude definitive differences in the cytogenetic responses at this time, but it appears to be a trend to greater CgR rate for the IMAC group. Data collection and patient accrual are ongoing and results with a 18 months follow up will be presented.

Preliminary Results

Response Imatinib Alone Imatinib + Ara-C CHR: Complete Hematologic Response, MCgR: Major Cytogenetic Response, mCgR: Minor Cytogenetic Response, CCgR: Complete Cytogenetic Response. CHR 20/23 (89.9%) 24/25 (96%) MCgR 11 (47.8%) 16 (64%) mCgR 5 (21.7%) 7 (28%) CCgR 0 0
CML with E8A2 BCR-ABL Fusion: The Fourth Breakpoint Cluster Region?.
Authors: Demehri Shadmehr , Lange Thoralf , Paschka Peter , Branford Susan , Koizumi Tamio , Sugimoto Takeshi , Lim Lay-Cheng , Schultheis Beate , Kegel Thomas , Martinelli Giovanni , Hochhaus Andreas , Druker Brian J. , Deininger Michael W.
Published: April 2020

In Ph+ leukemia, the breakpoints within BCR cluster in 3 distinct breakpoint cluster regions (bcr). Rearrangements in the minor (m−), major (M−) and micro (m−) breakpoint cluster region (bcr) give rise to e1a2, e13/14a2 and e19a2 BCR-ABL fusion proteins that are associated with Ph+ ALL, CML and chronic neutrophilic leukemia, respectively. Atypical BCR-ABL fusions have also been reported, mostly in isolated cases. Here, we describe eight patients with an unusual e8a2 BCR-ABL transcript and provide an overview of their common characteristics. The index case (#1) was a 56 year old man diagnosed with CML in 1993. Therapy with busulfan and hydrea induced a complete hematologic remission (CHR) that was maintained until March 2001, when accelerated disease developed. Treatment with imatinib and subsequently AML-type chemotherapy were only transiently effective and the patient died from myeloid blast crisis in March 2003. Cytogenetics demonstrated a standard t(9;22)(q34;q11). Unexpectedly, FISH was consistent with an m-bcr rearrangement and multiplex PCR showed an unusually large band. Sequencing identified a fusion between BCR exon e8 and ABL exon a2, with a 55 bp insert corresponding to an inverted segment of ABL intron Ib (corresponding to nt 29861–29915, Genbank U07561). Immunoblotting of bone marrow mononuclear cells with anti-ABL antibody identified a 200 kDa protein (p200BCR-ABL).

Seven additional patients with an e8a2 BCR-ABL fusion have been identified (table 1). These patients tend to have relatively high platelet counts (median 569 x 109/L, range 216 – 1123) and relatively low white counts (median 42 x 109/L, range 4.7 – 146) but no other distinguishing characteristics at diagnosis. With a median follow-up of 36 months (range, 4 –97), two patients had progressed to blast crisis and died, one died from an unrelated cause, and five were alive, one after allogeneic BMT. Remarkably, none of the patients treated with interferon-a achieved even a minor cytogenetic remission, similar to patients with p190-positive CML. Two patients besides case #1 have received imatinib, one has achieved a CHR at four months, and information on the other is not available. Compared to P190 and P210, p200 lacks the pleckstrin homology (PH) domain but retains the Dbl-like and CDC24 homology domains of BCR. Deletion of the PH domain may disrupt the function of the Dbl-like domain to serve as a GTP exchange factor for Rac, Cdc42 and Rho. This may lead to disruption of the actin cytoskeleton and would be expected to cause a disease that is biologically closer to p190 than to p210.
The G20210A Prothrombin Gene Mutation and the Plasminogen Activator Inhibitor (PAI) 844GG Genotype Increase the Risk of Premature Onset of Severe Preeclampsia.
Authors: Gerhardt Andrea , Goecke Tamme W. , Beckmann Matthias W. , Scharf Rudiger E. , Zotz Rainer B.
Published: April 2020

Obstetrical complications such as severe preeclampsia and HELLP syndrome are associated with abnormal placental vasculature and inadequate placental maternal-fetal circulation. Hereditary risk determinants of venous thrombosis have been reported to be associated with these obstetrical complications.The magnitude of the association between thrombophilia and the obstetrical complications varies in the published studies, according to type of obstetrical complication and type of thrombophilia. No data exist so far whether these risk determinants are related to premature onset of severe preeclampsia.

We used a case-control design in 99 women with severe preeclampsia (blood pressure higher than 160/100 mm Hg; urinary protein excretion greater than 5 g per day, platelet count of less than 100.000/μl; combination of hemolysis, high serum aminotransferase concentration, and platelet count below 100.000/μl; or eclampsia) in previous pregnancies and 277 normal women to assess hereditary risk factors of venous thrombosis as risk determinants for severe preeclampsia. Moreover, a case-only design was used to assess these risk factors as risk determinants for premature severe preeclampsia. We determined the genetic risk markers factor V Leiden G1691A (FVL), the G20210A prothrombin gene mutation, the methylenetetrahydrofolate reductase polymorphism (MTHFR C677T), and the PAI A844G polymorphism. None of the women had a combined or homozygous defect of the FVL or the G20210A prothrombin gene mutation. Women with antiphospholipid syndrome were excluded. None of the women had a deficiency of antithrombin, protein C, or protein S.

Using the case-control design, there was no significant risk association of the hereditary risk factors with severe preeclampsia (FVL p=0.680, prothrombin mutation p=0.479, MTHFR 677TT genotype p=0.565, PAI 844GG genotype p=0.641). In the case-only design, the onset of severe preeclampsia was significantly earlier in women with the G20210A prothrombin gene mutation (24.5 weeks vs. 30.5 weeks, p=0.04) and in women with the PAI 844GG genotype (27.2 weeks vs. 30.7, p=0.025). No such significant difference was observed in carriers of the FVL or the MTHFR 677TT genotype. Hereditary risk factors for venous thrombosis are not risk determinants for severe preeclampsia. However, women who are carriers of the G20210A prothrombin gene mutation and the PAI 844GG genotype are at risk for premature onset of severe preeclampsia. Based on our results it appears that these risk factors do not induce the pathomechanism but modulate the course of preeclampsia.
Single Knock-In PML-RARα Expressing Murine APL Tumors Provide a Unique Model for Studying In Vivo Sensitivity and Resistance to ATRA and Arsenic Trioxide.
Authors: Greenbaum Adam M. , Holt Matthew S. , Ley Timothy K. , DiPersio John F.
Published: April 2020

Although approximately 70% of patients with acute promyelocytic leukemia (APL) are cured after treatment with all-trans retinoic acid (ATRA) and anthracycline based chemotherapy, those who relapse cannot be cured even with chemotherapy or arsenic trioxide salvage therapy. In order to study the molecular mechanisms of resistance to ATRA, liposomal ATRA, and arsenic trioxide, we have utilized a murine model of APL generated by “knocking in” the PML/RARα gene into the murine cathepsin G locus (Westervelt et al. Blood. 102(5):1857). Of the 76 single knock-in (SKI) mice followed for a median time of 368 days, 30 (39%) suffered from rapid-onset leukocytosis, anemia, thrombocytopenia, and hepato-splenomegaly. Spleens from these leukemic animals were removed and the tumors cells (> 90% CD34+/Gr-1+ APL cells) were frozen in aliquots and banked for future passive transfer into genetically compatible recipients. The SKI mice exhibited the expected median time to death of 222 days. Attempts to expand these tumors in vitro failed, thus precluding the use of in vitro methods to generate ATRA and arsenic resistant SKI APL tumor cells. An alternate in vitro model of identifying de novo resistant SKI APL tumors to the drugs was established by incubating individual SKI APL tumors with ATRA, liposomal ATRA, and arsenic in vitro for only 3 days and using ELISA to measure upregulation of MMP-9 (gelatinase B), a surrogate marker for neutrophil differentiation. ATRA, liposomal ATRA, and arsenic induced 6.2 ± 4.4, 5.7 ± 3.5, 1.7 ± 1.0 fold increase in accumulated levels of MMP-9, respectively. These data suggest that ATRA and liposomal ATRA are more potent inducers of terminal differentiation than arsenic in these APL tumors. More importantly, the SKI APL tumors were also assessed for in vivo resistance to these agents by injecting 1 x 106 banked APL tumor cells into the peritoneal cavity of wild-type genetically compatible mice. The mice were then treated i.p. with either arsenic trioxide (0.4 mg q.d.), liposomal ATRA (0.4 mg q.d.), or diluent control. Doses were administered daily starting on day +5 until death. Tumors in the recipient mice were tracked by PCR for the transgene and FACS. The tumors proliferated in the peritoneal cavity (days 1–14) followed by migration to the bone marrow and spleen (days 14–28). By the eighth week post-injection, all mice suffered from leukocytosis and eventually died. Of the 22 banked tumors studied, only two tumors showed de novo resistance to ATRA both in vitro and in vivo. We will present data on preliminary RNA profiling and DNA sequencing of the PML-RARα transgenes in these APL tumors and attempt to correlate these results and the results of in vitro induction of MMP-9. The SKI APL tumors will provide us with unique reagents to study the biology of resistance to ATRA and arsenic trioxide.
Detection of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia by 4color Cytometry in International Multicenter Trial Minimini.
Authors: Mejstrikova Ester , Batinic Drago , Klara Dubravcic , Ng Margareth , Leung Yonna , Kappelmayer Janos , Luria Drorit , Izraeli Shai , Kalina Tomas , Vaskova Martina , Fronkova Eva , Stary Jan , Trka Jan , Hrusak Ondrej
Published: April 2020

FC is still not employed in MRD based treatment protocols. One problem is lack of standardization suitable for prospective trials involving multiple clinical centers and FC laboratories. Therefore, we established a MiniMini Project, an international collateral study within the ALL IC BFM 2002 treatment protocol for childhood acute lymphoblastic leukemia (ALL). The MiniMini Project provides a mainframe of minimal panel of monoclonal antibody combinations to evaluate MRD by FC. Patients (pts) are stratified according non-MRD criteria (prednisone response at day 8 in peripheral blood (PB), percentage of blasts at day 15 and day 33 in bone marrow (BM), leukocytosis, and age at diagnosis and presence of BCR/ABL or MLL/AF4 fusions). Identical immunophenotypic populations are reported in all pts regardless presenting phenotype. Each laboratory investigates at least 2 pts with B lineage ALL by the T ALL combinations and vice versa. These “cross-lineage controls” together with data on subpopulations that are negative at diagnosis were used to set the specificity cutoff values at each time point (diagnosis, day 8 BM and PB, day 15, day 33 day 52 BM). MRD levels obtained by Ig/TCR rearrangements RQ-PCR in 32 pts (24 pts BCP ALL, 8 pts T ALL) were used to define specificity thresholds. 185 pts were investigated in the participating laboratories. We used data from first Czech cohort of pts (92 pts in total, 16 pts T lineage, 74 pts B lineage, in standard risk group (SRG), n=36, IRG, n=40 and HRG, n=16) in whom clinical data as well as standard FC analysis results were available. We compared morphological percentage of blasts (used for stratification) to a level of residual disease by FC. There was high concordance in SRG of both methods, except 1 patient redirected into IRG group (M3 BM vs. only 14% of blasts by FC). In IRG, concordance was in 92.5% of pts, 3 pts should be placed in HRG group according FC. 98.9% of pts morphologically in complete remission at day 33 were confirmed by FC. Although FC data confirm a significant difference between PGR and PPR in PB specimens at day 8 (p=0.0014), there is an overlap in percentage of leukemic cells between these categories. In total, MRD level above 0.1% was observed in BM of 100, 99, 84, 32 and 3.5 % pts in days 0, 8, 15, 33 and 52, respectively and in PB of 95% pts at day 8. Our first results show feasibility of FC standardization. The choice of subpopulations and the cutoff points will be validated in an independent cohort within the same Project.
Patients with Lymphoplasmacytic Lymphoma Can Be Salvaged with Autologous Stem Cell Transplantation, Irrespectively of the Number of Previous Treatment Lines. Analysis of 146 Cases from the European Bone Marrow Transplant Registry (EBMT).
Authors: Kyriakou Charalampia A. , Goldstone Anthony H. , Sureda Anna , Yong Kwee , D’Sa Shirley , Taghipour Goli , de Elvira Carmen Ruiz , Linch David C. , Schmitz Norbert
Published: April 2020

Lymphoplasmacytic Lymphoma (LPL) is a relatively rare low-grade lymphoma which primarily affects elderly patients. Standard doses of alkylating agents, purine analogues and anti-CD20 monoclonal antibody effect response rates of up to 60%. However, complete response is infrequent and there is no cure. Due to indolent nature of the disease and older patients with comorbidities, evaluation of the role of high dose therapy with transplant has been infrequent in the past. Here we report a retrospective multicentre study of 146 LPL patients (94 male, 52 female), who underwent autologous stem cell transplantation (ASCT) between 1992 and 2004.

The median age was 60 years (54–67) and median time from diagnosis to transplant was 62 months (5–119). Twenty-six patients (18%) were in CR1, 35 (24%) in CR2, 30 (20%) in ≥CR3, 45 (31%) in PR, 10 (7%) primary refractory at transplant. Combination of GCSF with either Cyclophosphamide, ESHAP or AraC were mainly the stem cell mobilisation regimens used, and 18 patients with extensive prior use of purine analogues, required second attempt for harvesting. The conditioning regimens used were BEAM, Cyclophosphamide/TBI or Melphalan/TBI. The source of stem cells was PBSC in 129, BM in 11 and both in 6 patients. All patients except one had successful engraftment. With a median follow-up of 12 months (2–126), 131 (90%) patients are alive and 15 (10%) dead. Thirteen patients died from disease progression and 2 from regimen toxicity. Actuarial non- relapse mortality was 2.4% at 1 and 2 years. The actuarial OS was 90% at 1 year, 79% at 3 years and 69% at 5 years. The probability of relapse was 80% at 1 year, 53% at 3 years and 39% at 5 years. Relapse rate was not statistically significant for patients with chemosensitive disease. In conclusion this study shows that ASCT is safe, and a significant proportion of previously multitreated LPL patients can be salvaged and sustain prolonged DFS.
Elucidation of the Molecular Mechanisms by Which Inflammatory and Anti-Inflammatory Monokines Regulate Interferon (IFN)- γ Production.
Authors: Yu Jianhua , Becknell Brian , Liu Shujun , Trotta Rossana , Jaung Micheal S. , Hughes Tiffany , Marcucci Guido , Weinstein Michael B. , Caligiuri Michael A.
Published: April 2020

Pro-inflammatory monocyte-derived cytokines (monokines) such as interleukin (IL)-12, IL-15 and IL-18 work in concert to quickly induce IFN- γ in natural killer (NK) cells, while the anti-inflammatory monokine transforming growth factor beta 1 (TGF-β1) can suppress NK cell IFN- γ production. Here, we provide new molecular evidence as to how these monokines carry out their opposing functions. In the human NK-92 cell line we show that Smad proteins, mediators of TGF- β1 signaling, directly inhibit IFN- γ production. Using chromatin immunoprecipitation (ChIP), we found that both Smad2 and Smad4 associate with the IFN- γ promoter in the proximal region but not in other regions, such as exon 4. Luciferase reporter assays in 293T cells indicated that Smad2 alone, which does not possess a DNA binding domain, had little effect on the inhibition IFN-γ of promoter activity. In contrast, Smad3 and Smad4, both of which have DNA binding activity, dramatically suppressed IFN-γ promoter activity. Co-transfection of Smad2 and Smad4, or Smad3 and Smad4, in 293T cells resulted in synergistic repression. Interestingly, the Smad proteins also inhibited the transactivation of the IFN-γ promoter by T-BET, a recently discovered transcription factor controlling IFN- γ production in mouse T cells and NK cells. This was consistent with our data showing that TGF-β1 inhibited T-BET expression in human NK cells. Using IFN-γ promoter deletion constructs, we mapped the region responsible for Smad-mediated inhibition to the -204 proximal promoter, where Smad binding elements are enriched. In parallel, using micro-array analysis, western-blotting and semi-quantitative PCR in human primary NK cells and the NK-92 cell line, we demonstrated that the combination of the pro-inflammatory monkines IL-12 with IL-15 or IL-18 was able to antagonize multiple components of TGF- β1 signaling, including: 1) inhibition of the expression and the phosphorylation of Smad2; 2) suppression of Smad3 expression; and 3) down-regulation of the expression of the TGF- β receptor II subunit. Moreover, although these monokines had no effect on Smad4 expression, using ChIP assay we observed that Smad4 dissociated from the proximal IFN-γ promoter upon co-stimulation of NK cells with IL-12 and IL-18. In summary, our data show that TGF- β1 suppresses IFN- γ production via the direct binding of Smad proteins to the proximal IFN-γ promoter and via inhibition of T-BET, while the pro-inflammatory cytokines serve to inhibit or down modulate TGF- μ signaling components and reverse Smad binding to the proximal IFN-γ promoter. Thus, we suggest that NK cell production of IFN-γ is controlled by the integration of anti-inflammatory and pro-inflammatory monokine signals, leading to reciprocal antagonism.
A Molecular Signature of the Transcription Factor GATA1 in Acute Megakaryoblastic Leukemia of Childhood.
Authors: Bourquin Jean-Pierre , Langebrake Claudia , Subramanian Aravind , Li Xiaochun , Reinhardt Dirk , Bernard Olivier , Zwaan Christian M. , Hasle Henrik , Schrappe Martin , Golub Todd R. , Orkin Stuart H.
Published: April 2020

To investigate the pathogenesis of acute megakaryoblastic leukemia, AML M7 (M7), we analyzed the gene expression profiles of 113 patient samples on Affymetrix U133A GeneChips. Classification by unsupervised clustering discriminates 70 M7 samples from 12 with other AML FAB subtypes, 3 normal controls, 10 normal and remission samples of patients with Down Syndrome (DS) and 18 ALL samples from DS patients.

Further, M7 subclasses can be identified. DS samples (21 DS-M7 and 9 transient myeloproliferative disease (TMD) samples) cluster apart from non-DS M7 samples, with a few exceptions, most notably the 4 M7 samples with the translocation t(1;22). Smaller subgroups can be detected by consensus clustering in DS and non-DS M7.

The DS-non-DS distinction is not driven by differential expression of chromosome 21 genes, in particular RUNX1 expression levels are not increased in DS. Consistent with differences observed by flow cytometry, DS samples show a higher expression of ANK1, GYPA, GYPB and CD36, while non-DS M7 samples have higher VWF and CD34 expression, reflecting known morphologic differences. The hematopoietic transcription factor GATA1 is overexpressed in DS M7/TMD when compared to non-DS M7s or controls, and is among the most significant markers of the DS class. The mutation of GATA1 that is characteristic for DS is likely to affect its transcriptome specifically. By nearest neighbour analysis, about 300 genes follow the pattern of the GATA1 gene expression within a significant range by permutation testing. This GATA-1 signature is highly enriched in the DS samples and includes several known target genes of GATA1, such as GATA2, GYPA, ANK1 and ALAD. This approach should lead to the identification of genes contributing to cellular proliferation and differentiation in the context of the GATA1 mutation of DS M7.
Pilot Study to Test the Efficacy and Safety of Recombinant Factor VIIa (rFVIIa, NovoSeven™) in the Treatment of Refractory Hemorrhagic Cystitis Following High Dose Chemotherapy.
Authors: Ashrani Aneel A. , Gabriel Don A. , Gajewski James L. , Key Nigel S.
Published: April 2020

Background: Hemorrhagic cystitis (HC) is a known complication of high-dose cyclophosphamide, which is part of the conditioning regimen for stem cell transplantation, and is associated with significant morbidity. Treatment of HC is frequently unsatisfactory, leading to prolonged hospitalization and utilization of health care resources. High-dose recombinant factor VIIa (rFVIIa) is used as a hemostatic agent in patients with hemophilia with inhibitors. As rFVIIa enhances the generation of thrombin on activated platelets and facilitates the formation of a stable fibrin plug that is resistant to premature lysis, we conducted a pilot study to assess its efficacy and safety in the treatment of HC.

Methods: Subjects between 18–65 years with severe HC that was judged unresponsive to (a) optimization of hemostatic parameters, and (b) a trial of at least 24-hours of continuous bladder irrigation using a standardized protocol were eligible. Consented subjects were administered 80 μg/kg of rFVIIa for the first dose, and 120 μg/kg every 3 hours for up to 2 additional doses if hematuria was persistent. Response was evaluated by monitoring urine color photographically and by measuring urine hemoglobin content, using spectrophotometer. Subjects were followed for 24 hours. Complete response was defined as complete clearing of the color of urine at any time point in the 24-hour study period, and partial response was defined as slowing of hematuria, as evidenced by lightening of the color of urine.

Results: Of the 7 subjects who participated in the study, 4 had a complete response, 2 had a partial response, and 1 had no response. The response duration was temporary, and all the subjects required the administration of the three doses of rFVIIa. No major adverse effects were encountered.

Conclusion: rFVIIa appears to be effective in temporarily abating bleeding in HC. Further trials should include multiple dosing and/or addition of antifibrinolytic agents for a more durable effect.
Incidence and Risk Factors for Thromboembolism in Patients with Hematologic Malignancies Undergoing Allogeneic and Autologous Stem Cell Transplantation.
Authors: Kuderer Nicole M. , Khorana Alok A. , Friedberg Jonathan W. , Culakova Eva , Phillips Gordon L. , Francis Charles W. , Lyman Gary H.
Published: April 2020

Background: Thromboembolism (TE) is a common complication of hospitalized non-transplant cancer patients. To date, the extent and impact of TE in stem cell transplant patients is unknown, in part because it is considered a low risk group given the high prevalence of thrombocytopenia. The purpose of this study is to evaluate the incidence of and risk factors for TE in cancer patients undergoing stem cell transplantation.

Methods: We conducted a retrospective analysis of all discharge summaries from the 115 US academic health centers reporting to the University HealthSystem Consortium from 1995 to 2002. We identified a total of 7,087 patients with hematologic malignancies undergoing allogeneic and autologous stem cell transplantation. The incidence of and risk factors for venous and arterial TE was analyzed in univariate and multivariate logistic regression analysis with adjusted odds ratios as estimates of relative risk.

Results: TE was reported in 389 (5.5%) transplant patients with 4.8% patients developing venous and 0.7% arterial TE. The incidence of TE was greater in allogeneic (6.8%) compared to autologous (4.8%) transplant patients (p<0.0001). Among those receiving allogeneic transplantations, BMT patients experienced a higher rate of TE than PBSC patients (7.5% vs 5.6%; p<0.05). In multivariate logistic regression analysis, the following clinical variables were significantly associated with TE in stem call transplant patients with hematologic malignancies: gram negative sepsis (OR=1.76; 1.02–3.02; p=0.04), gram positive sepsis (OR=1.75; 1.25–2.45; p=0.001), line infections (OR=1.48; 1.11–1.97; p=0.008), central venous catheters (OR=1.74; 1.39–2.17; P<0.0001), pulmonary disease (OR=1.87; 1.47–2.37; p<0.0001), liver disease (OR=1.31; 1.01–1.70; p=0.04) and length of stay >30 days (OR=1.66; 1.30–2.13; p<0.0001). Hodgkin’s disease (OR= 0.59; 0.37–0.94; p=0.026) was associated with a lower risk of TE. In multivariate analysis, the type of transplant failed to remain an independent risk factor for TE after controlling for other transplant complications.

Conclusions: This is the first substantive report on the incidence of thromboembolism in stem cell transplant patients. We found that thromboembolic events are a frequent complication in patients with hematologic malignancies undergoing stem cell transplantation. The incidence of TE is high among most subgroups studied. Prospective studies are needed to evaluate the efficacy and safety of thromboprophylaxis in this high-risk population.
5′-AZA-2′-Deoxycytidine Induces p21/WAF Expression by Demethylation of p73 Leading to p53-Independent Apoptosis in Myeloid Leukemia.
Authors: Tamm Ingo , Wagner Mandy , Dörken Bernd , Schmelz Karin
Published: April 2020

The DNA methylation inhibitor 5′-Aza-2-deoxycytidine (5-Aza-CdR) has significant therapeutic value for the treatment of patients with myelodysplastic syndrome (MDS), acute and chronic myeloid leukemia (AML and CML). The demethylating effect of 5-Aza-CdR has been well characterized. In contrast, less is known about the molecular events downstream of the methylation inhibition effect. We found that 5-Aza-CdR induces apoptosis in AML cells (both, p53 mutant and wildtype) but not in epithelial or normal peripheral blood mononuclear cells (PBMC). Cell death was accompanied by activation of the mitochondrial apoptosis pathway as shown by early release of cytochrome c and AIF and loss of the mitochondrial membrane potential Δψm. Activation of caspase-3 but not -6 and -8 was detectable using western blot analysis and measurement of caspase enzymatic activity. 5-Aza-CdR treatment resulted in the induction of p21 which correlated with the arrest of AML cells in the G1 cell cycle phase. Induction of p21 expression was independent of its promoter methylation status but was mediated by 5-Aza-CdR-induced reexpression of the tumor suppressor p73, a known upstream regulator of p21. The p73 promoter was hypermethylated in AML cell lines and in primary AML cells but not in epithelial cells which were resistent towards 5-Aza-CdR. Therefore, 5-Aza-CdR-mediated specific killing of myeloid cells might be dependent on its ability to revert p73 promoter methylation and to reexpress p73 mRNA. In addition, exogenous expression of p73 rendered epithelial cells sensitive to apoptosis induced by 5-Aza-CdR or other cytostatic drugs. We therefore conclude that p73 is a relevant target for methylation-dependent efficacy of 5-Aza-CdR in AML cells.