Boundary States for GS superstrings in an Hpp wave background

We construct the boundary states preserving half the global supersymmetries in string theory propagating on a Hpp background.Comment: 13 pages, latex2e with JHEP3.0 class, no figures. V1: clarified the status of branes not sitting at the origin and added a constraint which boundary states must satisf

Quantitative detection of DNMT3A R882H mutation in acute myeloid leukemia

Background DNMT3A mutations represent one of the most frequent gene alterations detectable in acute myeloid leukemia (AML) with normal karyotype. Although various recurrent somatic mutations of DNMT3A have been described, the most common mutation is located at R882 in the methyltransferase domain of the gene. Because of their prognostic significance and high stability during disease evolution, DNMT3A mutations might represent highly informative biomarkers for prognosis and outcome of disease. Methods We describe an allele-specific PCR with a Blocking reagent for the quantitative detection of DNMT3A R882H mutation providing the possibility to analyze the quantitative amount of mutation during the course of disease. Next, we analyzed 62 follow- up samples from 6 AML patients after therapy and allogeneic stem cell transplantation (alloSCT). Results We developed an ASB-PCR assay for quantitative analysis of R882H DNMT3A mutation. After optimization of blocker concentration, a R882H-positive plasmid was constructed to enhance the accuracy of the sensitivity of quantitative detection. The assay displayed a high efficiency and sensitivity up to 10−3. The reproducibility of assay analyzed using follow-up samples showed the standard deviation less than 3.1 %. This assay displayed a complete concordance with sequencing and endonuclease restriction analysis. We have found persistence of DNMT3A R882H mutations in complete remission (CR) after standard cytoreduction therapy that could be indicating presence of DNMT3A mutation in early pre-leukemic stem cells that resist chemotherapy. The loss of correlation between NPM1 and DNMT3A in CR could be associated with evolution of pre-leukemic and leukemic clones. In patients with CR with complete donor chimerism after alloSCT, we have found no DNMT3A R882H. In relapsed patients, all samples showed an increasing of both NPM1 and DNMT3A mutated alleles. This suggests at least in part the presence of NPM1 and DNMT3A mutations in the same cell clone. Conclusion We developed a rapid and reliable method for quantitative detection of DNMT3A R882H mutations in AML patients. Quantitative detection of DNMT3A R882H mutations at different time points of AML disease enables screening of follow-up samples. This could provide additional information about the role of DNMT3A mutations in development and progression of AML

Molecular Aberrations in Bone Marrow Stromal Cells in Multiple Myeloma

Multiple myeloma (MM) is a B-cell malignancy characterized by an accumulation of malignant plasma cells within the bone marrow. Bone marrow mesenchymal stromal cells (BMMSCs) represent a crucial component of MM microenvironment supporting its progression and proliferation. Alterations in BMMSC of MM (MM-BMMSC) have become an important research focus. In this study, we analyzed MM-BMMSC and their modification through interaction with plasma cells in 128 MM patients. MM-BMMSC displayed a senescence-like state that was accompanied by an increase in senescence-associated β-galactosidase activity, a reduced number of colony-forming units, an accumulation of cells in S phase of the cell cycle, and the overexpression of microRNAs (miR-16, miR-223, miR-485-5p, and miR-519d) and p21. MM-BMMSC showed a reduced expression of mitochondrial stress response protein SIRT3 and an increased mitochondrial DNA mass that led to a higher amount of reactive oxygen species compared to healthy donor BMMSC. The interaction between MM cells and MM-BMMSC is a complex mechanism that relies on multiple interacting signaling pathways. Observed aberrations in MM-BMMSC should be confirmed in an in vivo model in order to clarify the importance for the pathogenesis of MM. Eventually, the result of MM therapy could be improved by understanding the interaction between MM cells and MM-BMSCs

PP Wave Limit and Enhanced Supersymmetry in Gauge Theories

We observe that the pp wave limit of $AdS_5\times M^5$ compactifications of type IIB string theory is universal, and maximally supersymmetric, as long as $M^5$ is smooth and preserves some supersymmetry. We investigate a specific case, $M^5=T^{1,1}$. The dual ${\cal N}=1$ SCFT, describing D3-branes at a conifold singularity, has operators that we identify with the oscillators of the light-cone string in the universal pp-wave background. The correspondence is remarkable in that it relies on the exact spectrum of anomalous dimensions in this CFT, along with the existence of certain exceptional series of operators whose dimensions are protected only in the limit of large `t Hooft coupling. We also briefly examine the singular case $M^5=S^5/Z_2$, for which the pp wave background becomes a $Z_2$ orbifold of the maximally supersymmetric background by reflection of 4 transverse coordinates. We find operators in the corresponding ${\cal N}=2$ SCFT with the right properties to describe both the untwisted and the twisted sectors of the closed string.Comment: 15 pages, LaTeX; v2: added more detail to a derivation, and a preprint number; v3: minor corrections, some remarks and references adde

Predicting sinusoidal obstruction syndrome after allogeneic stem cell transplantation with the EASIX biomarker panel

No biomarker panel is established for prediction of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), a major complication of allogeneic stem cell transplantation (alloSCT). We compared the potential of the Endothelial Activation and Stress Index (EASIX), based on lactate dehydrogenase, creatinine, and thrombocytes, with that of the SOS/VOD CIBMTR clinical risk score to predict SOS/VOD in two independent cohorts. In a third cohort, we studied the impact of endothelium-active prophylaxis with pravastatin and ursodeoxycholic acid (UDA) on SOS/VOD risk. The cumulative incidence of SOS/VOD within 28 days after alloSCT in the training cohort (Berlin, 2013-2015, n=446) and in the validation cohort (Heidelberg, 2002-2009, n=380) was 9.6% and 8.4%, respectively. In both cohorts, EASIX assessed at the day of alloSCT (EASIX-d0) was significantly associated with SOS/VOD incidence (p<0.0001), overall survival (OS) and non-relapse mortality (NRM). In contrast, the CIBMTR score showed no statistically significant association with SOS/VOD incidence, and did not predict OS and NRM. In patients receiving pravastatin/UDA, the cumulative incidence of SOS/VOD was significantly lower at 1.7% (p<0.0001, Heidelberg, 2010-2015, n=359) than in the two cohorts not receiving pravastatin/UDA. The protective effect was most pronounced in patients with high EASIX-d0. The cumulative SOS/VOD incidence in the highest EASIX-d0 quartiles were 18.1% and 16.8% in both cohorts without endothelial prophylaxis as compared to 2.2% in patients with pravastatin/UDA prophylaxis (p<0.0001). EASIX-d0 is the first validated biomarker for defining a subpopulation of alloSCT recipients at high risk for SOS/VOD. Statin/UDA endothelial prophylaxis could constitute a prophylactic measure for patients at increased SOS/VOD risk

Molecular monitoring of minimal residual disease in two patients with MLL-rearranged acute myeloid leukemia and haploidentical transplantation after relapse

This report describes the clinical courses of two acute myeloid leukemia patients. Both had MLL translocations, the first a t(10;11)(p11.2;q23) with MLL-AF10 and the second a t(11;19)(q23;p13.1) with MLL-ELL fusion. They achieved a clinical remission under conventional chemotherapy but relapsed shortly after end of therapy. Both had a history of invasive mycoses (one had possible pulmonary mycosis, one systemic candidiasis). Because no HLA-identical donor was available, a haploidentical transplantation was performed in both cases. Using a specially designed PCR method for the assessment of minimal residual disease (MRD), based on the quantitative detection of the individual chromosomal breakpoint in the MLL gene, all patients achieved complete and persistent molecular remission after transplantation. The immune reconstitution after transplantation is described in terms of total CD3+/CD4+, CD3+/CD8+, CD19+, and CD16+/CD56+ cell numbers over time. The KIR and HLA genotypes of donors and recipients are reported and the possibility of a KIR-mediated alloreactivity is discussed. This report illustrates that haploidentical transplantation may offer a chance of cure without chronic graft-versus-host disease in situations where no suitable HLA-identical donor is available even in a high-risk setting and shows the value of MRD monitoring in the pre- and posttransplant setting

Longitudinal fluorescence in situ hybridization reveals cytogenetic evolution in myeloma relapsing after autologous transplantation

To investigate cytogenetic evolution after upfront autologous stem cell transplantation for newly diagnosed myeloma we retrospectively analyzed fluorescence in situ hybridization results of 128 patients with paired bone marrow samples from the time of primary diagnosis and at relapse. High-risk cytogenetic abnormalities (deletion 17p and/or gain 1q21) occurred more frequently after relapse (odds ratio: 6.33; 95% confidence interval: 1.86–33.42; P<0.001). No significant changes were observed for defined IGH translocations [t(4;14); t(11;14); t(14;16)] or hyperdiploid karyotypes between primary diagnosis and relapse. IGH translocations with unknown partners occurred more frequently at relapse. New deletion 17p and/or gain 1q21 were associated with cytogenetic heterogeneity, since some de novo lesions with different copy numbers were present only in subclones. No distinct baseline characteristics were associated with the occurrence of new high-risk cytogenetic abnormalities after progression. Patients who relapsed after novel agent-based induction therapy had an increased risk of developing high-risk aberrations (odds ratio 10.82; 95% confidence interval: 1.65–127.66; P=0.03) compared to those who were treated with conventional chemotherapy. Survival analysis revealed dismal outcomes regardless of whether high-risk aberrations were present at baseline (hazard ratio, 3.53; 95% confidence interval: 1.53–8.14; P=0.003) or developed at relapse only (hazard ratio, 3.06; 95% confidence interval: 1.09–8.59; P=0.03). Our results demonstrate cytogenetic evolution towards high-risk disease after autologous transplantation and underline the importance of repeated genetic testing in relapsed myeloma (EudraCT number of the HD4 trial: 2004-000944-26)

Calculation of Ground State Energy for Confined Fermion Fields

A method for renormalization of the Casimir energy of confined fermion fields in (1+1)D is proposed. It is based on the extraction of singularities which appear as poles at the point of physical value of the regularization parameter, and subsequent compensation of them by means of redefinition of the "bare" constants. A finite ground state energy of the two-phase hybrid model of fermion bag with chiral boson-fermion interaction is calculated as the function of the bag's size.Comment: 10 pages, LaTeX; no figures. Version to appear in Phys. Lett. B (2001

BPS preons and tensionless super-p-brane in generalized superspace

Tensionless super-p-branes in a generalized superspace with additional tensorial central charge coordinates may provide an extended object model for BPS preons, i.e. for the hypothetical constituents of M-theory preserving 31 of 32 supersymmetries [hep-th/0101113].Comment: 11 pages, LaTeX, no figures. V.2: discussions in sec. 5 extended, references added, to appear in Phys. Lett.

CD4+ T Cell Dependent B Cell Recovery and Function After Autologous Hematopoietic Stem Cell Transplantation

Introduction: High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) represents a standard treatment regime for multiple myeloma (MM) patients. Common and potentially fatal side effects after auto-HSCT are infections due to a severely compromised immune system with hampered humoral and cellular immunity. This study delineates in depth the quantitative and functional B cell defects and investigates underlying extrinsic or intrinsic drivers. Methods: Peripheral blood of MM patients undergoing high-dose chemotherapy and auto-HSCT (before high-dose chemotherapy and in early reconstitution after HSCT) was studied. Absolute numbers and distribution of B cell subsets were analyzed ex vivo using flow cytometry. Additionally, B cell function was assessed with T cell dependent (TD) and T cell independent (TI) stimulation assays, analyzing proliferation and differentiation of B cells by flow cytometry and numbers of immunoglobulin secreting cells in ELISpots. Results: Quantitative B cell defects including a shift in the B cell subset distribution occurred after auto-HSCT. Functionally, these patients showed an impaired TD as well as TI B cell immune response. Individual functional responses correlated with quantitative alterations of CD19+, CD4+, memory B cells and marginal zone-like B cells. The TD B cell function could be partially restored upon stimulation with CD40L/IL-21, successfully inducing B cell proliferation and differentiation into plasmablasts and immunoglobulin secreting cells. Conclusion: Quantitative and functional B cell defects contribute to the compromised immune defense in MM patients undergoing auto-HSCT. Functional recovery upon TD stimulation and correlation with CD4+ T cell numbers, indicate these as extrinsic drivers of the functional B cell defect. Observed correlations of CD4+, CD19+, memory B and MZ-like B cell numbers with the B cell function suggest that these markers should be tested as potential biomarkers in prospective studies