Traditional chemotherapy for acute leukemia often causes life-threatening toxic effects due to a lack of specificity for hematopoietic cells. Monoclonal antibodies and fusion proteins that target ...cell surface antigens on leukemic blasts are being evaluated for their cytotoxic effects and as a means of delivering chemotherapeutic agents or radiation directly to malignant cells. It is hoped that this strategy might selectively ablate malignant cells without many of the toxic effects commonly associated with conventional chemotherapy. In acute myeloid leukemia (AML), the cell surface antigens CD33 and CD45 are especially suitable targets. Although CD33 is expressed on AML blast cells from about 90% of patients, normal hematopoietic stem cells lack this antigen, as do essentially all nonhematopoietic tissues. For that reason, anti-CD33 antibodies have been created to target malignant myeloid and immature normal cells selectively while sparing normal stem cells. Anti-CD33 antibodies have also been used to deliver radiation or a cytotoxic agent directly to leukemic cells. Since the vast majority of leukemias and normal stem cells express the cell surface antigen CD45, another targeting approach allows the delivery of myeloablative radiation to bone marrow and spleen, common sites of leukemic involvement. Consequently, 131I-labeled anti-CD45 antibody has been combined with traditional preparative regimens for patients receiving bone marrow transplantation for acute leukemia. Finally, fusion proteins such as those combining diphtheria toxin with granulocyte-macrophage colony-stimulating factor (GM-CSF) to target the GM-CSF receptor are now being evaluated in clinical trials. Both unconjugated and conjugated antibodies have shown promise in early clinical trials, and may represent appealing therapeutic alternatives for patients with AML.
Abstract
Background
Pilocytic astrocytoma (PA) is the most common pediatric brain tumor and a mitogen-activated protein kinase (MAPK)-driven disease. Oncogenic MAPK-signaling drives the majority of ...cells into oncogene-induced senescence (OIS). While OIS induces resistance to antiproliferative therapies, it represents a potential vulnerability exploitable by senolytic agents.
Methods
We established new patient-derived PA cell lines that preserve molecular features of the primary tumors and can be studied in OIS and proliferation depending on expression or repression of the SV40 large T antigen. We determined expression of anti-apoptotic BCL-2 members in these models and primary PA. Dependence of senescent PA cells on anti-apoptotic BCL-2 members was investigated using a comprehensive set of BH3 mimetics.
Results
Senescent PA cells upregulate BCL-XL upon senescence induction and show dependency on BCL-XL for survival. BH3 mimetics with high affinity for BCL-XL (BCL-XLi) reduce metabolic activity and induce mitochondrial apoptosis in senescent PA cells at nano-molar concentrations. In contrast, BH3 mimetics without BCL-XLi activity, conventional chemotherapy, and MEK inhibitors show no effect.
Conclusions
Our data demonstrate that BCL-XL is critical for survival of senescent PA tumor cells and provides proof-of-principle for the use of clinically available BCL-XL-dependent senolytics.
Children with neurofibromatosis type 1 (NF1) carry germline mutations in one allele of the NF1 gene and are predisposed to myeloid malignancies, particularly juvenile myelomonocytic leukemia (JMML). ...Disruption of the remaining NF1 allele can be found in malignant cells. Flow cytometric cell sorting techniques to isolate the malignant cell populations and molecular genetic methods to assay for somatic loss of the normal NF1 allele were used to study an unusual child with NF1 and JMML who subsequently had T-cell lymphoma. The data show that malignant JMML and lymphoma cells share a common loss of genetic material involving the normal NF1gene and approximately 50 Mb of flanking sequence, suggesting that the abnormal T-lymphoid and myeloid populations were derived from a common precursor cell. These data support the hypothesis that JMML can arise in a pluripotent hematopoietic cell.
Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E, an antimicrotubule agent, into CD30-expressing cells. In phase I studies, brentuximab ...vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory CD30-positive lymphomas.
In this multinational, open-label, phase II study, the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin's lymphoma (HL) after autologous stem-cell transplantation (auto-SCT). Patients had histologically documented CD30-positive HL by central pathology review. A total of 102 patients were treated with brentuximab vedotin 1.8 mg/kg by intravenous infusion every 3 weeks. In the absence of disease progression or prohibitive toxicity, patients received a maximum of 16 cycles. The primary end point was the overall objective response rate (ORR) determined by an independent radiology review facility.
The ORR was 75% with complete remission (CR) in 34% of patients. The median progression-free survival time for all patients was 5.6 months, and the median duration of response for those in CR was 20.5 months. After a median observation time of more than 1.5 years, 31 patients were alive and free of documented progressive disease. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea.
The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75% of patients with relapsed or refractory HL after auto-SCT. Durable CRs approaching 2 years were observed, supporting study in earlier lines of therapy.
Background: Most patients receiving therapy for acute myeloid leukemia (AML) enter an interval in which leukemic blast cells cannot be detected by light microscopy (i.e., morphologic remission). ...However, many of these patients experience a subsequent relapse. Multidimensional flow cytometry, which allows the discrimination of antigens expressed on normal and malignant cells, can detect small numbers of cancer cells in bone marrow or peripheral blood specimens. This technique enables the detection of one leukemic blast cell among 103 to 102 normal regenerating hematopoietic cells. Purpose: We determined whether the presence of residual leukemic blast cells, identified in the bone marrow of pediatric patients with AML by use of multidimensional flow cytometry, would be predictive of subsequent leukemic relapse. Methods: Multidimensional flow cytometry was performed on 205 marrow specimens collected throughout the course of treatment from 39 patients who had achieved morphologic remission. The analyses employed monoclonal antibodies directed against CD45 in combination with mixed pairs of monoclonal antibodies directed against 10 other antigens. A time-varying Cox regression analysis that controlled for sample time intervals, age, sex, morphologic classification of disease, and white blood cell count at diagnosis was used to relate the multidimensional flow cytometric results to the risk of relapse after achieving remission. Reported P values are two-sided. Results: Thirty-five of the 39 patients had bone marrow specimens available from the time that first morphologic remission was achieved. Leukemic blast cells were detected in the specimens from 19 (54%) of these 35 patients. Twenty-five of the 35 patients did not receive an allogeneic (i.e., from a different genetic background) bone marrow transplant during first morphologic remission, and 13 of 14 with residual leukemic cells experienced a relapse at a median time of 153 days after diagnosis (range, 48–863 days). Nine of the 11 patients who did not receive an allogeneic bone marrow transplant and lacked evidence of leukemic blast cells at first morphologic remission relapsed at a median time of 413 days after diagnosis (range, 321–794 days). Among the 10 individuals who received an allogeneic bone marrow transplant during first morphologic remission, five were positive for leukemic blast cells and five were negative; one of these patients (positive for leukemic blast cells) experienced a relapse 265 days after diagnosis, and three others died of transplant-related complications. The estimated risk of relapse during intervals of multidimensional flow cytometric positivity (i.e., intervals of remission for which the immediately preceding cytometry measurement was positive) was 2.8 times greater than that during negative intervals (95% confidence interval = 1.1–7.0; P = .02). Conclusions and Implications: Multidimensional flow cytometry identifies residual leukemia in more than half of the patients with AML who are in morphologic remission. The detection of leukemic blast cells in these patients by multidimensional flow cytometry is predictive of a more rapid relapse.
In this paper, we introduce a recently initiated research project conducted at Bushman Rock Shelter, on the northeastern edge of the Highveld plateau in Limpopo Province, South Africa. Previous ...excavations carried out at the site during the 1960s and 1970s exposed a deep and well-stratified sequence of c. 7 metres of archaeological deposits associated with Later and Middle Stone Age occupations (LSA and MSA). Owing to the lack of contextual information, Bushman Rock Shelter remains poorly studied despite recording cultural and palaeoenvironmental data that are key for the understanding of the South African Stone Age. Here, we propose a synthesis of the 1967-1976 excavations led by Hannes Eloffand provide general background information that will serve as a reference for future research. Our synthesis is based on previous publications by Ina Plug, as well as on Eloff's field diaries, which were thought to be lost. We complement these observations with data from our own 2014 field season, and pay tribute to the work previously done at the site. Finally, we discuss some aspects of the LSA/MSA contact at the site and comment on the presence of a bifacial lithic component in the upper MSA layers, which is reminiscent of the later Pietersburg.
Background. An acute type A aortic dissection is considered a surgical emergency. Review of the risk factors for a type A dissection showed that preoperative malperfusion was associated with a 22% ...(2/9) intraoperative mortality and an 89% (8/9) hospital mortality. Intraoperative deaths were secondary to pulmonary failure resulting from capillary leak; the remaining patients died of multiorgan failure resulting from reperfusion injury.
Methods. The surgical delay approach was adopted for malperfused patients, and treatment in these patients included percutaneous reperfusion, with aortic fenestration and branch stenting where appropriate. Twenty patients had a type A dissection and malperfusion shown by pulsed-wave Doppler echocardiography, transesophageal echocardiography, or spiral computed tomographic scanning. Malperfusion was documented by angiography. After reperfusion, all patients’ conditions were stabilized in the intensive care unit; intravenous beta-blockers were administered to decrease the maximum rate of increase of left ventricular pressure. Once patients completely recovered from the consequences of malperfusion, surgical repair was performed. Statistical comparison of the non-delay and delay groups was performed using Fisher’s exact test and Student’s
t test. Multiple logistic regression analysis was used to establish independent predictors for mortality.
Results. The mean delay to repair was 20 days (2 to 67 days). Four (31%) patients were discharged home and readmitted for operation. Three patients (15%) died preoperatively, 1 of retrograde dissection and rupture and 2 of reperfusion injury. Seventeen underwent surgical repair, with two deaths (12%); 15 (75%) were discharged, with an average follow-up of 16.8 months (
p < 0.003). Delay was the only independent predictor of outcome.
Conclusions. Patients with an acute type A dissection and malperfusion should undergo percutaneous reperfusion, and surgical repair should be delayed until the reperfusion injury resolves.
We study the polarization properties of extragalactic sources at 95 and 150 GHz in the SPTpol 500 deg2 survey. We estimate the polarized power by stacking maps at known source positions, and correct ...for noise bias by subtracting the mean polarized power at random positions in the maps. We show that the method is unbiased using a set of simulated maps with similar noise properties to the real SPTpol maps. We find a flux-weighted mean-squared polarization fraction $\langle$p2$\rangle$ = 8.9 ± 1.1 × 10-4 at 95 GHz and 6.9 ± 1.1 × 10-4 at 150 GHz for the full sample. This is consistent with the values obtained for a subsample of active galactic nuclei. For dusty sources, we find 95 percent upper limits of $\langle$p2$\rangle$95 < 16.9 × 10-3 and $\langle$p2$\rangle$150 < 2.6 × 10-3. We find no evidence that the polarization fraction depends on the source flux or observing frequency. The 1σ upper limit on measured mean-squared polarization fraction at 150 GHz implies that extragalactic foregrounds will be subdominant to the CMB E and B mode polarization power spectra out to at least ℓ ≲ 5700 (ℓ ≲ 4700) and ℓ ≲ 5300 (ℓ ≲ 3600), respectively, at 95 (150) GHz.
Here, we report the first detection of gravitational lensing due to galaxy clusters using only the polarization of the cosmic microwave background (CMB). The lensing signal is obtained using a new ...estimator that extracts the lensing dipole signature from stacked images formed by rotating the cluster-centered Stokes QU map cutouts along the direction of the locally measured background CMB polarization gradient. Using data from the SPTpol 500 deg2 survey at the locations of roughly 18 000 clusters with richness λ ≥ 10 from the Dark Energy Survey (DES) Year-3 full galaxy cluster catalog, we detect lensing at 4.8σ. The mean stacked mass of the selected sample is found to be (1.43 ± 0.40) × 1014M⊙ which is in good agreement with optical weak lensing based estimates using DES data and CMB-lensing based estimates using SPTpol temperature data. This measurement is a key first step for cluster cosmology with future low-noise CMB surveys, like CMB-S4, for which CMB polarization will be the primary channel for cluster lensing measurements.
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