AlloHSCT for inv(3)(q21;q26)/t(3;3)(q21;q26) AML : a report from the acute leukemia working party of the European society for blood and marrow transplantation

Acute myeloid leukemia with inv(3)(q21;q26.2)/t(3;3)(q21;q26.2) (3q26 AML) is a rare disease with poor prognosis and median survival ofPeer reviewe

On-target restoration of a split T cell-engaging antibody for precision immunotherapy

T cell-engaging immunotherapies are changing the landscape of current cancer care. However, suitable target antigens are scarce, restricting these strategies to very few tumor types. Here, we report on a T cell-engaging antibody derivative that comes in two complementary halves and addresses antigen combinations instead of single molecules. Each half, now coined hemibody, contains an antigen-specific single-chain variable fragment (scFv) fused to either the variable light (V-L) or variable heavy (V-H) chain domain of an anti-CD3 antibody. When the two hemibodies simultaneously bind their respective antigens on a single cell, they align and reconstitute the original CD3-binding site to engage T cells. Employing preclinical models for aggressive leukemia and breast cancer, we show that by the combinatorial nature of this approach, T lymphocytes exclusively eliminate dual antigen-positive cells while sparing single positive bystanders. This allows for precision targeting of cancers not amenable to current immunotherapies

PENGARUH ATOPI TERHADAP TIMBULNYA DERMATITIS KONTAK PADA MAHASISWIRNPENDIDIKAN DOKTER FAKULTAS KEDOKTERAN UNIVERSITAS SYIAH KUALA RNBANDA ACEH

Dermatitis kontak adalah inflamasi non infeksi pada kulit yang disebabkan karena pemaparan dengan suatu zat tertentu yang dapat mengiritasi kulit atau menyebabkan reaksi alergi. Perempuan lebih sering mengalami dermatitis kontak dibandingkan laki-laki. Atopi merupakan salah satu faktor predisposisi timbulnya dermatitis kontak. Penelitian ini bertujuan untuk mengetahui pengaruh atopi terhadap timbulnya dermatitis kontak pada mahasiswi Pendidikan Dokter Fakultas Kedokteran Universitas Syiah Kuala Banda Aceh. Penelitian ini bersifat analitik dengan pendekatan cross sectional. Data yang digunakan adalah data primer yang diperoleh dengan wawancara langsung pada responden. Uji statistik dengan menggunakan Chi Square diperoleh nilai p yang signifikan sebesar 0,00, ini berarti p < 0,05 maka secara statistik didapatkan hubungan antara atopi dengan dermatitis kontak dengan rasio prevalensi 2,17, artinya seseorang yang menderita atopi memiliki peluang sebesar 2,17 kali untuk mengalami dermatitis kontak dibandingkan dengan orang yang tidak menderita atopi. Bahan yang paling sering menyebabkan dermatitis kontak pada mahasiswi adalah deterjen dan kosmetik. Hasil penelitian yang diperoleh ada pengaruh atopi terhadap timbulnya dermatitis kontak pada mahasiswi Pendidikan Dokter FK Unsyiah Banda Aceh, dimana mahasiswi yang menderita atopi cenderung mengalami dermatitis kontak.Kata kunci: Atopi, Dermatitis kontak Alergi, Dermatitis kontak iritanBanda Ace

Final Evaluation of a Clinical Phase III Trial Comparing Treosulfan to Busulfan-Based Conditioning Therapy Prior to Allogeneic Hematopoietic Stem Cell Transplantation of Adult Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients Ineligible to Standard Myeloablative Regimens

Background Allogeneic hematopoietic stem cell transplantation (HCT) remains a challenge in elderly and comorbid AML and MDS patients. This patient population is at increased risk for non-relapse mortality (NRM) when treated with standard myeloablative conditioning and was selected to compare a newly developed treosulfan-based with a well-established reduced intensity busulfan-based preparative regimen in a prospective randomized clinical phase III trial. Methods Adult patients with AML in remission or MDS scheduled for HCT from matched related or unrelated donors, aged ≥50 years or with a comorbidity index (HCT-CI) of >2 were enrolled by a central stratified randomization procedure. Treatment arms consisted of intravenous (IV) treosulfan (10 g/m²/day [d-4 to d-2]) or IV busulfan (3.2 mg/kg/day [d-4 to d-3]), both combined with IV fludarabine (30 mg/m²/day [d-6 to d-2]). The primary objective was to compare event-free survival (EFS) at two years with relapse/progression of disease, graft failure, or death reported as events. Secondary endpoints were safety evaluation (according to CTCAE v4.03), engraftment, chimerism, overall survival (OS), relapse/progression incidence (RI), NRM and acute or chronic GvHD. After a previously conducted confirmatory interim analysis (based on 476 patients), which resulted in early termination of patient accrual due to significant non-inferiority of treosulfan treatment with improved EFS, NRM and OS (Beelen et al., ASH 2017), results of the final analysis of all 570 randomized patients including post surveillance data are provided here. Results Median age of the 551 patients (352 AML; 199 MDS) included in the full analysis set (268 treosulfan; 283 busulfan) was 60 years (range: 31, 70). Frequencies of early adverse events (d-6 to d+28) and incidences of acute and chronic GvHD were largely comparable between the two regimens, while extensive chronic GvHD was numerically in favor of treosulfan (19.7% vs. 26.7%; p=0.0750). Primary neutrophil recovery at day +28 was comparable, while the rate of complete donor-type chimerism (day +28) was higher after treosulfan (93.2% vs. 83.3%; p Conclusions Final evaluation of this phase III trial substantiates the previous confirmatory analysis resulting in significantly improved survival after treosulfan-based conditioning. Due to the reduction of NRM a major clinical benefit of the new treosulfan conditioning regimen was demonstrated in the selected AML/MDS patient population

Variant signaling topology at the cancer cell–T-cell interface induced by a two-component T-cell engager

No abstract available

Silencing of CDK2, but not CDK1, separates mitogenic from anti-apoptotic signaling, sensitizing p53 defective cells for synthetic lethality

<p>Small molecule inhibitors targeting CDK1/CDK2 have been clinically proven effective against a variety of tumors, albeit at the cost of profound off target toxicities. To separate potential therapeutic from toxic effects, we selectively knocked down CDK1 or CDK2 in p53 mutated HACAT cells by siRNA silencing. Using dynamic, cell cycle wide proteome arrays, we observed minor changes in overall abundance of proteins critically involved in cell cycle transition despite profound G₂/M or G₁/S arrest, respectively. Employing phospho site specific analyses, we identified uncoupled mitogenic, yet pro-apoptotic signaling from counter balancing anti-apoptotic activity in CDK2 disrupted cells. Moreover, a crucial role of CDK2 activity in early serum response was observed, extending well-established roles of CDKs outside their cell cycle regulating functions. In contrast, disruption of CDK1 only marginally affected phosphorylation events of crucial signaling nodes prior to G₂/S transition. The data presented here suggest that the temporal separation of pro- and anti-apoptotic pathways by selective inhibition of CDK2 disrupts coherent signaling modules and may synergize with anti-proliferative drugs, averting toxic side effects from CDK1 inhibition.</p