Functional characterization of the PI3K/AKT/MTOR signaling pathway for targeted therapy in B-precursor acute lymphoblastic leukemia.

B-cell precursor acute lymphoblastic leukemias (B-ALL) are characterized by the activation of signaling pathways, which are involved in survival and proliferation of leukemia cells. Using an unbiased shRNA library screen enriched for targeting signaling pathways, we identified MTOR as the key gene on which human B-ALL E2A-PBX1 RCH-ACV cells are dependent. Using genetic and pharmacologic approaches, we investigated whether B-ALL cells depend on MTOR upstream signaling pathways including PI3K/AKT and the complexes MTORC1 or MTORC2 for proliferation and survival in vitro and in vivo.

International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data.

The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification.

mTORC1 Inhibition Protects Human Regulatory T Cells From Granzyme-B-Induced Apoptosis.

Regulatory T cells (T) have shown great promise as a means of cellular therapy in a multitude of allo- and auto-immune diseases-due in part to their immunosuppressive potency. Nevertheless, the clinical efficacy of human T in patients has been limited by their poor homeostasis. To avert apoptosis, T require stable antigenic (CD3ζ/T-cell-receptor-mediated), co-stimulatory (CD28-driven), and cytokine (IL-2-dependent) signaling.

Oncological Safety and Recurrence in the Surgical Treatment of Atypical Fibroxanthoma and Pleomorphic Dermal Sarcoma of the Scalp.

Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are two distinct designations for a rare dermal sarcoma entity. These tumors arise predominantly in the sun-damaged skin of elderly patients. Although both AFX and PDS have a similar clinical presentation and nearly identical genetic features, they significantly differ in prognosis.

Integrated use of PD-1 inhibition and transarterial chemoembolization for hepatocellular carcinoma: evaluation of safety and efficacy in a retrospective, propensity score-matched study.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized treatment of advanced hepatocellular carcinoma. Integrated use of transarterial chemoembolization (TACE), a locoregional inducer of immunogenic cell death, with ICI has not been formally assessed for safety and efficacy outcomes.

Methods: From a retrospective multicenter dataset of 323 patients treated with ICI, we identified 31 patients who underwent >1 TACE 60 days before or concurrently, with nivolumab at a single center.

Sex similarities and differences in the reverse and anti-remodeling effect of pressure unloading therapy in a rat model of aortic banding and debanding.

Investigating the effect of sex on pressure unloading therapy in a clinical scenario is limited by several nonstandardized factors. Hence, we sought to study sex-related similarities and differences under laboratory conditions. Pressure overload was induced in male and female rats by aortic banding (AB) for 6 and 12 wk.

Age-related outcome of facial reanimation surgery using cross face nerve graft and gracilis free functional muscle transfer-A retrospective cohort study.

Background: Free functional muscle transfer has become the criterion standard for the treatment of long-standing flaccid facial paralysis. Clinical experience suggests that a two-stage approach using a cross-face nerve graft (CFNG) as a donor nerve for free functional muscle transfers (FFMT) is less successful in older patients when compared to the pediatric population. However, clear data and scientific evidence are still rare.

Comparison of fludarabine-melphalan and fludarabine-treosulfan as conditioning prior to allogeneic hematopoietic cell transplantation-a registry study on behalf of the EBMT Acute Leukemia Working Party.

In recent years considerable variations in conditioning protocols for allogeneic hematopoietic cell transplantation (allo-HCT) protocols have been introduced for higher efficacy, lower toxicity, and better outcomes. To overcome the limitations of the classical definition of reduced intensity and myeloablative conditioning, a transplantation conditioning intensity (TCI) score had been developed. In this study, we compared outcome after two frequently used single alkylator-based conditioning protocols from the intermediate TCI score category, fludarabine/melphalan 140 mg/m (FluMel) and fludarabine/treosulfan 42 g/m (FluTreo) for patients with acute myeloid leukemia (AML) in complete remission (CR).

The association between objective measurements of sleep quality and postural control in adults: A systematic review.

We systematically reviewed the association between objective sleep quality and postural control based on objective measurements. We searched the electronic databases PUBMED, CINAHL, SCOPUS and Web of Science for studies assessing the relationship between objective measurements of sleep and postural control or gait performance among adults above age 18. All types of articles until April 2020 were considered.

T cell-attracting CCL18 chemokine is a dominant rejection signal during limb transplantation.

Limb transplantation is a life-changing procedure for amputees. However, limb recipients have a 6-fold greater rejection rate than solid organ transplant recipients, related in part to greater immunogenicity of the skin. Here, we report a detailed immunological and molecular characterization of individuals who underwent bilateral limb transplantation at our institution.

Effect of Combination Antibiotic Empirical Therapy on Mortality in Neutropenic Cancer Patients with Pneumonia.

To assess the effect of combination antibiotic empirical therapy on 30-day case-fatality rate in neutropenic cancer patients with Pseudomonas aeruginosa (PA) bacteremic pneumonia. This was a multinational, retrospective cohort study of neutropenic onco-hematological patients with PA bloodstream infection (BSI) (2006−2018). The effect of appropriate empirical combination therapy, appropriate monotherapy and inappropriate empirical antibiotic therapy [IEAT] on 30-day case-fatality was assessed only in patients with PA bacteremic pneumonia.

Development of a NanoBRET assay to validate inhibitors of Sirt2-mediated lysine deacetylation and defatty-acylation that block prostate cancer cell migration.

Sirtuin2 (Sirt2) with its NAD-dependent deacetylase and defatty-acylase activities plays a central role in the regulation of specific cellular functions. Dysregulation of Sirt2 activity has been associated with the pathogenesis of many diseases, thus making Sirt2 a promising target for pharmaceutical intervention. Herein, we present new high affinity Sirt2 selective Sirtuin-Rearranging Ligands (SirReals) that inhibit both Sirt2-dependent deacetylation and defatty-acylation and in cells.

Neurodegeneration and neuroinflammation are linked, but independent of alpha-synuclein inclusions, in a seeding/spreading mouse model of Parkinson's disease.

A key pathological process in Parkinson's disease (PD) is the transneuronal spreading of α-synuclein. Alpha-synuclein (α-syn) is a presynaptic protein that, in PD, forms pathological inclusions. Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions.

Patterns-of-Care Analysis for Radiotherapy of Elderly Head-and-Neck Cancer Patients: A Trinational Survey in Germany, Austria and Switzerland.

Objectives: The number of elderly head-and-neck squamous cell carcinoma (HNSCC) patients is increasing, and clinical trials defining the standard of care either excluded or underrepresented elderly patients. This leaves physicians with a challenging and highly individual treatment decision largely lacking clinical evidence.

Methods: A tri-national patterns-of-care survey was sent to all members of the German (DEGRO), Austrian (ÖGRO), and Swiss (SRO/SSRO) national societies of radiation oncology.

Sex-related differences of early cardiac functional and proteomic alterations in a rat model of myocardial ischemia.

Background: Reduced cardiovascular risk in premenopausal women has been the focus of research in recent decades. Previous hypothesis-driven experiments have highlighted the role of sex hormones on distinct inflammatory responses, mitochondrial proteins, extracellular remodeling and estrogen-mediated cardioprotective signaling pathways related to post-ischemic recovery, which were associated with better cardiac functional outcomes in females. We aimed to investigate the early, sex-specific functional and proteomic changes following myocardial ischemia in an unbiased approach.

Designed membrane protein heterodimers and control of their affinity by binding domain and membrane linker properties.

Many membrane proteins utilize dimerization to transmit signals across the cell membrane regulation of the lateral binding affinity. The complexity of natural membrane proteins hampers the understanding of this regulation on a biophysical level. We designed simplified membrane proteins from well-defined soluble dimerization domains with tunable affinities, flexible linkers, and an inert membrane anchor.

Simple traumatic elbow dislocations; benefit from early functional rehabilitation: A systematic review with meta-analysis including PRISMA criteria.

Introduction: Elbow dislocation is the second most frequent joint dislocation after shoulder dislocation. They have a high relevance because they can result in subsequent damage and limitations in range of motion. The treatment options are controversially discussed.

Rationale and design of the CRAFT (Continuous ReAssessment with Flexible ExTension in Rare Malignancies) multicenter phase II trial.

Background: Approvals of cancer therapeutics are primarily disease entity specific. Current molecular diagnostic approaches frequently identify actionable alterations in rare cancers or rare subtypes of common cancers for which the corresponding treatments are not approved and unavailable within clinical trials due to entity-related eligibility criteria. Access may be negotiated with health insurances.

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia.

Decitabine (5-aza-2'-deoxycytidine) is a hypomethylating agent used in the treatment of acute myeloid leukemia (AML). Decitabine inhibits DNA methyltransferases, causing DNA hypomethylation, and leading amongst others to re-expression of silenced tumor suppressor genes. Decitabine is indicated for the treatment of adult patients with newly diagnosed de novo or secondary AML who are not eligible for standard induction chemotherapy.

Radical reduction and reconstruction for male genital elephantiasis: Superficial circumflex iliac artery perforator (SCIP) lymphatic flap transfer after elephantiasis tissue resection.

Background: Treatment of elephantiasis, the most severe lymphedema, is challenging. Management of male genital elephantiasis (MGE) is even more challenging than extremity elephantiasis due to its complicated shape and high risk of lymphorrhea and cellulitis. Complete resection of fibrous tissue and lymphatic reconstruction is considered to be ideal for the treatment of MGE.