Diminished γδ T Cells during Murine Allergic Skin Inflammation Is Mediated by IL-4 Signaling in Keratinocytes.

Atopic dermatitis results in diminished barrier function and altered production of antimicrobial peptides. Dendritic epidermal T cells (DETCs) play an important role in the wound repair and inflammation process. Our previous work identified an IL-4-dependent loss of DETCs in Stat6VT mice and in the MC903-induced skin inflammation mouse model. However, the mechanisms through which IL-4 mediates the loss of DETCs are unclear. In this study, we show that IL-4Rα germline knockout mice (Il4ra-/-) have increased DETCs, faster wound healing, and increased epidermal differentiation complex gene and fibronectin expression. The absence of IL-4Rα minimized the MC903-induced loss of DETCs, and reciprocal bone marrow chimera experiments in Il4ra-/- and wild-type mice demonstrated structural nonhematopoietic IL-4-responsive cell-mediated DETC homeostasis. Skin keratinocyte-derived IL-15 decreased dramatically in the MC903 model, while injection of IL-15 rescued DETC loss by promoting DETC proliferation and limiting apoptosis. Conditional deletion of IL-4Rα from keratinocytes using Il4rafl/fl K14-Cre mice showed an increase of DETCs, increased IL-15 production, and diminished skin inflammation following wounding. These results suggest that IL-4-dependent effects on DETCs in allergic skin inflammation are mediated by the IL-4Rα receptor of keratinocytes.

Onboard cone-beam CT-based replan evaluation for head and neck proton therapy.

PURPOSE: Quality assurance computed tomography (QACT) is the current clinical practice in proton therapy to evaluate the needs for replan. QACT could falsely indicate replan because of setup issues that would be solved on the treatment machine. Deforming the treatment planning CT (TPCT) to the pretreatment CBCT may eliminate this issue. We investigated the performance of replan evaluation based on deformed TPCT (TPCTdir) for proton head and neck (H&N) therapy. METHODS AND MATERIALS: Twenty-eight H&N datasets along with pretreatment CBCT and QACT were used to validate the method. The changes in body volume were analyzed between the no-replan and replan groups. The dose on the TPCTdir, the deformed QACT (QACTdir), and the QACT were calculated by applying the clinical plans to these image sets. Dosimetric parameters' changes, including ΔD95, ΔDmean, and ΔD1 for the clinical target volumes (CTVs) were calculated. Receiver operating characteristic curves for replan evaluation based on ΔD95 on QACT and TPCTdir were calculated, using ΔD95 on QACTdir as the reference. A threshold for replan based on ΔD95 on TPCTdir is proposed. The specificities for the proposed method were calculated. RESULTS: The changes in the body contour were 95.8 ± 83.8 cc versus 305.0 ± 235.0 cc (p < 0.01) for the no-replan and replan groups, respectively. The ΔD95, ΔDmean, and ΔD1 are all comparable for all the evaluations. The differences between TPCTdir and QACTdir evaluations were 0.30% ± 0.86%, 0.00 ± 0.22 Gy, and -0.17 ± 0.61 Gy for CTV ΔD95, ΔDmean, and ΔD1, respectively. The corresponding differences between the QACT and QACTdir were 0.12% ± 1.1%, 0.02 ± 0.32 Gy, and -0.01 ± 0.71 Gy. CTV ΔD95 > 2.6% in TPCTdir was chosen as the threshold to trigger QACT/replan. The corresponding specificity was 94% and 98% for the clinical practice and the proposed method, respectively. CONCLUSIONS: The replan evaluation based on TPCTdir provides better specificity than that based on the QACT.

A review of FLT3 inhibitors in acute myeloid leukemia.

FLT3 mutations are the most common genetic aberrations found in acute myeloid leukemia (AML) and associated with poor prognosis. Since the discovery of FLT3 mutations and their prognostic implications, multiple FLT3-targeted molecules have been evaluated. Midostaurin is approved in the U.S. and Europe for newly diagnosed FLT3 mutated AML in combination with standard induction and consolidation chemotherapy based on data from the RATIFY study. Gilteritinib is approved for relapsed or refractory FLT3 mutated AML as monotherapy based on the ADMIRAL study. Although significant progress has been made in the treatment of AML with FLT3-targeting, many challenges remain. Several drug resistance mechanisms have been identified, including clonal selection, stromal protection, FLT3-associated mutations, and off-target mutations. The benefit of FLT3 inhibitor maintenance therapy, either post-chemotherapy or post-transplant, remains controversial, although several studies are ongoing.

Sex- and context-dependent effects of acute isolation on vocal and non-vocal social behaviors in mice.

Humans are extraordinarily social, and social isolation has profound effects on our behavior, ranging from increased social motivation following short periods of social isolation to increased anti-social behaviors following long-term social isolation. Mice are frequently used as a model to understand how social isolation impacts the brain and behavior. While the effects of chronic social isolation on mouse social behavior have been well studied, much less is known about how acute isolation impacts mouse social behavior and whether these effects vary according to the sex of the mouse and the behavioral context of the social encounter. To address these questions, we characterized the effects of acute (3-day) social isolation on the vocal and non-vocal social behaviors of male and female mice during same-sex and opposite-sex social interactions. Our experiments uncovered pronounced effects of acute isolation on social interactions between female mice, while revealing more subtle effects on the social behaviors of male mice during same-sex and opposite-sex interactions. Our findings advance the study of same-sex interactions between female mice as an attractive paradigm to investigate neural mechanisms through which acute isolation enhances social motivation and promotes social behavior.

The development and clinical use of oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes: dawn of the total oral therapy era.

INTRODUCTION: Intravenous and subcutaneous hypomethylating agents have held a key role in myelodysplastic syndrome, chronic myelomonocytic leukemia and acute myeloid leukemia treatment. Following the approval of the cedazuridine/decitabine combination, ASTX727, as well as development of an oral formulation of azacitidine, CC-486, in the USA in 2020, these agents could gradually replace their injectable counterparts. AREAS COVERED: ASTX727 is approved for the treatment of adult patients with intermediate 1 or high-risk MDS as well as those with chronic myelomonocytic leukemia based on the findings from the ASTX727-01-B and ASCERTAIN trials. Oral azacitidine (CC-486) is approved for maintenance treatment of acute myeloid leukemia after induction chemotherapy for patients unfit for allogeneic hematopoietic cell transplant based on the findings from the QUAZAR AML-001 trial. EXPERT OPINION: Oral hypomethylating agent formulations have the potential to offer a convenient alternative to injectable hypomethylating agent. However, their current FDA-approved indications are narrow and efficacy needs to be shown in clinical trials before considering use beyond the approved indications. Areas of special interest include: identification of predictive biomarkers for clinical benefit, post-transplant maintenance therapy, and potential combination therapies with other oral agents such as venetoclax, IDH and FLT3 inhibitors.

Venetoclax for the treatment of elderly or chemotherapy-ineligible patients with acute myeloid leukemia: a step in the right direction or a game changer?

INTRODUCTION: Acute myeloid leukemia (AML) is an aggressive malignancy with poor prognosis and high rates of relapse, especially in elderly patients who are ineligible to receive intensive chemotherapy. Venetoclax, an oral BCL-2 inhibitor, is approved by the Food and Drug Administration in combination with hypomethylating agents or low-dose cytarabine in newly-diagnosed AML patients who are ineligible to receive intensive chemotherapy. Confirmatory phase III VIALE-A and VIALE-C trials showed a composite complete remission rate of 66.4% and 48%, respectively. Thus, further validating venetoclax as an attractive therapeutic option in the AML treatment landscape. AREAS COVERED: A review of venetoclax in AML, focusing on preclinical and clinical data, toxicity profile, and mechanisms of resistance; and its strengths and weaknesses in regards to its current and future role in AML treatment is discussed. To find relevant studies, authors searched PubMed/Medline and ClinicalTrials.gov. EXPERT OPINION: The introduction of venetoclax-based combination therapies has greatly expanded the therapeutic options for elderly and chemotherapy-ineligible AML patients. Additional studies with extended follow-up are necessary to address remaining open questions such as (I) durability of responses, (II) head-to-head comparisons with intensive chemotherapy in selected patients (e.g. TP53 mutations), and (III) novel triplet combinations using an HMA-venetoclax backbone.

High dose cyclophosphamide for cytoreduction in patients with acute myeloid leukemia with hyperleukocytosis or leukostasis.

Hyperleukocytosis may lead to multiple medical emergencies. Hydroxyurea, intensive chemotherapy, and leukapheresis are used for cytoreduction. However, there is little data regarding the best approach. Here, we report on the efficacy and safety of high dose cyclophosphamide (HDCy; 60 mg/kg). 27 patients with acute myeloid leukemia or blast phase chronic myeloid leukemia who presented with white blood cell count (WBC) of ≥50x109/L or symptoms of leukostasis were treated with HDCy. Primary endpoint was early mortality (death within seven days of admission). Median WBC was 107 × 109/L at time of HDCy; 74% had leukostasis symptoms at presentation. Eight (29.6%) patients died within seven days of admission. Sustained WBC reduction was achieved in 18/24 (75%) evaluable patients with median nadir of 0.25 × 109/L. Adverse effects attributed to HDCy included tumor lysis syndrome (n = 7; 25.9%), disseminated intravascular coagulopathy (n = 5; 18.5%), and hemorrhagic cystitis (n = 1; 3.7%). HDCy was effective for cytoreduction and adverse effects were acceptable.

Electrical Stimulation of pediatric cardiac-derived c-kit+ progenitor cells improves retention and cardiac function in right ventricular heart failure.

Nearly 1 in every 120 children born has a congenital heart defect. Although surgical therapy has improved survival, many of these children go on to develop right ventricular heart failure (RVHF). The emergence of cardiovascular regenerative medicine as a potential therapeutic strategy for pediatric HF has provided new avenues for treatment with a focus on repairing or regenerating the diseased myocardium to restore cardiac function. Although primarily tried using adult cells and adult disease models, stem cell therapy is relatively untested in the pediatric population. Here, we investigate the ability of electrical stimulation (ES) to enhance the retention and therapeutic function of pediatric cardiac-derived c-kit+ progenitor cells (CPCs) in an animal model of RVHF. Human CPCs isolated from pediatric patients were exposed to chronic ES and implanted into the RV myocardium of rats. Cardiac function and cellular retention analysis showed electrically stimulated CPCs (ES-CPCs) were retained in the heart at a significantly higher level and longer time than control CPCs and also significantly improved right ventricular functional parameters. ES also induced upregulation of extracellular matrix and adhesion genes and increased in vitro survival and adhesion of cells. Specifically, upregulation of ß1 and ß5 integrins contributed to the increased retention of ES-CPCs. Lastly, we show that ES induces CPCs to release higher levels of pro-reparative factors in vitro. These findings suggest that ES can be used to increase the retention, survival, and therapeutic effect of human c-kit+ progenitor cells and can have implications on a variety of cell-based therapies. Stem Cells 2019;37:1528-1541.

A drug safety evaluation of mogamulizumab for the treatment of cutaneous T-Cell lymphoma.

Introduction: Cutaneous T-cell lymphomas (CTCL) are rare non-Hodgkin lymphomas of skin-homing T-cells that initially or mainly manifest cutaneously. Treatment of CTCL is challenging given the disease states' varying presentation and prognosis. Systemic treatment options often lack comparative evidence and have relatively low response rates and short duration of response. The recent Food and Drug Administration (FDA) approval of mogamulizumab in adult patients with relapsed or refractory (R/R) CTCL after at least one prior line of therapy provided a new treatment option to patients with advanced disease. Areas covered: The authors discuss basic information about CTCL and mogamulizumab's mechanism of action. Then, the authors discuss the agent's efficacy. Finally, the authors evaluate the safety of mogamulizumab in comparison to other agents available in CTCL. Expert opinion: Mogamulizumab has been shown to be an effective and well tolerated therapy for patients with relapsed and refractory MF/SS with excellent activity in the circulating component of the disease.

A Review of Growth Factor Support in Bloodless Autologous Hematopoietic Stem Cell Transplant.

Bloodless autologous hematopoietic cell transplantation is associated with risks of severe bleeding and profound anemia. RBC or platelet transfusions are often used to prevent these hematologic complications. However, in patients such as Jehovah's Witnesses who refuse major blood components, the lack of transfusion support is not an absolute contraindication to an autologous hematopoietic cell transplant. Pennsylvania Hospital performed the world's first bloodless hematopoietic cell transplant more than 15 years ago and has gradually improved its technique with a sizable patient population. Erythropoiesis-stimulating agents were successfully employed as part of their pretransplant regimen to prevent severe anemia. Thrombopoietin agonists' potential role in bloodless transplant is also currently being explored. Although there is limited literature, available reports in combination with physiologic reasoning may support the use of these growth factors to promote transplant success. These agents offer potential benefit and may be of utility in minimizing complications of a bloodless transplant. In this review, we summarize the available literature and offer insight into how we may incorporate growth factors to allow bloodless autologous hematopoietic cell transplantation to be an available option to patients who may otherwise be denied.

Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis.

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal proliferation of differentiated myeloid cells leading to bone marrow fibrosis, cytopenias and extramedullary hematopoiesis. In late 2019, the FDA approved the highly selective JAK2 inhibitor, fedratinib, for intermediate-2 or high-risk primary or secondary MF, making it the second drug approved for MF after ruxolitinib, a JAK1/2 inhibitor, which was approved for MF in 2011. The approval of fedratinib was based on phase II trials and the phase III JAKARTA trial, in which the drug significantly reduced splenomegaly and symptom burden compared to placebo, including some patients previously treated with ruxolitinib. The main side effects of fedratinib include anemia, gastrointestinal symptoms, and elevations in liver transaminases. Fedratinib also has ablack box warning for encephalopathy, although this occurred only in about 1% of the treated patients, most of which were ultimately felt not to represent Wernicke's encephalopathy. Nonetheless, monitoring of thiamine levels and supplementation are recommended especially in high-risk patients. This concern has led to a prolonged clinical hold and delayed the drug approval by several years during which the drug exchanged manufacturers, highlighting the need for meticulous investigation and adjudication of serious, but rare, adverse events in drug development that could end up preventing drugs with favorable risk/benefit ratio from being approved. In this review, we discuss the pharmacokinetic data and efficacy, as well as the toxicity results of clinical trials of fedratinib. We also review ongoing trials of JAK inhibitors in MF and explore future treatment options for MF patients who are refractory to ruxolitinib.

Stakeholder views on returning research results.

While the disclosure of research findings is relevant to all types of biomedical research, it has garnered particular attention with respect to genetics and genomics research due to some of the unique aspects of the data and the high public profile of the field. In this chapter, we review the attitudes of stakeholders (research participants, policymakers, and researchers) to define areas of consensus regarding the issue of returning research results across and within groups. In addition to stakeholder attitudes about obligations and interest in research results, other major related issues related to returning research results, such as informed consent, communication of research results, and cost, are discussed. Given the consensus between stakeholders to return summary reports of a study's outcomes and individual research results of clinical significance, we conclude that the time has come to encourage, if not require, researchers to consider these issues in the developmental planning stages of a project and to plan and budget accordingly.

Benefits of Bt cotton counterbalanced by secondary pests? Perceptions of ecological change in China.

In the past, scientific research has predicted a decrease in the effectiveness of Bt cotton due to the rise of secondary and other sucking pests. It is suspected that once the primary pest is brought under control, secondary pests have a chance to emerge due to the lower pesticide applications in Bt cotton cultivars. Studies on this phenomenon are scarce. This article furnishes empirical evidence that farmers in China perceive a substantial increase in secondary pests after the introduction of Bt cotton. The research is based on a survey of 1,000 randomly selected farm households in five provinces in China. We found that the reduction in pesticide use in Bt cotton cultivars is significantly lower than that reported in research elsewhere. This is consistent with the hypothesis suggested by recent studies that more pesticide sprayings are needed over time to control emerging secondary pests, such as aphids, spider mites, and lygus bugs. Apart from farmers' perceptions of secondary pests, we also assessed their basic knowledge of Bt cotton and their perceptions of Bt cotton in terms of its strengths and shortcomings (e.g., effectiveness, productivity, price, and pesticide use) in comparison with non-transgenic cotton.

The enhancing effects of the light chain on heavy chain secretion in split delivery of factor VIII gene.

Coagulation factor VIII (FVIII) is secreted as a heterodimer consisting of a heavy chain (HC) and a light chain (LC), which can be expressed independently and reassociate with recovery of biological activity. Because of the size limitation of adeno-associated virus (AAV) vectors, a strategy for delivering the HC and LC separately has been developed. However, the FVIII HC is secreted 10-100-fold less efficiently than the LC. In this study, we demonstrated that the F309S mutation and enhanced B-domain glycosylations alone are not sufficient to improve FVIII HC secretion, which suggested a role of the FVIII LC in regulating HC secretion. To characterize this role of the FVIII LC, we compared FVIII HC secretion with and without the LC via post-translational protein trans-splicing. As demonstrated in vitro, ligation of the LC to the HC significantly increased HC secretion. Such HC secretion increases were also confirmed in vivo by hydrodynamic injection of FVIII intein plasmids into hemophilia A mice. Moreover, similar enhancement of HC secretion can also be observed when the LC is supplied in trans, which is probably due to the spontaneous association of the HC and the LC in the secretion pathway. In sum, enhancing the secretion of the FVIII HC polypeptide may require the proper association of the FVIII LC polypeptide in cis or in trans. These results may be helpful in designing new strategies to improve FVIII gene delivery.