DL4

During B cell development, cells progress through multiple developmental stages with the pro-B cell stage defining commitment to the B cell lineage. YY1 is a ubiquitous transcription factor that is capable of both activation and repression functions. We find here that knockout of YY1 at the pro-B cell stage eliminates B lineage commitment. YY1 knockout pro-B cells can generate T lineage cells in vitro using the OP9- DL4 feeder system, as well as in vivo after injection into sub-lethally irradiated Rag1 -/- mice...

BACKGROUND: Current approved chimeric antigen receptor (CAR) T-cell products are autologous cell therapies that are costly and poorly accessible to patients. We aimed to evaluate the safety and antitumor activity of a novel off-the-shelf anti-CD19 CAR-engineered allogeneic double-negative T cells (RJMty19) in patients with relapsed/refractory large B-cell lymphoma. We report the results from a first-in-human, open-label, single-dose, phase 1 study of allogeneic CD19-specific CAR double-negative T (CAR-DNT) cells...

OBJECTIVE: Platinum-resistant epithelial ovarian cancer (EOC), recurrent endometrial cancer (EC), and triple negative breast cancer (TNBC) are difficult to treat after failing standard therapies. This phase I study evaluated mirvetuximab soravtansine (MIRV) and gemcitabine in patients with recurrent FRα-positive EOC, EC, or TNBC to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) (primary endpoint). METHODS: FRα-positive patients with platinum-resistant EOC, EC, or TNBC with ≤4 prior chemotherapy regimens (2 for EC) were enrolled...

INTRODUCTION: Metastatic uveal melanoma (MUM) has a poor prognosis and treatment options are limited. These patients do not typically experience durable responses to immune checkpoint inhibitors (ICIs). Oncolytic viruses (OV) represent a novel approach to immunotherapy for patients with MUM. METHODS: We developed an OV with a Vesicular Stomatitis Virus (VSV) vector modified to express interferon-beta (IFN-β) and Tyrosinase Related Protein 1 (TYRP1) (VSV-IFNβ-TYRP1), and conducted a Phase 1 clinical trial with a 3 + 3 design in patients with MUM...

Controlling vertical phase separation of the active layer to enable efficient exciton dissociation and charge carrier transport is crucial to boost power conversion efficiencies (PCEs) of pseudo-planar heterojunction (PPHJ) organic solar cells (OSCs). However, how to optimize the vertical phase separation of PPHJ OSCs via molecule design is rarely reported yet. Herein, ternary polymerization strategy is employed to develop a series of polymer donors, DL1-DL4, and regulate their solubility, molecular aggregation, molecular orientation and miscibility, thus efficiently manipulating vertical phase separation in PPHJ OSCs...

The purposeful development of synthetic antibacterial compounds requires an understanding of the relationship between effects of compounds and their chemical structure. This knowledge can be obtained by studying changes in bacteria ultrastructure under the action of antibacterial compounds of a certain chemical structure. Our study was aimed at examination of ultrastructural changes in S. aureus cells caused by polycationic amphiphile based on 1,4‒diazabicyclo[2.2.2]octane (DL4 12), ciprofloxacin and their hybrid (DL5 Cip6); the samples were incubated for 15 and 45 min...

INTRODUCTION: Dermoscopy is a safe, rapid, and non-invasive tool that aids in the clinical examination of pigmented and non-pigmented lesions. The upward trend in the use of dermoscopy can be attributed to the availability of compact hand-held and sophisticated dermoscopes, that are small enough to be carried around in a pocket. The extent of dermoscopy is not only limited to the evaluation of cutaneous lesions but also involves its use in the assessment of mucosal lesions along with lesions of hair and nails...

INTRODUCTION: The evaluation of american cutaneous leishmaniasis (CL) and sporotrichosis (SP) with dermoscopy may improve the diagnosis accuracy and clinical monitoring. OBJECTIVES: To describe the dermoscopic findings and patterns of skin lesions of patients with CL and SP followed up at the Laboratory of Clinical Research and Surveillance in Leishmaniasis (LaPClinVigiLeish), Evandro Chagas National Institute of Infectious Diseases (INI), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil...

<b/>Electrochemical-assisted microbial degradation technology was considered a crucial strategy to reduce micropollutants, but the mechanism of the pulsed electric field (PEF) in affecting biodegradation had not been systematically studied. This study aimed to construct a bio-electrochemical system (BES) using PEF to investigate its effect on the degradation of triclosan (TCS) by the aerobic bacterium Bacillus sp. DL4. The operating optimal parameters for the BES (i.e., 0.01 A of the pulsed current, 1000 Hz of the pulse frequency, Fe (+) - C (-) of the plate materials, 4 cm of the plate spacing) were obtained by batch experiments...

Transduced mouse immature thymocytes can be differentiated into T cells in vitro using the delta-like 4-expressing bone marrow stromal cell line co-culture system (OP9-DL4). As retroviral transduction requires dividing cells for transgene integration, OP9-DL4 provides a suitable in vitro environment for cultivating hematopoietic progenitor cells. This is particularly advantageous when studying the effects of the expression of a specific gene during normal T cell development and leukemogenesis, as it allows researchers to circumvent the time-consuming process of generating transgenic mice...

BACKGROUND: In preclinical studies, combining M9241 (a novel immunocytokine containing interleukin (IL)-12 heterodimers) with avelumab (anti-programmed death ligand 1 antibody) resulted in additive or synergistic antitumor effects. We report dose-escalation and dose-expansion results from the phase Ib JAVELIN IL-12 trial investigating M9241 plus avelumab. METHODS: In the dose-escalation part of JAVELIN IL-12 (NCT02994953), eligible patients had locally advanced or metastatic solid tumors; in the dose-expansion part, eligible patients had locally advanced or metastatic urothelial carcinoma (UC) that had progressed with first-line therapy...

BACKGROUND: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) can inhibit tumor proliferation, angiogenesis, and restore apoptosis in preclinical pediatric solid tumor models. We conducted a phase 1 trial to determine the maximum tolerated dose (MTD) of simvastatin with topotecan and cyclophosphamide in children with relapsed/refractory solid and central nervous system (CNS) tumors. METHODS: Simvastatin was administered orally twice daily on days 1-21, with topotecan and cyclophosphamide intravenously on days 1-5 of a 21-day cycle...

Alopecia areata (AA) and trichotillomania (TTM) are the two common causes of localised non scarring alopecia. While AA is an autoimmune disorder, TTM is an impulse control disorder which makes the treatment of the two entities completely different. Trichoscopy is a non-invasive tool used to diagnose hair disorders, which not only is extremely helpful in diagnosing AA and TTM but also differentiates them from other hair disorders as well. The aim of our study is to describe the various trichoscopic features of AA and TTM and to compare the frequency of each trichoscopic feature in order to establish diagnostic clues for differentiating AA and TTM...

Introduction Hyperkeratotic lesions on the palms and soles are one of the most frequent clinical presentations encountered in dermatological practice, with a myriad of underlying etiologies that closely resemble one another and are clinically indistinguishable. Histopathological examination is the tool used by dermatologists to arrive at a final diagnosis, but it is invasive and not feasible under all circumstances. Dermoscopy is a new age, increasingly popular, noninvasive diagnostic technique of great value that is used to diagnose underlying etiology by acting as a bridge between clinical and histopathological pictures...

INTRODUCTION: The pathogenesis in systemic sclerosis (SSc) mainly involves vascular injury, fibrosis, and immune activation. Visualization of these microvascular changes by nailfold capillaroscopy (NFC) can help in the early diagnosis of the disease. Even though the gold standard for NFC is a videodermoscope, the ease, practicality, and accessibility make the hand-held dermoscope a more versatile and suitable device in the hands of the dermatologists in the busy outpatient department...

We previously reported that NOD. Scid mice lacking interleukin-15 (IL-15), or IL-15 receptor alpha-chain, develop T-acute lymphoblastic leukemia (T-ALL). To understand the mechanisms by which IL-15 signaling controls T-ALL development, we studied the thymocyte developmental events in IL-15-deficient Scid mice from NOD and C57BL/6 genetic backgrounds. Both kinds of mice develop T-ALL characterized by circulating TCR-negative cells expressing CD4, CD8 or both. Analyses of thymocytes in NOD. Scid.Il15-/- mice prior to T-ALL development revealed discernible changes within the CD4- CD8- double-negative (DN) thymocyte developmental stages and increased frequencies of CD4+ CD8+ double-positive cells with a high proportion of TCR-negative CD4+ and CD8+ cells...

For nearly a generation now, OP9-DL1 and OP9-DL4 cells have provided an efficient and reliable cell system to generate T cells from mouse and human hematopoietic stem cells (HSCs) and pluripotent stem cells. OP9-DL1 and OP9-DL4 were originally derived from the OP9 mouse bone marrow stromal cell line, which was transduced to ectopically express Delta-like 1 or 4 proteins, respectively. OP9-DL cells mimic the thymic microenvironment in that when cocultured with mouse or human (h) HSCs, they interact with and activate Notch receptors present on HSCs, required for T cell differentiation...

Introduction: Uveal melanoma (UM) is associated with poor outcomes in the metastatic setting and harbors activating mutations resulting in upregulation of MAPK signaling in almost all cases. The efficacy of selumetinib, an oral allosteric inhibitor of MEK1/2, was limited when administered at a continual dosing schedule of 75 mg BID. Preclinical studies demonstrate that intermittent MEK inhibition reduces compensatory pathway activation and promotes T cell activation. We hypothesized that intermittent dosing of selumetinib would reduce toxicity, allow for the administration of increased doses, and achieve more complete pathway inhibition, thus resulting in improved antitumor activity...

INTRODUCTION: Melasma is a common acquired disorder of pigmentation that presents as hyperpigmented macules and patches predominately in the sun exposed areas of the face. It is more commonly seen in women. OBJECTIVE: To compare the woods lamp and dermoscopic features of melasma. MATERIALS AND METHODS: A total of 50 patients were enrolled in this cross-sectional analytical study in a tertiary care hospital setting for over a duration of 3 months...

CONTEXT: IDH1-mutated (IDH1+) myeloid malignancies depend on the anti-apoptotic protein BCL-2 for survival. Combining the IDH1 inhibitor ivosidenib (IVO) with the BCL-2 inhibitor venetoclax (VEN) may improve outcomes. We report the completed P1b portion of a P1b/II study investigating IVO (500 mg PO daily D15-continuous) with VEN (D1-14), with or without azacitidine (AZA; 75 mg/m2 D1-7) every 28 days. OBJECTIVES: Primary P1b objectives included safety, tolerability, and IWG-defined overall response (ORR: CR+CRi+CRh+PR+MLFS)...