Search

•B-ALL patients benefit from first HCT post-CD19 CAR with prolonged LFS.•Not all patients with prior HCT benefit from consolidative HCT after CD19 CAR.•Relapse risk following short CD19 CAR BCA is mitigated by consolidative HCT.•B-ALL relapse risk reduction with HCT after short BCA is inclusive of second HCT.

Plant natural products have been used for centuries to treat human illnesses, as recreational substances, and as flavouring and colouring agents in our food. Nowadays commercial scale manufacturing of plant natural products using extraction from natural resources or chemical synthesis pose challenges for environmental sustainability, such as species overexploitation. Bio-based synthesis of plant natural products in microbial cell factories can offer an attractive alternative as these processes reduce the use of natural plant resources and instead rely on renewable feedstocks as raw materials. Here, we review the most recent developments on sustainable supply of plant natural products by bio-based synthesis in yeast, with special focus on newly discovered and implemented plant natural product biosynthetic pathways, approaches for chemical diversification of natural products, and optimization of platform yeast cell factories. From this we discuss environmental considerations and the main challenges towards sustainable and robust microbial production of plant natural products based on fermentation.

Tropical deep convective clouds are important drivers of large‐scale atmospheric circulation representing the main vertical transport pathway through the depth of the troposphere for heat, momentum, water, and chemical species. The strength and depth of this transport are impacted by the convective updraft size and intensity that are driven by buoyancy, dynamical forcing, and mixing of environmental air, that is, entrainment. In this study, we identify tropical deep convective systems with well‐defined forward anvils using Atmospheric Radiation Measurement (ARM) ground‐based profiling radars, at three ARM fixed sites in the Tropical Western Pacific (TWP; i.e., Manus, Nauru, and Darwin) and three ARM Mobile Facility deployments in Niamey, Niger; Gan Island, Maldives; and Manacapuru, Brazil. We use the difference between the level of neutral buoyancy (LNB) and the level of maximum detrainment (LMD) as a proxy for the effective bulk convective entrainment (εproxy). The LNB, the theoretical height that a parcel raised above the level of free convection would reach with no mixing, is calculated based on preconvection radiosonde measurements using parcel theory. The LMD is the height of the maximum reflectivity observed in forward anvil clouds by profiling radars. Deep convective systems over the TWP show higher LNBs that extend to 16.3 km on average and larger εproxy(median value of LNB minus LMD up to 6.5 km) compared to their continental counterparts in the Amazon and West Africa. Oceanic conditions show larger convective available potential energy (CAPE) coupled with higher moisture at low levels, which favors larger εproxy. In contrast, continental cases initiate and develop, under high convective inhibition, steeper environmental lapse rate, and high wind shear conditions, which show smaller offset between LNB and LMD. Deep convective cases that promote significant cold pools at the surface experience less εproxy. Using a Random Forest regression algorithm, CAPE is associated with the highest feature importance score for predicting convective εproxy, followed by low‐level relative humidity. For continental cases, the low‐level wind shear also indicates higher importance. A proxy for the effective bulk entrainment for tropical deep convection is estimated based on ARM radiosonde and radar observationsOceanic deep convection in the tropics suggests enhanced effective bulk entrainment, associated with higher CAPE and more moist conditionsFor continental events, higher prestorm CAPE, higher RH, and stronger wind shear favor increased effective bulk entrainment

Mycobacterium tuberculosisresides within the highly oxidative environment of the human macrophage and previous reports have indicated that these mycobacteria are susceptible to reactive nitrogen intermediates including peroxynitrite. This work provides evidence that theMycobacterium tuberculosishemoprotein KatG acts as an efficient peroxynitritase exhibiting akappof 1.4 × 105M−1s−1for peroxynitrite decomposition at pH 7.4 and 37°C. The ability of KatG to act as a peroxynitritase adds to its growing list of enzymatic activities and may in part explain the ability ofMycobacterium tuberculosisto persist in macrophages.

The kinetics and systemic bioavailability of intranasally administered buprenorphine have been investigated in 9 healthy volunteers in an intranasal/intravenous cross-over study. Each subject received a nominal 0·3 mg dose of buprenorphine intranasally followed one week later by a matched dose intravenously. For the intranasal administration mean tmaxand mean Cmaxwere 30·6 min and 1·77 ng mL−1, respectively. Mean intranasal bioavailability was 48·2 ± 8·3% (mean ± s.e.m.) of the intravenous value. Intranasal administration may represent a valuable new delivery route for buprenorphine.

Little is known about the disease-specific factors that predict responsiveness to CAR-T cell therapy, other the direct presence of the CAR-T target. Clinical outcomes at our center have demonstrated that durable responses to CD19-directed CAR-T therapy in pediatric pre-B-ALL (acute lymphoblastic leukemia) are associated with persistence of CAR-T cells in the peripheral blood, antigenic load (percent CD19-positive cells in marrow prior to CAR-T infusion), and apheresis product T-cell quality (Finney O, et al., 2019). However, in a small number of cases where both antigenic load and T-cell quality predicted a good response, the treatment failed rapidly. This led us to undertake a detailed investigation of the leukemia itself in order to discover potential disease-associated factors that correlate with resistance to CAR-T therapy.

Gardner: Abbvie: . Percival:Nohla Therapeutics: Research Funding; Pfizer Inc.: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Halpern:Bayer Pharmaceuticals: Research Funding; Pfizer Pharmaceuticals: Research Funding. Scott:Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Speakers Bureau. Oehler:Pfizer Inc.: Research Funding; Blueprint Medicines: Consultancy; NCCN: Consultancy. Walter:Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Amphivena Therapeutics: Consultancy, Equity Ownership; Agios: Consultancy; Amgen: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding. Becker:AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; Accordant Health Services/Caremark: Consultancy; The France Foundation: Honoraria. Jensen:Juno Therapeutics, a Celgene Company: Research Funding; Bluebird Bio: Research Funding.

Gardner: Novartis: Honoraria. Jensen:Bluebird Bio: Research Funding; Juno Therapeutics, a Celgene Company: Research Funding.

Pulsipher: Amgen: Other: Lecture; Bellicum: Consultancy; Miltenyi: Research Funding; Medac: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Other: Education for employees; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees. Wayne:AbbVie: Consultancy; Spectrum Pharmaceuticals: Consultancy, Research Funding; Servier: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Jensen:Bluebird Bio: Research Funding; Juno Therapeutics, a Celgene Company: Research Funding. Gardner:Novartis: Honoraria.

Objective:Much has been written about the patients’ perspective concerning weight management in health care. The purpose of this survey study was to assess perspectives of primary care providers (PCPs) and nurses toward patient weight management and identify possible areas of growth. Patients and Methods:We emailed a weight management–focused survey to 674 eligible participants (437 [64.8%] nurses and 237 [35.2%] PCPs) located in 5 outpatient primary care clinics. The survey focused on opportunities, practices, knowledge, confidence, attitudes, and beliefs. A total of 219 surveys were returned (137 [62.6%] from nurses and 82 [34.4%] from PCPs). Results:Among 219 responders, 85.8% were female and 93.6% were white non-Hispanic. In this study, PCPs and nurses believed obesity to be a major health problem. While PCPs felt more equipped than nurses to address weight management (P< .001) and reported receiving more training than nurses (50.0% vs 17.6%, respectively), both felt the need for more training on obesity (73.8% and 79.4%, respectively). Although, PCPs also spent more patient contact time providing weight management services versus nurses (P< .001), the opportunity/practicesscore was lower for PCPs than nurses (−0.35 ± 0.44 vs −0.17 ± 0.41, P< .001) with PCPs more likely to say they lacked the time to discuss weight and they worried it would cause a poor patient-PCP relationship. The knowledge/confidence scorealso differed significantly between the groups, with nurses feeling less equipped to deal with weight management issues than PCPs (−0.42 ± 0.43 vs −0.03 ± 0.55, P< .001). Neither group seemed very confident, with those in the PCP group only answering with an average score of neutral. Conclusion:By asking nurses and PCP general questions about experiences, attitudes, knowledge, and opinions concerning weight management in clinical care, this survey has identified areas for growth in obesity management. Both PCPs and nurses would benefit from additional educational training on weight management.

Biomaterial properties that modulate T cell activation, growth, and differentiation are of significant interest in the field of cellular immunotherapy manufacturing. In this work, a new platform technology that allows for the modulation of various activation particle design parameters important for polyclonal T cell activation is presented. Artificial antigen presenting cells (aAPCs) are successfully created using supported lipid bilayers on various cell‐templated silica microparticles with defined membrane fluidity and stimulating antibody density. This panel of aAPCs is used to probe the importance of activation particle shape, size, membrane fluidity, and stimulation antibody density on T cell outgrowth and differentiation. All aAPC formulations are able to stimulate T cell growth, and preferentially promote CD8+T cell growth over CD4+T cell growth when compared to commercially available pendant antibody‐conjugated particles. T cells cultured with HeLa‐ and red blood cell–templated aAPCs have a less‐differentiated and less‐exhausted phenotype than those cultured with spherical aAPCs with matched membrane coatings when cultured for 14 days. These results support continued exploration of silica‐supported lipid bilayers as an aAPC platform. Silica microparticles templated from monodisperse human cellsare used to create supported lipid bilayers displaying T cell activating antibodies with varying size, shape, membrane fluidity, and antibody loading density. These particles promote polyclonal human T cell expansion and demonstrate that antibody density and particle shape impact T cell differentiation during expansion.

Background:Pediatric patients with relapsed or refractory CD19+non-Hodgkin lymphoma (NHL) have poor outcomes despite use of chemotherapy and hematopoietic stem cell transplant (HSCT). Clinical trials of CD19 CAR T-cells have demonstrated efficacy in salvaging adult patients with relapsed and refractory NHL.

Pulsipher: Amgen: Honoraria; CSL Behring: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Adaptive Biotech: Consultancy, Research Funding. Park:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Jensen:Juno Therapeutics, Inc.: Consultancy, Patents & Royalties, Research Funding.

Park: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Jensen:Juno Therapeutics, Inc.: Consultancy, Patents & Royalties, Research Funding.

Jensen: Juno Therapeutics, Inc.: Consultancy, Patents & Royalties, Research Funding.

Park: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Jensen:Juno Therapeutics, Inc.: Consultancy, Patents & Royalties, Research Funding.

Chimeric antigen receptor (CAR) redirected T cells can induce remission in highly refractory leukemia and lymphoma subjects. Despite the potential of this emerging therapeutic modality, treatment with CD19 CAR T cells is not uniformly effective for remission induction, and remissions can be short-lived in a significant proportion of treated subjects.