Dual targeting of CD19 and CD22 with Bicistronic CAR-T cells in Patients with Relapsed/Refractory Large B Cell Lymphoma

Relapse following CD19-directed chimeric antigen receptor T-cells (CAR-T) for relapsed/refractory large B-cell lymphoma (r/r LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multi-antigen targeting and PD-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in r/r LBCL as inpatient or outpatient therapy (NCT03289455, https://clinicaltrials.gov/ct2/show/NCT03289455). Endpoints include toxicity (primary) and response rates (secondary). AUTO3 was manufactured for 62 patients using autologous leukapheresis, modified with a bicistronic transgene. 52 patients received AUTO3 (7/52,50x106; 45/52,150-450x106) and 48/52 received pembrolizumab. Median age was 59 years (range,27-83) and 46/52 had stage III/IV disease. Median follow-up was 21.6 months (range,15.1-51.3) at last data cut (Feb 28, 2022). AUTO3 was safe: grade 1-2 and grade 3 CRS affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), HLH affected 2 patients, and no Pembrolizumab-associated autoimmune sequalae were observed. On this basis, outpatient administration was tested in 20 patients, saving a median of 14 hospital days/patient. AUTO3 was effective: overall response rates were 66% (48.9%, CR; 17%, PR). For patients with CR, median DOR was not reached, with 54.4% (CI: 32.8, 71.7) projected to remain progression-free beyond 12 months after onset of remission. DOR for all responding patients was 8.3 months (95% CI: 3.0, NE) with 42.6% projected to remain progression-free beyond 12 months after onset of remission. Overall, AUTO3 +/- pembrolizumab for r/r LBCL was safe, lending itself to outpatient administration, and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation-AUTO3, engineered for superior expansion/persistence in vivo, and selection of CAR binders active at low antigen densities

Forest regeneration on European sheep pasture is an economically viable climate change mitigation strategy

Livestock production uses 37% of land globally and is responsible for 15% of anthropogenic greenhouse gas emissions. Yet livestock farmers across Europe receive billions of dollars in annual subsidies to support their livelihoods. This study evaluates whether diverting European subsidies into the restoration of trees on abandoned farmland represents a cost-effective negative-emissions strategy for mitigating climate change. Focusing on sheep farming in the United Kingdom, and on natural regeneration and planted native forests, we show that, without subsidies, sheep farming is not profitable when farmers are paid for their labour. Despite the much lower productivity of upland farms, upland and lowland farms are financially comparable per hectare. Conversion to 'carbon forests' is possible via natural regeneration when close to existing trees, which are seed sources. This strategy is financially viable without subsidies, meeting the net present value of poorly performing sheep farming at a competitive $4/tCO2eq. If tree planting is required to establish forests, then ~$55/tCO2eq is needed to break-even, making it uneconomical under current carbon market prices without financial aid to cover establishment costs. However, this break-even price is lower than the theoretical social value of carbon ($68/tCO2eq), which represents the economic cost of CO2 emissions to society. The viability of land-use conversion without subsidies therefore depends on low farm performance, strong likelihood of natural regeneration, and high carbon-market price, plus overcoming potential trade-offs between the cultural and social values placed on pastoral livestock systems and climate change mitigation. The morality of subsidising farming practices that cause high greenhouse gas emissions in Europe, whilst spending billions annually on protecting forest carbon in less developed nations to slow climate change is questionable

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Brief Imagery Training : Effects on Psychological, Physiological and Neuroendocrinological Measures of Stress and Pain

The present study investigated the influence of a brief, intensive biofeedback-assisted imagery training regimen on psychological, physiological and neuroendocrinological measures of pain and stress in injury related chronic pain patients. The subjects were 36 patients (myelography examcandidates) who were assigned to the imagery or wait-list control group by order of referral presentation and to formulate equivalent groups

There is a rib joint where the folks all meet [first line of chorus]

Performers: Bing Crosby, Connie BoswellPiano, Voice and Chord

Delivery of Antegrade Cerebral Perfusion During Descending Aortic Reconstruction: A Case Report.

Antegrade cerebral perfusion (ACP) has been demonstrated to be a safe and effective method of providing adequate protection to the brain during hypothermic circulatory arrest. By improving oxygen delivery to the cerebral capillaries, users of this technique have reported fewer temporary neurological deficits in postoperative periods, even after prolonged periods of circulatory arrest. Furthermore, ACP may be delivered with little alteration to the cardiopulmonary bypass (CPB) circuit. Surgical correction of a descending aortic aneurysm can provide a challenge when the left subclavian artery is involved. A period of hypothermic circulatory arrest is required to complete the proximal anastamosis of the graft. Access to the cerebral vessels for selective cerebral perfusion is limited during a left thoracotomy approach. A 54-year-old female presented with a computerized tomography (CT) scan of a descending aortic aneurysm, originating at the base of the left subclavian artery. Surgical intervention using CPB via femoral-femoral cannulation was employed. The patient was systemically cooled to 22 degrees C. Selective antegrade cerebral perfusion was administered via cannulation of the left common carotid artery. Antegrade cerebral perfusion lasted 19 minutes, with improved transcranial oximetry readings. The patient was successfully weaned from CPB. The patient was discharged on postoperative day nine with no evident suquelae. It is believed that the application of ACP in this procedure further improved patient outcome

Between 18th and 19th on chestnut street

Gift of Dr. Mary Jane Esplen.Piano vocal [instrumentation]Have you heard about a place in town [first line]There is a rib joint where the folks all meet [first line of chorus]E flat [key]Boogie woogie tempo [tempo]Popular song [form/genre]Orange streets restaurant ; Bing Crosby and Connie Boswell (photograph) [illustration]IM-HO [graphic artist]Publisher's advertisement on inside front and back cover [note