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Purpose: The solid tumor microenvironment (TME) drives T cell dysfunction and inhibits the effectiveness of immunotherapies such as chimeric antigen receptor-based T cell (CAR T) cells. Early data has shown that modulation of T cell metabolism can improve intratumoral T cell function in preclinical models., Experimental Design: We evaluated GPC3 expression in human normal and tumor tissue specimens. We developed and evaluated BOXR1030, a novel CAR T therapeutic co-expressing glypican-3 (GPC3)-targeted CAR and exogenous glutamic-oxaloacetic transaminase 2 (GOT2) in terms of CAR T cell function both in vitro and in vivo., Results: Cell surface expression of tumor antigen GPC3 was observed by immunohistochemical staining in tumor biopsies from hepatocellular carcinoma, liposarcoma, squamous lung cancer, and Merkel cell carcinoma patients. Compared to control GPC3 CAR alone, BOXR1030 (GPC3-targeted CAR T cell that co-expressed GOT2) demonstrated superior in vivo efficacy in aggressive solid tumor xenograft models, and showed favorable attributes in vitro including an enhanced cytokine production profile, a less-differentiated T cell phenotype with lower expression of stress and exhaustion markers, an enhanced metabolic profile and increased proliferation in TME-like conditions., Conclusions: Together, these results demonstrated that co-expression of GOT2 can substantially improve the overall antitumor activity of CAR T cells by inducing broad changes in cellular function and phenotype. These data show that BOXR1030 is an attractive approach to targeting select solid tumors. To this end, BOXR1030 will be explored in the clinic to assess safety, dose-finding, and preliminary efficacy (NCT05120271)., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: TLH is an employee of Takeda Pharmaceuticals, a former employee of Unum Therapeutics, has ownership interest in Unum Therapeutics (now Cogent Biosciences), and has issued patents: PCT/US18/00028 and PCT/US2018/015999-all outside the submitted work. EC is an employee of Catamaran Bio, Inc, a former employee of Unum Therapeutics; has ownership interest in Unum Therapeutics (now Cogent Biosciences) and Catamaran Bio, Inc; and has issued patents: PCT/US2010/0041032A1, PCT/US2019/0153061A1, PCT/US2019/0105348A1, and PCT/US2019/0284298A1-all outside the submitted work. KRW is an employee of SOTIO Biotech Inc., a former employee of Unum Therapeutics; has ownership interest in Unum Therapeutics (now Cogent Biosciences) and has issued patents: PCT/US2012/0282175A1 and PCT/US2010/0028346A1 all outside the submitted work. SM is an employee of SOTIO Biotech Inc., a former employee of Kiniksa Pharmaceuticals. TP is an employee of Novartis and a former employee of Unum therapeutics. TJ is an employee of Novartis, a former employee of Unum Therapeutics, and has ownership interest in Unum Therapeutics (now Cogent Biosciences). TF is an employee of Biogen and a former employee of Unum therapeutics. MG is an employee of Arrakis Therapeutics and a former employee of Unum therapeutics. BS is an employee of Tango Therapeutics, a former employee of Unum Therapeutics, and has issued patents: US9464333, US9388422, US9303250, WO2014055778A2, WO2016069774A1, and WO2017049094A1-all outside the submitted work. LB is an employee of Catamaran Bio, Inc. and a former employee of Unum therapeutics. KEM is an employee of Arrakis Therapeutics, a former employee of Unum Therapeutics, and a consultant for SOTIO Biotech Inc.; has ownership interest in Unum Therapeutics (now Cogent Biosciences), and ownership interests in Baxter International and Takeda Pharmaceutical Co. outside the submitted work; is an inventor multiple patents PCT/US2019/046550, PCT/US2019/050013, PCT/US2019/040346, and PCT/US2019/060287 related to the submitted work; and US 8,252,913, US 8,461,318, US 8,598,327, US 10,144,770, PCT/US2019/044512, PCT/US2018/015999, PCT/US2017/023064, PCT/US2010/023599-outside of the submitted work. SAE is an employee of BlueRock Therapeutics, a former employee of Unum Therapeutics, has ownership interest in Unum Therapeutics (now Cogent Biosciences), and is a co-inventor on patents filed related to this work. GTM is an employee of BlueRock Therapeutics, a former employee of Unum Therapeutics; has ownership interest in Unum Therapeutics (now Cogent Biosciences), and is a named inventor on many CAR-T patents. GJW is an employee of SOTIO Biotech Inc., a former employee of Unum Therapeutics; reports personal fees from Spring Bank Pharmaceuticals, Imaging Endpoints II, MiRanostics Consulting, Gossamer Bio, Paradigm, International Genomics Consortium, Angiex, IBEX Medical Analytics, GLG Council, Guidepoint Global, Genomic Health, Rafael Pharmaceuticals, SPARC-all outside this submitted work; has ownership interest in Unum Therapeutics (now Cogent Biosciences), and ownership interests in MiRanostics Consulting, Exact Sciences, Moderna, Agenus, Aurinia Pharmaceuticals, and Circulogene-outside the submitted work; and has issued patents: PCT/US2008/072787, PCT/US2010/043777, PCT/US2011/020612, and PCT/US2011/037616-all outside the submitted work and is an inventor on a patent filed related to this work. AJS is an employee of SOTIO Biotech Inc.; a former employee of bluebird bio; has ownership interest in bluebird bio, Pfizer, Regeneron, Exelixis, Bristol Myers Squibb, Celgene, and Alkermes-all outside the submitted work. All other authors have no other competing interests related to this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Altered metabolism is a hallmark of cancer. In addition to glucose, glutamine is an important nutrient for cellular growth and proliferation. Noninvasive imaging via PET may help facilitate precision treatment of cancer through patient selection and monitoring of treatment response. l-[5- 11 C]-glutamine ( 11 C-glutamine) is a PET tracer designed to study glutamine uptake and metabolism. The aim of this first-in-human study was to evaluate the radiologic safety and biodistribution of 11 C-glutamine for oncologic PET imaging. Methods: Nine patients with confirmed metastatic colorectal cancer underwent PET/CT imaging. Patients received 337.97 ± 44.08 MBq of 11 C-glutamine. Dynamic PET acquisitions that were centered over the abdomen or thorax were initiated simultaneously with intravenous tracer administration. After the dynamic acquisition, a whole-body PET/CT scan was acquired. Volume-of-interest analyses were performed to obtain estimates of organ-based absorbed doses of radiation. Results: 11 C-glutamine was well tolerated in all patients, with no observed safety concerns. The organs with the highest radiation exposure included the bladder, pancreas, and liver. The estimated effective dose was 4.46E-03 ± 7.67E-04 mSv/MBq. Accumulation of 11 C-glutamine was elevated and visualized in lung, brain, bone, and liver metastases, suggesting utility for cancer imaging. Conclusion: PET using 11 C-glutamine appears safe for human use and allows noninvasive visualization of metastatic colon cancer lesions in multiple organs. Further studies are needed to elucidate its potential for other cancers and for monitoring response to treatment., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

In embryonic stem cells (ESCs), the Tip60 histone acetyltransferase activates genes required for proliferation and silences genes that promote differentiation. Here we show that the class II histone deacetylase Hdac6 co-purifies with Tip60-p400 complex from ESCs. Hdac6 is necessary for regulation of most Tip60-p400 target genes, particularly those repressed by the complex. Unlike differentiated cells, where Hdac6 is mainly cytoplasmic, Hdac6 is largely nuclear in ESCs, neural stem cells (NSCs), and some cancer cell lines, and interacts with Tip60-p400 in each. Hdac6 localizes to promoters bound by Tip60-p400 in ESCs, binding downstream of transcription start sites. Surprisingly, Hdac6 does not appear to deacetylate histones, but rather is required for Tip60-p400 binding to many of its target genes. Finally, we find that, like canonical subunits of Tip60-p400, Hdac6 is necessary for robust ESC differentiation. These data suggest that Hdac6 plays a major role in the modulation of Tip60-p400 function in stem cells. DOI: http://dx.doi.org/10.7554/eLife.01557.001.

Study Objective: Because alkalinization of the renal tubules can theoretically protect against the mechanisms of acute kidney injury, we sought to determine whether a sodium bicarbonate infusion can prevent acute kidney injury after cardiac surgery., Design: Prospective, randomized, double-blind, controlled trial., Setting: Cardiac surgery service in a community hospital., Patients: Ninety-two patients with stage 3 or higher chronic kidney disease who underwent cardiac surgery using cardiopulmonary bypass., Intervention: Forty-eight patients received a perioperative intravenous infusion of 0.9% sodium chloride 154 mEq/L, and 44 patients received an infusion of sodium bicarbonate infusion 150 mEq/L in 5% dextrose solution; the infusions were started 1 hour preoperatively and continued for 6 hours after cardiopulmonary bypass., Measurements and Main Results: The primary outcome was the development of any stage of acute kidney injury within 5 days after surgery as defined by the Acute Kidney Injury Network criteria. No statistically significant difference in the primary outcome was noted between the two groups: 32% in the bicarbonate group versus 42% in the sodium chloride group (p=0.12). Likewise, no significant differences in the 30-day hospital mortality rate or other adverse outcomes were noted between the two groups., Conclusion: A perioperative infusion of sodium bicarbonate did not reduce the rate of acute kidney injury or adverse outcomes in patients with chronic kidney disease who underwent cardiac surgery., (© 2013 Pharmacotherapy Publications, Inc.)

Active genes in yeast can be targeted to the nuclear periphery through interaction of cis-acting "DNA zip codes" with the nuclear pore complex. We find that genes with identical zip codes cluster together. This clustering was specific; pairs of genes that were targeted to the nuclear periphery by different zip codes did not cluster together. Insertion of two different zip codes (GRS I or GRS III) at an ectopic site induced clustering with endogenous genes that have that zip code. Targeting to the nuclear periphery and interaction with the nuclear pore is a prerequisite for gene clustering, but clustering can be maintained in the nucleoplasm. Finally, we find that the Put3 transcription factor recognizes the GRS I zip code to mediate both targeting to the NPC and interchromosomal clustering. These results suggest that zip-code-mediated clustering of genes at the nuclear periphery influences the three-dimensional arrangement of the yeast genome., (Copyright © 2012 Elsevier Inc. All rights reserved.)