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The effect of prior inotuzumab ozogamicin (InO) treatment on brexucabtagene autoleucel (brexu-cel) outcomes remains unclear in adults with acute lymphoblastic leukemia (ALL), particularly the influence off previous InO response and the timing of administration. We conducted a retrospective multicenter analysis of 189 patients with relapsed/refractory (r/r) ALL treated with brexu-cel. Over half of the patients received InO before brexu-cel (InO-exposed). InO-exposed patients were more heavily pretreated (p= 0.02) and frequently had active marrow disease pre-apheresis (p= 0.03). Response rate and toxicity profile following brexu-cel were comparable for InO-exposed and InO-naïve; however, consolidation therapy post brexu-cel response was utilized at a higher rate in InO-naïve patients (p= 0.005). With a median follow up of 11.4 months, InO-exposed patients had inferior progression-free survival (PFS) (p=0.013) and overall survival (OS) (p=0.006) in univariate analyses; however, prior InO exposure did not influence PFS (HR 1.20, 95%CI, 0.71-2.03) in multivariate models. When InO-exposed patients were stratified according to prior InO response, InO responders had superior PFS (p=0.002) and OS (p<0.0001) relative to InO-refractory. The timing of administering InO did not affect brexu-cel outcomes, with comparable PFS (p=0.51) and OS (p=0.86) for patients receiving InO as bridging therapy or pre-apheresis. In conclusion, while InO exposure was associated with inferior survival outcomes following brexu-cel in unadjusted analyses, these associations were no longer significant in multivariate analyses, suggesting it is unlikely that InO negatively impacts brexu-cel efficacy. Our data instead imply that InO-exposed recipients of brexu-cel tend to be higher-risk patients with intrinsic adverse leukemia biology., (Copyright © 2024 American Society of Hematology.)

The cervical spine poses many complex challenges that require complex solutions. Anterior cervical discectomy and fusion (ACDF) has been one such technique often employed to address such issues. In order to address the problems with ACDF and assess the modifications that have been made to the technique over time, finite element analyses (FEA) have proven to be an effective tool. The variations of cervical spine FEA models that have been produced over the past couple of decades, particularly more recent representations of more complex geometries, have not yet been identified and characterized in any literature. Our objective was to present material property models and cervical spine models for various simulation purposes. The outlining and refinement of the FEA process will yield more reliable outcomes and provide a stable basis for the modeling protocols of the cervical spine.

Study Design: Cadaver study., Objectives: Assess the feasibility of robot-assisted cervical pedicle screw (RA-CPS) placement and understand the anatomical considerations of this technique., Methods: Four cadaver specimens free from bony pathology were acquired. Anatomical considerations, such as pedicle width (PW) and height (PH), transverse pedicle angle (TPA), and maximal screw length (MSL), were recorded from preoperative computational tomography (CT) scans. Intraoperative cone-beam CT was acquired and registered to the robotic system. After cervical levels were segmented, screw sizes and trajectories were planned, and RA-CPS were placed. Accuracy was assessed using Gertzbein and Robbin's classification on postoperative CT scans., Results: Thirty-five RA-CPS were placed. Major breaches (≥Grade C) occurred in 28.57% screws. Grade A or B accuracy was found in 71.43% of screws, with the most common direction of breach being medial (81.3%). The greatest proportion of breach per level occurred in the upper subaxial levels, (C3:71.4%, C4 66.6%, C5:50%) which had the smallest PW (C3: 4.34 ± .96 mm, C4: 4.48 ± .60, C5: 5.76 ± 1.11). PH was greatest at C2 (8.14 ± 1.89 mm) and ranged subaxial from 6.36 mm (C3) to 7.48 mm (C7). The mean PW was 5.37 mm and increased caudally from 4.34 mm (C3) to 6.31 mm (C7). The mean TPA was 39.9° and decreased moving caudally 46.9°) to C7 (34.4°). The MSL was 37.1 mm and increased from C2 (26.3 mm) to C7 (41.0 mm)., Conclusion: RA-CPS has the potential to be feasible, but technological and instrument modifications are necessary to increase the accuracy in the cervical region.

Background: Data regarding outcomes among patients with cancer and co-morbid cardiovascular disease (CVD)/cardiovascular risk factors (CVRF) after SARS-CoV-2 infection are limited., Objectives: To compare Coronavirus disease 2019 (COVID-19) related complications among cancer patients with and without co-morbid CVD/CVRF., Methods: Retrospective cohort study of patients with cancer and laboratory-confirmed SARS-CoV-2, reported to the COVID-19 and Cancer Consortium (CCC19) registry from 03/17/2020 to 12/31/2021. CVD/CVRF was defined as established CVD or no established CVD, male ≥ 55 or female ≥ 60 years, and one additional CVRF. The primary endpoint was an ordinal COVID-19 severity outcome including need for hospitalization, supplemental oxygen, intensive care unit (ICU), mechanical ventilation, ICU or mechanical ventilation plus vasopressors, and death. Secondary endpoints included incident adverse CV events. Ordinal logistic regression models estimated associations of CVD/CVRF with COVID-19 severity. Effect modification by recent cancer therapy was evaluated., Results: Among 10,876 SARS-CoV-2 infected patients with cancer (median age 65 [IQR 54-74] years, 53% female, 52% White), 6253 patients (57%) had co-morbid CVD/CVRF. Co-morbid CVD/CVRF was associated with higher COVID-19 severity (adjusted OR: 1.25 [95% CI 1.11-1.40]). Adverse CV events were significantly higher in patients with CVD/CVRF (all p <0.001). CVD/CVRF was associated with worse COVID-19 severity in patients who had not received recent cancer therapy, but not in those undergoing active cancer therapy (OR 1.51 [95% CI 1.31-1.74] vs. OR 1.04 [95% CI 0.90-1.20], p interaction <0.001)., Conclusions: Co-morbid CVD/CVRF is associated with higher COVID-19 severity among patients with cancer, particularly those not receiving active cancer therapy. While infrequent, COVID-19 related CV complications were higher in patients with comorbid CVD/CVRF. (COVID-19 and Cancer Consortium Registry [CCC19]; NCT04354701)., Competing Interests: R.M reports research funding from Bayer, Pfizer, and Tempus; and 18 personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Calithera, 19 Caris, Dendreon, Exelixis, Janssen, Johnson and Johnson, Merck & Co, Myovant, Novartis, Pfizer, Sanofi, Sorrento Therapeutics, Tempus, and Vividion. A.N. reports consulting fees from AstraZeneca, Takeda Oncology and Bantam Pharmaceuticals. B.B. reports research support to institution from Amgen, Bicycle Therapeutics, Boehringer Ingelheim, Ikena Oncology, Kahr Medical, Merck, Syros, Tarveda Therapeutics. Z.B. receives research support from 10.13039/100004328Genentech/imCORE and Bristol Myers Squibb. Personal fees from UpToDate. L.A.F reports clinical trial funding from BMS, EMDserono, Pfizer, Merck, Array, Kartos, Incyte, personal fees from Elsevier, ViaOncology, outside the submitted work. J.L.W. reports research funding from NIH/NCI during the conduct of the work, research funding from AACR, consulting fees from Westat, Roche, Flatiron Health, Melax Tech, other from HemOnc.org LLC (ownership), outside the submitted work. C.H reports stock holdings in Johnson and Johnson; research funding to institution from Merck, Bausch Health, Genentech, Bayer, and AstraZeneca, consultant fees from Tempus, Genzyme, and EMD Sorono, speaking fees from OncLive/MJH Life Sciences, travel fees from Merck, all outside the submitted work. The remaining authors have nothing to disclose., (© 2023 Published by Elsevier Inc.)

Objective: This study aimed to assess the risk of maintenance immunosuppression on the post-transplant risk of malignancy across all solid organ transplant types., Methods: This is a retrospective cohort study from a multicenter hospital system in the United States. The electronic health record was queried from 2000 to 2021 for cases of solid organ transplant, immunosuppressive medications, and post-transplant malignancy., Results: A total of 5,591 patients, 6,142 transplanted organs, and 517 post-transplant malignancies were identified. Skin cancer was the most common type of malignancy at 52.8%, whereas liver cancer was the first malignancy to present at a median time of 351 days post-transplant. Heart and lung transplant recipients had the highest rate of malignancy, but this finding was not significant upon adjusting for immunosuppressive medications (heart HR 0.96, 95% CI 0.72 - 1.3, p = 0.88; lung HR 1.01, 95% CI 0.77 - 1.33, p = 0.94). Random forest variable importance calculations and time-dependent multivariate cox proportional hazard analysis identified an increased risk of cancer in patients receiving immunosuppressive therapy with sirolimus (HR 1.41, 95% CI 1.05 - 1.9, p = 0.04), azathioprine (HR 2.1, 95% CI 1.58 - 2.79, p < 0.001), and cyclosporine (HR 1.59, 95% CI 1.17 - 2.17, p = 0.007), while tacrolimus (HR 0.59, 95% CI 0.44 - 0.81, p < 0.001) was associated with low rates of post-transplant neoplasia., Conclusion: Our results show varying risks of immunosuppressive medications associated with the development of post-transplant malignancy, demonstrating the importance of cancer detection and surveillance strategies in solid organ transplant recipients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shaw, Haque, Luu, O’Connor, Hamidi, Fitzsimons, Varda, Kwon, Whitcomb, Gregorowicz, Roloff, Bemiss, Kallwitz, Hagen and Berg.)

In recent years, advances in genetics and the integration of clinical-grade next-generation sequencing (NGS) assays into patient care have facilitated broader recognition of hereditary hematopoietic malignancy (HHM) among clinicians, in addition to the identification and characterization of novel HHM syndromes. Studies on genetic risk distribution within affected families and unique considerations of HHM biology represent exciting areas of translational research. More recently, data are now emerging pertaining to unique aspects of clinical management of malignancies arising in the context of pathogenic germline mutations, with particular emphasis on chemotherapy responsiveness. In this article, we explore considerations surrounding allogeneic transplantation in the context of HHMs. We review pre- and post-transplant patient implications, including genetic testing donor selection and donor-derived malignancies. Additionally, we consider the limited data that exist regarding the use of transplantation in HHMs and safeguards that might be pursued to mitigate transplant-related toxicities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 O’Connor, Shaw, Madero-Marroquin and Roloff.)

Background: Breakthrough SARS-CoV-2 infections following vaccination against COVID-19 are of international concern. Patients with cancer have been observed to have worse outcomes associated with COVID-19 during the pandemic. We sought to evaluate the clinical characteristics and outcomes of patients with cancer who developed breakthrough SARS-CoV-2 infections after 2 or 3 doses of mRNA vaccines., Methods: We evaluated the clinical characteristics of patients with cancer who developed breakthrough infections using data from the multi-institutional COVID-19 and Cancer Consortium (CCC19; NCT04354701). Analysis was restricted to patients with laboratory-confirmed SARS-CoV-2 diagnosed in 2021 or 2022, to allow for a contemporary unvaccinated control population; potential differences were evaluated using a multivariable logistic regression model after inverse probability of treatment weighting to adjust for potential baseline confounding variables. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) are reported. The primary endpoint was 30-day mortality, with key secondary endpoints of hospitalization and ICU and/or mechanical ventilation (ICU/MV)., Findings: The analysis included 2486 patients, of which 564 and 385 had received 2 or 3 doses of an mRNA vaccine prior to infection, respectively. Hematologic malignancies and recent receipt of systemic anti-neoplastic therapy were more frequent among vaccinated patients. Vaccination was associated with improved outcomes: in the primary analysis, 2 doses (aOR: 0.62, 95% CI: 0.44-0.88) and 3 doses (aOR: 0.20, 95% CI: 0.11-0.36) were associated with decreased 30-day mortality. There were similar findings for the key secondary endpoints of ICU/MV (aOR: 0.60, 95% CI: 0.45-0.82 and 0.37, 95% CI: 0.24-0.58) and hospitalization (aOR: 0.60, 95% CI: 0.48-0.75 and 0.35, 95% CI: 0.26-0.46) for 2 and 3 doses, respectively. Importantly, Black patients had higher rates of hospitalization (aOR: 1.47, 95% CI: 1.12-1.92), and Hispanic patients presented with higher rates of ICU/MV (aOR: 1.61, 95% CI: 1.06-2.44)., Interpretation: Vaccination against COVID-19, especially with additional doses, is a fundamental strategy in the prevention of adverse outcomes including death, among patients with cancer., Funding: This study was partly supported by grants from the National Cancer Institute grant number P30 CA068485 to C-YH, YS, SM, JLW; T32-CA236621 and P30-CA046592 to C.R.F; CTSA 2UL1TR001425-05A1 to TMW-D; ACS/FHI Real-World Data Impact Award, P50 MD017341-01, R21 CA242044-01A1, Susan G. Komen Leadership Grant Hunt to MKA. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH)., Competing Interests: TKC reports grants, personal fees and non-financial support from Merck, BMS, Exelixis, Astra Zeneca, Eli Lilly, Eisai, Novartis, GSK, Pfizer, EMD Serono; stocks in Pionyr, Tempest, outside the submitted work; In addition, TKC reports patent: pending International Patent Application No. PCT/US2018/12209, entitled “PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response,” filed January 3, 2018, claiming priority to U.S. Provisional Patent Application No. 62/445,094, filed January 11, 2017; pending International Patent Application No. PCT/US2018/058430, entitled “Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy,” filed October 31, 2018, claiming priority to U.S. Provisional Patent Application No. 62/581,175, filed November 3, 2017; TKC sits on National Comprehensive Cancer Network kidney panel. CL reports grants from Genentech/ImCore. ZB reports non-financial support from Bristol Myers Squibb, grants from Genentech/ImCore, personal fees from UpToDate, outside the submitted work. ALS reports non-financial support from Astellas and Pfizer outside the submitted work. GdLL reports personal fees from Boehringer Ingelheim, Pfizer, AstraZeneca; grants from AstraZeneca, Merck Sharp & Dohme, EMD Serono, AstraZeneca, Blueprint Medicines, Tesaro, Bavarian Nordic, Novartis, G1 Therapeutics, Adaptimmune, BMS, GSK, Abbvie, Rgenix, Pfizer, Roche, Genentech, Eli Lilly, Janssen; personal fees from Boehringer Ingelheim, Pfizer, E.R. Squibb Sons, LLC, Janssen; all outside the submitted work. CH reports grants from Merck, Bayer, Genentech, AstraZeneca, Bausch Health; Consulting fees from Tempus, Genzyme, EMD Sorono, payment or honoraria from OncLive/MJH Life Sciences, support for attending meetings and/or travel from Merck, participation on a data safety monitoring or advisory board of Henry Ford Cancer Institute, Hoosier Cancer Research Network; Leadership or fiduciary role in Wayne County Medical Society of Southeast Michigan; Stock or stock options in Johnson and Johnson, all outside the submitted work. EAG reports Consulting fees from Alexion Inc, Picnic Health, AbbVie, CTI Biopharma, Genentech Inc., Novartis, Celgene/Bristol Myers-Squibb, Takeda oncology, Taiho Oncology and Research Funding from Genentech Inc, Astex Pharmaceuticals, and BluePrint Medicines, outside the submitted work. SH reports grants/research supports from ASCO TAPUR, Astellas; honoraria or consultation fees from Sanofi, Aveo Oncology, outside the submitted work. SB reports Consulting fees from BMS, Exelexis, Eisai, Pfizer, Myovant, SeaGen; Payment or honoraria from Exelexis, Eisai, BMS; Participation on a Data Safety Monitoring Board or Advisory Board from SeaGen, Pfizer, Myovant; Stock or stock options in Natera; outside the submitted work. MJ reports grants from AstraZeneca, Pfizer; Eisai, personal fees from Seagen, Sanofi, outside the submitted work. NTNG reports personal fees from Novocure, outside the submitted work. RRM reports Advisory board/consultant—Aveo, AstraZeneca, Bayer, Bristol Myers Squib, Calithera, Caris, Dendreon, Exelixis, Janssen, Merck, Myovant, Novartis, Pfizer, Sanofi, Sorrento therapeutics, Pfizer, Tempus, Vividion, unrelated to this work. SMR reports advisory for Roche, Janssen, Sanofi, and EUSA Pharma, unrelated to this work. PV reports institutional research funding from Sanofi; stocks or stock options in Novavax, Biontech. HAZ acknowledges support from Georgia NCORP. CRF reports grants from Merck Foundation, grants from NCCN/Pfizer, grants from National Cancer Institute, other from National Cancer Institute, other from Patient-Centered Outcomes Research Institute, outside the submitted work. SM reports support from National Cancer Institute, and Intl Assoc. for the Study of Lung Cancer during the conduct of the study; and personal fees from National Geographic outside the submitted work. DF reports Grants or contracts from Merck, Viracor, Astellas; Support for attending meetings and/or travel from Viracor; outside the submitted work. JLW reports grants from NIH during the conduct of the study; personal fees from Roche, Westat, Flatiron Health, Melax Tech, IBM Watson Health, ownership of HemOnc.org LLC, grants from AACR; outside the submitted work. TMW-D reports grants from BMS, Merck & Co, GSK/Tesaro, Janssen; personal fees from Exicure, Shattuck Labs, SITC, Merck & Co, Caris Life Sciences, outside the submitted work. C-YH, SRKS, CJ, LBW, UW, TEO'C, OAP, EJK, HS, RN, TKN, RQ, MP, BHM, SADP, KR, BF, DYR, MKA, HS, DRR, YS, and SB have nothing to disclose. The content is solely the responsibility of the authors and does not necessarily represent the US Food and Drug Administration official views or policies., (© 2023 The Author(s).)

Study Design: This study compares four cervical endplate removal procedures, validated by finite element models., Purpose: To characterize the effect of biomechanical strength and increased contact area on the maximum von Mises stress, migration, and subsidence between the cancellous bone, endplate, and implanted cage., Overview of Literature: Anterior cervical discectomy and fusion (ACDF) has been widely used for treating patients with degenerative spondylosis. However, no direct correlations have been drawn that incorporate the impact of the contact area between the cage and the vertebra/endplate., Methods: Model 1 (M1) was an intact C2C6 model with a 0.5 mm endplate. In model 2 (M2), a cage was implanted after removal of the C4-C5 and C5-C6 discs with preservation of the osseous endplate. In model 3 (M3), 1 mm of the osseous endplate was removed at the upper endplate. Model 4 (M4) resembles M3, except that 3 mm of the osseous endplate was removed., Results: The range of motion (ROM) at C2C6 in the M2-M4 models was reduced by at least 9º compared to the M1 model. The von Mises stress results in the C2C3 and C3C4 interbody discs were significantly smaller in the M1 model and slightly increased in the M2-M3 and M3-M4 models. Migration and subsidence decreased from the M2-M3 model, whereas further endplate removal increased the migration and subsidence as shown in the transition from M3 to M4., Conclusions: The M3 model had the least subsidence and migration. The ROM was higher in the M3 model than the M2 and M4 models. Endplate preparation created small stress differences in the healthy intervertebral discs above the ACDF site. A 1 mm embedding depth created the best balance of mechanical strength and contact area, resulting in the most favorable stability of the construct.

Introduction There has been a surge in robot utilization in spine surgery over the past five years with the rapid development of new spine robotic platforms. This study aimed to compare a new robotic spine platform from Fusion Robotics TM  (Fusion Robotics, Helena, MT) with the widely used Mazor-X TM Stealth Edition robotic platform (Medtronic, Dublin, Ireland) in terms of workflow and lumbar pedicle screw placement accuracy. Methods A cadaver lab was conducted, which included four procedures with single-level lumbar pedicle screw placement using the Fusion Robotics TM system. These four procedures were compared to four propensity-score matched cases with single-level lumbar pedicle screw placement using the Mazor-X TM Stealth Edition. A single surgeon performed all surgeries. The cases were matched in terms of demographics (age, sex, race, BMI) and comorbidities (Charlson Comorbidity Index score). The primary outcome measure was the operative workflow efficiency (duration as measured with a stopwatch by an independent observer). The secondary outcome measures were pedicle screw accuracy and accuracy to plan. Results After propensity-score matching, there were four cases in each group with no significant between-group differences in terms of sex, race, BMI, or surgical levels; however, there were significant differences in terms of age (p=0.01) and comorbidities (p<0.001). The workflow efficiency measurement showed that the Fusion Robotics TM platform had a significantly shorter duration in terms of the system set-up time, planning to in-position time, and total procedure time (p<0.05). However, there was no significant difference between the robotic platforms in terms of creating a sterile barrier, scanning and importing images, creating a plan, screw placement, screw accuracy, and screw accuracy to plan. Conclusion Based on our findings, the Fusion Robotics TM  platform had a significantly shorter procedure workflow duration while maintaining the same accuracy as the most commonly used robotic platform (Mazor-X TM ). This is the first study to directly compare different spine surgery robotic systems., Competing Interests: Dr. Khan received a research grant from the Scoliosis Research Society to study scoliosis in Chiari patients., (Copyright © 2021, Soliman et al.)

Background: Takayasu arteritis (TA) is an idiopathic large-vessel vasculitis that can result in significant morbidity and mortality secondary to progressive stenosis and occlusion. Monitoring disease progression is crucial to preventing relapse, but is often complicated by the lack of clinical symptoms in the setting of active disease. Although acute phase reactants such as ESR and CRP are generally used as an indicator of inflammation and disease activity, mounting evidence suggests that these markers cannot reliably distinguish active from inactive TA., Case Presentation: We report a 24-year-old Hispanic female with a 5-year history of TA who presented with stroke-like symptoms and evidence of left MCA occlusion on imaging, despite a history of decreasing inflammatory markers. CTA revealed complete occlusion of the left common carotid artery, left subclavian, and left MCA from their origins. It also revealed a striking compensatory circulation supplying the left anterior circulation as well as the left subclavian as a response to progressive stenosis., Conclusion: Monitoring ESR and CRP levels alone may not be a reliable method to evaluate disease progression in patients with TA, and should be taken in context with both patient's clinical picture and the imaging. We recommend that serial imaging be performed regularly in the setting of active disease to monitor progression and allow for immediate therapy in response to evidence of disease advancement, with a relaxation of the imaging interval once the disease is presumed inactive.

Activation of angiotensin-converting enzyme 2 (ACE2), production of angiotensin-(1-7) [Ang-(1-7)] and stimulation of the Ang-(1-7) receptor Mas exert beneficial actions in various peripheral cardiovascular diseases, largely through opposition of the deleterious effects of angiotensin II via its type 1 receptor. Here we considered the possibility that Ang-(1-7) may exert beneficial effects against CNS damage and neurological deficits produced by cerebral ischaemic stroke. We determined the effects of central administration of Ang-(1-7) or pharmacological activation of ACE2 on the cerebral damage and behavioural deficits elicited by endothelin-1 (ET-1)-induced middle cerebral artery occlusion (MCAO), a model of cerebral ischaemia. The results of the present study demonstrated that intracerebroventricular infusion of either Ang-(1-7) or an ACE2 activator, diminazine aceturate (DIZE), prior to and following ET-1-induced MCAO significantly attenuated the cerebral infarct size and neurological deficits measured 72 h after the insult. These beneficial actions of Ang-(1-7) and DIZE were reversed by co-intracerebroventricular administration of the Mas receptor inhibitor, A-779. Neither the Ang-(1-7) nor the DIZE treatments altered the reduction in cerebral blood flow elicited by ET-1. Lastly, intracerebroventricular administration of Ang-(1-7) significantly reduced the increase in inducible nitric oxide synthase mRNA expression within the cerebral infarct that occurs following ET-1-induced MCAO. This is the first demonstration of cerebroprotective properties of the ACE2-Ang-(1-7)-Mas axis during ischaemic stroke, and suggests that the mechanism of the Ang-(1-7) protective action includes blunting of inducible nitric oxide synthase expression.

Endogenous levels of angiotensin II (Ang II) are increased in the cortex and hypothalamus following stroke, and Ang II type 1 receptor blockers (ARBs) have been shown to attenuate the deleterious effects in animal stroke models using middle cerebral artery (MCA) intraluminal occlusion procedures. However, the endothelin-1 (ET-1)-induced middle cerebral artery occlusion (MCAO) model of cerebral ischaemia is thought to more closely mimic the temporal events of an embolic stroke. This method provides rapid occlusion of the MCA and a gradual reperfusion that lasts for 16-22 h. The aim of the present study was to evaluate whether systemic administration of an ARB prior to ET-1-induced MCAO would provide cerebroprotection during this model of ischaemic stroke. Injection of 3 microl of 80 microM ET-1 adjacent to the MCA resulted in complete occlusion of the vessel that resolved over a period of 30-40 min. Following ET-1-inducedMCAO, rats had significant neurological impairment, as well as an infarct that consisted of 30% of the ipsilateral grey matter. Systemic pretreatment with 0.2 mg kg(-1) day(-1) candesartan for 7 days attenuated both the infarct size and the neurological deficits caused by ET-1-induced MCAO without altering blood pressure. This study confirms the cerebroprotective properties of ARBs during ischaemic stroke and validates the ET-1-induced MCAO model for examination of the role of the brain renin-angiotensin system in ischaemic stroke.

The antigenicity and composition of chromatins differ markedly in chromatin preparations obtained by different procedures. Rat Novikoff hepatoma chromatin (NC) obtained by the "salt precipitation" and the micrococcal nuclease digestion procedures using significant levels of EDTA and NaCl each shows a common complement fixation (CF) capacity, exceeding chromatin preparations obtained from normal rat liver when tested with rabbit antisera raised to dehistonized NC. In contrast, "structured" NC preparations, which have been postulated to retain a native physical conformation, show minimal CF capacity when tested with the same antiserum but show high CF following elution of histones. While further progressive elution of non-histone proteins (NHPs) did not alter the CF capacity per unit DNA, the completely separated DNA and NHP fractions each showed minimal CF. The data suggest that the antigens detected in the CF assay predominantly represent an artifactual but specific complex of DNA and NHP arising from a denaturation of the native chromatin following elution of metal ions or histones. A qualitatively similar profile of NHPs in salt-precipitated NCs shows a range of total protein/DNA ratios, suggesting that the NHPs found in chromatin preparations may not be intrinsic to the native chromatin structure.

Salt-precipitated chromatin was prepared from cultured MvlLu line mink lung cells and from these cells transformed by either of the oncogenes v-mos (MIMS-102 line) or v-fes (F3C7 line). Xenoantisera were raised to chromatin from each of the three cell types and cross-tested in microcomplement fixation assays to determine immunospecificity. Chromatin from cells transformed by either v-mos or v-fes revealed antigenic profiles statistically indistinguishable (P less than 0.2 to 0.5) from one another with their respective cross-tested antisera, but did not react significantly with antisera to chromatin from the untransformed parental cell line. Likewise, little cross-reaction was observed with chromatin from the untransformed cells and antisera raised to chromatin from either of the oncogenically transformed lines (P less than 0.001), although each chromatin demonstrated high reactivity with its homologous antiserum preparation. These immunological data are consistent with the observed normal or transformed characteristics for each cell type, including morphology, anchorage-independent growth, and growth in the absence of serum.

Stocks of inurine sarcoma virus show titration patterns ranging from one-to two-hit kinetics. The comparison of various titrations of this virus, both with and without added helper virus, to theoretical model systems composed of defined constituents, suggests the existence of a sarcoma virus that does not need coinfectinig murine leukemia virus to be manifested as a focus-forming unit. The behavior of such nondefective particles is compatible with a postulated leukemia-sarcoma virus hybrid.

The Rauscher leukemia virus separated as a single band upon density gradient centrifugation in cesium chloride, rubidium chloride, sucrose, potassium citrate, or potassium tartrate. Prolonged exposure to concentrated potassium citrate or potassium tartrate solutions caused lysis of the virus; the resulting products, having different densities, separated on the density gradients.

Incubated mixtures of PR8 influenza virus and Rauscher leukemia virus retained the egg infectivity and hemagglutinin of the influenza virus and the ability of the Rauscher virus to induce splenomegaly in mice. Density-gradient centrifugation on potassium citrate gradients revealed a new interviral product with an intermediate density as the principal constituent of such mixtures. Chicken erythrocytes adsorbed the Rauscher virus components as well as the influenza virus components of the interviral product from such mixtures at 4 degrees C, whereas the Rauscher virus alone was little adsorbed. The adsorbed interviral product was eluted from the erythrocyte complex after incubation at 37 degrees C.

Radiation leukemia virus does not propagate in tissue cultures from either Swiss or C57BL mouse embryos, but it does augment focus formation by the defective Moloney leukemia pseudotype of murine sarcoma virus in Swiss mouse cells and thus can be quantitatively assayed.

The murine leukemia viruses of Rauscher and Friend, derived from plasnma of infected Balb/c mice, was purified. Their antigenic relationship was studied by quantitative complement-fixation reactions with the virion antigen and homologous antiserums. The complement-fixation curves observed in cross-reactions indicated close antigenic similarity between these two leukemia viruses. Highly purified viral preparations contained detectable amounts of host antigens.