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Figure S1 - PDF file 105K, Figure S1. Neuroblastoma cell lines do not express 4-1BB, CD40 or CTLA-4. The expression of 4-1BB, CD40 and CTLA-4 on naive and activated splenocytes (0.5 mg anti-CD3 i.v. 48 hr) and the neuroblastoma cell lines was determined by indirect flow cytometry. Cells were incubated with 10 microg/ml unlabelled mAb, either isotype control (Mc39/16) anti-4-1BB (LOB12.3), anti-CD40 (3/23) or anti-CTLA-4 (UC10 4F10-11) prior to washing and incubation with PE-conjugated anti-mouse Fc. Expression of 4-1BB, CD40 and CTLA-4 could be observed on T-cells from activated splenocytes, but not on naive T-cells as expected. Expression of 4-1BB, CD40 and CTLA-4 was not evident on Neuro2a, AgN2a or NXS2 cell lines. Data represents an example of three experiments

Purpose: Neuroblastoma is one of the commonest extracranial tumors of childhood. The majority of patients present with metastatic disease for which outcome remains poor. Immunotherapy is an attractive therapeutic approach for this disease, and a number of neuroblastoma tumor antigens have been identified. Here, we examine the therapeutic potential of combining immunomodulatory monoclonal antibodies (mAb) with peptide vaccination in murine neuroblastoma models.Experimental Design: Neuroblastoma-bearing mice were treated with mAb targeting 4-1BB, CD40, and CTLA-4 alone, or in combination with a peptide derived from the tumor antigen survivin (GWEDPPNDI). Survivin-specific immune response and therapeutic efficacy were assessed.Results: In the Neuro2a model, treatment of established tumor with anti-4-1BB, anti-CD40, or anti-CTLA-4 mAb results in tumor regression and long-term survival in 40% to 60% of mice. This is dependent on natural killer (NK) and CD8+ T cells and is associated with tumor CD8+ lymphocyte infiltrate. Successful therapy is achieved only if mAb is given to mice once tumors are established, suggesting dependence on sufficient tumor to provide antigen. In the more aggressive AgN2a and NXS2 models, single-agent mAb therapy provides ineffective therapy. However, if mAb (anti-CTLA-4) is given in conjunction with survivin peptide vaccination, then 60% long-term survival is achieved. This is associated with the generation of survivin-specific T-cell immunity, which again is only shown in the presence of tumor antigen.Conclusions: These data suggest that the combination of antigen and costimulatory mAb may provide effective immunotherapy against neuroblastoma and may be of particular use in the minimal residual disease setting. Clin Cancer Res; 19(13); 3545–55. ©2013 AACR.

Purpose:In chronic lymphocytic leukemia (CLL), disease progression associates with surface IgM (sIgM) levels and signaling capacity. These are variably downmodulated in vivo and recover in vitro, suggesting a reversible influence of tissue-located antigen. Therapeutic targeting of sIgM function via ibrutinib, an inhibitor of Bruton tyrosine kinase (BTK), causes inhibition and tumor cell redistribution into the blood, with significant clinical benefit. Circulating CLL cells persist in an inhibited state, offering a tool to investigate the effects of drug on BTK-inhibited sIgM.Experimental Design:We investigated the consequences of ibrutinib therapy on levels and function of sIgM in circulating leukemic cells of patients with CLL.Results:At week 1, there was a significant increase of sIgM expression (64% increase from pretherapy) on CLL cells either recently released from tissue or persisting in blood. In contrast, surface IgD (sIgD) and a range of other receptors did not change. SIgM levels remained higher than pretherapy in the following 3 months despite gradual cell size reduction and ongoing autophagy and apoptotic activity. Conversely, IgD and other receptors did not increase and gradually declined. Recovered sIgM was fully N-glycosylated, another feature of escape from antigen, and expression did not increase further during culture in vitro. The sIgM was fully capable of mediating phosphorylation of SYK, which lies upstream of BTK in the B-cell receptor pathway.Conclusions:This specific IgM increase in patients underpins the key role of tissue-based engagement with antigen in CLL, confirms the inhibitory action of ibrutinib, and reveals dynamic adaptability of CLL cells to precision monotherapy.See related commentary by Burger, p. 2372

Supplementary Tables S1-S2 and Figures S1-S4 with legends

The primary aim of this laboratory-based human subject study was to evaluate the biomechanical loading associated with mining vehicles' multi-axial whole body vibration (WBV) by comparing joint torque and muscle activity in the neck and low back during three vibration conditions: mining vehicles' multi-axial, on-road vehicles' vertical-dominant, and no vibration. Moreover, the secondary aim was to determine the efficacy of a vertical passive air suspension and a prototype multi-axial active suspension seat in reducing WBV exposures and associated biomechanical loading measures. The peak joint torque and muscle activity in the neck and low back were higher when exposed to multi-axial vibration compared to the vertical-dominant or no vibration condition. When comparing the two suspension seats, there were limited differences in WBV, joint torque, and muscle activity. These results indicate that there is a need to develop more effective engineering controls to lower exposures to multi-axial WBV and related biomechanical loading.

Background: People living with cancer are reported to be at increased risk of hospitalization and death following infection with acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This is proposed to be dependent on a combination of intrinsic patient and cancer factors such as cancer subtype, and emerging SARS-CoV-2 variants with differing pathogenicity. However, COVID-19 phenotype evolution across the pandemic from 2020 has not yet been systematically evaluated in cancer patients. Methods: This study is a population-scale real-world evaluation of Coronavirus outcomes in the United Kingdom for cancer patients from 1st November 2020-31st August 2022. The cancer cohort comprises individuals from Public Health England’s national cancer dataset, excluding individuals less than 18 years old. Case-outcome rates, including hospitalization, intensive care and case-fatality rates were used to assess the evolution in disease phenotype of COVID-19 in cancer patients. Multivariable logistic regression models were fitted to compare risk of Coronavirus outcomes in the cancer cohort relative to the non-cancer population during the Omicron wave in 2022. Results: The cancer cohort comprised of 198,819 positive SARS-CoV-2 tests from 127,322 individual infections. Coronavirus case-outcome rates were evaluated by reference to 18,188,573 positive tests from 15,801,004 individual infections in the non-cancer population. From 2020 to 2022, the SARS-CoV-2 disease phenotype became less severe in both patients with cancer and the non-cancer population, though cancer patients remain at higher risk. In 2022, the relative risk of Coronavirus hospital admission, inpatient hospitalization, intensive care admission and mortality in cancer patients was 3.02x, 2.10x, 2.53x and 2.54x compared to the non-cancer population following multivariable adjustment, respectively. Higher risk of hospital admission and inpatient hospitalization were associated with receipt of B/T cell antibody and/or targeted therapy which also corresponded with an increased risk of Coronavirus mortality. Conclusions: The disease phenotype of SARS-CoV-2 in cancer patients in 2022 has evolved significantly from the disease phenotype in 2020. Direct effects of the virus in terms of SARS-CoV-2 hospitalization, intensive care and case fatality rates have fallen significantly over time. However, relative to the general population, people living with cancer and hematological malignancies remain at elevated risk. In order to mitigate the indirect effects of the SARS-CoV-2 pandemic in terms of disruption to cancer care, there should be increased focus on preventative measures. Used in conjunction with vaccination and early treatment programs, this will maximize quality of life for those with cancer during the ongoing pandemic and ensure the best cancer outcomes. Citation Format: Thomas Starkey, Maria C. Ionescu, Matthew W. Fittall, Michael Tilby, Alex Burnett, Rosie Hattersley, Sam Khan, Martin Little, Justin K. Liu, James R. Platt, Arvind Tripathy, Isabella Watts, Sophie Therese Williams, United Kingdom COVID Cancer Programme, Tom Fowler, Peter W. Johnson, Lennard Y. Lee. The temporal evolution in disease phenotype of COVID-19 hospitalisation, intensive care and case fatality rates in cancer patients across the United Kingdom (UKCCP) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 804.

219 HIV-negative adults ≤70 years with primary CNS lymphoma (PCNSL) were enrolled in the randomized IELSG32 trial. Enrolled patients were randomly assigned to receive methotrexate-cytarabine (arm A), or methotrexate-cytarabine-rituximab (B), or methotrexate-cytarabine-thiotepa-rituximab (MATRix; arm C). A second randomization allocated patients with responsive/stable disease to whole-brain irradiation (WBRT) or carmustine-thiotepa-conditioned autologous transplantation (ASCT). First results, after a median follow-up of 30 months, showed that MATRix significantly improves outcome, with both WBRT and ASCT being similarly effective. However, sound assessment of overall survival (OS), efficacy of salvage therapy, late complications, secondary tumors, and cognitive impairment requires longer follow-up. Herein, we report the results of this trial at a median follow-up of 88 months. As main findings, MATRix was associated with excellent long-lasting outcome, with a 7-year OS of 21%, 37%, and 56% respectively for arms A, B, and C. Notably, patients treated with MATRix and consolidation had a 7-year OS of 70%. The superiority of arm B on arm A suggests a benefit from the addition of rituximab. Comparable efficacy of WBRT and ASCT was confirmed. Salvage therapy was ineffective; benefit was recorded only in patients with late relapse re-treated with methotrexate. Eight (4%) patients developed a second cancer. Importantly, MATRix and ASCT did not result in higher non-relapse mortality or second tumors incidence. Patients who received WBRT experienced impairment in attentiveness and executive functions, whereas patients undergoing ASCT experienced improvement in these functions as well as in memory and quality of life.

In North America, Hispanic migrant farmworkers are being exposed to occupational ergonomic risks. Due to cultural differences in the perception and reporting of effort and pain, it was unknown whether standardized subjective ergonomic assessment tools could accurately estimate the directly measured their physical effort. This study investigated whether the subjective scales widely used in exercise physiology were associated with the direct measures of metabolic load and muscle fatigue in this population. Twenty-four migrant apple harvesters participated in this study. The Borg RPE in Spanish and the Omni RPE with pictures of tree-fruit harvesters were used for assessing overall effort at four time points during a full-day 8-h work shift. The Borg CR10 was used for assessing local discomfort at the shoulders. To determine whether there were associations between the subjective and direct measures of overall exertion measures, we conducted linear regressions of the percentage of heart rate reserve (% HRR) on the Borg RPE and Omni RPE. In terms of local discomfort, the median power frequency (MPF) of trapezius electromyography (EMG) was used for representing muscle fatigue. Then full-day measurements of muscle fatigue were regressed on the Borg CR10 changes from the beginning to the end of the work shift. The Omni RPE were found to be correlated with the % HRR. In addition, the Borg RPE were correlated to the % HRR after the break but not after the work. These scales might be useful for certain situations. In terms of local discomfort, the Borg CR10 were not correlated with the MPF of EMG and, therefore, could not replace direct measurement.

This chapter describes vibration exposure in the workplace and its adverse health consequences. Both whole-body vibration and hand-arm vibration are described. The deleterious effects from hand-arm vibration induced by power tools on peripheral nerves and small blood vessels have been documented for more than a century. Whole-body vibration increases spinal load and can contribute to muscle fatigue and deterioration of intervertebral lumbar discs. Neck pain and low back pain are also associated with whole-body vibration from various types of equipment and vehicles. The pathophysiology of various vibration-associated disorders are discussed. Prevention and control measures are described in detail. Control of whole-body vibration rests mainly on primary prevention and selection of appropriate equipment (primarily vehicle and equipment seating) to reduce whole-body vibration exposure.

Because of reported associations of psychosocial factors and computer related musculoskeletal symptoms, we investigated the effects of a workplace psychosocial factor, reward, in the presence of over-commitment, on trapezius muscle activity and shoulder, head, neck, and torso postures during computer use.We measured 120 office workers across four groups (lowest/highest reward/over-commitment), performing their own computer work at their own workstations over a 2-hr period.Median trapezius muscle activity (P = 0.04) and median neck flexion (P = 0.03) were largest for participants reporting simultaneously low reward and high over-commitment. No differences were observed for other muscle activities or postures.These data suggest that the interaction of reward and over-commitment can affect upper extremity muscle activity and postures during computer use in the real work environment. This finding aligns with the hypothesized biomechanical pathway connecting workplace psychosocial factors and musculoskeletal symptoms of the neck and shoulder.

Hepatitis C virus (HCV) infection is associated with some B-cell non-Hodgkin lymphoma (B cell-NHLs). Patients with HCV infection frequently show co-infections with GB virus C (GBV-C, formerly known as hepatitis G virus), and some studies have suggested a higher incidence of GBV-C infection in patients with B cell-NHLs. The aim of this study was to prospectively evaluate the association between HCV and/or GBV-C infection and B cell-NHLs in different geographic areas. One hundred thirty-seven lymphoma cases and 125 non-lymphoma matched controls were enrolled in an international case-control study conducted in Switzerland (Bellinzona), Spain (Barcelona) and England (Southampton) on samples collected from 2001 to 2002. In Bellinzona (41 cases and 81 controls), the overall prevalence of HCV was 3.3% (4.9% in NHLs), and the overall prevalence of GBV-C was 24% (22% in NHLs). In Barcelona (46 cases and 44 controls), the prevalence of HCV was 10% (8.7% in NHLs) and the prevalence of GBV-C 20% (13% in NHLs). There was no statistically significant difference in the frequency of both infections between patients with NHL and controls. In Southampton, 50 NHL cases were analysed, none of them was found to be HCV-positive; therefore, no control group was analysed and GBV-C analysis was not performed, too. Both in Bellinzona and in Barcelona, the seropositivity rate was significantly lower for HCV than for GBV-C, suggesting that their transmission can be independent. The incidence of HCV was significantly higher in Barcelona than that in Bellinzona. This study confirmed the existence of marked geographic differences in the prevalence of HCV in NHL but cannot provide any significant evidence for an association between HCV and/or GBV-C and B-cell NHLs.

Minnesota, Iowa, Illinois, Michigan, and Wisconsin electric and telephone utilities use an estimated 278,000 distribution poles annually, of which 180,000-245,000 are 35 or 40 ft long and in pole Class 1, 2 or 3. Most poles are southern pine, Douglas-fir or western red cedar. Red pine's current market share is only 7%. Most utilities surveyed expressed a willingness to use red pine poles if they could be purchased at the same or at a slightly lower price than they currently pay for southern pine poles. A local pole production facility would benefit from Wisconsin's lower stumpage prices and transportation costs relative to those in the Pacific Northwest and the South. Wages are somewhat higher in Wisconsin than in competing regions, but on balance Wisconsin producers should initially enjoy a net cost advantage of $18-$38 per pole. As pole production expands, some of this cost advantage is expected to be passed on to timber growers in the form of higher stumpage prices. A single pole-treatment facility could treat 10,000-15,000 poles annually, and retain an additional one to two million dollars per year in the state economy. The regional demand appears to be sufficient to support several such plants. Whether sufficient pole material supply would be forthcoming from Wisconsin forests to support such plants is a crucial question that remains to be addressed. North. J. Appl. For. 7:189-193, December 1990.

In the San Francisco Bay Region, the Regional Water Quality Control Board is now regulating approximately 140 sites where toxic chemicals have contaminated groundwater. Many of these were located through the Board's Underground Tank Leak Detection Program, which required subsurface investigations at sites with underground solvent tanks. New ordinances and state laws are expected to result in the discovery of hundreds more contamination sites in the next few years. The Regional Board is developing a ranking methodology to assign priorities among cases and a set of guidelines for establishment of clean‐up objectives on a site‐by‐site basis. Appropriate regulatory mechanisms have been selected to enforce the necessary investigation and cleanup activities.

During the past few years, contamination associated with underground chemical storage has been found to have caused extensive degradation of otherwise usable groundwater in many locations. In response, many cities within the San Francisco Bay area are presently implementing ordinances that require monitoring of underground tanks including fuel tanks. In addition, recently enacted state laws will require some form of rigorous monitoring for fuel tanks throughout California. Implementation of fuel leak monitoring programs will result in the discovery of a significant number of additional fuel leak sites. The authors project that 200 to 300 reports of subsurface fuel contamination will be generated during the next year in the San Francisco Bay area. To deal with this overwhelming increase in regulatory workload it is likely that some level of initial response to fuel leaks may be delegated to local governments. For the above reasons, the California Regional Water Quality Control Board, San Francisco Bay Region, is developing formalized response procedures to provide a consistent and adequate preliminary response to initial reports of suspected or confirmed underground fuel leaks. These procedures are intended to provide a screening process to minimize additional follow-up where it is not required and to ensure such follow-up where it is necessary. The proposed procedures will be the subject of several public workshops and at least one formal public hearing before they are considered final. They are described here in an attempt to stimulate further technical input to the public discussion process and to possibly provide a model for use by others who will be faced with similar decision-making needs as similar ordinances and regulations are adopted throughout the state and in other states.