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Cancer cachexia affects up to 80% of cancer patients and results in reduced quality of life and survival. We previously demonstrated that the transcriptional repressor Forkhead box P1 (FoxP1) is upregulated in skeletal muscle of cachectic mice and people with cancer, and when overexpressed in skeletal muscle is sufficient to induce pathological features characteristic of cachexia. However, the role of myofiber-derived FoxP1 in both normal muscle physiology and cancer-induced muscle wasting remains largely unexplored. To address this gap, we generated a conditional mouse line with myofiber-specific ablation of FoxP1 (FoxP1 SkmKO ) and found that in cancer-free mice, deletion of FoxP1 in skeletal myofibers resulted in increased myofiber size in both males and females, with a significant increase in muscle mass in males. In response to murine KPC pancreatic tumor burden, we found that myofiber-derived FoxP1 is required for cancer-induced muscle wasting and diaphragm muscle weakness in male mice. In summary, our findings identify myofiber-specific FoxP1 as a negative regulator of skeletal muscle with sex-specific differences in the context of cancer.

Cancer cachexia affects up to 80% of cancer patients and results in reduced quality of life and survival. We previously demonstrated that the transcriptional repressor Forkhead box P1 (FoxP1) is upregulated in skeletal muscle of cachectic mice and people with cancer, and when overexpressed in skeletal muscle is sufficient to induce pathological features characteristic of cachexia. However, the role of myofiber-derived FoxP1 in both normal muscle physiology and cancer-induced muscle wasting remains largely unexplored. To address this gap, we generated a conditional mouse line with myofiber-specific ablation of FoxP1 (FoxP1 SkmKO ) and found that in cancer-free mice, deletion of FoxP1 in skeletal myofibers resulted in increased myofiber size in both males and females, with a significant increase in muscle mass in males. In response to murine KPC pancreatic tumor burden, we found that myofiber-derived FoxP1 is required for cancer-induced muscle wasting and diaphragm muscle weakness in male mice. In summary, our findings identify myofiber-specific FoxP1 as a negative regulator of skeletal muscle with sex-specific differences in the context of cancer., Competing Interests: DISCLOSURES The authors declare no conflicts of interest.

Introduction: Cancer-associated cachexia (CC) is a progressive syndrome characterized by unintentional weight loss, muscle atrophy, fatigue, and poor outcomes that affects most patients with pancreatic ductal adenocarcinoma (PDAC). The ability to identify and classify CC stage along its continuum early in the disease process is challenging but critical for management., Objectives: The main objective of this study was to determine the prevalence of CC stage overall and by sex and race and ethnicity among treatment-naïve PDAC cases using clinical, nutritional, and functional criteria. Secondary objectives included identifying the prevalence and predictors of higher symptom burden, supportive care needs, and quality of life (QoL), and examining their influence on overall survival (OS)., Materials and Methods: A population-based multi-institutional prospective cohort study of patients with PDAC was conducted between 2018 and 2021 by the Florida Pancreas Collaborative. Leveraging patient-reported data and laboratory values, participants were classified at baseline into four stages [non-cachexia (NCa), pre-cachexia (PCa), cachexia (Ca), and refractory cachexia (RCa)]. Multivariate regression, Kaplan Meier analyses, and Cox regression were conducted to evaluate associations., Results: CC stage was estimated for 309 PDAC cases (156 females, 153 males). The overall prevalence of NCa, PCa, Ca, and RCa was 12.9%, 24.6%, 54.1%, and 8.4%, respectively. CC prevalence across all CC stages was highest for males and racial and ethnic minorities. Criteria differentiated NCa cases from other groups, but did not distinguish PCa from Ca. The most frequently reported symptoms included weight loss, fatigue, pain, anxiety, and depression, with pain significantly worsening over time. The greatest supportive care needs included emotional and physical domains. Males, Black people, and those with RCa had the worst OS., Conclusions: Using clinical, nutritional, and functional criteria, nearly one-quarter of the PDAC cases in our diverse, multi-institutional cohort had PCa and 62.5% had Ca or RCa at the time of diagnosis. The PCa estimate is higher than that reported in prior studies. We recommend these criteria be used to aid in CC classification, monitoring, and management of all incident PDAC cases. Findings also highlight the recommendation for continued emotional support, assistance in alleviating pain, and supportive care needs throughout the PDAC treatment journey., 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 © 2024 Permuth, Park, Chen, Basinski, Powers, Gwede, Dezsi, Gomez, Vyas, Biachi, Cortizas, Crowder, Genilo-Delgado, Green, Greene, Gregg, Hoffe, Jiang, Kim, Vasudevan, Garcialopez De Llano, Menon, Mo, MorenoUrazan, Mok, Parker, Rajasekhara, Rasool, Sinnamon, Sparks, Stewart, Tardif, Tassielli, Teer, Tran, Turner, Vadaparampil, Whelan, Douglas, Velanovich, Karachristos, Legaspi, Meredith, Molina-Vega, Huguet, Arnoletti, Bloomston, Trevino, Merchant, Pimiento, Hodul, Malafa, Fleming, Judge, Jeong and Judge.)

Cancer cachexia is a tumour-induced wasting syndrome, characterised by extreme loss of skeletal muscle. Defective mitochondria can contribute to muscle wasting; however, the underlying mechanisms remain unclear. Using a Drosophila larval model of cancer cachexia, we observed enlarged and dysfunctional muscle mitochondria. Morphological changes were accompanied by upregulation of beta-oxidation proteins and depletion of muscle glycogen and lipid stores. Muscle lipid stores were also decreased in Colon-26 adenocarcinoma mouse muscle samples, and expression of the beta-oxidation gene CPT1A was negatively associated with muscle quality in cachectic patients. Mechanistically, mitochondrial defects result from reduced muscle insulin signalling, downstream of tumour-secreted insulin growth factor binding protein (IGFBP) homologue ImpL2. Strikingly, muscle-specific inhibition of Forkhead box O (FOXO), mitochondrial fusion, or beta-oxidation in tumour-bearing animals preserved muscle integrity. Finally, dietary supplementation with nicotinamide or lipids, improved muscle health in tumour-bearing animals. Overall, our work demonstrates that muscle FOXO, mitochondria dynamics/beta-oxidation and lipid utilisation are key regulators of muscle wasting in cancer cachexia., (© 2024. The Author(s).)

Background: Pancreatic ductal adenocarcinoma (PDAC) is highly associated with cachexia and weight loss, which is driven by the tumour's effect on the body. Data are lacking on differences in these metrics based on PDAC anatomic location. We hypothesize that the primary tumour's anatomic region influences the prevalence and severity of unintentional weight loss., Methods: Treatment naïve patients with PDAC who underwent pancreatectomy at a single institution between 2012 and 2020 were identified retrospectively. Patients with pancreatic head or distal tumours were matched by sex, age, N and T stage. Serologic and anthropometric variables were obtained at the time of diagnosis. Skeletal muscle index (SMI), muscle radiation attenuation (MRA) and adiposity were measured. The primary outcome was presence of significant weight loss [>5% body weight (BW) loss in past 6 months]. Signed rank tests, Cochran Mantel Haenszel tests and Kaplan-Meier survival analysis are presented. RNA-seq of tumours was performed to explore enriched pathways related to cachexia and weight loss., Results: Pancreatic head tumours (n = 24) were associated with higher prevalence (70.8% vs. 41.7%, P = 0.081) and degree of weight loss (7.9% vs. 2.5%, P = 0.014) compared to distal tumours (n = 24). BMI (P = 0.642), SMI (P = 0.738) and MRA (P = 0.478) were similar between groups. Combining BW loss, SMI and MRA into a composite score, patients with pancreatic head cancers met more criteria associated with poor prognosis (P = 0.142). Serum albumin (3.9 vs. 4.4 g/dL, P = 0.002) was lower and bilirubin (4.5 vs. 0.4 mg/dL, P < 0.001) were higher with pancreatic head tumours. Survival differed by tumour location (P = 0.014) with numerically higher median overall survival with distal tumours (11.1 vs. 21.8 months; P = 0.066). Transcriptomic analysis revealed inactivation of appetite stimulation, weight regulation and nutrient digestion/metabolism pathways in pancreatic head tumours., Conclusions: Resectable pancreatic head PDAC is associated with higher prevalence of significant weight loss and more poor prognosis features. Pancreaticobiliary obstruction and hypoalbuminemia in patients with head tumours suggests compounding effects of nutrient malabsorption and systemic inflammation on molecular drivers of cachexia, possibly contributing to shorter survival. Therefore, PDAC-associated cachexia is a heterogenous syndrome, which may be influenced by the primary tumour location. Select patients with resectable pancreatic head tumours may benefit from nutritional rehabilitation to improve outcomes., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Muscle atrophy and weakness are prevalent and debilitating conditions in dogs that cannot be reliably prevented or treated by current approaches. In non-canine species, the natural dietary compound ursolic acid inhibits molecular mechanisms of muscle atrophy, leading to improvements in muscle health. To begin to translate ursolic acid to canine health, we developed a novel ursolic acid dietary supplement for dogs and confirmed its safety and tolerability in dogs. We then conducted a randomized, placebo-controlled, proof-of-concept efficacy study in older beagles with age-related muscle atrophy, also known as sarcopenia. Animals received placebo or ursolic acid dietary supplements once a day for 60 days. To assess the study's primary outcome, we biopsied the quadriceps muscle and quantified atrophy-associated mRNA expression. Additionally, to determine whether the molecular effects of ursolic acid might have functional correlates consistent with improvements in muscle health, we assessed secondary outcomes of exercise participation and T-maze performance. Importantly, in canine skeletal muscle, ursolic acid inhibited numerous mRNA expression changes that are known to promote muscle atrophy and weakness. Furthermore, ursolic acid significantly improved exercise participation and T-maze performance. These findings identify ursolic acid as a natural dietary compound that inhibits molecular mechanisms of muscle atrophy and improves functional performance in dogs.

The Bureau International des Poids et Mesures (BIPM) is developing a new transfer instrument to extend its centralized services for assessing the international equivalence of radioactive standards to new radionuclides. A liquid scintillation counter using the triple/double coincidence ratio method is being studied and tested in the CCRI(II)-P1.Co-60 pilot study. The pilot study, involving 13 participating laboratories with primary calibration capabilities, validated the approach against the original international reference system based on ionization chambers, which has been in operation since 1976. The results are in agreement and an accuracy suitable for purpose, below 5×10 -4 , is achieved. The pilot study also reveals an issue when impurities emitting low-energy electrons are present in the standard solution, which have a different impact on liquid scintillation counting compared to other primary measurement methods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Despite government-mandated restrictions on business and social activities worldwide, some sex workers continued to see clients in person throughout the COVID-19 pandemic. To better understand this behaviour, we compiled publicly available data from Internet advertisements posted on a popular website before and during the pandemic by male sex workers providing services to men. We first collected data in March 2019 from 172 advertisements - the complete number available at that time - posted by male sex workers advertising services in the Atlanta region. We then assessed whether these same sex workers continued to advertise their availability at three subsequent points during the COVID-19 pandemic: April 2020, January 2021 and February 2021. We also determined whether age and race were associated with advertising presence at each time point. While advertising rates declined among sex workers in all race categories (Black, White and 'other'), results from our mixed effects logistic regression model show that the odds of older male sex workers continuing to advertise were greater than the odds for their younger counterparts. Further, the predicted probability of continued advertising was highest for White male sex workers. Our findings provide additional insights into male sex work during a global pandemic.

Cancer-induced muscle wasting reduces quality of life, complicates or precludes cancer treatments, and predicts early mortality. Herein, we investigate the requirement of the muscle-specific E3 ubiquitin ligase, MuRF1, for muscle wasting induced by pancreatic cancer. Murine pancreatic cancer (KPC) cells, or saline, were injected into the pancreas of WT and MuRF1 -/- mice, and tissues analyzed throughout tumor progression. KPC tumors induces progressive wasting of skeletal muscle and systemic metabolic reprogramming in WT mice, but not MuRF1 -/- mice. KPC tumors from MuRF1 -/- mice also grow slower, and show an accumulation of metabolites normally depleted by rapidly growing tumors. Mechanistically, MuRF1 is necessary for the KPC-induced increases in cytoskeletal and muscle contractile protein ubiquitination, and the depression of proteins that support protein synthesis. Together, these data demonstrate that MuRF1 is required for KPC-induced skeletal muscle wasting, whose deletion reprograms the systemic and tumor metabolome and delays tumor growth., (© 2023. The Author(s).)

Background: Sixty percent of patients with esophageal cancer display signs of cachexia at diagnosis. Changes in body composition are common, and muscle mass and quality are measurable through imaging studies. Cachexia leads to functional impairments that complicate treatments, including surgery. We hypothesize that low muscle mass and quality associate with pulmonary function testing parameters, highlighting ventilatory deficits, and postoperative complications in patients receiving esophagectomy., Study Design: We performed a retrospective review of patients receiving esophagectomy between 2012 and 2021 at our facility. PET/CT scans were used to quantify skeletal muscle at the L3 and T4 levels. Patient characteristics were recorded, including pulmonary function testing parameters. Regression models were created to characterize predictive associations., Results: One hundred eight patients were identified. All were included in the final analysis. In linear regression adjusted for sex, age, and COPD status, low L3 muscle mass independently associated with low forced vital capacity (p < 0.005, β 0.354) and forced expiratory volume in 1 second (p < 0.001, β 0.392). Similarly, T4 muscle mass independently predicted forced vital capacity (p < 0.005, β 0.524) and forced expiratory volume in 1 second (p < 0.01, β 0.480). L3 muscle quality correlated with total lung capacity ( R 0.2463, p < 0.05). Twenty-six patients had pleural effusions postoperatively, associated with low muscle quality on L3 images (p < 0.05). Similarly, patients with hospitalization more than 2 weeks presented with lower muscle quality (p < 0.005)., Conclusions: Cachexia and low muscle mass are common. Reduced muscle mass and quality independently associate with impaired forced vital capacity, forced expiratory volume in 1 second, and total lung capacity. We propose that respiratory muscle atrophy occurs with weight loss. Body composition analyses may aid in stratifying patients. Pulmonary function testing may also serve as a functional endpoint for clinical trials. These findings highlight the need to study mechanisms that lead to respiratory muscle pathology and dysfunction in tumor-bearing hosts., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Immune cells can mount desirable anti-cancer immunity. However, some immune cells can support cancer disease progression. The presence of cancer can lead to production of immature myeloid cells from the bone marrow known as myeloid-derived suppressor cells (MDSCs). The immunosuppressive and pro-tumorigenic effects of MDSCs are well understood. Whether MDSCs are involved in promoting cancer cachexia is not well understood. We orthotopically injected the pancreas of mice with KPC cells or PBS. One group of tumor-bearing mice was treated with an anti-Ly6G antibody that depletes granulocytic MDSCs and neutrophils; the other received a control antibody. Anti-Ly6G treatment delayed body mass loss, reduced tibialis anterior (TA) muscle wasting, abolished TA muscle fiber atrophy, reduced diaphragm muscle fiber atrophy of type IIb and IIx fibers, and reduced atrophic gene expression in the TA muscles. Anti-ly6G treatment resulted in greater than 50% Ly6G+ cell depletion efficiency in the tumors and TA muscles. These data show that, in the orthotopic KPC model, anti-Ly6G treatment reduces the number of Ly6G+ cells in the tumor and skeletal muscle and reduces skeletal muscle atrophy. These data implicate Ly6G+ cells, including granulocytic MDSCs and neutrophils, as possible contributors to the development of pancreatic cancer-induced skeletal muscle wasting.

Activating transcription factor 4 (ATF4) is a multifunctional transcription regulatory protein in the basic leucine zipper superfamily. ATF4 can be expressed in most if not all mammalian cell types, and it can participate in a variety of cellular responses to specific environmental stresses, intracellular derangements, or growth factors. Because ATF4 is involved in a wide range of biological processes, its roles in human health and disease are not yet fully understood. Much of our current knowledge about ATF4 comes from investigations in cultured cell models, where ATF4 was originally characterized and where further investigations continue to provide new insights. ATF4 is also an increasingly prominent topic of in vivo investigations in fully differentiated mammalian cell types, where our current understanding of ATF4 is less complete. Here, we review some important high-level concepts and questions concerning the basic biology of ATF4. We then discuss current knowledge and emerging questions about the in vivo role of ATF4 in one fully differentiated cell type, mammalian skeletal muscle fibers., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest of all common malignancies. Treatment is difficult and often complicated by the presence of cachexia. The clinical portrait of cachexia contributes to the poor prognosis experienced by PDAC patients and worsens therapeutic outcomes. We propose that low bone mineral density is a component of cachexia, which we explore herein through a retrospective review of all patients at our facility that underwent surgery for PDAC between 2011 and 2018 and compared to sex-, age- and comorbidity-matched control individuals. Data were abstracted from the medical record and pre-operative computed tomography scans. Muscle mass and quality were measured at the L3 level and bone mineral density was measured as the radiation attenuation of the lumbar vertebral bodies. Patients with PDAC displayed typical signs of cachexia such as weight loss and radiologically appreciable deterioration of skeletal muscle. Critically, PDAC patients had significantly lower bone mineral density than controls, with 61.2% of PDAC patients categorized as osteopenic compared to 36.8% of controls. PDAC patients classified as osteopenic had significantly reduced survival (1.01 years) compared to patients without osteopenia (2.77 years). The presence of osteopenia was the strongest clinical predictor of 1- and 2-year disease-specific mortality, increasing the risk of death by 107% and 80%, respectively. Osteopenia serves as a test of 2-year mortality with sensitivity of 76% and specificity of 58%. These data therefore identify impaired bone mineral density as a key component of cachexia and predictor of postoperative survival in patients with PDAC. The mechanisms that lead to bone wasting in tumor-bearing hosts deserve further study., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Skeletal muscle wasting is a devastating consequence of cancer that affects up to 80% of cancer patients and associates with reduced survival. Herein, we investigated the biological significance of Forkhead box P1 (FoxP1), a transcriptional repressor that we demonstrate is up-regulated in skeletal muscle in multiple models of cancer cachexia and in cachectic cancer patients., Methods: Inducible, skeletal muscle-specific FoxP1 over-expressing (FoxP1 iSkmTg/Tg ) mice were generated through crossing conditional Foxp1a transgenic mice with HSA-MCM mice that express tamoxifen-inducible Cre recombinase under control of the skeletal muscle actin promoter. To determine the requirement of FoxP1 for cancer-induced skeletal muscle wasting, FoxP1-shRNA was packaged and targeted to muscles using AAV9 delivery prior to inoculation of mice with Colon-26 Adenocarcinoma (C26) cells., Results: Up-regulation of FoxP1 in adult skeletal muscle was sufficient to induce features of cachexia, including 15% reduction in body mass (P < 0.05), and a 16-27% reduction in skeletal muscle mass (P < 0.05) that was characterized by a 20% reduction in muscle fibre cross-sectional area of type IIX/B muscle fibres (P = 0.020). Skeletal muscles from FoxP1 iSkmTg/Tg mice also showed significant damage and myopathy characterized by the presence of centrally nucleated myofibres, extracellular matrix expansion, and were 19-26% weaker than controls (P < 0.05). Transcriptomic analysis revealed FoxP1 as a potent transcriptional repressor of skeletal muscle gene expression, with enrichment of pathways related to skeletal muscle structure and function, growth signalling, and cell quality control. Because FoxP1 functions, at least in part, as a transcriptional repressor through its interaction with histone deacetylase proteins, we treated FoxP1 iSkmTg/Tg mice with Trichostatin A, and found that this completely prevented the loss of muscle mass (p = 0.007) and fibre atrophy (P < 0.001) in the tibialis anterior. In the context of cancer, FoxP1 knockdown blocked the cancer-induced repression of myocyte enhancer factor 2 (MEF2)-target genes critical to muscle differentiation and repair, improved muscle ultrastructure, and attenuated muscle fibre atrophy by 50% (P < 0.05)., Conclusions: In summary, we identify FoxP1 as a novel repressor of skeletal muscle gene expression that is increased in cancer cachexia, whose up-regulation is sufficient to induce skeletal muscle wasting and weakness, and required for the normal wasting response to cancer., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background : Well-annotated, high-quality biorepositories provide a valuable platform to support translational research. However, most biorepositories have poor representation of minority groups, limiting the ability to address health disparities. Methods : We describe the establishment of the Florida Pancreas Collaborative (FPC), the first state-wide prospective cohort study and biorepository designed to address the higher burden of pancreatic cancer (PaCa) in African Americans (AA) compared to Non-Hispanic Whites (NHW) and Hispanic/Latinx (H/L). We provide an overview of stakeholders; study eligibility and design; recruitment strategies; standard operating procedures to collect, process, store, and transfer biospecimens, medical images, and data; our cloud-based data management platform; and progress regarding recruitment and biobanking. Results : The FPC consists of multidisciplinary teams from fifteen Florida medical institutions. From March 2019 through August 2020, 350 patients were assessed for eligibility, 323 met inclusion/exclusion criteria, and 305 (94%) enrolled, including 228 NHW, 30 AA, and 47 H/L, with 94%, 100%, and 94% participation rates, respectively. A high percentage of participants have donated blood (87%), pancreatic tumor tissue (41%), computed tomography scans (76%), and questionnaires (62%). Conclusions : This biorepository addresses a critical gap in PaCa research and has potential to advance translational studies intended to minimize disparities and reduce PaCa-related morbidity and mortality.

Abstract: Given the stigma surrounding sex work and the illegal nature of many aspects of commercial sex activity, empirical research is lacking regarding the health-related behaviors of sex workers, particularly male sex workers who have sex with men (MSM sex workers). To better understand the MSM sex worker community and their potential health needs, we analyzed certain sexual health-related behaviors as advertised online by MSM sex workers in the San Francisco area. Using descriptive and bivariate statistical tests, we examined whether age- and race-related differences existed among these sex workers in the following publicly advertised behaviors: use of pre-exposure prophylaxis and a willingness to engage in illicit drug use or condomless anal intercourse. Although we found no significant differences by race in terms of advertised pre-exposure prophylaxis use or willingness to engage in condomless sex, our results show statistically significant differences by race with respect to willingness to use drugs. This difference could be driven by the younger average age of the non-White sex workers in our sample. These findings help inform our understanding of MSM sex work and its associated risks., (Copyright © 2020 Association of Nurses in AIDS Care.)

The β decay of ^{208}Hg into the one-proton hole, one neutron-particle &#95;{81}^{208}Tl&#95;{127} nucleus was investigated at CERN-ISOLDE. Shell-model calculations describe well the level scheme deduced, validating the proton-neutron interactions used, with implications for the whole of the N>126, Z<82 quadrant of neutron-rich nuclei. While both negative and positive parity states with spin 0 and 1 are expected within the Q&#95;{β} window, only three negative parity states are populated directly in the β decay. The data provide a unique test of the competition between allowed Gamow-Teller and Fermi, and first-forbidden β decays, essential for the understanding of the nucleosynthesis of heavy nuclei in the rapid neutron capture process. Furthermore, the observation of the parity changing 0^{+}→0^{-}β decay where the daughter state is core excited is unique, and can provide information on mesonic corrections of effective operators.

Re-entrant ionization chambers (ICs) are essential to radionuclide metrology and nuclear medicine for maintaining standards and measuring half-lives. The requirements of top-level metrology demand that systems must be precise and stable to 0.1 % over many years, and linear from 10 -14 A to 10 -8 A. Thus, laboratories depend on bespoke current measurement systems and often rely on sealed sources to generate reference currents. To maintain and improve present capabilities, metrologists need to overcome two looming challenges: ageing electronics and decreasing availability of sealed sources. Possible solutions using Ultrastable Low-Noise Current Amplifiers (ULCAs), resistive-feedback electrometers, and (quantum) single-electron pumps are reviewed. Broader discussions of IC design and methodology are discussed. ULCAs show promise and resistive-feedback systems which take advantage of standard resistor calibrations offer an alternative., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: Cancer cachexia is a life-threatening metabolic syndrome that causes significant loss of skeletal muscle mass and significantly increases mortality in cancer patients. Currently, there is an urgent need for better understanding of the molecular pathophysiology of this disease so that effective therapies can be developed. The majority of pre-clinical studies evaluating skeletal muscle's response to cancer have focused on one or two pre-clinical models, and almost all have focused specifically on limb muscles. In the current study, we reveal key differences in the histology and transcriptomic signatures of a limb muscle and a respiratory muscle in orthotopic pancreatic cancer patient-derived xenograft (PDX) mice., Methods: To create four cohorts of PDX mice evaluated in this study, tumours resected from four pancreatic ductal adenocarcinoma patients were portioned and attached to the pancreas of immunodeficient NSG mice., Results: Body weight, muscle mass, and fat mass were significantly decreased in each PDX line. Histological assessment of cryosections taken from the tibialis anterior (TA) and diaphragm (DIA) revealed differential effects of tumour burden on their morphology. Subsequent genome-wide microarray analysis on TA and DIA also revealed key differences between their transcriptomes in response to cancer. Genes up-regulated in the DIA were enriched for extracellular matrix protein-encoding genes and genes related to the inflammatory response, while down-regulated genes were enriched for mitochondria related protein-encoding genes. Conversely, the TA showed up-regulation of canonical atrophy-associated pathways such as ubiquitin-mediated protein degradation and apoptosis, and down-regulation of genes encoding extracellular matrix proteins., Conclusions: These data suggest that distinct biological processes may account for wasting in different skeletal muscles in response to the same tumour burden. Further investigation into these differences will be critical for the future development of effective clinical strategies to counter cancer cachexia., (© 2020 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Skeletal muscle wasting is a devastating consequence of cancer that contributes to increased complications and poor survival, but is not well understood at the molecular level. Herein, we investigated the role of Myocilin (Myoc), a skeletal muscle hypertrophy-promoting protein that we showed is downregulated in multiple mouse models of cancer cachexia. Loss of Myoc alone was sufficient to induce phenotypes identified in mouse models of cancer cachexia, including muscle fiber atrophy, sarcolemmal fragility, and impaired muscle regeneration. By 18 months of age, mice deficient in Myoc showed significant skeletal muscle remodeling, characterized by increased fat and collagen deposition compared with wild-type mice, thus also supporting Myoc as a regulator of muscle quality. In cancer cachexia models, maintaining skeletal muscle expression of Myoc significantly attenuated muscle loss, while mice lacking Myoc showed enhanced muscle wasting. Furthermore, we identified the myocyte enhancer factor 2 C (MEF2C) transcription factor as a key upstream activator of Myoc whose gain of function significantly deterred cancer-induced muscle wasting and dysfunction in a preclinical model of pancreatic ductal adenocarcinoma (PDAC). Finally, compared with noncancer control patients, MYOC was significantly reduced in skeletal muscle of patients with PDAC defined as cachectic and correlated with MEF2c. These data therefore identify disruptions in MEF2c-dependent transcription of Myoc as a novel mechanism of cancer-associated muscle wasting that is similarly disrupted in muscle of patients with cachectic cancer. SIGNIFICANCE: This work identifies a novel transcriptional mechanism that mediates skeletal muscle wasting in murine models of cancer cachexia that is disrupted in skeletal muscle of patients with cancer exhibiting cachexia., (©2020 American Association for Cancer Research.)

Smoking is highly associated with pancreatic cancer. Nicotine, the addictive component of tobacco, is involved in pancreatic cancer tumorigenesis, metastasis, and chemoresistance. This work aimed to describe the role of nicotine within the pancreatic cancer tumor microenvironment. Nicotine treatment was used in vitro to assess its effect on tumor-associated stromal cells and pancreatic cancer cells. Nicotine treatment was then used in a pancreatic cancer patient-derived xenograft model to study the effects in vivo. Nicotine induced secretion of interleukin 8 (IL-8) by tumor-associated stroma cells in an extracellular signal-regulated kinase (ERK)-dependent fashion. The secreted IL-8 and nicotine acted on the pancreatic cancer cell, resulting in upregulation of IL-8 receptor. Nicotine treatment of mice bearing pancreatic cancer patient-derived xenografts had significantly increased tumor mass, increased tumor-free weight loss, and decreased muscle mass. These represent important pathways through which nicotine acts within the tumor microenvironment and worsens pancreatic cancer-induced cachexia, potentially representing future therapeutic targets.

Tumor-derived cytokines are known to drive the catabolism of host tissues, including skeletal muscle. However, our understanding of the specific cytokines that initiate this process remains incomplete. In the current study, we conducted multiplex analyte profiling of cytokines in conditioned medium (CM) collected from human pancreatic cancer (PC) cells, human tumor-associated stromal (TAS) cells, and their co-culture. Of the factors identified, interleukin-8 (IL-8) is released at high levels from PC cells and PC/TAS co-culture and has previously been associated with low muscle mass in cancer patients. We, therefore, treated C2C12 myotubes with IL-8 which led to the activation of ERK1/2, STAT, and Smad signaling, and induced myotube atrophy. Moreover, the treatment of mice with IL-8 also induced significant muscle wasting, confirming the in vivo relevance of IL-8 on muscle. Mechanistically, IL-8-induced myotube atrophy is inhibited by treatment with the CXCR2 antagonist, SB225002, or by treatment with the ERK1/2 inhibitor, U0126. We further demonstrate that this axis mediates muscle atrophy induced by pancreatic cancer cell CM, as neutralization of IL-8 or treatment with SB225002 or U0126 significantly inhibit CM-induced myotube atrophy. Thus, these data support a key role of IL-8 released from human PC cells in initiating atrophy of muscle cells via CXCR2-ERK1/2.​., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of skeletal muscle mass associated with significant functional impairment. Cachexia robs patients of their strength and capacity to perform daily tasks and live independently. Effective treatments are needed urgently. Here, we investigated the therapeutic potential of activating the "alternative" axis of the renin-angiotensin system, involving ACE2, angiotensin-(1-7), and the mitochondrial assembly receptor (MasR), for treating cancer cachexia. Plasmid overexpression of the MasR or pharmacologic angiotensin-(1-7)/MasR activation did not affect healthy muscle fiber size in vitro or in vivo but attenuated atrophy induced by coculture with cancer cells in vitro . In mice with cancer cachexia, the MasR agonist AVE 0991 slowed tumor development, reduced weight loss, improved locomotor activity, and attenuated muscle wasting, with the majority of these effects dependent on the orexigenic and not antitumor properties of AVE 0991. Proteomic profiling and IHC revealed that mechanisms underlying AVE 0991 effects on skeletal muscle involved miR-23a-regulated preservation of the fast, glycolytic fibers. MasR activation is a novel regulator of muscle phenotype, and AVE 0991 has orexigenic, anticachectic, and antitumorigenic effects, identifying it as a promising adjunct therapy for cancer and other serious muscle wasting conditions. SIGNIFICANCE: These findings demonstrate that MasR activation has multiple benefits of being orexigenic, anticachectic, and antitumorigenic, revealing it as a potential adjunct therapy for cancer. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/4/706/F1.large.jpg. See related commentary by Rupert et al., p. 699 ., (©2018 American Association for Cancer Research.)

Background: Cancer cachexia is a metabolic wasting syndrome that is strongly associated with a poor prognosis. The initiating factors causing fat and muscle loss are largely unknown. Previously, we found that leukaemia inhibitory factor (LIF) secreted by C26 colon carcinoma cells was responsible for atrophy in treated myotubes. In the present study, we tested whether C26 tumour-derived LIF is required for cancer cachexia in mice by knockout of Lif in C26 cells., Methods: A C26 Lif null tumour cell line was made using CRISPR-Cas9. Measurements of cachexia were compared in mice inoculated with C26 vs. C26 Lif-/- tumour cells, and atrophy was compared in myotubes treated with medium from C26 vs. C26 Lif-/- tumour cells. Levels of 25 cytokines/chemokines were compared in serum of mice bearing C26 vs. C26 Lif-/- tumours and in the medium from these tumour cell lines., Results: At study endpoint, C26 mice showed outward signs of sickness while mice with C26 Lif-/- tumours appeared healthy. Mice with C26 Lif-/- tumours showed a 55-75% amelioration of body weight loss, muscle loss, fat loss, and splenomegaly compared with mice with C26 tumours (P < 0.05). The heart was not affected by LIF levels because the loss of cardiac mass was the same in C26 and C26 Lif-/- tumour-bearing mice. LIF levels in mouse serum was entirely dependent on secretion from the tumour cells. Serum levels of interleukin-6 and G-CSF were increased by 79-fold and 68-fold, respectively, in C26 mice but only by five-fold and two-fold, respectively, in C26 Lif-/- mice, suggesting that interleukin-6 and G-CSF increases are dependent on tumour-derived LIF., Conclusions: This study shows the first use of CRISPR-Cas9 knockout of a candidate cachexia factor in tumour cells. The results provide direct evidence for LIF as a major cachexia initiating factor for the C26 tumour in vivo. Tumour-derived LIF was also a regulator of multiple cytokines in C26 tumour cells and in C26 tumour-bearing mice. The identification of tumour-derived factors such as LIF that initiate the cachectic process is immediately applicable to the development of therapeutics to treat cachexia. This is a proof of principle for studies that when carried out in human cells, will make possible an understanding of the factors causing cachexia in a patient-specific manner., (© 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.)

Cancer cachexia is a debilitating condition seen frequently in patients with pancreatic ductal adenocarcinoma (PDAC). The underlying mechanisms driving cancer cachexia are not fully understood but are related, at least in part, to the immune response to the tumor both locally and systemically. We hypothesize that there are unique differences in cytokine levels in the tumor microenvironment and systemic circulation between PDAC tumors and that these varying profiles affect the degree of cancer cachexia observed. Patient demographics, operative factors, oncologic factors, and perioperative data were collected for the two patients in the patient derived xenograft (PDX) model. Human pancreatic cancer PDX were created by implanting fresh surgical pancreatic cancer tissues directly into immunodeficient mice. At PDX end point, mouse tumor, spleen and muscle tissues were collected and weighed, muscle atrophy related gene expression measured, and tumor and splenic soluble proteins were analyzed. PDX models were created from surgically resected patients who presented with different degrees of cachexia. Tumor free body weight and triceps surae weight differed significantly between the PDX models and control (P < 0.05). Both PDX groups had increased atrophy related gene expression in muscle compared to control (FoxO1, Socs3, STAT3, Acvr2b, Atrogin-1, MuRF1; P < 0.05). Significant differences were noted in splenic soluble protein concentrations in 14 of 15 detected proteins in tumor bearing mice when compared to controls. Eight splenic soluble proteins were significantly different between PDX groups (P < 0.05). Tumor soluble proteins were significantly different between the two PDX groups in 15 of 24 detected proteins (P < 0.05). PDX models preserve the cachectic heterogeneity found in patients and are associated with unique cytokine profiles in both the spleen and tumor between different PDX. These data support the use of PDX as a strategy to study soluble cachexia protein markers and also further efforts to elucidate which cytokines are most related to cachexia in order to provide potential targets for immunotherapy., Competing Interests: The authors declare no conflict of interest.

Background: Cancer cachexia is a catabolic condition characterized by skeletal muscle wasting, consequent to tumor burden, which negatively impacts tolerance to cancer therapies and contributes to increased mortality. Partly because of the limited knowledge of the underlying mechanisms of cancer cachexia derived from human studies, however, the ability to therapeutically intervene remains elusive. The purpose of the current study was therefore to better define the phenotype of skeletal muscle obtained from patients with pancreatic ductal adenocarcinoma (PDAC), which has one of the highest rates of cachexia., Methods: Morphological analyses were performed on rectus abdominis muscle biopsies obtained from resectable PDAC patients undergoing tumor resection surgery (N = 20) and from weight-stable non-cancer control subjects undergoing benign abdominal surgery (N = 16). PDAC patients with a body weight loss of greater than 5% during the previous 6 months were considered cachectic (N = 15). Statistical tests were two sided., Results: Skeletal muscle from cachectic PDAC patients had increased collagen content compared with non-cancer control subjects (1.43% vs 9.66%, P  = .0004, Dunn test). Across all PDAC patients, collagen content positively correlated with body weight loss (P  = .0016, r  = 0.672), was increased in patients with lymph node metastasis ( P  = .007, Mann-Whitney U test), and was associated with survival on univariate (HR = 1.08, 95% confidence interval [CI] = 1.02 to 1.04, P  = .008) and multivariable analyses (HR = 1.08, 95% CI = 1.00 to 1.17, P  = .038). Cachectic PDAC patients also displayed increased lipid deposition (2.63% vs 5.72%, P  = .042), infiltration of CD68+ macrophages (63.6 cells/mm 2 vs 233.8 cells/mm 2 , P  = .0238), calcium deposition (0.21% vs 2.51%, P  = .030), and evidence of deficient cellular quality control mechanisms (Mann-Whitney U test). Transcriptional profiling of all patients supported these findings by identifying gene clusters related to wounding, inflammation, and cellular response to TGF-β upregulated in cachectic PDAC patients compared with non-cancer control subjects., Conclusions: To our knowledge, this work is the first to demonstrate increased collagen content in cachectic PDAC patients that is associated with poor survival.

Objective: Limitations associated with current animal models serve as a major obstacle to reliable preclinical evaluation of therapies in pancreatic cancer (PC). In an effort to develop more reliable preclinical models, we have recently established a subcutaneous patient-derived xenograft (PDX) model. However, critical aspects of PC responsible for its highly lethal nature, such as the development of distant metastasis and cancer cachexia, remain underrepresented in the flank PDX model. The purpose of this study was to evaluate the degree to which an orthotopic PDX model of PC recapitulates these aspects of the human disease., Methods: Human PDX-derived PC tumors were implanted directly into the pancreas of NOD.Cg-Prkdc Il2rg/SzJ mice. Tumor growth, metastasis, and muscle wasting were then evaluated., Results: Orthotopically implanted PDX-derived tumors consistently incorporated into the murine pancreatic parenchyma, metastasized to both the liver and lungs and induced muscle wasting directly proportional to the size of the tumor, consistent of the cancer cachexia syndrome., Conclusions: Through the orthotopic implantation technique described, we demonstrate a highly reproducible model that recapitulates both local and systemic aspects of human PC.

Background: The relationship between myopenia, nutritional status, and long-term oncologic outcomes remains poorly characterized in patients with clinically resectable pancreatic cancer. We sought to reliably quantify prognostic indicators of preoperative cachexia in a manner applicable to any clinical setting., Methods: Preoperative computed tomographies were available electronically and suitable for analysis in 73 of 82 consecutive patients with pancreatic cancer undergoing pancreatoduodenectomy between November 2010 and February 2014. The psoas index was computed from the cross-sectional area of the psoas muscles normalized to vertebral body area at the third lumbar vertebra. Correlation and proportional hazards analyses were performed to identify relationships between muscularity, preoperative nutritional markers, clinicopathologic parameters, and long-term survival., Results: The psoas index correlated strongly with preoperative hemoglobin and albumin levels (P = .001 and .014, respectively) identifying a pattern of preoperative frailty. High psoas index and the albumin and hemoglobin levels were associated with improved long-term survival (hazard ratio 0.014, P < .001; hazard ratio 0.43, P < .001; and hazard ratio = 0.80, P = .014); however, on multivariate analysis, the psoas index proved to be the only independent predictor of survival (hazard ratio 0.021; P = .003). Rapid decreases in the psoas index during neoadjuvant chemotherapy were associated with poor postoperative outcomes, as were decreases in the psoas index during the postoperative period., Conclusion: The data indicate that the psoas index, a calculation derived from a clinically mandated, preoperative computed tomography, is a statistically powerful and easily calculated predictor of survival in pancreatic cancer when compared to tumor grade and stage as well as previously validated nutritional parameters., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Cancer cachexia represents a debilitating syndrome that diminishes quality of life and augments the toxicities of conventional treatments. Cancer cachexia is particularly debilitating in patients with pancreatic cancer (PC). Mechanisms responsible for cancer cachexia are under investigation and are largely derived from observations in syngeneic murine models of cancer which are limited in PC. We evaluate the effect of human PC cells on both muscle wasting and the systemic inflammatory milieu potentially contributing to PC-associated cachexia. Specifically, human PC xenografts were generated by implantation of pancreatic cancer cells, L3.6pl and PANC-1, either in the flank or orthotopically within the pancreas. Mice bearing orthotopic xenografts demonstrated significant muscle wasting and atrophy-associated gene expression changes compared to controls. Further, despite the absence of adaptive immunity, splenic tissue from orthotopically engrafted mice demonstrated elevations in several pro-inflammatory cytokines associated with cancer cachexia, including TNFα, IL1β, IL6 and KC (murine IL8 homologue), when compared to controls. Therefore, data presented here support further investigation into the complexity of cancer cachexia in PC to identify potential targets for this debilitating syndrome.

We present a brief report on the progress towards the construction of the National Nuclear Array (NANA), a gamma-ray coincidence spectrometer for discrete-line nuclear structure and decay measurements. The proposed spectrometer will combine a gamma-ray energy resolution of approximately 3% at 1MeV with sub-nanosecond timing discrimination between successive gamma rays in mutually coincident decay cascades. We also review a number of recent measurements using coincidence fast-timing gamma-ray spectroscopy for nuclear structure studies, which have helped to inform the design criteria for the NANA spectrometer., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

This study examines the practice environment for nurse practitioners (NPs) in New Mexico and assesses whether the future supply of NPs will be adequate to meet the health care needs of a varied population in a sparsely populated state with a relatively low average standard of living, yet one that offers a broad scope of practice authority for its NPs. The study's models forecast decreasing numbers of New Mexico NPs between the ages of 40 and 60 in the state's metropolitan counties. These decreases are not offset by gains in other age brackets. Thus, over time, the state's metro areas may not maintain their 2013 NP-to-insured and NP-to-senior population ratios. In contrast, the study's models forecast improving ratios in nonmetropolitan counties. The future need for NPs in New Mexico and similarly situated states may therefore be greatest in fast-growing urban areas, where the number of newly insured individuals with primary care needs is likely to be high.

Skeletal muscle atrophy is a consequence of several physiological and pathophysiological conditions including muscle disuse, aging and diseases such as cancer and heart failure. In each of these conditions, the predominant mechanism contributing to the loss of skeletal muscle mass is increased protein turnover. Two important mechanisms which regulate protein stability and degradation are lysine acetylation and ubiquitination, respectively. However our understanding of the skeletal muscle proteins regulated through acetylation and ubiquitination during muscle atrophy is limited. Therefore, the purpose of the current study was to conduct an unbiased assessment of the acetylation and ubiquitin-modified proteome in skeletal muscle during a physiological condition of muscle atrophy. To induce progressive, physiologically relevant, muscle atrophy, rats were cast immobilized for 0, 2, 4 or 6 days and muscles harvested. Acetylated and ubiquitinated peptides were identified via a peptide IP proteomic approach using an anti-acetyl lysine antibody or a ubiquitin remnant motif antibody followed by mass spectrometry. In control skeletal muscle we identified and mapped the acetylation of 1,326 lysine residues to 425 different proteins and the ubiquitination of 4,948 lysine residues to 1,131 different proteins. Of these proteins 43, 47 and 50 proteins were differentially acetylated and 183, 227 and 172 were differentially ubiquitinated following 2, 4 and 6 days of disuse, respectively. Bioinformatics analysis identified contractile proteins as being enriched among proteins decreased in acetylation and increased in ubiquitination, whereas histone proteins were enriched among proteins increased in acetylation and decreased in ubiquitination. These findings provide the first proteome-wide identification of skeletal muscle proteins exhibiting changes in lysine acetylation and ubiquitination during any atrophy condition, and provide a basis for future mechanistic studies into how the acetylation and ubiquitination status of these identified proteins regulates the muscle atrophy phenotype.

Chaperones, also called heat shock proteins (HSPs), transiently interact with proteins to aid their folding, trafficking, and degradation, thereby directly influencing the transport of newly synthesized molecules. Induction of chaperones provides a potential therapeutic approach for protein misfolding disorders, such as peripheral myelin protein 22 (PMP22)-associated peripheral neuropathies. Cytosolic aggregates of PMP22, linked with a demyelinating Schwann cell phenotype, result in suppression of proteasome activity and activation of proteostatic mechanisms, including the heat shock pathway. Although the beneficial effects of chaperones in preventing the aggregation and improving the trafficking of PMP22 have been repeatedly observed, the requirement for HSP70 in events remains elusive. In this study, we show that activation of the chaperone pathway in fibroblasts from PMP22 duplication-associated Charcot-Marie-Tooth disease type 1A patient with an FDA-approved small molecule increases HSP70 expression and attenuates proteasome dysfunction. Using cells from an HSP70.1/3(-/-) (inducible HSP70) mouse model, we demonstrate that under proteotoxic stress, this chaperone is critical in preventing the aggregation of PMP22, and this effect is aided by macroautophagy. When examined at steady-state, HSP70 appears to play a minor role in the trafficking of wild-type-PMP22, while it is crucial for preventing the buildup of the aggregation-prone Trembler-J-PMP22. HSP70 aids the processing of Trembler-J-PMP22 through the Golgi and its delivery to lysosomes via Rab7-positive vesicles. Together, these results demonstrate a key role for inducible HSP70 in aiding the processing and hindering the accumulation of misfolded PMP22, which in turn alleviates proteotoxicity within the cells., (© The Author(s) 2015.)

Background: Evidence from cachectic cancer patients and animal models of cancer cachexia supports the involvement of Forkhead box O (FoxO) transcription factors in driving cancer-induced skeletal muscle wasting. However, the genome-wide gene networks and associated biological processes regulated by FoxO during cancer cachexia are unknown. We hypothesize that FoxO is a central upstream regulator of diverse gene networks in skeletal muscle during cancer that may act coordinately to promote the wasting phenotype., Methods: To inhibit endogenous FoxO DNA-binding, we transduced limb and diaphragm muscles of mice with AAV9 containing the cDNA for a dominant negative (d.n.) FoxO protein (or GFP control). The d.n.FoxO construct consists of only the FoxO3a DNA-binding domain that is highly homologous to that of FoxO1 and FoxO4, and which outcompetes and blocks endogenous FoxO DNA binding. Mice were subsequently inoculated with Colon-26 (C26) cells and muscles harvested 26 days later., Results: Blocking FoxO prevented C26-induced muscle fiber atrophy of both locomotor muscles and the diaphragm and significantly spared force deficits. This sparing of muscle size and function was associated with the differential regulation of 543 transcripts (out of 2,093) which changed in response to C26. Bioinformatics analysis of upregulated gene transcripts that required FoxO revealed enrichment of the proteasome, AP-1 and IL-6 pathways, and included several atrophy-related transcription factors, including Stat3, Fos, and Cebpb. FoxO was also necessary for the cancer-induced downregulation of several gene transcripts that were enriched for extracellular matrix and sarcomere protein-encoding genes. We validated these findings in limb muscles and the diaphragm through qRT-PCR, and further demonstrate that FoxO1 and/or FoxO3a are sufficient to increase Stat3, Fos, Cebpb, and the C/EBPβ target gene, Ubr2. Analysis of the Cebpb proximal promoter revealed two bona fide FoxO binding elements, which we further establish are necessary for Cebpb promoter activation in response to IL-6, a predominant cytokine in the C26 cancer model., Conclusions: These findings provide new evidence that FoxO-dependent transcription is a central node controlling diverse gene networks in skeletal muscle during cancer cachexia, and identifies novel candidate genes and networks for further investigation as causative factors in cancer-induced wasting.

The discipline of radionuclide metrology at national standards institutes started in 1913 with the certification by Curie, Rutherford and Meyer of the first primary standards of radium. In early years, radium was a valuable commodity and the aim of the standards was largely to facilitate trade. The focus later changed to providing standards for the new wide range of radionuclides, so that radioactivity could be used for healthcare and industrial applications while minimising the risk to patients, workers and the environment. National measurement institutes responded to the changing demands by developing new techniques for realising primary standards of radioactivity. Looking ahead, there are likely to be demands for standards for new radionuclides used in nuclear medicine, an expansion of the scope of the field into quantitative imaging to facilitate accurate patient dosimetry for nuclear medicine, and an increasing need for accurate standards for radioactive waste management and nuclear forensics., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

High resolution gamma spectrometry offers a rapid method to characterise waste materials on a decommissioning nuclear site. To meet regulatory requirements, measurements must be traceable to national standards, meaning that the spectrometers must be calibrated for a wide range of materials. Semi-empirical modelling software (such as ANGLE™) offers a convenient method to carry out such calibrations. This paper describes an assessment of the modelling software for use by a small laboratory based on a nuclear site. The results confirmed the need for accurate information on the detection construction if the calibration were to be accurate to within 10%., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The purpose of this study was to partially characterize the steroid binding activity of murine renal tumor cells in continuous culture. The steroid receptor content of a cloned renal tumor cell line (RAG) and a subline RAG-2 was examined by sucrose gradient analysis, hydroxylapatite and dextran-coated charcoal methods. The RAG cells lacked estrogen- and progestin-binding activity, whereas specific 5 alpha-dihydrotestosterone (DHT) and dexamethasone (Dx) binding activities were detected as 8S peaks on low salt gradients. The specificity of DHT binding was examined by sucrose gradient analysis: DHT, R1881 and ORG2058 all completely inhibited [3H]DHT binding whereas diethylstilbestrol and Dx were ineffective. The androgen receptor content of the RAG cells was approx. 15 fmol/mg cytosol protein by the hydroxylapatite-filter assay, with an estimated Kd for methyltrienolone (R1881) of 5 nM at 0 degrees C. Scatchard analysis of [3H]Dx binding by RAG cytosol showed a Kd of 6 nM for Dx and 44 nM for corticosterone at 0 degrees C. Glucocorticoid receptor levels were estimated to be 182 fmol/mg cytosol protein by dextran-coated charcoal assay. Metabolism of [3H]testosterone and [3H]DHT by RAG cells was examined 1, 4 and 6 h after exposure to labeled hormone. Radioactive DHT was the primary intracellular metabolite recovered after exposure to [3H]testosterone. There was little conversion of DHT to androstanediol.

The purpose of this study was to examine the lactogenic response of human mammary cancer cell lines to hormones in vitro. Progesterone was found to stimulate the incorporation of 14C from [14C]acetate into triglycerides (TG) and to promote accumulation of TG with a fatty acid composition similar to that of human milk fat in T-47D cells. Lipid droplets were observed in larger numbers without concomitant accumulation of casein granules in cells incubated with progesterone, but secretion of lipid into the medium did not occur. An effect of progesterone on TG accumulation was detectable after 12 hr and was maximal at 72 hr. Increasing doses of progesterone (10(-9) to 10(-5) M) caused a progressive increase in TG accumulation. The presence of cortisol and/or prolactin did not alter TG formation nor the dose response of the cells to progesterone. The growth rate of T-47D cells was not altered by the presence of progesterone in the medium. Neither of the human mammary cancer cell lines, MCF-7 and HBL-100, nor the human fibroblast cell lines, 28 and 857, responded to progesterone. The data indicate that, while the normally lactogenic hormones do not stimulate milk product biosynthesis in the cell lines tested, progesterone specifically stimulated synthesis and accumulation of TG in the T-47D cells.

Measurements of the relative emission rates of the 776 keV gamma ray, the positrons and the K x-rays in the decay of 82Rb have been repeated. This has led to the finding that the gamma ray to positron ratio is 0.1578 +/- 0.0019 and that the 776 keV gamma-ray probability per decay is (15.12 +/- 0.18)%.

A specific and sensitive gas chromatographic method was used to investigate the concentration of pregnanediol glucuronide in urine in relation to the time of ovulation. Serum LH and progesterone concentrations in the same subjects were used as evidence for the occurrence of ovulation. The urinary concentration of pregnanediol glucuronide in 24-hour collections and in overnight specimens increased 2-fold or more from the day of the midcycle LH peak to the time of predicted ovulation (24-48 hour after the LH peak) in parallel with the rise in serum progesterone concentration.

The relationship between growth factor responses and androgen-induced cell proliferation was studied in a mouse renal tumor (RAG) cell line, a hybrid (F614B16) rat prostate x RAG cell line, and an 8-azaguanine-resistant revertant of the F614B16 cell line. The hybrid F614B16 cells are very sensitive to androgens; treatment with 20 nM 5 alpha-dihydrotestosterone accelerated cell growth in the presence or absence of serum. In contrast, the RAG cells and 8-azaguanine-resistant F614B16 cells responded to 5 alpha-dihydrotestosterone only in the absence of serum. Variation in the proliferative response to androgens among these cell lines was associated with variation in growth factor sensitivity. Basic fibroblast growth factor (bFGF) stimulated basal and androgen-induced growth of F614B16 cells in serum-free and serum-supplemented media, whereas it inhibited RAG cell growth. Basic FGF stimulated basal, but not androgen-induced growth of revertant F614B16 cells. The cell lines also differed in sensitivity to epidermal growth factor, which had no effect on hybrid cell growth but inhibited RAG and revertant cell growth in a dose-dependent fashion in serum-free media. The results of these studies suggest that androgen-sensitivity is associated with a positive response to FGF and insensitivity to exogenous epidermal growth factor.