Twenty-five year occupational homicide mortality trends in North Carolina: 1992-2017.

INTRODUCTION: Determining industry of decedents and victim-perpetrator relationships is crucial to inform and evaluate occupational homicide prevention strategies. In this study, we examine occupational homicide rates in North Carolina (NC) by victim characteristics, industry and victim-perpetrator relationship from 1992 to 2017. METHODS: Occupational homicides were identified from records of the NC Office of the Chief Medical Examiner system and the NC death certificates. Sex, age, race, ethnicity, class of worker, manner of death, victim-perpetrator relationship and industry were abstracted. Crude and age-standardised homicide rates were calculated as the number of homicides that occurred at work divided by an estimate of worker-years (w-y). Rate ratios and 95% CIs were calculated, and trends over calendar time in occupational homicide rates were examined overall and by industry. RESULTS: 456 homicides over 111 573 049 w-y were observed. Occupational homicide rates decreased from 0.82 per 100 000 w-y for the period 1992-1995 to 0.21 per 100 000 w-y for the period 2011-2015, but increased to 0.32 per 100 000 w-y in the period 2016-2017. Fifty-five per cent (252) of homicides were perpetrated by strangers. Taxi drivers experienced an occupational homicide rate that was 110 times (95% CI 76.52 to 160.19) the overall occupational homicide rate in NC; however, this rate declined by 76.5% between 1992 and 2017. Disparities were observed among workers 65+ years old, racially and ethnically minoritised workers and self-employed workers. CONCLUSION: Our findings identify industries and worker demographics that experienced high occupational homicide fatality rates. Targeted and tailored mitigation strategies among vulnerable industries and workers are recommended.

25-Year fatal workplace suicide trends in North Carolina: 1992-2017.

BACKGROUND: Suicide is a serious public health problem in the United States, but limited evidence is available investigating fatal suicides at work. There is a substantial need to characterize workplace suicides to inform suicide prevention interventions and target high-risk settings. This study aims to examine workplace suicide rates in North Carolina (NC) by worker characteristics, means of suicide used, and industry between 1992 and 2017. METHODS: Fatal workplace suicides were identified from records of the NC Office of the Chief Medical Examiner system and the NC death certificate. Sex, age, race, ethnicity, class of worker, manner of death, and industry were abstracted. Crude and age-standardized homicide rates were calculated as the number of suicides that occurred at work divided by an estimate of worker-years (w-y). Rate ratios and 95% confidence intervals (CIs) were calculated, and trends over calendar time for fatal workplace suicides were examined overall and by industry. RESULTS: 81 suicides over 109,464,430 w-y were observed. Increased rates were observed in workers who were male, self-employed, and 65+ years old. Firearms were the most common means of death (63%) followed by hanging (16%). Gas service station workers experienced the highest fatal occupational suicide rate, 11.5 times (95% CI: 3.62-36.33) the overall fatal workplace suicide rate, followed by Justice, Public Order, and Safety workers at 3.23 times the overall rate (95% CI: 1.31-7.97). CONCLUSION: Our findings identify industries and worker demographics that were vulnerable to workplace suicides. Targeted and tailored mitigation strategies for vulnerable industries and workers are recommended.

Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo.

Inactivation of phosphatase and tensin homology deleted on chromosome 10 (PTEN) is linked to increased PI3K-AKT signaling, enhanced organismal growth, and cancer development. Here we generated and analyzed Pten knock-in mice harboring a C2 domain missense mutation at phenylalanine 341 (Pten(FV)), found in human cancer. Despite having reduced levels of PTEN protein, homozygous Pten(FV/FV) embryos have intact AKT signaling, develop normally, and are carried to term. Heterozygous Pten(FV/+) mice develop carcinoma in the thymus, stomach, adrenal medulla, and mammary gland but not in other organs typically sensitive to Pten deficiency, including the thyroid, prostate, and uterus. Progression to carcinoma in sensitive organs ensues in the absence of overt AKT activation. Carcinoma in the uterus, a cancer-resistant organ, requires a second clonal event associated with the spontaneous activation of AKT and downstream signaling. In summary, this PTEN noncatalytic missense mutation exposes a core tumor suppressor function distinct from inhibition of canonical AKT signaling that predisposes to organ-selective cancer development in vivo.

In Vivo Tumorigenesis, Osteolytic Sarcomas, and Tumorigenic Cell Lines from Transgenic Mice Expressing the Human T-Lymphotropic Virus Type 1 (HTLV-1) Tax Viral Oncogene.

Human T-lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia, a disease commonly associated with hypercalcemia and osteolysis. There is no effective treatment for HTLV-1, and the osteolytic mechanisms are not fully understood. Mice expressing the HTLV-1 oncogene Tax, driven by the human granzyme B promoter (Tax+), develop osteolytic tumors. To investigate the progression of the bone-invasive malignancies, wild-type, Tax+, and Tax+/interferon-γ-/- mice were assessed using necropsy, histologic examination, IHC analysis, flow cytometry, and advanced imaging. Tax+ and Tax+/interferon-γ-/- malignancies of the ear, tail, and foot comprised poorly differentiated, round to spindle-shaped cells with prominent neutrophilic infiltrates. Tail tumors originated from muscle, nerve, and/or tendon sheaths, with frequent invasion into adjacent bone. F4/80+ and anti-mouse CD11b (Mac-1)+ histiocytic cells predominated within the tumors. Three Tax+/interferon-γ-/- cell lines were generated for in vivo allografts, in vitro gene expression and bone resorption assays. Two cell lines were of monocyte/macrophage origin, and tumors formed in vivo in all three. Differences in Pthrp, Il6, Il1a, Il1b, and Csf3 expression in vitro were correlated with differences in in vivo plasma calcium levels, tumor growth, metastasis, and neutrophilic inflammation. Tax+ mouse tumors were classified as bone-invasive histiocytic sarcomas. The cell lines are ideal for further examination of the role of HTLV-1 Tax in osteolytic tumor formation and the development of hypercalcemia and tumor-associated inflammation.

Thermal ecology of Northern Water Snakes (Nerodia sipedon) in a northern wetland in central Michigan.

Semi-aquatic north-temperate reptiles experience challenging environmental conditions for thermoregulation on both seasonal and daily bases. We studied the thermal biology of north-temperate Northern Water Snakes (Nerodia sipedon) in central Michigan by remote radiotelemetry monitoring of snake body temperature (Tb) using surgically implanted thermally-sensitive radio-transmitters and by measuring operative temperatures (Te) across a range of microhabitats using biophysical models. Our goals included evaluation of thermoregulatory capabilities at a locality that we viewed to be a fine-grained thermal environment, seasonal variations in patterns of thermoregulation, and the effects of sex on thermoregulation. During summer, snakes showed diel Tb cycling apparently using the open Sphagnum mat for late morning warming and shuttling among different microhabitats until early evening when a monotonic decline in Tb ensued and continued through the early morning hours. Snakes attained Tb within their laboratory-determined preferred body temperature range (Tset = 28-33 °C) mostly during late afternoon and with average percentages of Tb values for individual snakes within Tset range when permitted by operative temperatures (Ex) between 68 and 70% of the time depending on method of measurement. Relatively high investment in thermoregulation when thermal conditions were poor occurred only during September but declined thereafter as snakes prepared to overwinter. We did not detect differences in thermoregulation among reproductive females, non-reproductive females, and males. Relative to a population of N. sipedon at a higher latitude in Ontario our snakes showed a relatively high Tset range and thermoregulated more effectively, particularly during the daylight hours. It remains unclear how much inter-population variation in thermoregulation is due to potential adaptations to latitude, to habitat differences, or variations in methodologies.

Clinical Measures of Adolescent Softball Players With and Without Upper-Extremity Pain: A Preliminary Study.

CONTEXT: Upper-extremity (UE) pain is a concern among softball adolescent athletes. However, research on preseason screening of demographic characteristics and clinical measures among those with and without UE pain among adolescent softball athletes is underreported. This study sought to present functional outcomes and clinical measures of shoulder and hip complex flexibility, range of motion (ROM), and strength in adolescent softball athletes with and without UE pain. DESIGN: Cross-sectional study. METHODS: Sixty-seven athletes were assessed at the start of the spring season. The Kerlan-Jobe Orthopedic Clinic Shoulder and Elbow Questionnaire was administered to determine UE function. UE measurements included shoulder ROM, flexibility, and strength; lower-extremity measurements included hip ROM and strength. These variables were reported for players with and without UE pain as mean and SD. Independent samples t tests were performed to analyze differences between the groups. RESULTS: Thirteen (19.4%) athletes reported UE pain during preseason screening. Mean Kerlan-Jobe Orthopedic Clinic Shoulder and Elbow Questionnaire score among athletes with UE pain was 58.0 (17.6) compared with 97.1 (6.9) for athletes reporting no UE pain (P < .001). Athletes with UE pain presented with significantly less dominant side external rotation ROM (UE pain: 106.5 [10.4], no UE pain: 114.6 [11.3]) and total ROM (UE pain: 163.7 [14.5], no UE Pain: 174.8 [14.3]). CONCLUSION: These findings inform clinicians on function and preseason clinical measures in adolescent softball athletes who present with or without UE pain. Athletes with UE pain demonstrated lower outcome scores indicating likely impact on overall UE function. These athletes also appeared to demonstrate UE ROM differences compared with athletes without UE pain. Further research is needed to investigate larger sample sizes and positional differences at baseline and throughout the season to determine if clinical measures used in the current study are risk factors for pain and injury.

Diel and seasonal variations in the thermal biology of San Cristobal Lava Lizards (Microlophus bivittatus).

Thermal biology, and therefore energy acquisition and survival, of ectotherms can be affected by diel and seasonal patterns of environmental temperatures. Galápagos Lava Lizards live in seasonal environments that are characterized by a warm and wet period when reproductive activity is maximal, and cooler and drier period. With the use of radiotelemetric techniques to record lizard surface temperatures (Ts), we studied the thermal ecology of the San Cristóbal Lava Lizard (Microlophus bivittatus) during both the warm and cool seasons over two years. During the diel activity period and when operative temperatures exceeded Tset-min, at least on rock faces without canopy, 52% or less of the Ts observations fell within the laboratory-determined Tset range (36-40 °C). Therefore, lizards may have avoided very warm midday temperatures in shaded microhabitats and the lag times in changes in Ts values occurred as operative temperatures rose rapidly during late morning warming phase. Lizards effectively thermoregulated during a year with moderate warm season temperatures and during a cool season that was unseasonably warm. In contrast, lizards less effectively thermoregulated during the warmest and coolest years of the study. We did not detect intersexual differences in thermoregulation although males may thermoregulate less effectively than do females during the cool season although we were unable to detect significant differences using our nonparametric statistical techniques.

Cutaneous Phaeohyphomycosis Caused by Exophiala attenuata in a Domestic Cat.

A 7-year-old female-spayed, domestic short-haired cat was presented to her veterinarian with a mass on the hind paw. Histopathologic examination of a tissue biopsy revealed nodular pyogranulomatous panniculitis with intralesional pigmented fungal hyphae. A dematiaceous fungal isolate was isolated with a micromorphological phenotype consistent with the anamorphic genus Exophiala: budding cells, torulose mycelium and annellidic conidiogenesis from simple conidiophores consisting of terminal and lateral cells that tapered to a short beak at the apex. Sequence homology of the internal transcribed spacer region of the rDNA gene confirmed the identification of the isolate as Exophiala attenuata. Reported here is the first confirmed case of feline phaeohyphomycosis caused by E. attenuata in North America. Similar to historical cases of feline phaeohyphomycosis caused by Exophiala spp., there was no history or postmortem evidence to suggest the patient was in an immunocompromised state (e.g., suffering from FeLV or FIV). Although aggressive surgical excision of local lesions is recommended prior to drug treatment when dealing with subcutaneous phaeohyphomycosis, surgery followed by itraconazole treatment did not resolve the E. attenuata infection in this cat.

Expression of mPGES1 and p16 in feline and human oral squamous cell carcinoma: A comparative oncology approach.

Comparative cancer studies help us determine if discoveries in one species apply to another. Feline and human oral squamous cell carcinoma (FOSCC and HOSCC) are invasive tumours in which inflammation and abnormal p16 expression are reported. Immunohistochemistry was used to determine the expression of p16 and microsomal prostaglandin E2 synthase 1 (mPGES1) in 42 HOSCC and 45 FOSCC samples with known expression of cyclooxygenase 2 (COX2) and cluster of differentiation 147 (CD147). High p16 expression was more common in HOSCC tumour cells compared to adjacent stroma and oral epithelium (p < .05), with a similar but statistically nonsignificant pattern in FOSCC. Interestingly, high mPGES1 expression in FOSCC was more common in the adjacent epithelium compared to the other compartments (p < .05). In HOSCC, mPGES1 was more similar between compartments but was numerically more common in the tumour compartment (p > .05). There were nominal (p > 0.05) differences in marker expression between high and low mPGES1 expressing tumours in both species, including high p16 observed more commonly in high mPGES1 tumours, and COX-2 positive tumours being more common in low mPGES1 tumours. High CD147 HOSCC tumours were more common in the high mPGES1 HOSCC group (p < .05). In the FOSCC cohort, where there was no statistical difference in CD147 expression between high and low mPGES1 tumours, there were numerically higher CD147 cases in the high mPGES1group. Different expression patterns in FOSCC and HOSCC could be related to different risk factors. For example, p16 is a marker of papillomavirus-driven HOSCC, but a causal relationship between papillomaviruses and FOSCC has yet to be definitively demonstrated. The significance of high P16 expression in the absence of papillomavirus infection deserves further study, and the relative contributions of COX2 and mPGES1 to tumour inflammation and progression should be explored. The findings reveal potential similarities in FOSCC and HOSCC biology, while also demonstrating differences that may relate to risk factors and pathogenesis that are unique to each species.

Initial versus Subsequent Injury and Illness and Temporal Trends Among Professional Hockey Players.

Background: Research is limited investigating injuries/illness incidence among National Hockey League (NHL) players. This study sought to establish injury/illness incidence, initial versus subsequent injury risk among NHL players, and determine temporal trends of injury and illness incidence. Hypothesis: Variations in injury incidence by body region, and initial versus subsequent injury would be observed among positions. Study Design: Retrospective cohort study. Methods: Publicly available data were utilized. NHL players 18 years or older between 2007-2008 to 2018-2019 were included. Injury and illness was stratified by position and body segment. Incidence rate (IR), and initial versus subsequent injury and illness risk ratios were calculated. Temporal trends were reported. Results: Nine thousand, seven-hundred and thirty four injuries and illnesses were recorded. Centers had the highest overall IR at 15.14 per 1000 athlete game exposures (AGEs) (95%CI:15.12-15.15) and were 1.4 times more likely to sustain a subsequent injury compared to other positions. The groin/hip/thigh was the most commonly injured body region with an IR of 1.14 per 1000 AGEs (95%CI:1.06-1.21), followed by the head/neck (0.72 per 1000 AGEs, 95%CI:0.66-0.78). Combined injury and illness IR peaked in 2009-2010 season at 12.01 (95%CI: 11.22-12.79). The groin/hip/thigh demonstrated peak incidence during the 2007-2008 season (2.53, 95%CI:2.17-2.90); head/neck demonstrated a peak incidence in 2010-2011 season (Overall: 1.03, 95%CI:0.81-1.26). Injuries reported as 'lower body' increased over time. Conclusions: Positional differences were observed; centers demonstrated the highest overall IR, and subsequent injury risk. Injury by body region was similar to previous literature. Head/neck and concussion decreased over time supporting rule changes in body checking and visor wear. Clinicians should be aware that 'lower body' injuries increased over time; therefore, injuries to the groin/hip/thigh or knee are likely underreported. Level of Evidence: Level 3.

Elbow Injuries Among MLB Pitchers Increased During Covid-19 Disrupted Season, But Not Other Baseball Injuries.

Background: The 2020 Major League Baseball Season (MLB) demonstrated season disruptions due to the COVID-19 pandemic. Changes in training and seasonal time frames may be associated with higher rates of injury. Purpose: To use publicly available data to compare injury rates during the 2015-2019 seasons, COVID-19 shortened season (2020), and the 2021 season stratified by body region and position (pitchers versus position players). Study Design: A retrospective cohort study utilizing publicly available data. Methods: MLB players who competed in 1+ seasons between 2015-2021 were included and stratified by position (pitcher, position player). Incidence rate (IR), reported by 1000 x Athlete-Game Exposures (AGEs), was calculated for each season, and stratified by position and body region. Poisson regressions were performed for all injuries and stratified by position to determine association between season and injury incidence. Subgroup analyses were performed on the elbow, groin/hip/thigh, shoulder. Results: Four thousand, two hundred and seventy-four injuries and 796,502 AGEs across 15,152 players were documented. Overall IR was similar across seasons (2015-2019:5.39; 2020:5.85; 2021:5.04 per 1000 AGEs). IR remained high for the groin/hip/thigh for position players (2015-2019:1.7; 2020:2.0; 2021:1.7 per 1000 AGEs). There was no difference in injury rates between 2015-2019 and 2020 seasons [1.1 (0.9-1.2), p=0.310]. The 2020 season demonstrated a significant increase in elbow injuries [2.7 (1.8-4.0), p<0.001]; when stratified by position, this increase remained significant for pitchers [pitchers: 3.5 (2.1-5.9), p<0.001; position players: 1.8 (0.9-3.6), p=0.073]. No other differences were observed. Conclusion: The groin/hip/thigh demonstrated the highest IR in 2020 among position players across all season time frames, indicating that continued injury mitigation for this region is necessary. When stratified by body region, elbow injury rates among pitchers demonstrated 3.5 times the rate of injury in 2020 compared to previous seasons, impacting injury burden for the most vulnerable body region among pitchers. Level of Evidence: Level III.

Efficacy of a Novel Telehealth Application in Health Behavior Modification and Symptomology in Military Service Members at Risk for Post-traumatic Osteoarthritis.

INTRODUCTION: Mobile applications (apps) may be beneficial to promote self-management strategies to mitigate the risk of developing post-traumatic osteoarthritis in military members following a traumatic knee injury. This study investigated the efficacy of a mobile app in facilitating behavior modification to improve function and symptomology among military members. MATERIALS AND METHODS: This is a preliminary pre and post hoc analysis of a randomized control trial. The MARX scale, Intermittent and Constant Osteoarthritis Pain (ICOAP) questionnaire, and the Knee Injury and Osteoarthritic Outcome Score Readiness to Manage Osteoarthritis Questionnaire were completed at baseline, 6-week, 6-month, and 12-month follow-up. Participants in the treatment arm completed the System Usability Scale. Data were analyzed using descriptive statistics, the Wilcoxon sum of ranks test, the Wilcoxon signed-rank test, and Cohen's d effect size. RESULTS: A total of 28 participants were included. Between-group differences for baseline and 6-week follow-up were significantly improved in the injured knee ICOAP constant pain score for the treatment group (treatment: -4.2 ± 12, 95% CI: -11.5, 3.1; control: 5.5 ± 9.9, 95% CI: 0.9, 10.1; P = .035, effect size = 0.905). Within-group differences for baseline and 6-week follow-up demonstrated a significant decline in the injured knee ICOAP constant pain score among the control group (signed-rank: 16.0, P = .031, Cohen's d = 0.339). No other significant differences were observed. A good System Usability Scale score for usability was found (76.6 ± 8.8). CONCLUSIONS: These results indicate that the mobile app is easy to use and may contribute to improved constant pain symptomology for patients at risk for post-traumatic osteoarthritis.

Shoulder Range of Motion Measurements and Baseball Elbow Injuries: Ambiguity in Scientific Models, Approach, and Execution is Hurting Overhead Athlete Health.

Elbow injuries are a significant and increasing issue in baseball. Elbow injuries account for 16% of all injuries sustained at the professional level and collegiate level. Because of the continued rise in injury rates, loss of performance value, and medical burden, sports medicine clinicians have attempted to research the causes underlying this injury epidemic in an attempt to help mitigate baseball elbow injuries. Shoulder range of motion (ROM) is the most researched clinical metric related to elbow injuries in baseball and has the greatest consensus as a viable prognostic factor specifically for medial elbow injury. Shoulder ROM is easy to measure, can be modified through stretching and manual therapy interventions, and can be easily assessed during preseason screening throughout all baseball levels. Despite a large number of studies and the widespread use of shoulder ROM in injury risk screening, current findings are unclear as to whether there is a true cause-effect relation with baseball elbow injuries. We argue that the conflicting findings revolving around the value of shoulder ROM measurements associated with baseball elbow injuries are the result of 4 gaps in the research approaches implemented to date: ambiguous research questions, mixed study populations, statistical models used, and shoulder ROM methodology. Specifically, there is a mismatch of methods, statistical models, and conclusions such as (1) investigating the association (i.e., correlation) between shoulder ROM measurements and injury and (2) investigating the cause-effect relation of shoulder ROM to baseball injuries. The purpose of this article is to detail the required scientific steps to evaluate whether preseason shoulder ROM is a potential causal factor for pitching elbow injury. We also provide recommendations to allow for future causal inferences to be made between shoulder ROM and elbow injury. This information will ultimately assist in informing clinical models of care and decision making for baseball throwers.

Development of health literacy in persons and caregivers living with dementia: A qualitative directed content analysis.

BACKGROUND: Persons living with dementia and their caregivers need health information to understand and manage daily life. Previous studies focused on the associations of health literacy and cognitive impairment with less exploring if and how individuals develop health literacy during the course of the disease. PURPOSE: This descriptive qualitative study aimed to explore the development of health literacy competencies among persons living with dementia and their caregivers. METHODS: Directed content analysis of six focus groups conducted in the community setting (15 persons living with dementia and 28 caregivers) was completed, using predetermined categories from the Integrated Model of Health Literacy: access, understand, appraise, and apply health information. FINDINGS: Participants described developing health literacy competencies over time, moving from a dependence on health care providers to becoming their own experts. Although health care providers were involved in the diagnosis and medication management, most participants admitted that they provided very little information on how to manage their daily life with dementia and often failed to inform them of community resources. CONCLUSION: Participants seemed to find dementia resources on their own for both education and support, often stumbling upon them by accident. Health care providers should promote the health literacy competencies of their patients and caregivers by more intentionally providing dementia health and community resource information.

Return to performance following severe ankle, knee, and hip injuries in National Basketball Association players.

The purpose of this study was to compare basketball performance markers 1 y prior to initial severe lower extremity injury, including ankle, knee, and hip injuries, to 1 and 2 y following injury during the regular National Basketball Association (NBA) season. Publicly available data were extracted through a reproducible extraction computed programmed process. Eligible participants were NBA players with at least three seasons played between 2008 and 2019, with a time-loss injury reported during the study period. Basketball performance was evaluated for season minutes, points, and rebounds. Prevalence of return to performance and linear regressions were calculated. A total of 285 athletes sustained a severe lower extremity injury. A total of 196 (69%) played for 1 y and 130 (45%) played for 2 y following the injury. A total of 58 (30%) players participated in a similar number of games and 57 (29%) scored similar points 1 y following injury. A total of 48 (37%) participated in a similar number of games and 55 (42%) scored a similar number of points 2 y following injury. Fewer than half of basketball players who suffered a severe lower extremity injury were participating at the NBA level 2 y following injury, with similar findings for groin/hip/thigh, knee, and ankle injuries. Fewer than half of players were performing at previous preinjury levels 2 y following injury. Suffering a severe lower extremity injury may be a prognostic factor that can assist sports medicine professionals to educate and set performance expectations for NBA players.

Dickkopf-1 (DKK-1) stimulated prostate cancer growth and metastasis and inhibited bone formation in osteoblastic bone metastases.

BACKGROUND: Osteoblastic bone metastasis is the predominant phenotype observed in prostate cancer patients and is associated with high patient mortality and morbidity. However, the mechanisms determining the development of this phenotype are not well understood. Prostate cancer cells secrete several osteogenic factors including Wnt proteins, which are not only osteoinductive but also oncogenic. Therefore, the purpose of the study was to investigate the contribution of the Wnt signaling pathway in prostate cancer growth, incidence of bone metastases, and osteoblastic phenotype of bone metastases. The strategy involved overexpressing the Wnt antagonist, DKK-1, in the mixed osteoblastic and osteolytic Ace-1 prostate cancer cells. METHODS: Ace-1 prostate cancer cells stably expressing human DKK-1 or empty vector were established and transduced with lentiviral yellow fluorescent protein (YFP)-luciferase (Luc). The Ace-1/vector(YFP-LUC) and Ace-1/DKK-1(YFP-LUC) cells were injected subcutaneously, intratibially, or in the left cardiac ventricle in athymic mice. RESULTS: Unexpectedly, DKK-1 significantly increased Ace-1 subcutaneous tumor mass and the incidence of bone metastases after intracardiac injection of Ace-1 cells. DKK-1 increased Ace-1 tumor growth associated with increased phospho46 c-Jun amino-terminal kinase by the Wnt noncanonical pathway. As expected, DKK-1 decreased the Ace-1 osteoblastic phenotype of bone metastases, as confirmed by radiographic, histopathologic, and microcomputed tomographic analysis. DKK-1 decreased osteoblastic activity via the Wnt canonical pathway evidenced by an inhibition of T-cell factor activity in murine osteoblast precursor ST2 cells. CONCLUSION: The present study showed that DKK-1 is a potent inhibitor of bone growth in prostate cancer-induced osteoblastic metastases.

Development of a brain metastatic canine prostate cancer cell line.

BACKGROUND: Prostate cancer in men has a high mortality and morbidity due to metastatic disease. The pathobiology of prostate cancer metastasis is not well understood and cell lines and animal models that recapitulate the complex nature of the disease are needed. Therefore, the goal of the study was to establish and characterize a new prostate cancer line derived from a dog with spontaneous prostate cancer. METHODS: A new cell line (Leo) was derived from a dog with spontaneous prostate cancer. Immunohistochemistry and PCR were used to characterize the primary prostate cancer and xenografts in nude mice. Subcutaneous tumor growth and metastases in nude mice were evaluated by bioluminescent imaging, radiography and histopathology. In vitro chemosensitivity of Leo cells to therapeutic agents was measured. RESULTS: Leo cells expressed the secretory epithelial cytokeratins (CK)8, 18, and ductal cell marker, CK7. The cell line grew in vitro (over 75 passages) and was tumorigenic in the subcutis of nude mice. Following intracardiac injection, Leo cells metastasized to the brain, spinal cord, bone, and adrenal gland. The incidence of metastases was greatest to the central nervous system (80%) with a lower incidence to bone (20%) and the adrenal glands (16%). In vitro chemosensitivity assays demonstrated that Leo cells were sensitive to Velcade and an HDAC-42 inhibitor with IC(50) concentrations of 1.9 nm and 0.95 µm, respectively. CONCLUSION: The new prostate cancer cell line (Leo) will be a valuable model to investigate the mechanisms of the brain and bone metastases.

Intersecting Mechanisms of Hypoxia and Prostaglandin E2-Mediated Inflammation in the Comparative Biology of Oral Squamous Cell Carcinoma.

The importance of inflammation in the pathogenesis of cancer was first proposed by Rudolph Virchow over 150 years ago, and our understanding of its significance has grown over decades of biomedical research. The arachidonic acid pathway of inflammation, including cyclooxygenase (COX) enzymes, PGE2 synthase enzymes, prostaglandin E2 (PGE2) and PGE2 receptors has been extensively studied and has been associated with different diseases and different types of cancers, including oral squamous cell carcinoma (OSCC). In addition to inflammation in the tumour microenvironment, low oxygen levels (hypoxia) within tumours have also been shown to contribute to tumour progression. Understandably, most of our OSCC knowledge comes from study of this aggressive cancer in human patients and in experimental rodent models. However, domestic animals develop OSCC spontaneously and this is an important, and difficult to treat, form of cancer in veterinary medicine. The primary goal of this review article is to explore the available evidence regarding interaction between hypoxia and the arachidonic acid pathway of inflammation during malignant behaviour of OSCC. Overlapping mechanisms in hypoxia and inflammation can contribute to tumour growth, angiogenesis, and, importantly, resistance to therapy. The benefits and controversies of anti-inflammatory and anti-angiogenic therapies for human and animal OSCC patients will be discussed, including conventional pharmaceutical agents as well as natural products.

Annuloaortic ectasia in a four-month-old male Newfoundland dog: long-term follow-up and immunofluorescent study.

A 4 month-old, 14.8 kg, male Newfoundland dog was presented for cardiovascular evaluation following detection of a heart murmur. Echocardiography revealed enlargement of the sinuses of Valsalva and marked, diffuse dilation of the ascending aorta (annuloaortic ectasia, AAE), with mild/equivocal subaortic stenosis (SAS). The dog was monitored over the duration of its lifetime, with serial echocardiograms performed at 5, 6, and 8 months and 1, 2, 3, 4, 8, and 10 years demonstrating persistent, diffuse dilation of the ascending aorta. The dog lived until it was 10 years old and died of metastatic carcinoma. Postmortem examination confirmed AAE and mild SAS. Hematoxylin and eosin and Weigert van Gieson stains were used to compare the ascending aorta to the descending aorta and left subclavian artery, and to compare aortic samples to those of three control dogs. Histopathologic evaluation revealed mild medial degeneration in the ascending aorta of all four dogs. Immunofluorescent microscopy was used for determining the deposition of proteins known to play a role in aortic aneurysms in humans: fibrillin-1 (FBN1), latent transforming growth factor beta binding protein 4 (LTBP4) and fibronectin. The ascending aorta of the AAE case demonstrated reduced deposition of FBN1, indicating that its loss may have contributed to aortic dilation. Diffuse, primary ascending aortic dilation is uncommonly reported in dogs; when it is, it carries a poor prognosis. This case provides an important example of marked dilation of the ascending aorta in a dog that lived with no associated adverse effects for 10 years.