Quality of Life Gain Following Treatment Among Breast Cancer Survivors With and Without HIV.

PURPOSE: Women living with HIV (WLWH) experience decreased breast cancer survival. We sought to determine whether WLWH surviving breast cancer also experienced different quality of life (QOL) gain. METHODS: Women who enrolled in the Thabatse Cancer Cohort across oncology centers in Botswana for the initial treatment of stage I-III breast cancer from October 2010 to February 2022 were included. Exclusion criteria were no documented definitive therapy and incomplete data at treatment end or 24 ± 3 months after treatment. QOL was measured quarterly using the SF-8 questionnaire. G methods using weighted exposure and outcome modules were used to mitigate potential bias from imbalances in demographic and cancer characteristics by HIV status. Primary analysis was change in physical component summary (PCS) and mental component summary (MCS) from treatment end to 24 months after treatment for WLWH compared with women without HIV. RESULTS: Of 603 women enrolled, the final analysis included 298, comprising 85 WLWH and 213 women without HIV. Most common reasons for exclusion were no documented definitive treatment (n = 114) and death before 21 months after treatment (n = 137). WLWH were younger, were less wealthy, and had more estrogen receptor/progesterone receptor positive tumors. Overall, PCS and MCS significantly increased from treatment end to 24 months after treatment, from 50.8 to 52.8 and 51.8 to 53.7, respectively. There was no difference in the change of the PCS or MCS with HIV infection, 2.2 (95% CI, -0.4 to 4.9) and 0.6 (95% CI, -1.7 to 2.9), respectively. CONCLUSION: HIV infection did not impede QOL gain at 24 months after treatment in women surviving breast cancer. Further work is needed to clarify the role of HIV on specific treatment-related morbidities and in other malignancies.

Local Therapy for Metastatic Colorectal Cancer: A Case-Based Review.

ABSTRACT: The oligometastatic disease state, defined as a cancer with 5 or fewer sites of metastasis, is a therapeutic opportunity to improve oncologic outcomes. Colorectal cancer (CRC) was among the first for which oligometastatic treatment was used in routine clinical practice, and recent studies have shown potential for improved overall survival with metastasis-directed therapies. As CRC is the third most common cause of cancer death in men and women, improving oncologic outcomes in this population is of paramount importance. The relatively recent identification of this treatment paradigm and paucity of high-quality data have led to heterogeneity in clinical practice. This review will explore perspectives of a panel of surgical and radiation oncologists for complex or controversial cases of metastatic CRC.

Variation in Androgen Deprivation Therapy Use Among Men With Intermediate-Risk Prostate Cancer: Results From a Statewide Radiation Oncology Quality Consortium.

PURPOSE: For men with intermediate-risk prostate cancer treated with definitive therapy, the addition of androgen deprivation therapy (ADT) reduces the risk of distant metastasis and cancer-related mortality. However, the absolute benefit of ADT varies by baseline cancer risk. Estimates of prognosis have improved over time, and little is known about ADT decision making in the modern era. We sought to characterize variability and identify factors associated with intended ADT use within the Michigan Radiation Oncology Quality Consoritum (MROQC). MATERIALS AND METHODS: Patients with localized prostate cancer undergoing definitive radiation therapy were enrolled from June 9, 2020, to June 26, 2023 (n = 815). Prospective data were collected using standardized patient, physician, and physicist forms. Intended ADT use was prospectively defined and was the primary outcome. Associations with patient, tumor, and practice-related factors were tested with multivariable analyses. Random intercept modeling was used to estimate facility-level variability. RESULTS: Five hundred seventy patients across 26 facilities were enrolled with intermediate-risk disease. ADT was intended for 46% of men (n = 262/570), which differed by National Comprehensive Cancer Network favorable intermediate-risk (23.5%, n = 38/172) versus unfavorable intermediate-risk disease (56.3%, n = 224/398; P < .001). After adjusting for the statewide case mix, the predicted probability of intended ADT use varied significantly across facilities, ranging from 15.4% (95% CI, 5.4%-37.0%) to 71.7% (95% CI, 57.0%-82.9%), with P < .01. Multivariable analyses showed that grade group 3 (OR, 4.60 [3.20-6.67]), ≥50% positive cores (OR, 2.15 [1.43-3.25]), and prostate-specific antigen 10 to 20 (OR, 1.87 [1.24-2.84]) were associated with ADT use. Area under the curve was improved when incorporating MRI adverse features (0.76) or radiation treatment variables (0.76), but there remained significant facility-level heterogeneity in all models evaluated (P < .05). CONCLUSIONS: Within a state-wide consortium, there is substantial facility-level heterogeneity in intended ADT use for men with intermediate-risk prostate cancer. Future efforts are necessary to identify patients who will benefit most from ADT and to develop strategies to standardize appropriate use.

Intricacies of Human-AI Interaction in Dynamic Decision-Making for Precision Oncology: A Case Study in Response-Adaptive Radiotherapy.

Background: Adaptive treatment strategies that can dynamically react to individual cancer progression can provide effective personalized care. Longitudinal multi-omics information, paired with an artificially intelligent clinical decision support system (AI-CDSS) can assist clinicians in determining optimal therapeutic options and treatment adaptations. However, AI-CDSS is not perfectly accurate, as such, clinicians' over/under reliance on AI may lead to unintended consequences, ultimately failing to develop optimal strategies. To investigate such collaborative decision-making process, we conducted a Human-AI interaction case study on response-adaptive radiotherapy (RT). Methods: We designed and conducted a two-phase study for two disease sites and two treatment modalities-adaptive RT for non-small cell lung cancer (NSCLC) and adaptive stereotactic body RT for hepatocellular carcinoma (HCC)-in which clinicians were asked to consider mid-treatment modification of the dose per fraction for a number of retrospective cancer patients without AI-support (Unassisted Phase) and with AI-assistance (AI-assisted Phase). The AI-CDSS graphically presented trade-offs in tumor control and the likelihood of toxicity to organs at risk, provided an optimal recommendation, and associated model uncertainties. In addition, we asked for clinicians' decision confidence level and trust level in individual AI recommendations and encouraged them to provide written remarks. We enrolled 13 evaluators (radiation oncology physicians and residents) from two medical institutions located in two different states, out of which, 4 evaluators volunteered in both NSCLC and HCC studies, resulting in a total of 17 completed evaluations (9 NSCLC, and 8 HCC). To limit the evaluation time to under an hour, we selected 8 treated patients for NSCLC and 9 for HCC, resulting in a total of 144 sets of evaluations (72 from NSCLC and 72 from HCC). Evaluation for each patient consisted of 8 required inputs and 2 optional remarks, resulting in up to a total of 1440 data points. Results: AI-assistance did not homogeneously influence all experts and clinical decisions. From NSCLC cohort, 41 (57%) decisions and from HCC cohort, 34 (47%) decisions were adjusted after AI assistance. Two evaluations (12%) from the NSCLC cohort had zero decision adjustments, while the remaining 15 (88%) evaluations resulted in at least two decision adjustments. Decision adjustment level positively correlated with dissimilarity in decision-making with AI [NSCLC: ρ = 0.53 ( p < 0.001); HCC: ρ = 0.60 ( p < 0.001)] indicating that evaluators adjusted their decision closer towards AI recommendation. Agreement with AI-recommendation positively correlated with AI Trust Level [NSCLC: ρ = 0.59 ( p < 0.001); HCC: ρ = 0.7 ( p < 0.001)] indicating that evaluators followed AI's recommendation if they agreed with that recommendation. The correlation between decision confidence changes and decision adjustment level showed an opposite trend [NSCLC: ρ = -0.24 ( p = 0.045), HCC: ρ = 0.28 ( p = 0.017)] reflecting the difference in behavior due to underlying differences in disease type and treatment modality. Decision confidence positively correlated with the closeness of decisions to the standard of care (NSCLC: 2 Gy/fx; HCC: 10 Gy/fx) indicating that evaluators were generally more confident in prescribing dose fractionations more similar to those used in standard clinical practice. Inter-evaluator agreement increased with AI-assistance indicating that AI-assistance can decrease inter-physician variability. The majority of decisions were adjusted to achieve higher tumor control in NSCLC and lower normal tissue complications in HCC. Analysis of evaluators' remarks indicated concerns for organs at risk and RT outcome estimates as important decision-making factors. Conclusions: Human-AI interaction depends on the complex interrelationship between expert's prior knowledge and preferences, patient's state, disease site, treatment modality, model transparency, and AI's learned behavior and biases. The collaborative decision-making process can be summarized as follows: (i) some clinicians may not believe in an AI system, completely disregarding its recommendation, (ii) some clinicians may believe in the AI system but will critically analyze its recommendations on a case-by-case basis; (iii) when a clinician finds that the AI recommendation indicates the possibility for better outcomes they will adjust their decisions accordingly; and (iv) When a clinician finds that the AI recommendation indicate a worse possible outcome they will disregard it and seek their own alternative approach.

The Effect of Wire Versus Magnetic Seed Localization on Lumpectomy Cavity Size.

PURPOSE: Our purpose was to assess whether an association exists between surgical localization technique and lumpectomy cavity size on radiation therapy planning computed tomography (CT) scan. METHODS AND MATERIALS: A single-institution retrospective review was conducted of women undergoing breast conserving surgery with wire or magnetic seed guided lumpectomy followed by adjuvant radiation therapy from 2018 to 2021. Patients of a surgeon only performing 1 localization technique or undergoing bracketed localization were excluded. The primary outcome was lumpectomy cavity size on simulation CT. Confounding due to imbalance in patient and tumor factors was addressed with overlap weights derived from a propensity score analysis and used in a weighted multivariable analysis. Secondary outcomes included positive margins, total pathologic volume, boost delivery, and boost modality. RESULTS: Of 617 women who received lumpectomy during the study period, 387 were included in final analysis. Tumors of patients undergoing seed localization were more likely unifocal, assessable by ultrasound, and smaller. Seed use rates ranged from 27.7% to 70.7% per surgeon. There was no difference in positive margins (6.4 vs 5.4%, P = .79) or second surgeries (9.4 vs 8.1%, P = .79) between groups. Close margin rates were similar for ductal carcinoma in situ (P = .35) and invasive carcinoma (P = .97). In unadjusted bivariable analyses, wire localization was associated with larger total pathology volume (P = .004), but localization technique showed no association with CT cavity volume (P = .15). After adjusting for potentially confounding variables, multivariable analysis failed to show an association between localization technique and either CT cavity (P = .35) or total path volume (P = .08). There was no difference in indicated-boost delivery (P = .15) or electron boost (P = .14) by localization technique. CONCLUSIONS: There was no significant difference in CT cavity size by localization technique, suggesting choice between surgical techniques does not impede radiation therapy boost delivery.

Cannabis Use in Patients Seen in an Academic Radiation Oncology Department.

PURPOSE: Cannabis use rates are increasing in the United States. Patients with cancer use cannabis for many reasons, even without high-quality supporting data. This study sought to characterize cannabis use among patients seen in radiation oncology in a state that has legalized adult nonmedical use cannabis and to identify key cannabis-related educational topics. METHODS AND MATERIALS: Cannabis history was documented by providers using a structured template at patient visits in an academic radiation oncology practice October 2020 to November 2021. Cannabis use data, including recency/frequency of use, reason, and mode of administration, were summarized, and logistic regression was used to explore associations between patient and disease characteristics and recent cannabis use. A multivariable model employed stepwise variable selection using the Akaike Information Criterion. RESULTS: Of 3143 patients total, 91 (2.9%) declined to answer cannabis use questions, and 343 (10.9%) endorsed recent use (≤1 month ago), 235 (7.5%) noted nonrecent use (>1 month ago), and 2474 (78.7%) denied history of cannabis use. In multivariable analyses, those ≥50 years old (odds ratio [OR], 0.409; 95% confidence interval [CI], 0.294-0.568; P < .001) or with history of prior courses of radiation (OR, 0.748; 95% CI, 0.572-0.979; P = .034) were less likely, and those with a mental health diagnosis not related to substance use (OR, 1.533; 95% CI, 1.171-2.005; P = .002) or who smoked tobacco (OR, 3.003; 95% CI, 2.098-4.299; P < .001) were more likely to endorse recent cannabis use. Patients reported pain, insomnia, and anxiety as the most common reasons for use. Smoking was the most common mode of administration. CONCLUSIONS: Patients are willing to discuss cannabis use with providers and reported recent cannabis use for a variety of reasons. Younger patients new to oncologic care and those with a history of mental illness or tobacco smoking may benefit most from discussions about cannabis given higher rates of cannabis use in these groups.

Trends in Radiation Oncology Treatment Fractionation at a Single Academic Center, 2010 to 2020.

Purpose: Recent clinical trials suggest hypofractionated treatment regimens are appropriate for treatment of many cancers. It is important to understand and document hypofractionation adoption because of its implications for treatment center patient volumes. There is no recent U.S. study of trends in hypofractionation adoption that includes comparisons of multiple disease sites and data since the onset of COVID-19. In this context, this study describes trends in treatment fractionation at a single academic center from 2010 to 2020. Methods and Materials: From an institutional database, records were extracted for treatment of 4 disease site categories: all cancers, breast cancer, prostate cancer, and bone metastases. For each disease site, the mean number of fractions per treatment course was reported for each year of the study period. To explore whether the COVID-19 pandemic was associated with increased hypofractionation adoption, piecewise linear regression models were used to estimate a changepoint in the time trend of mean monthly number of fractions per treatment course and to evaluate whether this changepoint coincided with pandemic onset. Results: The data set included 22,865 courses of radiation treatment and 375,446 treatment fractions. The mean number of fractions per treatment course for all cancers declined from 17.5 in 2010 to 13.6 in 2020. There was increased adoption of hypofractionation at this institution for all cancers and specifically for both breast and prostate cancer. For bone metastases, hypofractionation had largely been adopted before the study period. For most disease sites, adoption of hypofractionated treatment courses occurred before pandemic onset. Bone metastases was the only disease site where a pandemic-driven increase in hypofractionation adoption could not be ruled out. Conclusions: This study reveals increasing use of hypofractionated regimens for a variety of cancers throughout the study period, which largely occurred before the onset of the COVID-19 pandemic at this institution.

Utilization and predictors of postmastectomy radiation receipt in an Oncology Center in Zimbabwe.

PURPOSE: Few sub-Saharan African studies have ascertained utilization for postmastectomy radiation (PMRT) for breast cancer, the second most common cancer among African women. We estimated PMRT utilization and identified predictors of PMRT receipt in Zimbabwe. METHODS: Retrospective patient cohort included non-metastatic breast cancer patients treated from 2014 to 2019. PMRT eligibility was assigned per NCCN guidelines. Patients receiving chemotherapy for non-metastatic disease were also included. The primary endpoint was receipt of PMRT, defined as chest wall with/without regional nodal radiation. Predictors of receiving PMRT were identified using logistic regression. Model performance was evaluated using the c statistic and Hosmer-Lemeshow test for goodness-of-fit. RESULTS: 201 women with localized disease and median follow-up of 11.4 months (IQR 3.3-17.9) were analyzed. PMRT was indicated in 177 women and utilized in 59(33.3%). Insurance coverage, clinical nodal involvement, higher grade, positive margins, and hormone therapy receipt were associated with higher odds of PMRT receipt. In adjusted models, no hormone therapy (aOR 0.12, 95% CI 0.043, 0.35) and missing grade (aOR 0.07, 95% CI 0.01, 0.38) were associated with lower odds of PMRT receipt. The resulting c statistic was 0.84, with Hosmer-Lemeshow p-value of 0.93 indicating good model fit. CONCLUSION: PMRT was utilized in 33% of those meeting NCCN criteria. Missing grade and no endocrine therapy receipt were associated with reduced likelihood of PMRT utilization. In addition to practice adjustments such as increasing hypofractionation and increasing patient access to standard oncologic testing at diagnosis could increase postmastectomy utilization.

Prolonged cadmium exposure alters benign uterine fibroid cell behavior, extracellular matrix components, and TGFB signaling.

The heavy metal Cadmium (Cd), a widespread environmental contaminant, poses serious hazards to human health and is considered a metallohormone and carcinogen. In women with uterine fibroids, there is a significant association between blood Cd levels and increased fibroid tumor size. The aim of this study was to determine if benign human uterine leiomyoma (fibroid) cells could be malignantly transformed in vitro by continuous Cd exposure and, if so, explore a molecular mechanism by which this could occur. We found when fibroid cells were exposed to 10 µM CdCl2 for 8 weeks, a robust and fast-growing Cd-Resistant Leiomyoma (CR-LM) cell culture was established. The CR-LM cells formed viable colonies in soft agar and had increased cytoplasmic glycogen aggregates, enhanced cell motility, a higher percentage of cells in G2/M phase, and increased expression of the proliferation marker Ki-67. NanoString analysis showed downregulation of genes encoding for extracellular matrix (ECM) components, such as collagens, fibronectins, laminins, and SLRP family proteins, whereas genes involved in ECM degradation (MMP1, MMP3, and MMP10) were significantly upregulated. A volcano plot showed that the top differentially genes favored cancer progression. Functional analysis by ingenuity pathway analysis predicted a significant inhibition of TGFB1 signaling, leading to enhanced proliferation and attenuated fibrosis. Prolonged Cd exposure altered phenotypic characteristics and dysregulated genes in fibroid cells predicative of progression towards a cancer phenotype. Therefore, continuous Cd exposure alters the benign characteristics of fibroid cells in vitro, and Cd exposure could possibly pose a health hazard for women with uterine fibroids.

A Call for One Health in Medical Education: How the COVID-19 Pandemic Underscores the Need to Integrate Human, Animal, and Environmental Health.

During the early stages of the COVID-19 pandemic in 2020, the first author, then a fourth-year student at Harvard Medical School, was enrolled in a One Health clinical experience at Zoo New England where he was introduced to a transdisciplinary approach to integrate human, animal, and ecosystem health. Seeing the vast impact of the pandemic and knowing its roots as a zoonotic disease, he realized this approach was critical to his medical education and for preparation against future novel infectious diseases. Zoonotic diseases have been emerging into human populations with increasing frequency, leading to public health emergencies such as Ebola, avian influenza, and SARS. The SARS-CoV-2 narrative, starting in bats and then mutating through an intermediate host into humans, is another striking example of the interconnectedness between human, animal, and ecosystem health that underlies these infections. Preventing future pandemics will require a transdisciplinary One Health approach, and physicians should be prepared to participate in these discussions while advocating for One Health initiatives for the benefit of their current and future patients. Integration of One Health education into medical school curricula will also prepare future physicians for other complex and urgently important health issues such as climate change, antimicrobial resistance, and the impact of biodiversity loss. As the consequences of the COVID-19 pandemic persist, education in One Health must become a priority; it is essential to break down the conventional disciplinary silos of human medicine, veterinary medicine, environmental health, public health, and the social sciences, so that future health crises can be prevented and mitigated collaboratively.

Impact of Community-Based Clinical Breast Examinations in Botswana.

PURPOSE: We evaluated a clinical breast examination (CBE) screening program to determine the prevalence of breast abnormalities, number examined per cancer diagnosis, and clinical resources required for these diagnoses in a middle-income African setting. METHODS: We performed a retrospective review of a CBE screening program (2015-2018) by Journey of Hope Botswana, a Botswana-based nongovernmental organization (NGO). Symptomatic and asymptomatic women were invited to attend. Screening events were held in communities throughout rural and periurban Botswana, with CBEs performed by volunteer nurses. Individuals who screened positive were referred to a private tertiary facility and were followed by the NGO. Data were obtained from NGO records. RESULTS: Of 6,120 screened women (50 men excluded), 452 (7.4%) presented with a symptom and 357 (5.83%) were referred for further evaluation; 257 ultrasounds, 100 fine-needle aspirations (FNAs), 58 mammograms, and 31 biopsies were performed. In total, 6,031 were exonerated from cancer, 78 were lost to follow-up (67 for ≤ 50 years and 11 for > 50 years), and 11 were diagnosed with cancer (five for 41-50 years and six for > 50 years, 10 presented with symptoms). Overall breast cancer prevalence was calculated to be 18/10,000 (95% CI, 8 to 29/10,000). The number of women examined per breast cancer diagnosis was 237 (95% CI, 126 to 1910) for women of age 41-50 years and 196 (95% CI, 109 to 977) for women of age > 50 years. Median time to diagnosis for all women was 17.5 [1 to 32.5] days. CBE-detected tumors were not different than tumors presenting through standard care. CONCLUSION: In a previously unscreened population, yield from community-based CBE screening was high, particularly among symptomatic women, and required modest diagnostic resources. This strategy has potential to reduce breast cancer mortality.

Medical Students' Response to the COVID-19 Pandemic: Experience and Recommendations from Five Countries.

The COVID-19 pandemic has provided medical students around the globe with unique challenges and opportunities. With formal medical school education and training interrupted, medical students sought innovative ways to contribute to their health-care systems and communities. Their responses could be organized into three categories: clinical (remote clinical care and triage, helping in COVID testing or treatment centers, and contact tracing), nonclinical (PPE acquisition, COVID-related policy and research, and supporting vulnerable groups in the community), and educational (creating materials to educate peers, the community, or community health workers). We present examples of responses developed by students from five countries: Brazil, Nepal, the Philippines, Rwanda, and the United States. We discuss the challenges, outcomes, and recommendations for each case. One critical opportunity for growth is strengthening international collaborations. We hope that these examples provide a framework for medical students to plan coordinated and effective responses to the next pandemic, and further medical student engagement in international collaboration.

Differential inflammatory response dynamics in normal lung following stereotactic body radiation therapy with protons versus photons.

BACKGROUND AND PURPOSE: To compare time-dependent changes in lung parenchyma of early-stage non-small cell lung carcinoma (NSCLC) patients after stereotactic body radiation therapy with protons (SBPT) or photons (SBRT). MATERIALS AND METHOD: We retrospectively identified NSCLC patients treated with SBPT and matched each one with a SBRT patient by patient, tumor, and treatment characteristics. Lung parenchyma on serial post-treatment chest computer tomography (CT) scans was deformably registered with the treatment plan to analyze lung density changes as function of dose, quantified by Houndsfield Unit (HU)/Gy. A thoracic radiologist also evaluated the CTs using an established grading system. RESULTS: We matched 23 SBPT/SBRT pairs, including 5 patients treated with both modalities (internally matched cohort). Normal lung response following SBPT significantly increased in the early time period (CTs acquired <6 months, median 3 months) post-treatment, and then did not change significantly in the later time period (CTs acquired 6-14 months, median 9 months). For SBRT, the normal lung response was similar to SBPT in the early time period, but then increased significantly from the early to the late time period (p = 0.007). These differences were most pronounced in sensitive (response >6 HU/Gy) patients and in the internally matched cohort. However, there was no significant difference in the maximum observed response in the entire cohort over all time periods, median 3.4 [IQR, 1.0-5.4] HU/Gy (SBPT) versus 2.5 [1.6-5.2] HU/Gy (SBRT). Qualitative radiological evaluation was highly correlated with the quantitative analysis (p < 0.0001). CONCLUSION: While there was no significant difference in maximum response after SBPT versus SBRT, dose-defined lung inflammation occurred earlier after proton irradiation. Further investigation is warranted into the mechanisms of inflammation and therapeutic consequences after proton versus photon irradiation.

ENVIRONMENTAL FUNGAL LOADS IN AN INDOOR-OUTDOOR AFRICAN PENGUIN ( SPHENISCUS DEMERSUS) EXHIBIT.

Aspergillosis continues to be one of the most important causes of disease in captive penguins. As such, designing exhibits and holding areas that minimize the risk of aspergillosis is of great interest; however, very little has been published regarding this topic. The goal of this study was to assess total fungal spore loads as well as the loads of Aspergillus spp. encountered in multiple indoor and outdoor microenvironments around the exhibit for a large colony of African penguins ( Spheniscus demersus). Air samples were collected via impaction at the microenvironments on a monthly basis over a 1-yr period. Results of this study indicated seasonal trends in both total fungal spore loads as well as Aspergillus spp. loads, with the lowest levels encountered during January through April. During the warmer, more humid spring, summer, and fall months when outdoor microenvironments experienced the highest fungal loads, the air-handling system and the pleated filters used indoors are thought to have reduced the fungal loads in the indoor microenvironments compared with the outdoor microenvironments. Additionally, surrounding planting beds were thought to contribute to the higher total fungal loads and Aspergillus spp. loads in the outdoor microenvironments. Results of this study are useful in understanding the factors that contribute to Aspergillus spp. loads in areas that house penguins, and can be used in guiding design, construction, and landscaping of penguin enclosures.

NTP/NIEHS Global Contributions to Toxicologic Pathology.

National Toxicology Program (NTP) pathologists are engaged in important initiatives that have significant global impact. These initiatives build on its leadership in pathology peer review and publications in the areas of toxicologic pathology, clinical pathology, and laboratory animal medicine. Over the past decade, NTP/National Institute of Environmental Health Sciences research initiatives have focused on cancer and noncancer hazard identification, with the goal of understanding cellular and molecular mechanisms of disease. New initiatives of significant global impact include the web-based nonneoplastic lesion atlas and an NTP partnership with international scientists to investigate molecular mechanisms at the whole genome level, which will be used to inform potential mechanisms of environmental exposures in human cancers. Also, we are dedicated to contributing to pathology and toxicology organizations through service on executive committees and editorial boards, participating in international projects and symposiums, and providing training for future leaders in toxicologic pathology. Herein, we provide highlights of our global contributions.

Fusarium solani species complex associated with carapace lesions and branchitis in captive American horseshoe crabs Limulus polyphemus.

Captive American horseshoe crabs Limulus polyphemus housed at the National Aquarium presented with a variety of shell and gill lesions over a 3 yr period. Carapace lesions were located on both the dorsal and ventral prosoma and opisthosoma and included multifocal circular areas of tan discoloration, ulcerations, and/or pitting lesions, extending from superficial to full thickness. Gill lesions involved both the book gill cover (operculum) and individual book gill leaflets and included multifocal circular areas of tan discoloration, tan to off-white opaque proliferative lesions, and/or areas of black discoloration. Histopathology revealed fungal hyphae, with variable morphology throughout the thickened and irregular cuticle of the carapace and occasionally penetrating into subcuticular tissues, with associated amebocytic inflammation. Book gill leaflets were infiltrated by fungal hyphae and contained necrotic debris and amebocytes. Thirty-eight of 39 animals (97%) evaluated via histopathological examination had intralesional fungal hyphae. Fungal cultures of carapace and gill lesions were attempted in 26 tissue samples from 15 individuals and were positive in 13 samples (50%), with 10 cultures (77%) yielding identification to genus. Fusarium sp. was identified in 8 of the 10 cultures (80%) via culture morphology. The Fusarium solani species complex was confirmed in 6 of these 8 (75%) via polymerase chain reaction amplification of 2 different ribosomal-specific sequences of isolated fungal DNA. Ante-mortem systemic and topical treatments were performed on some affected individuals, but no appreciable change in lesions was observed. Mycotic dermatitis and branchitis are serious health issues for captive American horseshoe crabs.

Silver nanoparticle behavior, uptake, and toxicity in Caenorhabditis elegans: effects of natural organic matter.

Significant progress has been made in understanding the toxicity of silver nanoparticles (Ag NPs) under carefully controlled laboratory conditions. Natural organic matter (NOM) is omnipresent in complex environmental systems, where it may alter the behavior of nanoparticles in these systems. We exposed the nematode Caenorhabditis elegans to Ag NP suspensions with or without one of two kinds of NOM, Suwannee River and Pony Lake fulvic acids (SRFA and PLFA, respectively). PLFA rescued toxicity more effectively than SRFA. Measurement of total tissue silver content indicated that PLFA reduced total organismal (including digestive tract) uptake of ionic silver, but not of citrate-coated Ag NPs (CIT-Ag NPs). The majority of the CIT-Ag NP uptake was in the digestive tract. Limited tissue uptake was detected by hyperspectral microscopy but not by transmission electron microscopy. Co-exposure to PLFA resulted in the formation of NOM-Ag NP composites (both in medium and in nematodes) and rescued AgNO3- and CIT-Ag NP-induced cellular damage, potentially by decreasing intracellular uptake of CIT-Ag NPs.

Capillary pressure as related to water holding in polyacrylamide and chicken protein gels.

UNLABELLED: The ability of food gels to hold water affects product yield and organoleptic quality. Most researchers believe that water is held by capillarity such that gels having smaller mean pore diameter and a more hydrophilic surface hold water more tightly. To date, however, only qualitative evidence relating pore size to water holding (WH) properties has been provided. The present study sought to provide quantitative confirmation of this hypothesis. Scanning electron microscopy coupled with image analysis was used to measure pore size, and water contact angle with the gel surface was measured by the captive bubble method, in both model polyacrylamide gels and heat-induced protein (minced chicken breast) gels. These were related to water lost during cooking of meat pastes to form gels (cooking loss (CL)), as well as water lost upon centrifugation (expressible water (EW)) or by capillary suction (CSL) of all prepared gels, as inverse measures of WH. As predicted by the Young-Laplace equation for calculating capillary pressure, the presumed mechanism of WH, gels with lower water losses exhibited a more hydrophilic surface (smaller contact angle). Yet, both lower CL and CSL correlated with larger mean pore diameter of gels, not smaller as had been expected. Polyacrylamide gels varied more in WH than did prepared meat gels, yet only the capillary suction method was sensitive enough to detect these differences. PRACTICAL APPLICATION: The ability of gels to hold water is important for economics of processing, food quality, and food safety. This study investigated the prevailing theory for how gels hold water, capillarity. Both the pore sizes of gel microstructures and the degree of hydrophilicity of the polymers comprising each gel were quantitatively assessed and related to water holding (WH) properties, and this was the first report using such methodologies. It appeared that the degree of hydrophilicity was much more important explaining WH properties than pore size, and that future research of this kind should be carried out.

FoxJ1-dependent gene expression is required for differentiation of radial glia into ependymal cells and a subset of astrocytes in the postnatal brain.

Neuronal specification occurs at the periventricular surface of the embryonic central nervous system. During early postnatal periods, radial glial cells in various ventricular zones of the brain differentiate into ependymal cells and astrocytes. However, mechanisms that drive this time- and cell-specific differentiation remain largely unknown. Here, we show that expression of the forkhead transcription factor FoxJ1 in mice is required for differentiation into ependymal cells and a small subset of FoxJ1(+) astrocytes in the lateral ventricles, where these cells form a postnatal neural stem cell niche. Moreover, we show that a subset of FoxJ1(+) cells harvested from the stem cell niche can self-renew and possess neurogenic potential. Using a transcriptome comparison of FoxJ1-null and wild-type microdissected tissue, we identified candidate genes regulated by FoxJ1 during early postnatal development. The list includes a significant number of microtubule-associated proteins, some of which form a protein complex that could regulate the transport of basal bodies to the ventricular surface of differentiating ependymal cells during FoxJ1-dependent ciliogenesis. Our results suggest that time- and cell-specific expression of FoxJ1 in the brain acts on an array of target genes to regulate the differentiation of ependymal cells and a small subset of astrocytes in the adult stem cell niche.

Comb candidiasis affecting roosters in a broiler breeder flock.

A cutaneous mycosis caused by Candida albicans that involved the combs and less frequently the wattles, facial skin, ear lobes, and neck of male broiler breeders is described. Roosters were 35 wk old and housed with hens in two conventional broiler breeder houses on a farm in western North Carolina. Morbidity was approximately 10% in one house and less than 2% in the other house. Mortality and flock fertility were not affected. Three birds from the most affected house were examined. All birds had white adherent material on their combs that presented as crusty patches or lighter diffuse areas. Often, lesions were roughly circular or had a defined margin. Small black scabs were present in a few lesions. Similar but less extensive lesions were located on the wattles, facial skin, ear lobes, and rictus. In one bird, lesions extended down the neck, and they were accompanied by hyperemia and feather loss. Hyperkeratosis with little to no inflammation and intralesional fungi occurring as yeast and pseudohyphae were seen microscopically. High numbers of C. albicans were isolated and identified from the lesions.