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Aims: Patients with PTEN hamartoma tumour syndrome (PHTS) have an increased risk of developing cancer due to a pathogenic germline variant in the PTEN tumour suppressor gene. Early recognition of PHTS facilitates initiation of cancer surveillance which is highly effective in preventing the development of advanced malignancies. PHTS is rare and due to its varied phenotype, even within families, oral abnormalities may be a valuable tool in the identification of these patients at an early stage before cancer development., Materials and Methods: Between 1997 and 2020, phenotypic characteristics were evaluated in 81 paediatric (median age: 9 years) and 86 adult (median age: 40 years) PHTS patients by one of 2 medical experts during yearly surveillance visits at a Dutch PHTS expertise centre. Oral features evaluated included gingival hypertrophy, oral papillomas, and high palate (in adults)., Results: Within adults, gingival hypertrophy was present in 94%, oral papillomas in 88%, and a high palate in 89%. All adult patients had at least one of these oral features, and 99% showed at least 2 oral features. Oral features were less common in paediatric patients, especially under 11 years of age. Gingival hypertrophy was observed in 44% and oral papillomas in 54% of paediatric patients., Conclusions: The presence of 2 or 3 oral features may indicate PHTS in adults or adolescents, especially if macrocephaly is present. Dental professionals are well-positioned to recognise these oral manifestations could be related to PHTS. They can initiate an overall clinical assessment of the patient by alerting the patient's medical practitioner of the findings and the possible need for genetic testing. This could significantly improve outcomes, including life expectancy, for patients and possibly for their relatives., Clinical Relevance: Dental professionals are ideally placed to recognise oral features and initiate early assessment of PHTS which could significantly improve patient outcomes., Competing Interests: Conflict of interest None disclosed., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The limited literature on Asian family communication of hereditary cancer risk and cascade genetic testing for pathogenic variants (PVs) in BRCA1 and BRCA2 has reported that Asian patients have selective communication of test results and lower cascade testing rates. To better understand the factors that impact communication and cascade testing in Asian families, we conducted an in-depth qualitative study guided by the Health Belief Model. Participants with heterozygous PVs in ATM, BRCA1, BRCA2, CHEK2, or PALB2, who identified their family's origins to an Asian country, were recruited from the Stanford Cancer Genetics Research Database in October-November 2021. Utilizing a constructivist approach, we conducted sixteen semi-structured interviews around family communication and cascade genetic testing. The research team analyzed the transcript data using a reflexive thematic approach. Extensive discussions between the research team resulted in three primary themes presented in this paper: (1) the role of family health beliefs in cascade genetic testing, (2) changes in communication as a result of genetic testing, and (3) genetics providers' role in supporting family discussions on cascade genetic testing. Certain health beliefs, such as perceived susceptibility to cancer and self-efficacy to take action, were co-created by family members and these shared beliefs influenced decisions about genetic testing, family communication, and family support during the cascade genetic testing process. Participants shared strategies for how genetics providers can prepare Asian patients for more effective conversations with relatives and better address potential testing barriers by tailoring information and providing anticipatory guidance. This study represents an important contribution to the literature about cascade testing among an underrepresented group. Shared family health beliefs about genetic testing may be particularly relevant for this community and these findings can inform strategies to increase cascade genetic testing in Asian families., (© 2024 National Society of Genetic Counselors.)

Humans have made profound changes to the Earth. The resulting societal challenges of the Anthropocene (e.g., climate change and impacts, renewable energy, adaptive infrastructure, disasters, pandemics, food insecurity, and biodiversity loss) are complex and systemic, with causes, interactions, and consequences that cascade across a globally connected system of systems. In this Critical Review, we turn to our "origin story" for insight, briefly tracing the formation of the Universe and the Earth, the emergence of life, the evolution of multicellular organisms, mammals, primates, and humans, as well as the more recent societal transitions involving agriculture, urbanization, industrialization, and computerization. Focusing on the evolution of the Earth, genetic evolution, the evolution of the brain, and cultural evolution, which includes technological evolution, we identify a nested evolutionary sequence of geophysical, biophysical, sociocultural, and sociotechnical systems, emphasizing the causal mechanisms that first formed, and then transformed, Earth systems into Anthropocene systems. Describing how the Anthropocene systems coevolved, and briefly illustrating how the ensuing societal challenges became tightly integrated across multiple spatial, temporal, and organizational scales, we conclude by proposing an evolutionary, system-of-systems, convergence paradigm for the entire family of interdependent societal challenges of the Anthropocene.

Bird-window collisions are a major source of human-caused mortality for which there are multiple mitigation and prevention options available. Despite growing availability of products designed to reduce collisions (e.g., glass with etched patterns or markers and films adhered over existing glass), few replicated field tests have been conducted to assess their effectiveness after installation on glass. We conducted a field study to evaluate the effectiveness of a commercially marketed product (Feather Friendly ® markers) in reducing bird-window collisions at glass-walled bus shelters in Stillwater, Oklahoma, USA. This study included a before-after control-impact (BACI) analysis comparing numbers of collisions at 18 bus shelters in both pre-treatment (2016) and post-treatment (2020) periods, and an analysis comparing 18 treated and 18 untreated shelters during 2020. For the BACI analysis, collisions were significantly reduced between 2016 and 2020 at shelters treated with the Feather Friendly ® markers even though collisions increased at shelters that remained untreated. For the 2020 analysis, there were significantly fewer collisions at treated than untreated shelters. Relative to a baseline study in 2016, we estimated that treating half of Stillwater's bus shelters resulted in a 64% reduction in total annual bird collisions. Together, these analyses provide a rigorous field test of the effectiveness of this treatment option in reducing bird-window collisions. Our research provides a model for similar studies at both bus shelters and buildings to evaluate and compare products designed to reduce bird-window collisions, and therefore, contribute to reducing this major mortality source affecting bird populations., Supplementary Information: The online version contains supplementary material available at 10.1007/s11252-022-01304-w., Competing Interests: Competing interestsThe authors have no relevant financial or non-financial interests to disclose., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Isoniazid (INH) is one of the two most effective first-line antitubercular drugs and is still used at the present time as a scaffold for developing new compounds to fight TB. In a previous study, we have observed that an INH derivative, an hydrazide N'-substituted with a C 10 acyl chain, was able to counterbalance its smaller reactivity with a higher membrane permeability. This resulted in an improved performance against the most prevalent Mycobacterium tuberculosis (Mtb) resistant strain (S315T), compared to INH. In this work, we have designed two new series of INH derivatives (alkyl hydrazides and hydrazones) with promising in silico properties, namely membrane permeabilities and spontaneous IN* radical formation. The kinetics, cytotoxicity, and biological activity evaluations confirmed the in silico predictions regarding the very high reactivity of the alkyl hydrazides. The hydrazones, on the other hand, showed very similar behavior compared to INH, particularly in biological tests that take longer to complete, indicating that these compounds are being hydrolyzed back to INH. Despite their improved membrane permeabilities, the reactivities of these two series are too high, impairing their overall performance. Nevertheless, the systematic data gathered about these compounds have showed us the need to find a balance between lipophilicity and reactivity, which is paramount to devise better INH-based derivatives aimed at circumventing Mtb resistance., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

System-of-systems approaches for integrated assessments have become prevalent in recent years. Such approaches integrate a variety of models from different disciplines and modeling paradigms to represent a socio-environmental (or social-ecological) system aiming to holistically inform policy and decision-making processes. Central to the system-of-systems approaches is the representation of systems in a multi-tier framework with nested scales. Current modeling paradigms, however, have disciplinary-specific lineage, leading to inconsistencies in the conceptualization and integration of socio-environmental systems. In this paper, a multidisciplinary team of researchers, from engineering, natural and social sciences, have come together to detail socio-technical practices and challenges that arise in the consideration of scale throughout the socio-environmental modeling process. We identify key paths forward, focused on explicit consideration of scale and uncertainty, strengthening interdisciplinary communication, and improvement of the documentation process. We call for a grand vision (and commensurate funding) for holistic system-of-systems research that engages researchers, stakeholders, and policy makers in a multi-tiered process for the co-creation of knowledge and solutions to major socio-environmental problems., Competing Interests: None to declare., (© 2020 Elsevier Ltd. All rights reserved.)

Environmentally transformative human use of land accelerated with the emergence of agriculture, but the extent, trajectory, and implications of these early changes are not well understood. An empirical global assessment of land use from 10,000 years before the present (yr B.P.) to 1850 CE reveals a planet largely transformed by hunter-gatherers, farmers, and pastoralists by 3000 years ago, considerably earlier than the dates in the land-use reconstructions commonly used by Earth scientists. Synthesis of knowledge contributed by more than 250 archaeologists highlighted gaps in archaeological expertise and data quality, which peaked for 2000 yr B.P. and in traditionally studied and wealthier regions. Archaeological reconstruction of global land-use history illuminates the deep roots of Earth's transformation and challenges the emerging Anthropocene paradigm that large-scale anthropogenic global environmental change is mostly a recent phenomenon., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Collisions with glass are a serious threat to avian life and are estimated to kill hundreds of millions of birds per year in the United States. We monitored 22 buildings at the Virginia Tech Corporate Research Center (VTCRC) in Blacksburg, Virginia, for collision fatalities from October 2013 through May 2015 and explored possible effects exerted by glass area and surrounding land cover on avian mortality. We documented 240 individuals representing 55 identifiable species that died due to collisions with windows at the VTCRC. The relative risk of fatal collisions at all buildings over the study period were estimated using a Bayesian hierarchical zero-inflated Poisson model adjusting for percentage of tree and lawn cover within 50 m of buildings, as well as for glass area. We found significant relationships between fatalities and surrounding lawn area (relative risk: 0.96, 95% credible interval: 0.93, 0.98) as well as glass area on buildings (RR: 1.30, 95% CI [1.05-1.65]). The model also found a moderately significant relationship between fatal collisions and the percent land cover of ornamental trees surrounding buildings (RR = 1.02, 95% CI [1.00-1.05]). Every building surveyed had at least one recorded collision death. Our findings indicate that birds collide with VTCRC windows during the summer breeding season in addition to spring and fall migration. The Ruby-throated Hummingbird ( Archilochus colubris ) was the most common window collision species and accounted for 10% of deaths. Though research has identified various correlates with fatal bird-window collisions, such studies rarely culminate in mitigation. We hope our study brings attention, and ultimately action, to address this significant threat to birds at the VTCRC and elsewhere., Competing Interests: The authors declare there are no competing interests.

Wildlife residing in urban landscapes face many human-related threats to their survival. For birds, collision with glass on manmade structures has been identified as a major hazard, causing hundreds of millions of avian fatalities in North America every year. Although research has investigated factors associated with bird-glass collision mortality at buildings, no prior studies have focused on bird fatalities at glass-walled bus shelters. Our objectives in this study were to describe the magnitude of bird-bus shelter collisions in the city of Stillwater, Oklahoma and assess potential predictors of collision risk, including characteristics of shelters (glass area) and surrounding land cover (e.g., vegetative features). We surveyed for bird carcasses and indirect collision evidence at 18 bus shelters over a five-month period. Linear regression and model selection results revealed that the amount of glass on shelters and the area of lawn within 50 m of shelters were both positively related to fatal bird collisions; glass area was also positively associated with observations of collision evidence on glass surfaces. After accounting for scavenger removal of carcasses, we estimate that a minimum of 34 birds are killed each year between May and September by collision with the 36 bus shelters in the city of Stillwater. While our study provides an initial look at bird fatalities at bus shelters, additional research is needed to generate a large-scale estimate of collision mortality and to assess species composition of fatalities at a national scale. Designing new bus shelters to include less glass and retrofitting existing shelters to increase visibility of glass to birds will likely reduce fatal bird collisions at bus shelters and thus reduce the cumulative magnitude of anthropogenic impacts to birds in cities.

The evolution of Mediterranean landscapes during the Holocene has been increasingly governed by the complex interactions of water and human land use. Different land-use practices change the amount of water flowing across the surface and infiltrating the soil, and change water's ability to move surface sediments. Conversely, water amplifies the impacts of human land use and extends the ecological footprint of human activities far beyond the borders of towns and fields. Advances in computational modelling offer new tools to study the complex feedbacks between land use, land cover, topography and surface water. The Mediterranean Landscape Dynamics project (MedLand) is building a modelling laboratory where experiments can be carried out on the long-term impacts of agropastoral land use, and whose results can be tested against the archaeological record. These computational experiments are providing new insights into the socio-ecological consequences of human decisions at varying temporal and spatial scales.

Objective: To assess the effect of simulation-based learning on doctor of pharmacy (PharmD) students' ability to perform accurate blood pressure assessments and to measure student satisfaction with this novel teaching method., Methods: Didactic lectures on blood pressure assessment were combined with practical sessions using a high-fidelity computerized patient simulator. Before and after the simulation sessions, students completed a written objective examination to assess knowledge and completed a survey instrument to determine their attitudes regarding the learning experience. Individual clinical skills were assessed using the patient simulator., Results: Ninety-five students completed the study. Significant improvement was seen in students' knowledge and their ability to accurately determine blood pressure following simulation sessions. Survey responses indicated that students felt confident that simulation-based learning would improve their ability to perform accurate blood pressure assessments., Conclusion: Pharmacy students showed significant improvement in clinical skills performance and in their knowledge of the pharmacotherapy of hypertension. Students expressed high levels of satisfaction with this type of learning experience.

Objective: To design and implement a simulated patient-case assessment using a mannequin for critical care pharmacotherapeutic education of doctor of pharmacy students and to evaluate student satisfaction with the simulation., Design: During the second year of the doctor of pharmacy program, all students were required to complete Introduction to Critical Care. This course consisted of didactic education, written patient-case sessions, and an interactive patient simulation session. Information on the patient case was distributed to students after completing the didactic portion of the course. Patient information was programmed into a simulation mannequin, which demonstrated characteristics of a critically ill human. Students were surveyed post-simulation to determine the effectiveness of the learning experience., Assessment: The majority of students (88%) were extremely satisfied with the experience. The facilitator was considered to be extremely useful in 75% of responses., Conclusion: By simulating a patient case, the facilitator was able to control students' learning environment, adapt the simulation to the level of the students' performance, and debrief students immediately. Ultimately, by involving students in actual patient cases early in the pharmacy curriculum, this type of education could produce pharmacists with a high level of expertise and confidence.

Background: Eniluracil is an effective inactivator of dihydropyrimidine dehydrogenase, the initial and rate limiting enzyme in the catabolism of fluorouracil. The current study was done to determine the objective tumour response of a 28-day oral regimen of eniluracil-fluorouracil in patients with advanced breast cancer., Patients and Methods: This was a multicentre, phase II study in patients with anthracycline-refractory (AR) or anthracycline- and taxane-refractory (ATR) advanced breast cancer. Oral eniluracil (10 mg/m2) and fluorouracil (1 mg/m2) were taken twice daily for 28 days of each 35-day treatment course., Results: In this study, 106 patients received treatment: 62 patients in the AR stratum and 44 patients in the ATR stratum. The objective tumour response rate in the intent-to-treat population was 18% (95% confidence intervals (CI): 11%-27%), including three complete responses. The response rate was similar in both strata: 19% in the AR and 16% in the ATR stratum. The overall median duration of response was 23.6 weeks. The treatment was well tolerated with a low incidence of grade 3 or 4 toxicities that were considered attributable to study medication., Conclusion: Treatment with oral eniluracil-fluorouracil was well tolerated by patients with advanced breast cancer. The efficacy data were comparable with those of other published studies in this group of refractory patients.

Purpose: Eniluracil (776C85) is an effective inactivator of dihydropyrimidine dehydrogenase that allows continuous low-dose oral fluorouracil (5-FU) to be given with predicable oral bioavailability. We have assessed this as first-line oral chemotherapy for patients with advanced/metastatic breast cancer., Patients and Methods: Patients with histologically proven, locally advanced or metastatic breast cancer without previous chemotherapy for advanced disease were entered onto this open-label phase II study. Patients received oral 5-FU 1.0 mg/m(2) with eniluracil 10 mg/m(2), both given twice daily for the first 28 days of each 35-day cycle, continuing until disease progression or unmanageable toxicity., Results: Thirty-three patients were entered, with a median age of 53 years. Sixteen partial responses were seen in twenty-nine assessable patients (55%; 95% confidence interval, 37% to 73%), including responses in four (40%) out of 10 patients who had received prior adjuvant 5-FU. Seven patients had stable disease for at least 3 months with symptom improvement. Median response duration was 14 months (range, 10 to 18+ months). Toxicity was low. There were only two episodes of drug-related grade 3 nonhematologic toxicity (diarrhea and infection), and only 6%, 3%, and 3% of patients developed granulocytopenia, thrombocytopenia, and neutropenic sepsis, respectively. Mild (grade 1/2) diarrhea occurred in 39% of patients, hand-foot syndrome in 15%, nausea in 27%, and mucositis in 18%. Toxicity-associated delay and dose reduction occurred in only 2% and 5% of courses, respectively., Conclusion: First-line treatment with the combination of oral 5-FU and eniluracil has high activity in patients with advanced breast cancer comparable with the most active conventional cytotoxic agents but with strikingly less toxicity.

Evidence of RB1 allele loss was found in only 6% of pancreatic cancers, and we found no significant sequence abnormalities nor loss of RB protein expression in a panel of tumors and cell lines. Using reverse transcription-polymerase chain reaction and Southern blot analysis, we found no evidence for loss of DCC expression in pancreatic cancer cell lines, and allele loss only rarely in tumor biopsies. These findings suggest that abnormalities of RB1 and DCC are unlikely to play a major role in pancreatic carcinogenesis.

Alterations in the tumor suppressor gene p53 are associated with the pathogenesis of blastic transformation of chronic myeloid leukemia (CML), but their exact role, particularly their relationship with the chimeric protein p210BCR/ABL, is poorly defined. Point mutations in p53 have been found in some cases of blast crisis and CML blastic cell lines, but it is not clear whether complete inactivation of p53 tumor suppressor function, with or without the production of a mutant protein, can by itself trigger the process of blastic transformation. By using retroviral gene transfer, we showed that the introduction of a mutant human p53 cDNA into hematopoietic progenitor cells from patients with CML in chronic phase, which already contain p210BCR/ABL, could promote their proliferation in vitro, and occasionally even lead to the growth of factor-independent colonies. We conclude that a mutant p53 may act in synergy with p210BCR/ABL and promote the survival and proliferation of CML hematopoietic stem and progenitor cells in vitro.

We developed a high-titer amphotropic retroviral vector that expresses mutant (Ala143) human p53 to test directly the response of genetically normal human epithelial cells to p53 mutation. Contrary to our prediction, we found that in pancreatic epithelium (whose tumors display a high frequency of p53 mutation) but not in thyroid (whose tumors show an exceptionally low mutation frequency), expression of mutant p53 induced a dramatic, though self-limiting, proliferative response. This result questions the assumption that p53 mutation is relevant only to the later stages of tumorigenesis.

The epidermal growth factor receptor (EGFR) and its ligands are thought to be important in the control of proliferation of many epithelial systems, including the exocrine pancreas. Abnormalities in expression of two of the known ligands of the EGFR, transforming growth factor alpha and epidermal growth factor, occur frequently in ductal adenocarcinoma of the human pancreas. We have examined an archival series of cases of pancreatic pathology for expression of the EGFR using the anti-EGFR antiserum 12E and found that there is almost ubiquitous overexpression of EGFR in pancreatic cancer and in chronic pancreatitis. Southern blot analysis showed no evidence of amplification or rearrangement of the EGFR gene. We conclude that an autocrine loop involving the EGFR system may be involved in the genesis of both neoplasia and reactive hyperplasia of pancreatic ductal epithelium.

Overexpression of the epidermal growth factor receptor (EGFR) has been reported as an important molecular abnormality in human pancreatic cancer. There is in vitro evidence that simultaneous overproduction of one of its ligands, transforming growth factor alpha (TGF-alpha), might result in an autocrine loop with an increased proliferation signal. We analysed by immunocytochemical staining a retrospective series of human pancreatic cancers, chronic pancreatitis, and normal fetal and adult pancreatic tissues for the presence of TGF-alpha and epidermal growth factor (EGF). Ductal epithelial cells showed TGF-alpha immunoreactivity in both normal tissue and chronic pancreatitis, and 95 per cent of tumours showed strong immunoreactivity. In contrast, EGF immunoreactivity was not found in normal pancreas, but was expressed in 12 per cent of pancreatic carcinomas. Well-defined areas of EGF immunoreactivity in exocrine ducts showing reactive changes in pancreatitis might represent a benign response to tissue damage similar to that previously described in the gastric mucosa.

The gene for the alpha polypeptide chain (alpha s) of the heterotrimeric G protein Gs can be activated to the putative oncogene gsp by specific point mutations at codons 201 and 227. Such mutations have been reported in 40% of human growth hormone-secreting pituitary adenomas and in a single autonomously functioning thyroid adenoma. We examined an archival series of 45 differentiated human thyroid tumors by polymerase chain reaction amplification and oligonucleotide hybridization to identify point mutations at each of the affected codons. Successful amplification was achieved in 38 cases, and activating mutations were identified in 5 of 13 (38%) autonomously functioning adenomas, but in none of 16 nonfunctioning adenomas, six papillary carcinomas, or three follicular carcinomas. Our results confirm that the gsp oncogene is involved in the pathogenesis of autonomously functioning tumors but do not support a role in other thyroid tumors.

Nerve cells have generally been assumed to have a diploid DNA content, typical of non-dividing somatic cells. However several reports have suggested that certain nerve cells types, notably Purkinje cells of the cerebellum, are polyploid. Other studies have contradicted these findings, stating Purkinje cells to be diploid. In this paper we reinvestigate the DNA status of Purkinje cells, in a variety of mammalian species. Cell DNA content is measured on tissue smears by Feulgen microspectrophotometry. Results show that for all species examined by us, Purkinje cells have, without exception, a DNA content comparable to that of somatic cells. A critical appraisal of the techniques used in those studies claiming a tetraploid DNA content for Purkinje cells leads us to believe our findings to be correct.

We have found that with accumulation of neuromelanin granules within cell bodies of neurones of the human substantia nigra there is a reduction in cytoplasmic RNA and a decrease in nucleolar volume. These observations imply a gradual decrease in the functional capacity of the cell such that eventually, the cell is unable to produce sufficient protein to maintain its metabolic economy with atrophy and death ensuing. This reduction in protein synthesis may result from the mechanical displacement and disruption of the endoplasmic reticulum by the accumulated pigment granules.

Results of a cytophotometric study have shown a widespread reduction in cytoplasmic RNA of nerve cells. It appears, therefore, that although certain aspects of the symptomatology of senile dementia may be accounted for by lesions in particular anatomical sites, the main part of the neurological disturbance is related to more broadly based changes in nerve cell metabolism affecting much, if not all, of the CNS.

A study of post-mortem changes in human central nervous tissue has shown that within 100 h of death, no significant change occurs in the amount of nerve cell DNA and nucleolar RNA nor in some membrane-associated enzymes such as succinate dehydrogenase, NADH and NADPH diaphorase, and cytochrome oxidase. Low molecular weight RNA species, probably transfer and messenger RNA are quickly lost, but there is little alteration in ribosomal RNA content. Cytoplasmic enzymes show variable changes; phosphofructokinase activity is rapidly decreased; hexokinase is unaltered but lactate dehydrogenase, pyruvate kinase and glucose-6-phosphate dehydrogenase initially show increases in activity which subsequently decline. Oxygen uptake diminishes quickly. These findings indicate that mechanical alterations in cell structure, following death, render organelles physiologically ineffective long before any significant changes in certain constituent biochemicals are detected. This report emphasizes the great importance necessary in the selection of appropriately time matched post-mortem tissues if accurate comparative studies of many of the cells constituents are to be made.

Evidence is presented here that the decrease in mean melanin content we have measured in old age is due, not to a general decline in melanin in all cells, but rather to a selective loss of those nerve cells containing greatest amounts of pigment. This cell loss is likely to be caused by the physical affects of pigment accumulation, per se, upon capacity for protein synthesis, as marked by losses of cytoplasmic RNA and nucleolar shrinkage in melanin rich cells.