Field cancerization in breast cancer

Breast cancer affects one in seven women worldwide during their lifetime. Widespread mammographic screening programs and education campaigns allow for early detection of the disease, often during its asymptomatic phase. Current practice in treatment and recurrence monitoring is based primarily on pathological evaluations but can also encompass genomic evaluations, both of which focus on the primary tumor. Although breast cancer is one of the most studied cancers, patients still recur at a rate of up to 15% within the first 10 years post‐surgery. Local recurrence was originally attributed to tumor cells contaminating histologically normal (HN) tissues beyond the surgical margin, but advances in technology have allowed for the identification of distinct aberrations that exist in the peri‐tumoral tissues themselves. One leading theory to explain this phenomenon is the field cancerization theory. Under this hypothesis, tumors arise from a field of molecularly altered cells that create a permissive environment for malignant evolution, which can occur with or without morphological changes. The traditional histopathology paradigm dictates that molecular alterations are reflected in the tissue phenotype. However, the spectrum of inter‐patient variability of normal breast tissue may obfuscate recognition of a cancerized field during routine diagnostics. In this review, we explore the concept of field cancerization focusing on HN peri‐tumoral tissues: we present the pathological and molecular features of field cancerization within these tissues and discuss how the use of peri‐tumoral tissues can affect research. Our observations suggest that pathological and molecular evaluations could be used synergistically to assess risk and guide the therapeutic management of patients. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

Longitudinal profiling of circulating tumour DNA for tracking tumour dynamics in pancreatic cancer.

BACKGROUND: The utility of circulating tumour DNA (ctDNA) for longitudinal tumour monitoring in pancreatic ductal adenocarcinoma (PDAC) has not been explored beyond mutations in the KRAS proto-oncogene. Here, we aimed to characterise and track patient-specific somatic ctDNA variants, to assess longitudinal changes in disease burden and explore the landscape of actionable alterations. METHODS: We followed 3 patients with resectable disease and 4 patients with unresectable disease, including 4 patients with ≥ 3 serial follow-up samples, of whom 2 were rare long survivors (> 5 years). We performed whole exome sequencing of tumour gDNA and plasma ctDNA (n = 20) collected over a ~ 2-year period from diagnosis through treatment to death or final follow-up. Plasma from 3 chronic pancreatitis cases was used as a comparison for analysis of ctDNA mutations. RESULTS: We detected > 55% concordance between somatic mutations in tumour tissues and matched serial plasma. Mutations in ctDNA were detected within known PDAC driver genes (KRAS, TP53, SMAD4, CDKN2A), in addition to patient-specific variants within alternative cancer drivers (NRAS, HRAS, MTOR, ERBB2, EGFR, PBRM1), with a trend towards higher overall mutation loads in advanced disease. ctDNA alterations with potential for therapeutic actionability were identified in all 7 patients, including DNA damage response (DDR) variants co-occurring with hypermutation signatures predictive of response to platinum chemotherapy. Longitudinal tracking in 4 patients with follow-up > 2 years demonstrated that ctDNA mutant allele fractions and clonal trends were consistent with CA19-9 measurements and/or clinically reported disease burden. The estimated prevalence of 'stem clones' was highest in an unresectable patient where changes in ctDNA dynamics preceded CA19-9 levels. Longitudinal evolutionary trajectories revealed ongoing subclonal evolution following chemotherapy. CONCLUSION: These results provide proof-of-concept for the use of exome sequencing of serial plasma to characterise patient-specific ctDNA profiles, and demonstrate the sensitivity of ctDNA in monitoring disease burden in PDAC even in unresectable cases without matched tumour genotyping. They reveal the value of tracking clonal evolution in serial ctDNA to monitor treatment response, establishing the potential of applied precision medicine to guide stratified care by identifying and evaluating actionable opportunities for intervention aimed at optimising patient outcomes for an otherwise intractable disease

Fast Likelihood-Based Change Point Detection

Change point detection plays a fundamental role in many real-world applications, where the goal is to analyze and monitor the behaviour of a data stream. In this paper, we study change detection in binary streams. To this end, we use a likelihood ratio between two models as a measure for indicating change. The first model is a single bernoulli variable while the second model divides the stored data in two segments, and models each segment with its own bernoulli variable. Finding the optimal split can be done in O(n) time, where n is the number of entries since the last change point. This is too expensive for large n. To combat this we propose an approximation scheme that yields (1 - epsilon) approximation in O(epsilon(-1) log(2) n) time. The speed-up consists of several steps: First we reduce the number of possible candidates by adopting a known result from segmentation problems. We then show that for fixed bernoulli parameters we can find the optimal change point in logarithmic time. Finally, we show how to construct a candidate list of size O(epsilon(-1) log n) formodel parameters. We demonstrate empirically the approximation quality and the running time of our algorithm, showing that we can gain a significant speed-up with a minimal average loss in optimality.Peer reviewe

Case study on the efficacy of a lanthanum-enriched clay (Phoslock®) in controlling eutrophication in Lake Het Groene Eiland (The Netherlands)

Lake Het Groene Eiland was created in the beginning of 2008 by construction of dikes for isolating it from the surrounding 220-ha water body. This so-called claustrum of 5 ha was treated using lanthanum-modified clay (Phoslock®) to control eutrophication and mitigate cyanobacterial nuisance. Cyanobacteria chlorophyll-a were significantly lower in the claustrum than those in the reference water body, where a massive bloom developed in summer, 2008. However, PO4-P and TP did not statistically differ in these two waters. TN and NO3-N were significantly lower in the claustrum, where dense submerged macrophytes beds developed. Lanthanum concentrations were elevated after the applications of the modified clay in the claustrum, but filterable lanthanum dropped rapidly below the Dutch standard of 10.1 μg l−1. During winter, dozens of Canada geese resided at the claustrum. Geese droppings contained an average of 2 mg PO4-P g−1 dry weight and 12 mg NH3-N g−1 dry weight and might present a growing source of nutrients to the water. Constructing the claustrum enabled unrestricted bathing in subsequent three summers, as no swimming bans had to be issued due to cyanobacteria blooms. However, the role of the modified clay in this positive outcome remains unclear, and longevity of the measures questionable.

Characterization of four subtypes in morphologically normal tissue excised proximal and distal to breast cancer

Widespread mammographic screening programs and improved self-monitoring allow for breast cancer to be detected earlier than ever before. Breast-conserving surgery is a successful treatment for select women. However, up to 40% of women develop local recurrence after surgery despite apparently tumor-free margins. This suggests that morphologically normal breast may harbor early alterations that contribute to increased risk of cancer recurrence. We conducted a comprehensive transcriptomic and proteomic analysis to characterize 57 fresh-frozen tissues from breast cancers and matched histologically normal tissues resected proximal to (<2 cm) and distant from (5–10 cm) the primary tumor, using tissues from cosmetic reduction mammoplasties as baseline. Four distinct transcriptomic subtypes are identified within matched normal tissues: metabolic; immune; matrisome/epithelial–mesenchymal transition, and non-coding enriched. Key components of the subtypes are supported by proteomic and tissue composition analyses. We find that the metabolic subtype is associated with poor prognosis (p < 0.001, HR6.1). Examination of genes representing the metabolic signature identifies several genes able to prognosticate outcome from histologically normal tissues. A subset of these have been reported for their predictive ability in cancer but, to the best of our knowledge, these have not been reported altered in matched normal tissues. This study takes an important first step toward characterizing matched normal tissues resected at pre-defined margins from the primary tumor. Unlocking the predictive potential of unexcised tissue could prove key to driving the realization of personalized medicine for breast cancer patients, allowing for more biologically-driven analyses of tissue margins than morphology alone

Satellite Tracking Reveals Long Distance Coastal Travel and Homing by Translocated Estuarine Crocodiles, Crocodylus porosus

Crocodilians have a wide distribution, often in remote areas, are cryptic, secretive and are easily disturbed by human presence. Their capacity for large scale movements is poorly known. Here, we report the first study of post-release movement patterns in translocated adult crocodiles, and the first application of satellite telemetry to a crocodilian. Three large male Crocodylus porosus (3.1–4.5 m) were captured in northern Australia and translocated by helicopter for 56, 99 and 411 km of coastline, the last across Cape York Peninsula from the west coast to the east coast. All crocodiles spent time around their release site before returning rapidly and apparently purposefully to their capture locations. The animal that circumnavigated Cape York Peninsula to return to its capture site, travelled more than 400 km in 20 days, which is the longest homeward travel yet reported for a crocodilian. Such impressive homing ability is significant because translocation has sometimes been used to manage potentially dangerous C. porosus close to human settlement. It is clear that large male estuarine crocodiles can exhibit strong site fidelity, have remarkable navigational skills, and may move long distances following a coastline. These long journeys included impressive daily movements of 10–30 km, often consecutively

SARS-CoV-2 neutralizing antibodies: Longevity, breadth, and evasion by emerging viral variants.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) antibody neutralization response and its evasion by emerging viral variants and variant of concern (VOC) are unknown, but critical to understand reinfection risk and breakthrough infection following vaccination. Antibody immunoreactivity against SARS-CoV-2 antigens and Spike variants, inhibition of Spike-driven virus-cell fusion, and infectious SARS-CoV-2 neutralization were characterized in 807 serial samples from 233 reverse transcription polymerase chain reaction (RT-PCR)-confirmed Coronavirus Disease 2019 (COVID-19) individuals with detailed demographics and followed up to 7 months. A broad and sustained polyantigenic immunoreactivity against SARS-CoV-2 Spike, Membrane, and Nucleocapsid proteins, along with high viral neutralization, was associated with COVID-19 severity. A subgroup of "high responders" maintained high neutralizing responses over time, representing ideal convalescent plasma donors. Antibodies generated against SARS-CoV-2 during the first COVID-19 wave had reduced immunoreactivity and neutralization potency to emerging Spike variants and VOC. Accurate monitoring of SARS-CoV-2 antibody responses would be essential for selection of optimal responders and vaccine monitoring and design

Taking tissue seriously means taking communities seriously

<p>Abstract</p> <p>Background</p> <p>Health research is increasingly being conducted on a global scale, particularly in the developing world to address leading causes of morbidity and mortality. While research interest has increased, building scientific capacity in the developing world has not kept pace. This often leads to the export of human tissue (defined broadly) from the developing to the developed world for analysis. These practices raise a number of important ethical issues that require attention.</p> <p>Discussion</p> <p>In the developed world, there is great heterogeneity of regulatory practices regarding human tissues. In this paper, we outline the salient ethical issues raised by tissue exportation, review the current ethical guidelines and norms, review the literature on what is known empirically about perceptions and practices with respect to tissue exportation from the developing to the developed world, set out what needs to be known in terms of a research agenda, and outline what needs to be done immediately in terms of setting best practices. We argue that the current status of tissue exportation is ambiguous and requires clarification lest problems that have plagued the developed world occur in the context of global heath research with attendant worsening of inequities. Central to solutions to current ethical concerns entail moving beyond concern with individual level consent and embracing a robust interaction with communities engaged in research.</p> <p>Conclusion</p> <p>Greater attention to community engagement is required to understand the diverse issues associated with tissue exportation.</p

Foodways in transition: food plants, diet and local perceptions of change in a Costa Rican Ngäbe community

Background Indigenous populations are undergoing rapid ethnobiological, nutritional and socioeconomic transitions while being increasingly integrated into modernizing societies. To better understand the dynamics of these transitions, this article aims to characterize the cultural domain of food plants and analyze its relation with current day diets, and the local perceptions of changes given amongst the Ngäbe people of Southern Conte-Burica, Costa Rica, as production of food plants by its residents is hypothesized to be drastically in recession with an decreased local production in the area and new conservation and development paradigms being implemented. Methods Extensive freelisting, interviews and workshops were used to collect the data from 72 participants on their knowledge of food plants, their current dietary practices and their perceptions of change in local foodways, while cultural domain analysis, descriptive statistical analyses and development of fundamental explanatory themes were employed to analyze the data. Results Results show a food plants domain composed of 140 species, of which 85 % grow in the area, with a medium level of cultural consensus, and some age-based variation. Although many plants still grow in the area, in many key species a decrease on local production–even abandonment–was found, with much reduced cultivation areas. Yet, the domain appears to be largely theoretical, with little evidence of use; and the diet today is predominantly dependent on foods bought from the store (more than 50 % of basic ingredients), many of which were not salient or not even recognized as ‘food plants’ in freelists exercises. While changes in the importance of food plants were largely deemed a result of changes in cultural preferences for store bought processed food stuffs and changing values associated with farming and being food self-sufficient, Ngäbe were also aware of how changing household livelihood activities, and the subsequent loss of knowledge and use of food plants, were in fact being driven by changes in social and political policies, despite increases in forest cover and biodiversity. Conclusions Ngäbe foodways are changing in different and somewhat disconnected ways: knowledge of food plants is varied, reflecting most relevant changes in dietary practices such as lower cultivation areas and greater dependence on food from stores by all families. We attribute dietary shifts to socioeconomic and political changes in recent decades, in particular to a reduction of local production of food, new economic structures and agents related to the State and globalization

Pathologies in Asymptotically Lifshitz Spacetimes

There has been significant interest in the last several years in studying possible gravitational duals, known as Lifshitz spacetimes, to anisotropically scaling field theories by adding matter to distort the asymptotics of an AdS spacetime. We point out that putative ground state for the most heavily studied example of such a spacetime, that with a flat spatial section, suffers from a naked singularity and further point out this singularity is not resolvable by any known stringy effect. We review the reasons one might worry that asymptotically Lifshitz spacetimes are unstable and employ the initial data problem to study the stability of such systems. Rather surprisingly this question, and even the initial value problem itself, for these spacetimes turns out to generically not be well-posed. A generic normalizable state will evolve in such a way to violate Lifshitz asymptotics in finite time. Conversely, enforcing the desired asymptotics at all times puts strong restrictions not just on the metric and fields in the asymptotic region but in the deep interior as well. Generically, even perturbations of the matter field of compact support are not compatible with the desired asymptotics.Comment: 36 pages, 1 figure, v2: Enhanced discussion of singularity, including relationship to Gubser's conjecture and singularity in RG flow solution, plus minor clarification