The Digital Health Revolution: Exploring the Impact of Online Cancer Information on Self-Reported Preventive Behaviors.

Cancer, one of the leading causes of death worldwide, is a disease characterized by uncontrolled cell growth within the body. While there have been many improvements in the treatment of cancer clinically, there is now an urgent need to improve cancer-related communication. This study explores the impact of online health information, specifically cancer-related information and prevention, among members of the general public. Through a randomized survey, we examined what information leads people to take action to minimize their cancer risk and communicate with their providers. Through evaluation of the various modes of communication, we were able to provide insight into which are more effective and better received by members of the general public. Through this, ways of bettering these avenues of communication and strengthening the bond between them will be highlighted and more easily elaborated on by future studies. The results of our study indicated that 60% of participants asserted that they are motivated by online preventive information to take steps to limit their cancer risk, while only roughly 44% of participants overall agreed that their doctor has communicated with them about when proper cancer screenings should be scheduled for the future. Although patients may be turning to the Internet now more than ever due to various reasons, when comparing self-reported rates of comprehension among the study participants, 35% agreed that the cancer-related information they can access online is confusing, while fewer than 22% of participants agreed that the cancer-related information they receive directly from their doctor is confusing. This is indicative of the limitations the Internet may have when undertaking the role of being a medical resource, especially when acting as a replacement for in-person medical appointments where patients can communicate directly with their physicians. Ultimately, these results provide a unique perspective into how people receive, evaluate, and implement cancer-preventive steps and general health-related information in a post-COVID-19 world, where the Internet is now strongly embedded in healthcare.

Stronger Together: Cancer Clones Cooperate to Alleviate Growth Barriers in Critical Cancer Progression Transitions.

Hershey and colleagues recently showed how clones in a triple-negative breast cancer cell line cooperate for their mutual fitness benefit. In this system, clones exchange soluble metabolites to increase their in vitro growth rate at low population densities, therefore mitigating the documented growth barrier that reduces individual fitness in small tumor cell populations (Allee effect). Such cooperation could aid important transitions in cancer progression in which cancer cell populations are small, like invasion or metastasis. Using orthotopic transplantation, the authors demonstrate that this cooperation is functional in one such transition in vivo, increasing the metastatic load and number of metastases, which are usually polyclonal. Together, these findings highlight the need to consider ecologic interactions to properly understand tumor growth dynamics, and how they complement the standing evolutionary model of cancer progression in our quest to understand and treat cancer.

The relationship between diet, plasma glucose, and cancer prevalence across vertebrates.

Could diet and mean plasma glucose concentration (MPGluC) explain the variation in cancer prevalence across species? We collected diet, MPGluC, and neoplasia data for 160 vertebrate species from existing databases. We found that MPGluC negatively correlates with cancer and neoplasia prevalence, mostly of gastrointestinal organs. Trophic level positively correlates with cancer and neoplasia prevalence even after controlling for species MPGluC. Most species with high MPGluC (50/78 species = 64.1%) were birds. Most species in high trophic levels (42/53 species = 79.2%) were reptiles and mammals. Our results may be explained by the evolution of insulin resistance in birds which selected for loss or downregulation of genes related to insulin-mediated glucose import in cells. This led to higher MPGluC, intracellular caloric restriction, production of fewer reactive oxygen species and inflammatory cytokines, and longer telomeres contributing to longer longevity and lower neoplasia prevalence in extant birds relative to other vertebrates.

Cancer Prevalence Across Vertebrates.

Cancer is pervasive across multicellular species, but what explains differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades (amphibians, sauropsids and mammals) we found that neoplasia and malignancy prevalence increases with adult weight (contrary to Peto's Paradox) and somatic mutation rate, but decreases with gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%) the black-footed penguin (<0.4%), ferrets (63%) and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer.

Is chimerism associated with cancer across the tree of life?

Chimerism is a widespread phenomenon across the tree of life. It is defined as a multicellular organism composed of cells from other genetically distinct entities. This ability to 'tolerate' non-self cells may be linked to susceptibility to diseases like cancer. Here we test whether chimerism is associated with cancers across obligately multicellular organisms in the tree of life. We classified 12 obligately multicellular taxa from lowest to highest chimerism levels based on the existing literature on the presence of chimerism in these species. We then tested for associations of chimerism with tumour invasiveness, neoplasia (benign or malignant) prevalence and malignancy prevalence in 11 terrestrial mammalian species. We found that taxa with higher levels of chimerism have higher tumour invasiveness, though there was no association between malignancy or neoplasia and chimerism among mammals. This suggests that there may be an important biological relationship between chimerism and susceptibility to tissue invasion by cancerous cells. Studying chimerism might help us identify mechanisms underlying invasive cancers and also could provide insights into the detection and management of emerging transmissible cancers.

Life history and cancer in birds: clutch size predicts cancer.

Cancer is a disease that affects nearly all multicellular life, including birds. However, little is known about what factors explain the variance in cancer prevalence among species. Litter size is positively correlated with cancer prevalence in managed species of mammals, and larger body size, but not incubation or nestling period, is linked to tumor prevalence in wild birds. Also, birds that produce more elaborate sexual traits are expected to have fewer resources for cancer defenses and thus higher cancer prevalence. In this study, we examined whether cancer prevalence is associated with a wide variety of life history traits (clutch size, incubation length, body mass, lifespan, and the extent of sexual dimorphism) across 108 species of managed birds in 25 different zoological facilities, sanctuaries, and veterinary clinics. We found that clutch size was positively correlated with cancer and neoplasia (both benign and malignant) prevalence, even after controlling for body mass. Cancer prevalence was not associated with incubation length, body mass, lifespan, or sexual dimorphism. The positive correlations of clutch size with cancer prevalence and neoplasia prevalence suggest that there may be life-history trade-offs between reproductive investment and somatic maintenance (in the form of cancer prevention mechanisms) in managed birds.

Cancer Prevalence Across Vertebrates.

Cancer is pervasive across multicellular species. Are there any patterns that can explain differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades (amphibians, sauropsids and mammals) we found that neoplasia and malignancy prevalence increases with adult weight and decreases with gestation time, contrary to Peto’s Paradox. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%) the black-footed penguin (<0.4%), ferrets (63%) and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer.

Chromosome segregation fidelity requires microtubule polyglutamylation by the cancer downregulated enzyme TTLL11.

Regulation of microtubule (MT) dynamics is key for mitotic spindle assembly and faithful chromosome segregation. Here we show that polyglutamylation, a still understudied post-translational modification of spindle MTs, is essential to define their dynamics within the range required for error-free chromosome segregation. We identify TTLL11 as an enzyme driving MT polyglutamylation in mitosis and show that reducing TTLL11 levels in human cells or zebrafish embryos compromises chromosome segregation fidelity and impairs early embryonic development. Our data reveal a mechanism to ensure genome stability in normal cells that is compromised in cancer cells that systematically downregulate TTLL11. Our data suggest a direct link between MT dynamics regulation, MT polyglutamylation and two salient features of tumour cells, aneuploidy and chromosome instability (CIN).

Healthy but smaller herds: Predators reduce pathogen transmission in an amphibian assemblage.

Predators and pathogens are fundamental components of ecological communities that have the potential to influence each other via their interactions with victims and to initiate density- and trait-mediated effects, including trophic cascades. Despite this, experimental tests of the healthy herds hypothesis, wherein predators influence pathogen transmission, are rare. Moreover, no studies have separated effects mediated by density vs. traits. Using a semi-natural mesocosm experiment, we investigated the interactive effects of predatory dragonfly larvae (caged or lethal [free-ranging]) and a viral pathogen, ranavirus, on larval amphibians (grey treefrogs and northern leopard frogs). We determined the influence of predators on ranavirus transmission and the relative importance of density- and trait-mediated effects on observed patterns. Lethal predators reduced ranavirus infection prevalence by 57%-83% compared to no-predator and caged-predator treatments. The healthy herds effect was more strongly associated with reductions in tadpole density than behavioural responses to predators. We also assessed whether ranavirus altered the responses of tadpoles to predators. In the absence of virus, tadpoles reduced activity levels and developed deeper tails in the presence of predators. However, there was no evidence that virus presence or infection altered responses to predators. Finally, we compared the magnitude of trophic cascades initiated by individual and combined natural enemies. Lethal predators initiated a trophic cascade by reducing tadpole density, but caged predators and ranavirus did not. The absence of a virus-induced trophic cascade is ostensibly the consequence of limited virus-induced mortality and the ability of infected individuals to continue interacting within the community. Our results provide support for the healthy herds hypothesis in amphibian communities. We uniquely demonstrate that density-mediated effects of predators outweigh trait-mediated effects in driving this pattern. Moreover, this study was one of the first to directly compare trophic cascades caused by predators and pathogens. Our results underscore the importance of examining the interactions between predators and pathogens in ecology.

Identification of regulatory elements recapitulating early expression of L-plastin in the zebrafish enveloping layer and embryonic periderm.

We have cloned and characterized an intronic fragment of zebrafish lymphocyte cytosolic protein 1 (lcp1, also called L-plastin) that drives expression to the zebrafish enveloping layer (EVL). L-plastin is a calcium-dependent actin-bundling protein belonging to the plastin/fimbrin family of proteins, and is necessary for the proper migration and attachment of several adult cell types, including leukocytes and osteoclasts. However, in zebrafish lcp1 is abundantly expressed much earlier, during differentiation of the EVL. The cells of this epithelial layer migrate collectively, spreading vegetally over the yolk. L-plastin expression persists into the larval periderm, a transient epithelial tissue that forms the first larval skin. This finding establishes that L-plastin is activated in two different embryonic waves, with a distinct regulatory switch between the early EVL and the later leukocyte. To better study L-plastin expressing cells we attempted CRISPR/Cas9 homology-driven recombination (HDR) to insert a self-cleaving peptide (Cre-P2A-EGFP-CAAX) downstream of the native lcp1 promoter. This produced a stable zebrafish line expressing Cre recombinase in EVL nuclei and green fluorescence in EVL cell membranes. In vivo tracking of these labeled cells provided enhanced views of EVL migration behavior, membrane extensions, and mitotic events. Finally, we experimentally dissected key elements of the targeted lcp1 locus, discovering a ∼300 bp intronic sequence sufficient to drive EVL expression. The lcp1: Cre-P2A-EGFP-CAAX zebrafish should be useful for studying enveloping layer specification, gastrulation movements and periderm development in this widely used vertebrate model. In addition, the conserved regulatory sequences we have isolated predict that L-plastin orthologs may have a similar early expression pattern in other vertebrate embryos.

Targeted deletion of the zebrafish actin-bundling protein L-plastin (lcp1).

Regulation of the cytoskeleton is essential for cell migration in health and disease. Lymphocyte cytosolic protein 1 (lcp1, also called L-plastin) is a hematopoietic-specific actin-bundling protein that is highly conserved in zebrafish, mice and humans. In addition, L-plastin expression is documented as both a genetic marker and a cellular mechanism contributing to the invasiveness of tumors and transformed cell lines. Despite L-plastin's role in both immunity and cancer, in zebrafish there are no direct studies of its function, and no mutant, knockout or reporter lines available. Using CRISPR-Cas9 genome editing, we generated null alleles of zebrafish lcp1 and examined the phenotypes of these fish throughout the life cycle. Our editing strategy used gRNA to target the second exon of lcp1, producing F0 mosaic fish that were outcrossed to wild types to confirm germline transmission. F1 heterozygotes were then sequenced to identify three unique null alleles, here called 'Charlie', 'Foxtrot' and 'Lima'. In silico, each allele truncates the endogenous protein to less than 5% normal size and removes both essential actin-binding domains (ABD1 and ABD2). Although none of the null lines express detectable LCP1 protein, homozygous mutant zebrafish (-/-) can develop and reproduce normally, a finding consistent with that of the L-plastin null mouse (LPL -/-). However, such mice do have a profound immune defect when challenged by lung bacteria. Interestingly, we observed reduced long-term survival of zebrafish lcp1 -/- homozygotes (~30% below the expected numbers) in all three of our knockout lines, with greatest mortality corresponding to the period (4-6 weeks post-fertilization) when the innate immune system is functional, but the adaptive immune system is not yet mature. This suggests that null zebrafish may have reduced capacity to combat opportunistic infections, which are more easily transmissible in the aquatic environment. Overall, our novel mutant lines establish a sound genetic model and an enhanced platform for further studies of L-plastin gene function in hematopoiesis and cancer.

Clinically nonmetastatic renal cell carcinoma with sarcomatoid dedifferentiation: Natural history and outcomes after surgical resection with curative intent.

PURPOSE: Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is an aggressive malignancy associated with a poor prognosis. Although existing literature focuses on patients presenting with metastatic disease, characteristics and outcomes for patients with localized disease are not well described. We aimed to evaluate postnephrectomy characteristics, outcomes, and predictors of survival in patients with sRCC who presented with clinically localized disease. PATIENTS AND METHODS: An institutional review board-approved review from 1986 to 2011 identified 77 patients who presented with clinically localized disease, underwent nephrectomy, and had sRCC in their primary kidney tumor. Clinical and pathologic variables were captured for each patient. Overall survival (OS) and recurrence-free survival (RFS) were calculated for all patients and those who had no evidence of disease (NED) following nephrectomy, respectively. Comparisons were made with categorical groupings in proportional hazards regression models for univariable and multivariable analyses. RESULTS: OS for the entire cohort (n = 77) at 2 years was 50%. A total of 56 (77%) patients of the 73 who has NED following nephrectomy experienced a recurrence, with a median time to recurrence of 26.2 months. On multivariable analysis, tumor stage, pathologically positive lymph nodes, and year of nephrectomy were significant predictors of both OS and recurrence-free survival. Limitations include the retrospective nature of this study and relatively small sample size. CONCLUSIONS: Long-term survival for patients with sRCC, even in clinically localized disease, is poor. Aggressive surveillance of those who have NED following nephrectomy is essential, and further prospective studies evaluating the benefit of adjuvant systemic therapies in this cohort are warranted.

Salvage surgery after energy ablation for renal masses.

OBJECTIVES: To evaluate the feasibility, safety, pathological, radiological and functional outcomes of salvage surgery after previous renal mass ablation therapy. PATIENTS AND METHODS: After institutional review board approval, we reviewed our renal tumour database, and described the characteristics and outcomes of patients who experienced a local recurrence after energy ablation for renal masses and underwent salvage surgical therapy. RESULTS: A total of 14 patients fit the inclusion criteria. The median (interquartile range [IQR]) age was 65 (59-77) years, with a median (IQR) Charlson comorbidity index score of 2 (0.75-3.00). Three patients had a solitary kidney. Seven patients received their ablation therapies at an outside institution. Ten patients had undergone percutaneous radiofrequency ablation, three percutaneous cryoablation and one laparoscopic cryoablation. The median (IQR) R.E.N.A.L. nephrometry score at time of surgery was 7 (5-9), while the median (IQR) time from ablation to surgery was 26.5 (16.3-39.3) months. Of the 14 patients, 11 underwent partial nephrectomy and three underwent planned radical nephrectomy. The median (IQR) surgery time was 203 (177-265) min and the median length of stay was 5.5 days. There was one microscopic positive surgical margin. The median tumour size at final pathology was 3.1 cm. In all, 13 patients had renal cell carcinoma and one had no tumour present. Nine were pT1a, 1 pT1b, 2 pT3a, and 1 pT3b tumours. There were four Clavien grade III complications in four patients. The median preoperative estimated glomerular filtration rate (eGFR) and the eGFR at last follow-up were 66 and 66 mL/min/1.73 m(2) . There had been no deaths by the median (IQR) follow-up of 26.5 (10.5-49.5) months. CONCLUSIONS: Patients who have undergone previous renal ablation therapy can be salvaged with partial or radical nephrectomy with good intermediate-term outcomes. These procedures may be associated with a high rate of adverse events. Longer follow-up is necessary.