Lynch syndrome is a highly penetrant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes. We estimated the risks of primary cancers other than colorectal ...cancer following a diagnosis of colorectal cancer in mutation carriers.
We obtained data from the Colon Cancer Family Registry for 764 carriers of an MMR gene mutation (316 MLH1, 357 MSH2, 49 MSH6, and 42 PMS2), who had a previous diagnosis of colorectal cancer. The Kaplan-Meier method was used to estimate their cumulative risk of cancers 10 and 20 years after colorectal cancer. We estimated the age-, sex-, country- and calendar period-specific standardized incidence ratios (SIRs) of cancers following colorectal cancer, compared with the general population.
Following colorectal cancer, carriers of MMR gene mutations had the following 10-year risk of cancers in other organs: kidney, renal pelvis, ureter, and bladder (2%, 95% confidence interval CI = 1% to 3%); small intestine, stomach, and hepatobiliary tract (1%, 95% CI = 0.2% to 2%); prostate (3%, 95% CI = 1% to 5%); endometrium (12%, 95% CI = 8% to 17%); breast (2%, 95% CI = 1% to 4%); and ovary (1%, 95% CI = 0% to 2%). They were at elevated risk compared with the general population: cancers of the kidney, renal pelvis, and ureter (SIR = 12.54, 95% CI = 7.97 to 17.94), urinary bladder (SIR = 7.22, 95% CI = 4.08 to 10.99), small intestine (SIR = 72.68, 95% CI = 39.95 to 111.29), stomach (SIR = 5.65, 95% CI = 2.32 to 9.69), and hepatobiliary tract (SIR = 5.94, 95% CI = 1.81 to 10.94) for both sexes; cancer of the prostate (SIR = 2.05, 95% CI = 1.23 to 3.01), endometrium (SIR = 40.23, 95% CI = 27.91 to 56.06), breast (SIR = 1.76, 95% CI = 1.07 to 2.59), and ovary (SIR = 4.19, 95% CI = 1.28 to 7.97).
Carriers of MMR gene mutations who have already had a colorectal cancer are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers.
The cell-of-origin of high grade serous ovarian carcinoma (HGSOC) remains controversial, with fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) both considered candidates. Here, by ...using genetically engineered mouse models and organoids, we assessed the tumor-forming properties of FTE and OSE harboring the same oncogenic abnormalities. Combined RB family inactivation and Tp53 mutation in Pax8 + FTE caused Serous Tubal Intraepithelial Carcinoma (STIC), which metastasized rapidly to the ovarian surface. These events were recapitulated by orthotopic injection of mutant FTE organoids. Engineering the same genetic lesions into Lgr5 + OSE or OSE-derived organoids also caused metastatic HGSOC, although with longer latency and lower penetrance. FTE- and OSE-derived tumors had distinct transcriptomes, and comparative transcriptomics and genomics suggest that human HGSOC arises from both cell types. Finally, FTE- and OSE-derived organoids exhibited differential chemosensitivity. Our results comport with a dualistic origin for HGSOC and suggest that the cell-of-origin might influence therapeutic response.
The area of surface reconstruction has seen substantial progress in the past two decades. The traditional problem addressed by surface reconstruction is to recover the digital representation of a ...physical shape that has been scanned, where the scanned data contain a wide variety of defects. While much of the earlier work has been focused on reconstructing a piece‐wise smooth representation of the original shape, recent work has taken on more specialized priors to address significantly challenging data imperfections, where the reconstruction can take on different representations—not necessarily the explicit geometry. We survey the field of surface reconstruction, and provide a categorization with respect to priors, data imperfections and reconstruction output. By considering a holistic view of surface reconstruction, we show a detailed characterization of the field, highlight similarities between diverse reconstruction techniques and provide directions for future work in surface reconstruction.
The area of surface reconstruction has seen substantial progress in the past two decades. The traditional problem addressed by surface reconstruction is to recover the digital representation of a physical shape that has been scanned, where the scanned data contain a wide variety of defects. While much of the earlier work has been focused on reconstructing a piece‐wise smooth representation of the original shape, recent work has taken on more specialized priors to address significantly challenging data imperfections, where the reconstruction can take on different representations—not necessarily the explicit geometry
The aging of the US population is expected to lead to a large increase in the number of adults with dementia, but some recent studies in the United States and other high-income countries suggest that ...the age-specific risk of dementia may have declined over the past 25 years. Clarifying current and future population trends in dementia prevalence and risk has important implications for patients, families, and government programs.
To compare the prevalence of dementia in the United States in 2000 and 2012.
We used data from the Health and Retirement Study (HRS), a nationally representative, population-based longitudinal survey of individuals in the United States 65 years or older from the 2000 (n = 10 546) and 2012 (n = 10 511) waves of the HRS.
Dementia was identified in each year using HRS cognitive measures and validated methods for classifying self-respondents, as well as those represented by a proxy. Logistic regression was used to identify socioeconomic and health variables associated with change in dementia prevalence between 2000 and 2012.
The study cohorts had an average age of 75.0 years (95% CI, 74.8-75.2 years) in 2000 and 74.8 years (95% CI, 74.5-75.1 years) in 2012 (P = .24); 58.4% (95% CI, 57.3%-59.4%) of the 2000 cohort was female compared with 56.3% (95% CI, 55.5%-57.0%) of the 2012 cohort (P < .001). Dementia prevalence among those 65 years or older decreased from 11.6% (95% CI, 10.7%-12.7%) in 2000 to 8.8% (95% CI, 8.2%-9.4%) (8.6% with age- and sex-standardization) in 2012 (P < .001). More years of education was associated with a lower risk for dementia, and average years of education increased significantly (from 11.8 years 95% CI, 11.6-11.9 years to 12.7 years 95% CI, 12.6-12.9 years; P < .001) between 2000 and 2012. The decline in dementia prevalence occurred even though there was a significant age- and sex-adjusted increase between years in the cardiovascular risk profile (eg, prevalence of hypertension, diabetes, and obesity) among older US adults.
The prevalence of dementia in the United States declined significantly between 2000 and 2012. An increase in educational attainment was associated with some of the decline in dementia prevalence, but the full set of social, behavioral, and medical factors contributing to the decline is still uncertain. Continued monitoring of trends in dementia incidence and prevalence will be important for better gauging the full future societal impact of dementia as the number of older adults increases in the decades ahead.
Thirty years of research on the p53 family of genes has generated almost fifty thousand publications. The first of these papers detected the p53 protein associated with a viral oncogene product in ...transformed cells and tumors and focused the field on cancer biology. Subsequent manuscripts have shown a wide variety of functions for the p53 family of genes and their proteins. These proteins are involved in reproduction, genomic repair, fidelity and recombination, the regulation of metabolic processes, longevity, surveillance of the stability of development, the production of stem cells and changes in epigenetic marks, the development of the nervous system (p73), the immune system (p73) and skin (p63), as well as the better known roles for the family in tumor suppression. The p53 family of genes has been found in the modern day ancestors of organisms with over one billion years of evolutionary history where they play a role in germ-line fidelity over that time span. As the body plan of the vertebrates emerged with the regeneration of tissues by stem cells over a lifetime, the p53 gene and its protein were adapted to be a tumor suppressor of somatic stem and progenitor cells complementing its' past functions in the germ line. Because the p53 family of genes has played a role in germ-line fidelity and preservation of the species, even in times of stress, these genes have been under constant selection pressure to change and adapt to new situations. This has given rise to this diversity of functions all working to preserve homeostatic processes that permit growth and reproduction in a world that is constantly challenging the fidelity of information transfer at each generation. The p53 family of gene products has influenced the rates of evolutionary change, just as evolutionary changes have altered the p53 family and its functions.
The inflammatory reflex is a physiological mechanism through which the nervous system maintains immunologic homeostasis by modulating innate and adaptive immunity. We postulated that the reflex might ...be harnessed therapeutically to reduce pathological levels of inflammation in rheumatoid arthritis by activating its prototypical efferent arm, termed the cholinergic anti-inflammatory pathway. To explore this, we determined whether electrical neurostimulation of the cholinergic anti-inflammatory pathway reduced disease severity in the collagen-induced arthritis model.
Rats implanted with vagus nerve cuff electrodes had collagen-induced arthritis induced and were followed for 15 days. Animals underwent active or sham electrical stimulation once daily from day 9 through the conclusion of the study. Joint swelling, histology, and levels of cytokines and bone metabolism mediators were assessed.
Compared with sham treatment, active neurostimulation of the cholinergic anti-inflammatory pathway resulted in a 52% reduction in ankle diameter (p = 0.02), a 57% reduction in ankle diameter (area under curve; p = 0.02) and 46% reduction overall histological arthritis score (p = 0.01) with significant improvements in inflammation, pannus formation, cartilage destruction, and bone erosion (p = 0.02), accompanied by numerical reductions in systemic cytokine levels, not reaching statistical significance. Bone erosion improvement was associated with a decrease in serum levels of receptor activator of NF-κB ligand (RANKL) from 132±13 to 6±2 pg/mL (mean±SEM, p = 0.01).
The severity of collagen-induced arthritis is reduced by neurostimulation of the cholinergic anti-inflammatory pathway delivered using an implanted electrical vagus nerve stimulation cuff electrode, and supports the rationale for testing this approach in human inflammatory disorders.
Changes in epigenetic marks such as DNA methylation and histone acetylation are associated with a broad range of disease traits, including cancer, asthma, metabolic disorders, and various ...reproductive conditions. It seems plausible that changes in epigenetic state may be induced by environmental exposures such as malnutrition, tobacco smoke, air pollutants, metals, organic chemicals, other sources of oxidative stress, and the microbiome, particularly if the exposure occurs during key periods of development. Thus, epigenetic changes could represent an important pathway by which environmental factors influence disease risks, both within individuals and across generations. We discuss some of the challenges in studying epigenetic mediation of pathogenesis and describe some unique opportunities for exploring these phenomena.
Many controversies in statistics are due primarily or solely to poor quality control in journals, bad statistical textbooks, bad teaching, unclear writing, and lack of knowledge of the historical ...literature. One way to improve the practice of statistics and resolve these issues is to do what initiators of the 2016 ASA statement did: take one issue at a time, have extensive discussions about the issue among statisticians of diverse backgrounds and perspectives and eventually develop and publish a broadly supported consensus on that issue. Upon completion of this task, we then move on to deal with another core issue in the same way. We propose as the next project a process that might lead quickly to a strong consensus that the term "statistically significant" and all its cognates and symbolic adjuncts be disallowed in the scientific literature except where focus is on the history of statistics and its philosophies and methodologies. Calculation and presentation of accurate p-values will often remain highly desirable though not obligatory.
Supplementary materials
for this article are available online in the form of an appendix listing the names and institutions of 48 other statisticians and scientists who endorse the principal propositions put forward here.
Rheumatoid arthritis (RA) is a heterogeneous, prevalent, chronic autoimmune disease characterized by painful swollen joints and significant disabilities. Symptomatic relief can be achieved in up to ...50% of patients using biological agents that inhibit tumor necrosis factor (TNF) or other mechanisms of action, but there are no universally effective therapies. Recent advances in basic and preclinical science reveal that reflex neural circuits inhibit the production of cytokines and inflammation in animal models. One well-characterized cytokine-inhibiting mechanism, termed the “inflammatory reflex,” is dependent upon vagus nerve signals that inhibit cytokine production and attenuate experimental arthritis severity in mice and rats. It previously was unknown whether directly stimulating the inflammatory reflex in humans inhibits TNF production. Here we show that an implantable vagus nerve-stimulating device in epilepsy patients inhibits peripheral blood production of TNF, IL-1β, and IL-6. Vagus nerve stimulation (up to four times daily) in RA patients significantly inhibited TNF production for up to 84 d. Moreover, RA disease severity, as measured by standardized clinical composite scores, improved significantly. Together, these results establish that vagus nerve stimulation targeting the inflammatory reflex modulates TNF production and reduces inflammation in humans. These findings suggest that it is possible to use mechanism-based neuromodulating devices in the experimental therapy of RA and possibly other autoimmune and autoinflammatory diseases.
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a highly aggressive monogenic cancer driven by SMARCA4 mutations. Here, we report responses to anti-PD1 immunotherapy in four ...patients and characterize the immune landscape of SCCOHT tumors using quantitative immunofluorescence and gene expression profiling. Unexpectedly for a low mutation burden cancer, the majority of the tumors (eight of 11 cases) demonstrated PD-L1 expression with strong associated T-cell infiltration (R2 = 0.60-0.95). PD-L1 expression was detected in both tumor and stromal cells, with macrophages being the most abundant PD-L1-positive cells in some tumors (three of 11 cases). Transcriptional profiling revealed increased expression of genes related to Th1 and cytotoxic cell function in PD-L1-high tumors, suggesting that PD-L1 acts as a pathway of adaptive immune resistance in SCCOHT. These findings suggest that although SCCOHT are low-mutational burden tumors, their immunogenic microenvironment resembles the landscape of tumors that respond well to treatment with PD-1/PD-L1 blockade.
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