Abstract
This work emphasizes the effect of the physical activation using CO
2
and steam agents on the physicochemical properties of activated carbon produced from
Dicranopteris linearis
(
D. ...linearis
), a fern species widely distributed across tropic and subtropic ecoregions. The
D. linearis
-derived chars produced under pyrolysis at 400 °C for 1 h were activated in various CO
2
-steam proportions. As revealed by the IR and Raman spectra, the structure of the activated chars was heavily dependent on the relative proportion of CO
2
and steam. The total specific surface area (SSA) of the activated chars proportionally increased with the increase in steam proportion and was comparable to the values of commercial activated char products. Specifically, the activation under CO
2
−
and steam-saturated conditions has correspondingly resulted in SSA increasing from 89 to 653 m
2
g
−1
and from 89 to 1015 m
2
g
−1
. Steam also enhanced the development of mesoporous structures of the
D. linearis
-derived char products, thereby extending their potential applications, particularly for industries that require high rigidity in the product such as pharmaceutical and cosmetic sectors.
Risk-reducing salpingo-oophorectomy (RRSO) lowers mortality from ovarian/tubal and breast cancers among BRCA1/2 mutation carriers. Uncertainties persist regarding potential benefits of RRSO among ...high-risk noncarriers, optimal surgical age, and anatomic origin of clinically occult cancers detected at surgery. To address these topics, we analyzed surgical treatment arm results from Gynecologic Oncology Group Protocol-0199 (GOG-0199), the National Ovarian Cancer Prevention and Early Detection Study.
This analysis included asymptomatic high-risk women age ≥ 30 years who elected RRSO at enrollment. Women provided risk factor data and underwent preoperative cancer antigen 125 (CA-125) serum testing and transvaginal ultrasound (TVU). RRSO specimens were processed according to a standardized tissue processing protocol and underwent central pathology panel review. Research-based BRCA1/2 mutation testing was performed when a participant's mutation status was unknown at enrollment. Relationships between participant characteristics and diagnostic findings were assessed using univariable statistics and multivariable logistic regression.
Invasive or intraepithelial ovarian/tubal/peritoneal neoplasms were detected in 25 (2.6%) of 966 RRSOs (BRCA1 mutation carriers, 4.6%; BRCA2 carriers, 3.5%; and noncarriers, 0.5%; P < .001). In multivariable models, positive BRCA1/2 mutation status (P = .0056), postmenopausal status (P = .0023), and abnormal CA-125 levels and/or TVU examinations (P < .001) were associated with detection of clinically occult neoplasms at RRSO. For 387 women with negative BRCA1/2 mutation testing and normal CA-125 levels, findings at RRSO were benign.
Clinically occult cancer was detected among 2.6% of high-risk women undergoing RRSO. BRCA1/2 mutation, postmenopausal status, and abnormal preoperative CA-125 and/or TVU were associated with cancer detection at RRSO. These data can inform management decisions among women at high risk of ovarian/tubal cancer.
Genetic testing for several cancer susceptibility syndromes is clinically available; however, existing data suggest limited population awareness of such tests.
To examine awareness regarding cancer ...genetic testing in the U.S. population aged ≥25 years in the 2000, 2005, and 2010 National Health Interview Surveys.
The weighted percentages of respondents aware of cancer genetic tests, and percent changes from 2000-2005 and 2005-2010, overall and by demographic, family history, and healthcare factors were calculated. Interactions were used to evaluate the patterns of change in awareness between 2005 and 2010 among subgroups within each factor. To evaluate associations with awareness in 2005 and 2010, percentages were adjusted for covariates using multiple logistic regression. The analysis was performed in 2012.
Awareness decreased from 44.4% to 41.5% (p<0.001) between 2000 and 2005, and increased to 47.0% (p<0.001) in 2010. Awareness increased between 2005 and 2010 in most subgroups, particularly among individuals in the South (pinteraction=0.03) or with a usual place of care (pinteraction=0.01). In 2005 and 2010, awareness was positively associated with personal or family cancer history and high perceived cancer risk, and inversely associated with racial/ethnic minorities, age 25-39 or ≥60 years, male gender, lower education and income levels, public or no health insurance, and no provider contact in 12 months.
Despite improvement from 2005 to 2010, ≤50% of the U.S. adult population was aware of cancer genetic testing in 2010. Notably, disparities persist for racial/ethnic minorities and individuals with limited health care access or income.
Li-Fraumeni syndrome, caused primarily by pathogenic or likely pathogenic germline TP53 variants, is a rare, variably penetrant, cancer predisposition syndrome with very high risks of cancer starting ...in childhood, including the risk of multiple primary malignancies over an individual's lifespan. We aimed to characterise and quantify cancer incidence, patterns, and genotype–phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants.
This observational cohort study was done in 480 carriers of pathogenic or likely pathogenic germline TP53 variants enrolled in the National Cancer Institute's referral-based longitudinal Li-Fraumeni syndrome study between Aug 1, 2011, and March 24, 2020. Data on personal and family history of cancer were obtained through study questionnaires and validated by medical records. Variants were categorised on the basis of both loss-of-function (LOF) and dominant-negative effect (DNE) properties. Cancer incidence associated with Li-Fraumeni syndrome was compared with that of the general population using the Surveillance, Epidemiology, and End Results (SEER) 1975–2017 registry. Cancer incidence was evaluated with family-clustered Cox regression models and competing risk methods. This study is registered with ClinicalTrials.gov, NCT01443468.
Individuals with Li-Fraumeni syndrome had a nearly 24 times higher incidence of any cancer than the general population (standardised incidence ratio 23·9; 95% CI 21·9–26·0), with the highest comparative incidence from childhood to 30 years of age. The overall cancer incidence remained 10·3 (95% CI 7·9–13·2) times higher than that of the general population after age 50 years. In women, when considering breast cancer as a competing risk, the probability of a first diagnosis of a non-breast cancer malignancy was substantially lower than that of any first cancer (24·4% 95% CI 19·6–30·5 vs 50·4% 43·5–56·5 by age 33·7 years). Overall, DNE_LOF and notDNE_LOF variants were associated with earlier age at first and second cancer compared with notDNE_notLOF and DNE_notLOF variants. The time interval from first to second cancer was shorter among carriers whose first cancer diagnoses were later in life. Multiple cancers were diagnosed within a short timeframe in some individuals, regardless of the order of cancer occurrence.
This study adds granularity to the understanding of cancer incidence and patterns in individuals with pathogenic or likely pathogenic germline TP53 variants. Integration of age range-specific cancer incidence estimates, cancer-free survival by functional variant group, the potential impact of risk-reducing mastectomy on female cancer incidence, and data on subsequent malignancies will be important for the development of strategies to optimise cancer screening and management for these individuals.
Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Institutes of Health.
Variants of uncertain significance (VUS) are commonly identified in genetic testing. The rate at which a VUS is reclassified depends on multiple factors. However, as the amount of time it might take ...for a VUS to be reclassified varies, some patients with a VUS genetic testing result might have passed away before the VUS is reclassified. A VUS that is reclassified after the patient's death has clinical implications for the deceased patient's family members. The disclosure of reclassified VUS results for a deceased patient has complex legal and ethical implications. There are no established guidelines on how the reclassified VUS result for a deceased patient should be disclosed to at-risk relatives. An online survey was sent to members of the National Society of Genetic Counselors (NSGCs) to elicit practices and opinions regarding this issue. A total of 153 (4%) NSGC members completed the survey. Thirty-seven (24.2%) respondents reported having received a reclassified VUS for a deceased patient. Respondents were more likely to attempt disclosure if the variant was reclassified as pathogenic (93.5%) versus benign (76.5%), although the difference did not reach statistical significance (p = 0.06). Respondents more often reported the impact on family members (85.5%) than the decedent's right to privacy (15.0%) as extremely important when considering disclosure to family members. A legal mechanism to allow disclosure to relatives was supported by 70.6% of respondents and 97.4% felt the issue was important enough to pursue if such a process was in place. Only 9.8% of respondents supported a legal requirement of consent before disclosing to family members when a VUS is reclassified after the patient has passed away. Our results indicate that there is no consensus for how these results should be handled and a mechanism for disclosure of reclassified results to family members is supported.
CONTEXT Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2 -related EOC was ...associated with an improved prognosis, but the effect of BRCA1 remains unclear. OBJECTIVE To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. DESIGN, SETTING, AND PARTICIPANTS A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). MAIN OUTCOME MEASURE Five-year overall mortality. RESULTS The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio HR, 0.78; 95% CI, 0.68-0.89; P < .001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P < .001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P < .001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P < .001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity = .003). CONCLUSION Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis.
Gail and Mai discuss Amir et al's study reviewing models for estimating the probability of carrying a mutation in the Breast Cancer Risk Assessment (BRCA1 or BRCA2) genes and models for estimating ...the risk of developing breast cancer. The aim of the review was to distill the diverse literature and provide practicing clinicians with an overview of the available risk assessment methods. Arnir et al describe the risk factors that are used in various models for predicting breast cancer risk. Other differences among these models are also important.
Germline pathogenic variants in TP53 are associated with Li‐Fraumeni syndrome, a cancer predisposition disorder inherited in an autosomal dominant pattern associated with a high risk of malignancy, ...including early‐onset breast cancers, sarcomas, adrenocortical carcinomas, and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants is associated with reduced cancer‐related mortality. Accurate and consistent classification of germline variants across clinical and research laboratories is important to ensure appropriate cancer surveillance recommendations. Here, we describe the work performed by the Clinical Genome Resource TP53 Variant Curation Expert Panel (ClinGen TP53 VCEP) focused on specifying the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification to the TP53 gene. Specifications were developed for 20 ACMG/AMP criteria, while nine were deemed not applicable. The original strength level for the 10 criteria was also adjusted due to current evidence. Use of TP53‐specific guidelines and sharing of clinical data among experts and clinical laboratories led to a decrease in variants of uncertain significance from 28% to 12% compared with the original guidelines. The ClinGen TP53 VCEP recommends the use of these TP53‐specific ACMG/AMP guidelines as the standard strategy for TP53 germline variant classification.
Here, we detail the work of the ClinGen TP53 Variant Curation Expert Panel focused on adapting the ACMG/AMP variant curation guidelines to germline variants in TP53. The use of these guidelines and sharing of clinical data led to a reduction in the number of variants of uncertain significance. Moreover, the use of these guidelines is recommended as the standard strategy for TP53 variant classification.
The mechanisms through which the bone marrow (BM) microenvironment regulates hematopoietic stem cell (HSC) fate remain incompletely understood. We examined the role of the heparin-binding growth ...factor pleiotrophin (PTN) in regulating HSC function in the niche. PTN−/− mice displayed significantly decreased BM HSC content and impaired hematopoietic regeneration following myelosuppression. Conversely, mice lacking protein tyrosine phosphatase receptor zeta, which is inactivated by PTN, displayed significantly increased BM HSC content. Transplant studies revealed that PTN action was not HSC autonomous, but rather was mediated by the BM microenvironment. Interestingly, PTN was differentially expressed and secreted by BM sinusoidal endothelial cells within the vascular niche. Furthermore, systemic administration of anti-PTN antibody in mice substantially impaired both the homing of hematopoietic progenitor cells to the niche and the retention of BM HSCs in the niche. PTN is a secreted component of the BM vascular niche that regulates HSC self-renewal and retention in vivo.
Display omitted
► Pleiotrophin (PTN) regulates hematopoietic stem cell self-renewal in vivo ► Deletion of protein tyrosine phosphatase receptor zeta amplifies the hematopoietic stem cell pool ► PTN is expressed and secreted by bone marrow endothelial cells ► PTN regulates hematopoietic progenitor cell homing and retention
Much remains unknown regarding how the bone marrow (BM) microenvironment regulates hematopoietic stem cell (HSC) fate. Chute and colleagues demonstrate that BM endothelial cells secrete pleiotrophin (PTN), a heparin-binding growth factor, in the HSC niche. Mice lacking PTN contained decreased BM HSCs and a severe defect in hematopoietic regenerative capacity. Antibody blockade of PTN inhibited HSC homing to the niche and promoted HSC mobilization to the blood. Thus, PTN is a secreted component of the vascular niche that regulates HSC retention and self-renewal.
PDF
