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Abnormal expression of long non-coding RNAs (lncRNAs) is associated with the dysfunctions of human trophoblast cells and the occurrence of miscarriage (abnormal early embryo loss). BBC3/PUMA (BCL2 binding component 3) plays significant roles in regulation of cell apoptosis. However, whether specific lncRNAs might regulate BBC3 in trophoblast cells and further induce apoptosis and miscarriage remains completely unclear. Through screening, we identified a novel lnc-HZ12, which was significantly highly expressed in villous tissues of recurrent miscarriage (RM) patients relative to their healthy control (HC) group. Lnc-HZ12 suppressed chaperone-mediated autophagy (CMA) degradation of BBC3, promoted trophoblast cell apoptosis, and was associated with miscarriage. In mechanism, lnc-HZ12 downregulated the expression levels of chaperone molecules HSPA8 and LAMP2A in trophoblast cells. Meanwhile, lnc-HZ12 (mainly lnc-HZ12-SO2 region in F2 fragment) and HSPA8 competitively bound with the 169RVLYNL174 patch on BBC3, which prevented BBC3 from interactions with HSPA8 and impaired the formation of BBC3-HSPA8-LAMP2A complex for CMA degradation of BBC3. Thus, lnc-HZ12 upregulated the BBC3-CASP9-CASP3 pathway and induced trophoblast cell apoptosis. In villous tissues, lnc-HZ12 was highly expressed, CMA degradation of BBC3 was suppressed, and the apoptosis levels were higher in RM vs HC villous tissues, all of which were associated with miscarriage. Interestingly, knockdown of murine Bbc3 could efficiently suppress placental apoptosis and alleviate miscarriage in a mouse miscarriage model. Taken together, our results indicated that lnc-HZ12 and BBC3 played important roles in trophoblast cell apoptosis and miscarriage and might act as attractive targets for miscarriage treatment.Abbreviation: 7-AAD: 7-aminoactinomycin D; BaP: benzopyrene; BBC3/PUMA: BCL2 binding component 3; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; CMA: chaperone-mediated autophagy; CQ: chloroquine; DMSO: dimethyl sulfoxide; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HC: healthy control; HSPA8: heat shock protein family A (Hsp70) member 8; IP: immunoprecipitation; LAMP2A: lysosomal associated membrane protein 2; LncRNA: long non-coding RNA; mRNA: messenger RNA; MT: mutant-type; NC: negative control; NSO: nonspecific oligonucleotide; PARP1: poly(ADP-ribose) polymerase 1; RIP: RNA immunoprecipitation; RM: recurrent miscarriage; TBP: TATA-box binding protein; WT: wild-type. [ABSTRACT FROM AUTHOR]

Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) leads to dysfunctions of human trophoblast cells and further induces miscarriage. In our previous study, we have found that lnc-HZ03 and miR-hz03 are upregulated in BPDE-exposed human trophoblast cells and in recurrent miscarriage tissues; and the upregulated miR-hz03 caused by lnc-HZ03 further promotes the apoptosis of human trophoblast cells and induces miscarriage. However, how lnc-HZ03 upregulates miR-hz03 is completely unknown. In this study, we find that lnc-HZ03 upregulates the expression level of a transcription factor TFIID (a TATA-binding protein) and promotes TFIID-mediated transactivation response element RNA-binding protein (TRBP) transcription. Subsequently, the upregulated TRBP promotes the maturation of miR-hz03 by splicing its precursor pre-miR-hz03 in human trophoblast cells. In BPDE-exposed trophoblast cells or in recurrent miscarriage tissues, lnc-HZ03 was upregulated, which accelerates the TFIID-mediated TRBP transcription and thus promotes TRBP-mediated miR-HZ03 maturation. Subsequently, the upregulated miR-hz03 further promotes the apoptosis of human trophoblast cells and induces miscarriage. This work provides new insights into the regulation of miRNA expression levels by lncRNAs in BPDE-exposed human trophoblast cells. [ABSTRACT FROM AUTHOR]

Introduction: Encouraging family communication about possible genetic risk has become among the most important avenues for achieving the full potential of genomic discovery for primary and secondary prevention. Yet, effective family-wide risk communication (i.e., conveying genetic risk status and its meaning for other family members) remains a critical gap in the field. We aim to describe the iterative process of developing a scalable population-based communication outreach intervention, Your Family Connects, to reach ovarian cancer survivors and close relatives to communicate the potential for inherited risk and to consider genetic counseling. Methods: Relational-level theories (e.g., interdependence theory) suggest that interventions to promote family cancer risk communication will be most effective if they consider the qualities of specific relationships and activate motives to preserve the relationship. Informed by these theories, we collaborated with 14 citizen scientists (survivors of ovarian cancer or relatives) and collected 261 surveys and 39 structured interviews over 12 weeks of citizen science activities in 2020. Results: The citizen science findings and consideration of relational-level theories informed the content and implementation of Your Family Connects (www.yourfamilyconnects.org). CS results showed survivors favor personal contact with close relatives, but relatives were open to alternative contact methods, such as through health professionals. Recognizing the need for varied approaches based on relationship dynamics, we implemented a relative contact menu to enable survivors identify at-risk relatives and provide multiple contact options (i.e., survivor contact, health professional contact, and delayed contact). In line with relational autonomy principles, we included pros and cons for each option, assisting survivors in choosing suitable contact methods for each relative. Discussion: Our developed intervention represents a novel application of relational-level theories and partnership with citizen scientists to expand genetic services reach to increase the likelihood for fair distribution of cancer genomic advances. The Your Family Connects intervention as part of a randomized trial in collaboration with the Georgia Cancer Registry compared with standard outreach. [ABSTRACT FROM AUTHOR]

Background: Inherited risk is a family issue. Identifying family members who carry a pathogenic genetic variant that increases risk of cancers and other chronic diseases can be lifesaving for those affected.Objective: The research questions are: (1) which family communication frameworks have been applied, (2) how do intervention strategies employed map to these theories, and (3) to what extent were families receptive to these strategies and communication increased?Methods: Manuscripts published between January 2010 and August 2020 were searched in three databases: PubMed, PsycINFO, and Web of Science.Results: Nine intervention trials were identified. All interventions were evaluated in clinical genetic counseling contexts using at least one individual-level strategy (e.g. increase knowledge). Only three focused on dyadic conversations such as preparing for relatives' information needs.Conclusions: This systematic review posed the question whether theoretically based approaches have been applied to foster family genetic risk communication. Greater attention needs to be paid to the utilization of dyadic level and family system level theories to guide intervention developments.Practical Implications: We conclude by calling for accelerating and broadening the development of interventions to enable family communication about inherited risk that are theory-based, incorporate family-systems thinking, and are conducted outside of specialty clinic settings. [ABSTRACT FROM AUTHOR]

Purpose: In this brief report, we ask whether women's interpretation of breast cancer risk based on their low likelihood of carrying a BRCA1/2 mutation is associated with their information-sharing behavior, and whether misinterpretation is associated with motives for sharing the result. Methods: Women in mammography clinics who completed a brief family history assessment and deemed to be at low likelihood of carrying a BRCA1/2 mutation were asked to complete a 1-time online survey between June 2016 and January 2017. Results: One-third (44/148) of women shared their family history screen result with someone in their social network. Result information was shared largely with a first-degree female relative to express feelings of relief (77%, 33/43). There were no differences in likelihood of sharing based on breast cancer risk interpretation. However, women who misinterpreted the implications of the result for general breast cancer risk reported more motives to share the result with their social network than those who accurately interpreted their breast cancer risk. Conclusions: As family history-based screening for hereditary breast cancer is broadly implemented, the communication needs of the majority of women who will be unlikely of carrying a BRCA1/2 mutation must be considered. The motives of women who misinterpreted the implications of this result for breast cancer risk suggest the possibility that miscommunication could be spread to the broader family network. [ABSTRACT FROM AUTHOR]

• Beside the main phase of zincblende, a small amount of wurtzite is existed in CVD ZnS. • The mechanical properties of CVD ZnS were characterized with a slight variation of Zn/S ratio. • Zn 46.84 S 53.16 presents a high flexural strength of 133.8 MPa. • XRD, SEM, and Raman spectra of CVD ZnS were conducted. Polycrystalline ZnS samples with a slight composition fluctuation are grown by chemical vapor deposition (CVD) method, and their optical and mechanical properties and microstructure were investigated in detail. The CVD samples present a maximum transmittance of ∼73% in the 7–10 μm region. By changing the sulfur content, a maximum Knoop hardness of 2.375 GPa was found in the Zn 50.06 S 49.94 sample, while Zn 46.84 S 53.16 presents a high flexural strength of 133.8 MPa. The microstructural origin of this abnormal changing of mechanical properties was discussed according to the results of micrographs, XRD patterns and Raman spectra. The results suggest that beside the main phase of zincblende, a small amount of wurtzite is existed. This composited microstructure is responsible for the higher hardness and strength of CVD ZnS. [ABSTRACT FROM AUTHOR]

Effective communication of cancer-related genetic and genomic testing (CGT) with patients and the public is paramount to transforming and managing cancer prevention, detection, and care. Behavioral and social science theories could improve communication effectiveness and, in turn, health outcomes. In this study, we characterized the use of theory in recent research on communication about CGT from 2010 to 2017. Of 513 empirical papers focusing on communication about CGT, only 119 (23%) utilized any theory in the study design. Behavior change and health psychology/cognitive representation theories (24.2% and 21.9%, respectively) were the most commonly used with minimal use of communication theories (3%). Theories were primarily used to guide hypotheses or research question development (73.9%), and for selecting measures or codes (68.9%). Approximately half of the papers (48.3%) related their study findings to the referenced theory. Fewer papers (14.3%) discussed implications of the findings for the theory. While theories are being utilized to inform study design, few discuss their results in the context of theoretical implications and thus decrease potential generalizability. Greater use of theory could help scholars to identify and develop theories suited to this clinical context and inform our understanding of related communication processes more broadly. • Atheoretical approaches are more prominent in communication of CGT scholarship. • These approaches limit evidence-based policy, research foci, standards of care. • Theory-driven studies use theory for RQ development and measure selection. • Majority of studies did not discuss their results to cited theory nor implications. • More theory-driven studies are needed to enhance generalizability of findings. [ABSTRACT FROM AUTHOR]

Human trophoblast cells are crucial for healthy pregnancy. However, whether the defective homologous recombination (HR) repair of dsDNA break (DSB) in trophoblast cells may induce miscarriage is completely unknown. Moreover, the abundance of BRCA1 (a crucial protein for HR repair), its recruitment to DSB foci, and its epigenetic regulatory mechanisms, are also fully unexplored. In this work, it is identified that a novel lnc‐HZ10, which is highly experssed in villous tissues of recurrent miscarriage (RM) vs their healthy control group, suppresses HR repair of DSB in trophoblast cell. Lnc‐HZ10 and AhR (aryl hydrocarbon receptor) form a positive feedback loop. AhR acts as a transcription factor to promote lnc‐HZ10 transcription. Meanwhile, lnc‐HZ10 also increases AhR levels by suppressing its CUL4B‐mediated ubiquitination degradation. Subsequently, AhR suppresses BRCA1 transcription; and lnc‐HZ10 (mainly 1‐447 nt) interacts with γ‐H2AX; and thus, impairs its interactions with BRCA1. BPDE exposure may trigger this loop to suppress HR repair in trophoblast cells, possibly inducing miscarriage. Knockdown of murine Ahr efficiently recovers HR repair in placental tissues and alleviates miscarriage in a mouse miscarriage model. Therefore, it is suggested that AhR/lnc‐HZ10/BRCA1 axis may be a promising target for alleviation of unexplained miscarriage. [ABSTRACT FROM AUTHOR]

Citizen science (CS) approaches involving non-professional researchers (citizens) as research collaborators has been used infrequently in health promotion generally and specifically, in cancer prevention. Standardized CS approaches may be especially useful for developing communication interventions to encourage families to consider cancer genetic services. We engaged survivors of ovarian cancer and their close relatives as CS collaborators to collect and help interpret data to inform content for a website, printed invitation materials, and short-message reminders. We applied an implementation quality framework, and posed four research questions regarding the feasibility of CS: recruitment, data collection, data quality and evaluation of the experience. CS members were recruited through three networks: clinical sites, local and national cancer support organizations, and online ovarian cancer patient support groups. The professional research team operationalized theory-aligned CS tasks, five data collection options, question banks/scripts for creating surveys, structured interviews, online training and ongoing support from research coaches. 14 CS members agreed to the 12-week and 20-hour commitment for an honorarium. CS members opted to do both qualitative and quantitative assessments. CS members collected 261 surveys and 39 structured interviews. The largest number of surveys were collected for Task 1 (n = 102) to assess survivors' reactions to different possible options for motivating survivors to visit a study website; 77% of this data were complete (i.e., no missing values). Data collected for tasks 2, 3, 4, and 5 (e.g., assessment of survivors' and relatives' respective communication preferences) ranged from 10 to 58 surveys (80% to 84% completeness). All data were collected within the specified time frame. CSs reported 17 hours of work on average and regarded the experience positively. Our experience suggests that CS engagement is feasible, can yield comprehensive quantitative and qualitative data, and is achievable in a relatively a short timeline. [ABSTRACT FROM AUTHOR]

Earthworms may influence soil N 2 O emissions by stimulating free-living denitrifiers due to the restructuring of the soil environment, and by inoculating gut-stimulated denitrifying bacteria during the excretion process. However, the relative importance of each effect on soil N 2 O emissions is still not clear. To determine the differences in earthworm ( Eisenia fetida )-induced N 2 O emissions, sterilized (from which the impacts of indigenous soil microbes are limited) and unsterilized soils were used in the 30-days microcosm experiment. Earthworm inoculation improved soil ammonium ( N H 4 + –N ) , nitrate ( N O 3 − –N ) and dissolved organic carbon (DOC) concentrations in both soils. Soil N 2 O emission also increased with the addition of earthworms, but the significant difference on cumulative N 2 O emissions were only detected in the sterilized soil (362.22 and 645.86 μg N 2 O–N kg −1 dry soil with and without earthworm inoculation, respectively). Redundancy analysis indicated that the earthworm inoculation changed the soil microbial community structure in both soils. The relative density of nirS genes was significantly increased due to earthworm inoculation in sterilized soil, but no obvious difference was detected in the unsterilized soil. In conclusion, by changing the soil bacterial community via gut-stimulated denitrifiers, earthworms may increase N 2 O emissions in the sterilized soil, while this effect may be diminished by competition with indigenous soil microorganisms in unsterilized soil. [ABSTRACT FROM AUTHOR]

BPDE up-regulates lnc-HZ11, which down-regulates EGR1/NF-κB/CXCL12 pathway and suppresses trophoblast cell migration/invasion at intracellular levels. BPDE promotes donor trophoblast cells to secrete more EV-HZ11, which suppresses migration/invasion of the recipient trophoblast cells at intercellular levels, and is associated with unexplained miscarriage. Knockdown of murine lnc-Hz11 by EV-AS-Hz11 could efficiently alleviate miscarriage in BaP-exposed mice. The levels of EV-HZ11 in serum could predict the risk of miscarriage. [Display omitted] • BPDE up-regulates lnc-HZ11, which suppresses EGR1/NF-κB/CXCL12 and migration/invasion of trophoblast cells. • BPDE or lnc-HZ11 promotes trophoblast cells to secrete more EV-HZ11. • EV-HZ11 is transferred from donor cells to recipient cells and suppresses their migration/invasion. • Lnc-HZ11 and EV-HZ11 are closely associated with miscarriage. • Knockdown of murine lnc-Hz11 recovers migration/invasion and alleviates mouse miscarriage. • EV-HZ11 in serum predicts miscarriage risk. Extracellular vesicles (EVs) mediate the intercellular crosstalk by transferring functional cargoes. Recently, we have discovered that BaP/BPDE exposure suppresses trophoblast cell migration/invasion and induces miscarriage, which are also regulate by lncRNAs at intracelluar levels. However, the EVs-mediated intercellular regulatory mechanisms are completely unexplored. Specifically, whether EVs might transfer BPDE-induced toxic lncRNA to fresh recipient trophoblast cells and suppress their migration/invasion to further induce miscarriage is completely unknown. In this study, we find that BPDE exposure up-regulates a novel lnc-HZ11, which suppresses EGR1/NF-κB/CXCL12 pathway and migration/invasion of trophoblast cells. Intercellular studies show that EV-HZ11 (lnc-HZ11 in EVs), which is highly expressed in BPDE-exposed donor cells, suppresses EGR1/NF-κB/CXCL12 pathway and migration/invasion in recipient cells by transferring lnc-HZ11 through EVs. Analysis of villous tissues collected from UM (unexplained miscarriage) patients and HC (healthy control) group shows that the levels of BPDE-DNA adducts, lnc-HZ11 or EV-lnc-HZ11, and EGR1/NF-κB/CXCL12 pathway are all associated with miscarriage. Mouse assays show that BaP exposure up-regulates the levels of lnc-Hz11 or EV-Hz11, suppresses Egr1/Nf-κb/Cxcl12 pathway, and eventually induces miscarriage. Knockdown of lnc-Hz11 by injecting EV-AS-Hz11 could effectively alleviate miscarriage in BaP-exposed mice. Furthermore, EV-HZ11 in serum samples could well predict the risk of miscarriage. Collectively, this study not only discovers EVs-HZ11-mediated intercellular mechanisms that BaP/BPDE suppresses trophoblast cell migration/invasion and induces miscarriage but also provides new approach for treatment against unexplained miscarriage through EV-HZ11. [ABSTRACT FROM AUTHOR]

Dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) are two typical non-volatile disinfection by-products (DBPs) found in drinking water. Increasing evidence has demonstrated that they show reproductive toxicity. However, whether they might have endocrine disrupting properties remains largely unknown. To discover this, we treated male mice or pregnant mice with 0, 1-, 102-, 103-, 104-, or 5 × 104-fold maximal concentration level (MCL) of DCAA or TCAA in drinking water. In male mice, the levels of testosterone in serum and androgen receptor (AR) in testis were declined with ≥ 103-fold MCL of DCAA (26.4 mg/kg/d) or TCAA (52.7 mg/kg/d). In pregnant mice, miscarriage rates were increased with ≥ 104-fold MCL of DCAA (264 mg/kg/d) or ≥ 103-fold MCL of TCAA. The levels of FSH in serum were increased and those of estradiol and progesterone were reduced with ≥ 103-fold MCL of DCAA or TCAA. The protein levels of estrogen receptors (ERα and ERβ) in ovary were reduced with ≥ 102-fold MCL of DCAA (2.64 mg/kg/d) or TCAA (5.27 mg/kg/d). Exposure to some certain fold MCL of DCAA or TCAA also altered the protein levels of ERα and ERβ in uterus and placenta. Exposure to 5 × 104-fold MCL of both DCAA and TCAA showed the combined effects. Therefore, both DCAA and TCAA could be considered as novel reproductive endocrine disrupting chemicals, which might be helpful for further assessment of the toxicological effects of DCAA and TCAA and the awareness of reproductive endocrine disrupting properties caused by DCAA and TCAA in drinking water. [Display omitted] • DCAA and TCAA function as endocrine-disrupting chemicals. • DCAA and TCAA reduce the levels of testosterone in serum and androgen receptor (AR) in testis of male mice. • DCAA and TCAA induce pregnant mouse miscarriage. • DCAA and TCAA increase follicle stimulating hormone levels and reduce estradiol and progesterone levels in serum of pregnant mice. • DCAA and TCAA reduce the levels of estrogen receptors (ERα and ERβ) in ovaries, uterus, and placenta of pregnant mice. [ABSTRACT FROM AUTHOR]

Normal pregnancy is essential for human reproduction. However, BaP (benzo(a)pyrene) and its metabolite BPDE (benzo(a)pyrene‐7,8‐dihydrodiol‐9,10‐epoxide) could cause dysfunctions of human trophoblast cells and might further induce miscarriage. Yet, the underlying mechanisms remain largely unknown. Herein, we identified a novel upregulated lnc‐HZ04 and a novel downregulated miR‐hz04 in villous tissues of unexplained recurrent miscarriage (RM) relative to those in healthy control tissues and also in BPDE‐treated human trophoblast cells. Lnc‐HZ04 directly and specifically bound with miR‐hz04, diminished the reduction effects of miR‐hz04 on IP3R1 mRNA expression level and on IP3R1 mRNA stability, and then activated the Ca2+‐mediated IP3R1/p‐CaMKII/SGCB pathway, which further promoted trophoblast cell apoptosis. The miR‐hz04 target site on lnc‐HZ04 played crucial roles in these regulations. In normal trophoblast, relatively less lnc‐HZ04 and more miR‐hz04 suppressed this apoptosis pathway and gave normal pregnancy. After exposure to BPDE or in RM tissues, p53 was upregulated, which might promote p53‐mediated lnc‐HZ04 transcription. Relatively more lnc‐HZ04 and less miR‐hz04 activated this apoptosis pathway and might further induce miscarriage. BaP could also induce mice miscarriage by upregulating its corresponding murine apoptosis pathway. Therefore, BPDE‐induced apoptosis of human trophoblast cells was associated with the occurrence of miscarriage. This work discovered the regulation roles of lnc‐HZ04 and miR‐hz04 and provided scientific and clinical understanding of the occurrence of unexplained miscarriage. [ABSTRACT FROM AUTHOR]

PURPOSE: National Comprehensive Cancer Network guidelines for germline genetic testing have included pancreatic cancer in the context of additional family cancer history for many years but this was not recommended for patients with pancreatic ductal adenocarcinoma (PDAC) independent of a family history until 2019. This hypothesis-generating study reports the results from multigene panel testing for PDAC patients at an academic medical center. PATIENTS AND METHODS: This prospective longitudinal feasibility study examined responses to genetic counseling and multigene panel testing among PDAC and breast or ovarian cancer (BrOv) patients between October 2016 and November 2017. Pre- and post-test surveys assessed perceptions of genetic risk and testing, recall, comprehension, and emotional reactions to results using open-ended and closed-ended items. RESULTS: Forty-six BrOv and 33 PDAC patients were enrolled, and 44 BrOv and 31 PDAC participants underwent genetic testing. Seven pathogenic variants were identified in six BrOv participants (13.6%), and three pathogenic variants were identified in three PDAC participants (9.7%). The majority of both cohorts expressed similar attitudes about the importance of genetic testing for their personal and family medical management and expressed accurate understanding of implications of their results. Although sample size was small, there were no significant differences between the BrOv and PDAC cohorts for positive or negative emotions. CONCLUSION: This study points to high rates of positive emotions and low rates of negative emotions following genetic test results, suggesting that the emotional reactions to genetic test results are similar for patients with BrOv and PDAC, despite poor prognosis with PDAC diagnoses. Because of the unique needs of the PDAC population following diagnosis, a multidisciplinary approach to germline genetic testing following diagnosis may result in best patient and family member outcomes. [ABSTRACT FROM AUTHOR]

Context: This systematic review aims to (1) characterize strategies used to identify individuals at increased risk for hereditary breast and ovarian cancer syndrome and Lynch syndrome outside of oncology and clinical genetic settings, (2) describe the extent to which these strategies have extended the reach of genetic services to underserved target populations, and (3) summarize indicators of the potential scalability of these strategies.Evidence Acquisition: Investigators searched PubMed, EMBASE, and PsycINFO for manuscripts published from October 2005 to August 2019. Eligible manuscripts were those published in English, those that described strategies to identify those at risk for hereditary breast and ovarian cancer syndrome or Lynch syndrome, those implemented outside of an oncology or genetic specialty clinic, and those that included measures of cancer genetic services uptake. This study assessed strategies used to increase the reach of genetic risk screening and counseling services. Each study was evaluated using the 16-item quality assessment tool, and results were reported according to the PRISMA guidelines.Evidence Synthesis: Of the 16 eligible studies, 11 were conducted in clinical settings and 5 in public health settings. Regardless of setting, most (63%, 10/16) used brief screening tools to identify people with a family history suggestive of hereditary breast and ovarian cancer syndrome or Lynch syndrome. When reported, genetic risk screening reach (range =11%-100%) and genetic counseling reach (range =11%-100%) varied widely across studies. Strategies implemented in public health settings appeared to be more successful (median counseling reach=65%) than those implemented in clinical settings (median counseling reach=26%). Most studies did not describe fundamental components relevant for broad scalability.Conclusions: Efforts to expand cancer genomic services are limited outside of traditional oncology and genetic clinics. This is a missed opportunity because evidence thus far suggests that these efforts can be successful in expanding the reach of genetic services with the potential to reduce health inequities in access. This review highlights the need for accelerating research that applies evidence-based implementation strategies and frameworks along with process evaluation to understand barriers and facilitators to scalability of strategies with high reach. [ABSTRACT FROM AUTHOR]

PURPOSE: National Comprehensive Cancer Network guidelines for germline genetic testing have included pancreatic cancer in the context of additional family cancer history for many years but this was not recommended for patients with pancreatic ductal adenocarcinoma (PDAC) independent of a family history until 2019. This hypothesis-generating study reports the results from multigene panel testing for PDAC patients at an academic medical center. PATIENTS AND METHODS: This prospective longitudinal feasibility study examined responses to genetic counseling and multigene panel testing among PDAC and breast or ovarian cancer (BrOv) patients between October 2016 and November 2017. Pre- and post-test surveys assessed perceptions of genetic risk and testing, recall, comprehension, and emotional reactions to results using open-ended and closed-ended items. RESULTS: Forty-six BrOv and 33 PDAC patients were enrolled, and 44 BrOv and 31 PDAC participants underwent genetic testing. Seven pathogenic variants were identified in six BrOv participants (13.6%), and three pathogenic variants were identified in three PDAC participants (9.7%). The majority of both cohorts expressed similar attitudes about the importance of genetic testing for their personal and family medical management and expressed accurate understanding of implications of their results. Although sample size was small, there were no significant differences between the BrOv and PDAC cohorts for positive or negative emotions. CONCLUSION: This study points to high rates of positive emotions and low rates of negative emotions following genetic test results, suggesting that the emotional reactions to genetic test results are similar for patients with BrOv and PDAC, despite poor prognosis with PDAC diagnoses. Because of the unique needs of the PDAC population following diagnosis, a multidisciplinary approach to germline genetic testing following diagnosis may result in best patient and family member outcomes. [ABSTRACT FROM AUTHOR]

BaP/BPDE exposure up-regulated free Fe2+ level and accelerated lipid peroxidation. Meanwhile, BaP/BPDE exposure also up-regulated MARCHF1 protein level, promoted its mediated ubiquitination degradation of GPX4, and hence decreased GPX4 protein level. Both pathways led to ferroptosis and further suppressed angiogenesis, which possibly induced miscarriage. Supplement with Gpx4 could efficiently suppress ferroptosis and recover angiogenesis in BPDE-exposed HUVECs and also alleviate miscarriage in BaP-exposed mouse miscarriage model. This study discovered novel toxicological effects and their underlying mechanisms that BaP/BPDE exposure induced ferroptosis, suppressed angiogenesis, and eventually induced miscarriage, as well as provided a promising approach to predict and treat against miscarriage. [Display omitted] • BPDE promoted HUVEC ferroptosis and suppressed angiogenesis by down-regulating GPX4 level. • BPDE promoted MARCHF1-mediated ubiquitination degradation of GPX4. • High level of BPDE-DNA adduct, ferroptosis, and defective angiogenesis in decidual tissues were associated with miscarriage. • Supplement with GPX4 suppressed ferroptosis, recovered angiogenesis, and alleviated miscarriage in BaP-exposed mouse model. • The levels of free Fe2+ and VEGFA in serum might reflect the risk of miscarriage. Environmental benzo(a)pyrene (BaP) and its ultimate metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) are universal and inevitable persistent organic pollutants and endocrine disrupting chemicals. Angiogenesis in placental decidua plays a pivotal role in healthy pregnancy. Ferroptosis is a newly identified and iron-dependent cell death mode. However, till now, BaP/BPDE exposure, ferroptosis, defective angiogenesis, and miscarriage have never been correlated; and their regulatory mechanisms have been rarely explored. In this study, we used assays with BPDE-exposed HUVECs (human umbilical vein endothelial cells), decidual tissues and serum samples collected from unexplained recurrent miscarriage and their matched healthy control groups, and placental tissues of BaP-exposed mouse miscarriage model. We found that BaP/BPDE exposure caused ferroptosis and then directly suppressed angiogenesis and eventually induced miscarriage. In mechanism, BaP/BPDE exposure up-regulated free Fe2+ level and promoted lipid peroxidation and also up-regulated MARCHF1 (a novel E3 ligase of GPX4) level to promote the ubiquitination degradation of GPX4, both of which resulted in HUVEC ferroptosis. Furthermore, we also found that GPX4 protein down-regulated the protein levels of VEGFA and ANG-1, two key proteins function for angiogenesis, and thus suppressed HUVEC angiogenesis. In turn, supplement with GPX4 could suppress ferroptosis, recover angiogenesis, and alleviate miscarriage. Moreover, the levels of free Fe2+ and VEGFA in serum might predict the risk of miscarriage. Overall, this study uncovered the crosstalk among BaP/BPDE exposure, ferroptosis, angiogenesis, and miscarriage, discovering novel toxicological effects of BaP/BPDE on human reproductive health. This study also warned the public to avoid exposure to polycyclic aromatic hydrocarbons during pregnancy to effectively prevent adverse pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Environmental Benzo(a)pyrene (BaP) and its ultimate metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) are typical persistent organic pollutants and endocrine disrupting chemicals. BaP/BPDE exposure might cause human trophoblast cell dysfunctions and induce miscarriage. However, the underlying mechanisms remain largely elusive. In this study, we found that BPDE exposure induced human trophoblast cell pyroptosis by up-regulating NLRP3/Caspase1/GSDMD pathway. We also identified that lnc-HZ14 was highly expressed in BPDE-exposed trophoblast cells and in recurrent miscarriage (RM) vs healthy control (HC) villous tissues. Lnc-HZ14 promoted trophoblast cell pyroptosis by promoting IRF1-mediated ZBP1 transcription, increasing METTL3-mediated m6A methylation on NLRP3 mRNA and its stability, and also enhancing ZBP1/NLRP3 protein interactions. Knockdown of lnc-HZ14/ZBP1/NLRP3 axis could efficiently alleviate BPDE-induced trophoblast cell pyroptosis. Higher level of pyroptosis, as indicated by the up-regulation of lnc-HZ14/ZBP1/NLRP3 axis, was found in RM vs HC villous tissues. In BaP-exposed mouse model, BaP exposure induced placental tissue pyroptosis and miscarriage by up-regulating murine Zbp1/Nlrp3 axis, and knockdown of Nlrp3 could efficiently reduce placenta pyroptosis and alleviate BaP-induced mouse miscarriage. Serum IL-1β protein level might act as a promising indicator to predict the risk of miscarriage. These findings provided new insights into BaP/BPDE-induced trophoblast cell pyroptosis and miscarriage and might be helpful for further assessment of the toxicological effects of BaP/BPDE on the female reproduction. [Display omitted] • BPDE induced trophoblast pyroptosis by up-regulating lnc-HZ14/ZBP1/NLRP3 axis. • Lnc-HZ14 promoted ZBP1 transcription, increased NLRP3 mRNA stability, and enhanced ZBP1/NLRP3 interactions. • Higher level of pyroptosis was found in RM vs HC villous tissues. • BaP induced murine placenta pyroptosis and mouse miscarriage via Zbp1/Nlrp3 axis. • IL-1β protein level in serum might predict the risk of miscarriage [ABSTRACT FROM AUTHOR]

Winter-flooded paddy is a typical rice-based cropping system to conserve water for the next rice growing season. Conversion of winter-flooded paddy to rice-wheat rotation has been widely adopted with the development of the water conservation infrastructure and the government's encouragement of winter agriculture in China in recent decades. However, the effects of this conversion on N 2 O emission are still not clear. Three winter-flooded paddy fields were studied in a split-plot design. One-half of each field was converted to rice-wheat rotation (RW), and the other half remained winter-flooded as rice-fallow (RF). Each plot of RW and RF was further divided into four subplots: three subplots for conventional N fertilizer application (RW-N C and RF-N C ) and one for unfertilized treatment (RW-N 0 and RF-N 0 ). Conversion of RF-N C to RW-N C increased the N 2 O emission up to 6.6-fold in the first year and 4.4-fold in the second year. Moreover, N 2 O emissions for the entire wheat season were 1.74–3.74 kg N ha −1 and 0.24–0.31 kg N ha −1 from RW-N C and RW-N 0 , respectively, and accounted for 78%–94% and 78%–97% of the total annual amount. N 2 O emitted during the first 11–21 days of the wheat season from RW-N C was 1.48–3.28 kg N ha −1 and that from RW-N 0 was 0.14–0.17 kg N ha −1 , which contributed to 66%–82% and 45%–71% of the total annual amount, respectively. High N 2 O fluxes occurred when the soil water-filled pore space (WFPS) was in the range of 68%–72% and the ratio of available carbon to nitrogen in the soil was <1.42. The contribution of WFPS and dissolved organic carbon (DOC) explained most of the variation of the N 2 O fluxes compared with the other measured environmental and soil factors. These findings suggest that the conversion of winter-flooded paddy to rice-wheat rotation increased N 2 O emissions that could be mitigated by controlling the soil moisture and ratio of available soil carbon to nitrogen. [ABSTRACT FROM AUTHOR]

The conversion from rice to vegetable production widely occurs in China. However, the effects of this conversion on N 2 O emission and the underlying mechanisms are not well understood. In the present study, 12 rice paddies (R) were selected and half of them converted to vegetable fields (V) with the following treatments: rice paddies without N-fertilizer (R-CK), rice paddies with conventional N-fertilizer (R-CN), converted vegetable fields without N-fertilizer (V-CK), and converted vegetable fields with conventional N-fertilizer (V-CN) in a randomized block design with 3 replicates. N 2 O emissions were measured with static chambers from December 2012 to December 2015. Within each V-CN plot, a root exclusion subplot was established to measure soil heterotrophic respiration (CO 2 effluxes), a proxy for soil organic matter mineralization. Conversion of rice paddies to vegetable production dramatically increased N 2 O emissions. The three-year cumulative N 2 O emissions were 0.59, 1.90, 55.50 and 160.14 kg N ha − 1 for R-CK, R-CN, V-CK and V-CN, respectively. The annual N 2 O emissions from vegetable fields ranged between 5.99 and 113.45 kg N ha − 1 yr − 1 , with substantially higher emissions in the first year. N 2 O fluxes from V-CN were significantly and positively related to CO 2 fluxes and inorganic N concentrations. The linear relationship between natural logarithms of N 2 O and CO 2 fluxes was stronger and the regression coefficient higher in the first year, showing the dependence of N 2 O on soil organic matter mineralization. These results suggest that soil organic matter and N mineralization contributes significantly to N 2 O emission following conversion of rice paddies to vegetable production. [ABSTRACT FROM AUTHOR]