Blocking Oncostatin M receptor abrogates STAT3 mediated integrin signaling and overcomes chemoresistance in ovarian cancer.

Chemotherapy such as cisplatin is widely used to treat ovarian cancer either before or after surgical debulking. However, cancer relapse due to chemotherapy resistance is a major challenge in the treatment of ovarian cancer. The underlying mechanisms related to chemotherapy resistance remain largely unclear. Therefore, identification of effective therapeutic strategies is urgently needed to overcome therapy resistance. Transcriptome-based analysis, in vitro studies and functional assays identified that cisplatin-resistant ovarian cancer cells express high levels of OSMR compared to cisplatin sensitive cells. Furthermore, OSMR expression associated with a module of integrin family genes and predominantly linked with integrin αV (ITGAV) and integrin ß3 (ITGB3) for cisplatin resistance. Using ectopic expression and knockdown approaches, we proved that OSMR directly regulates ITGAV and ITGB3 gene expression through STAT3 activation. Notably, targeting OSMR using anti-OSMR human antibody inhibited the growth and metastasis of ovarian cancer cells and sensitized cisplatin treatment. Taken together, our results underscore the pivotal role of OSMR as a requirement for cisplatin resistance in ovarian cancer. Notably, OSMR fostered the expression of a distinct set of integrin genes, which in turn resulted into a crosstalk between OSMR and integrins for signaling activation that is critical for cisplatin resistance. Therefore, targeting OSMR emerges as a promising and viable strategy to reverse cisplatin-resistance in ovarian cancer.

The association of obesity with post-cesarean inpatient opioid consumption.

BACKGROUND: Obesity and prescription opioid misuse are important public health concerns in the United States. A common intersection occurs when women with obesity undergo cesarean birth and receive narcotic medications for postpartum pain. OBJECTIVE: To examine the association between obesity and inpatient opioid use after cesarean birth. METHODS: A retrospective cohort study of patients that underwent cesarean birth in 2015-2018. Primary outcome was post-cesarean delivery opioid consumption starting 24 h after delivery measured as morphine milliequivalents per hour (MME/h). Secondary outcome was MME/h consumption in the highest quartile of all subjects. Opioid consumption was compared between three BMI groups: non-obese BMI 18.5-29.9 kg/m2; obese BMI 30.0-39.9 kg/m2; and morbidly obese BMI ≥ 40.0 kg/m2 using univariable and multivariable analyses. RESULTS: Of 1620 patients meeting inclusion criteria, 496 (30.6%) were in the non-obese group, 753 (46.5%) were in the obese group, and 371 (22.9%) were in the morbidly obese group. In the univariate analysis, patients with obesity and morbid obesity required higher MME/h than patients in the non-obese group [1.3 MME/h (IQR 0.1, 2.4) vs. 1.6 MME/h (IQR 0.5, 2.8) vs. 1.8 MME/h (IQR 0.8, 2.9), for non-obese, obese, and morbidly obese groups respectively, p < 0.001]. In the multivariable analysis, this association did not persist. In contrast, subjects in the obese and morbidly obese groups were more likely to be in the highest quartile of MME/h opioid consumption compared with those in the non-obese group (23.5% vs. 48.1% vs. 28.4%, p < 0.001, respectively); with aOR 1.42 (95% CI 1.07-1.89, p = 0.016) and aOR 1.60 (95% CI 1.16-2.22, p = 0.005) for patients with obesity and morbid obesity, respectively. CONCLUSION: Maternal obesity was not associated with higher hourly MME consumption during inpatient stay after cesarean birth. However, patients with obesity and morbid obesity were significantly more likely to be in the top quartile of MME hourly consumption.

Needle biopsy accelerates pro-metastatic changes and systemic dissemination in breast cancer: Implications for mortality by surgery delay.

Increased breast cancer (BC) mortality risk posed by delayed surgical resection of tumor after diagnosis is a growing concern, yet the underlying mechanisms remain unknown. Our cohort analyses of early-stage BC patients reveal the emergence of a significantly rising mortality risk when the biopsy-to-surgery interval was extended beyond 53 days. Additionally, histology of post-biopsy tumors shows prolonged retention of a metastasis-permissive wound stroma dominated by M2-like macrophages capable of promoting cancer cell epithelial-to-mesenchymal transition and angiogenesis. We show that needle biopsy promotes systemic dissemination of cancer cells through a mechanism of sustained activation of the COX-2/PGE2/EP2 feedforward loop, which favors M2 polarization and its associated pro-metastatic changes but are abrogated by oral treatment with COX-2 or EP2 inhibitors in estrogen-receptor-positive (ER+) syngeneic mouse tumor models. Therefore, we conclude that needle biopsy of ER+ BC provokes progressive pro-metastatic changes, which may explain the mortality risk posed by surgery delay after diagnosis.

Genomic structures and regulation patterns at HPV integration sites in cervical cancer.

Human papillomavirus (HPV) integration has been implicated in transforming HPV infection into cancer, but its genomic consequences have been difficult to study using short-read technologies. To resolve the dysregulation associated with HPV integration, we performed long-read sequencing on 63 cervical cancer genomes. We identified six categories of integration events based on HPV-human genomic structures. Of all HPV integrants, defined as two HPV-human breakpoints bridged by an HPV sequence, 24% contained variable copies of HPV between the breakpoints, a phenomenon we termed heterologous integration. Analysis of DNA methylation within and in proximity to the HPV genome at individual integration events revealed relationships between methylation status of the integrant and its orientation and structure. Dysregulation of the human epigenome and neighboring gene expression in cis with the HPV-integrated allele was observed over megabase-ranges of the genome. By elucidating the structural, epigenetic, and allele-specific impacts of HPV integration, we provide insight into the role of integrated HPV in cervical cancer.

Decision regret among couples experiencing infertility: a mixed methods longitudinal cohort study.

BACKGROUND: Decisions for how to resolve infertility are complex and may lead to regret. We examined whether couples and individuals who sought a consultation from a reproductive specialist for infertility later expressed decisional regret about their family-building choices and whether regret was associated with parental role, family-building paths, or outcomes. METHODS: This longitudinal mixed methods study included women and their partners who completed a questionnaire prior to their initial consultation with a reproductive specialist and 6 years later. The six-year questionnaire included the Ottawa Decision Regret Scale referencing "the decisions you made about how to add a child to your family." A score of 25+ indicates moderate-to-severe regret. Additional items invited reflections on family-building decisions, treatments, and costs. A systematic content analysis assessed qualitative themes. RESULTS: Forty-five couples and 34 individuals participated in the six-year questionnaire (76% retention rate), Half (n = 61) of participants expressed no regret, which was similar by role (median 0 for women and supporting partners, F = .08; p = .77). One in 5 women and 1 in 7 partners expressed moderate-to-severe regret. Women who did not pursue any treatment had significantly higher regret (median 15; F = 5.6, p < 0.01) compared to those who pursued IVF (median 0) or other treatments (median 0). Women who did not add a child to their family had significantly higher regret (median 35; F = 10.1, p < 0.001) than those who added a child through treatment (median 0), through fostering/adoption (median 0), or naturally (median 5). Among partners, regret scores were not associated with family-building paths or outcomes. More than one-quarter of participants wished they had spent less money trying to add a child to their family. Qualitative themes included gratitude for parenthood despite the burdensome process of family-building as well as dissatisfaction or regret about the process. Results should be confirmed in other settings to increase generalizability. CONCLUSION: This longitudinal study provides new insight into the burden of infertility. For women seeking parenthood, any of the multiple paths to parenthood may prevent future decision regret. Greater psychosocial, financial, and decision support is needed to help patients and their partners navigate family-building with minimal regret.

When people experience infertility, there are many decisions that can be challenging, such as whether to seek fertility treatments, to pursue fostering/adoption, and how to manage costs. With each decision, there is an opportunity for regret. The goal of this study was to look at whether people who were experiencing infertility and made an appointment with a doctor who specializes in infertility felt any regret about their decisions 6 years later. We also looked at whether different roles (that is, women seeking pregnancy or their supporting partners), different family-building paths (that is, medical treatments or not), or different outcomes (that is, adding a child to their family or not) were associated with different levels of regret. Results showed that half of the 120 people in the study did not have any regret 6 years after meeting with a specialty doctor. However, some patients did have regret, including 20% of women and 14% of partners who expressed moderate-to-severe regret. Women who did not add a child to their family in the six years during the study reported higher regret compared to women who did add a child to their family. There were no such differences among partners. About 25% of participants wished they had tried more, fewer, or different treatments. More than 25% wished they spent less money to try to add a child to their family. For people who want to add a child to their family, there are multiple ways to become a parent, any of which may be linked to lower decision regret. Decision regret is experienced differently between women seeking to add a child to their family and their partners. Would-be parents need more emotional, financial, and decision making support to help them navigate family-building with minimal regret.

Preclinical activity of selinexor in combination with eribulin in uterine leiomyosarcoma.

Leiomyosarcoma (LMS) is a rare soft tissue sarcoma (STS) that begins in smooth muscle tissue and most often initiates in the abdomen or uterus. Compared with other uterine cancers, uterine LMS (ULMS) is an aggressive tumor with poor prognosis and a high risk of recurrence and death, regardless of the stage at presentation. Selinexor is a first-in-class selective inhibitor of nuclear export (SINE) compound that reversibly binds to exportin 1 (XPO1), thereby reactivating tumor suppressor proteins and downregulating the expression of oncogenes and DNA damage repair (DDR) proteins. In this study, we evaluated the effects of selinexor in combination with doxorubicin and eribulin in the LMS tumor model in vitro and in vivo. Treatment of selinexor combined with eribulin showed synergistic effects on tumor growth inhibition in SK-UT1 LMS-derived xenografts. Immunohistochemical assessment of the tumor tissues showed a significantly reduced expression of proliferation (Ki67) and XPO1 markers following combination therapy compared to the control group. Global transcriptome analyses on tumor tissue revealed that the combination therapy regulates genes from several key cancer-related pathways that are differentially expressed in ULMS tumors. To our knowledge, this is the first preclinical study demonstrating the anti-cancer therapeutic potential of using a combination of selinexor and eribulin in vivo. Results from this study further warrant clinical testing a combination of chemotherapy agents with selinexor to reduce the morbidity and mortality from ULMS.

Machine learning reveals genetic modifiers of the immune microenvironment of cancer.

Heritability in the immune tumor microenvironment (iTME) has been widely observed yet remains largely uncharacterized. Here, we developed a machine learning approach to map iTME modifiers within loci from genome-wide association studies (GWASs) for breast cancer (BrCa) incidence. A random forest model was trained on a positive set of immune-oncology (I-O) targets, and then used to assign I-O target probability scores to 1,362 candidate genes in linkage disequilibrium with 155 BrCa GWAS loci. Cluster analysis of the most probable candidates revealed two subfamilies of genes related to effector functions and adaptive immune responses, suggesting that iTME modifiers impact multiple aspects of anticancer immunity. Two of the top ranking BrCa candidates, LSP1 and TLR1, were orthogonally validated as iTME modifiers using BrCa patient biopsies and comparative mapping studies, respectively. Collectively, these data demonstrate a robust and flexible framework for functionally fine-mapping GWAS risk loci to identify translatable therapeutic targets.

Frequent upregulation of HER2 protein in hormone-receptor-positive HER2-negative breast cancer after short-term neoadjuvant endocrine therapy.

BACKGROUND: Endocrine resistant metastatic disease develops in ~ 20-25% of hormone-receptor-positive (HR+) breast cancer (BC) patients despite endocrine therapy (ET) use. Upregulation of HER family receptor tyrosine kinases (RTKs) represent escape mechanisms in response to ET in some HR+ tumors. Short-term neoadjuvant ET (NET) offers the opportunity to identify early endocrine escape mechanisms initiated in individual tumors. METHODS: This was a single arm, interventional phase II clinical trial evaluating 4 weeks (± 1 week) of NET in patients with early-stage HR+/HER2-negative (HER2-) BC. The primary objective was to assess NET-induced changes in HER1-4 proteins by immunohistochemistry (IHC) score. Protein upregulation was defined as an increase of ≥ 1 in IHC score following NET. RESULTS: Thirty-seven patients with cT1-T3, cN0, HR+/HER2- BC were enrolled. In 35 patients with evaluable tumor HER protein after NET, HER2 was upregulated in 48.6% (17/35; p = 0.025), with HER2-positive status (IHC 3+ or FISH-amplified) detected in three patients at surgery, who were recommended adjuvant trastuzumab-based therapy. Downregulation of HER3 and/or HER4 protein was detected in 54.2% of tumors, whereas HER1 protein remained low and unchanged in all cases. While no significant volumetric reduction was detected radiographically after short-term NET, significant reduction in tumor proliferation rates were observed. No significant associations were identified between any clinicopathologic covariates and changes in HER1-4 protein expression on multivariable analysis. CONCLUSION: Short-term NET frequently and preferentially upregulates HER2 over other HER family RTKs in early-stage HR+/HER2- BC and may be a promising strategy to identify tumors that utilize HER2 as an early endocrine escape pathway. CLINICAL TRIAL REGISTRY: Trial registration number: NCT03219476.

NNAT is a novel mediator of oxidative stress that suppresses ER + breast cancer.

BACKGROUND: Neuronatin (NNAT) was recently identified as a novel mediator of estrogen receptor-positive (ER+) breast cancer cell proliferation and migration, which correlated with decreased tumorigenic potential and prolonged patient survival. However, despite these observations, the molecular and pathophysiological role(s) of NNAT in ER + breast cancer remains unclear. Based on high protein homology with phospholamban, we hypothesized that NNAT mediates the homeostasis of intracellular calcium [Ca2+]i levels and endoplasmic reticulum (EndoR) function, which is frequently disrupted in ER + breast cancer and other malignancies. METHODS: To evaluate the role of NNAT on [Ca2+]i homeostasis, we used a combination of bioinformatics, gene expression and promoter activity assays, CRISPR gene manipulation, pharmacological tools and confocal imaging to characterize the association between ROS, NNAT and calcium signaling. RESULTS: Our data indicate that NNAT localizes predominantly to EndoR and lysosome, and genetic manipulation of NNAT levels demonstrated that NNAT modulates [Ca2+]i influx and maintains Ca2+ homeostasis. Pharmacological inhibition of calcium channels revealed that NNAT regulates [Ca2+]i levels in breast cancer cells through the interaction with ORAI but not the TRPC signaling cascade. Furthermore, NNAT is transcriptionally regulated by NRF1, PPARα, and PPARγ and is strongly upregulated by oxidative stress via the ROS and PPAR signaling cascades. CONCLUSION: Collectively, these data suggest that NNAT expression is mediated by oxidative stress and acts as a regulator of Ca2+ homeostasis to impact ER + breast cancer proliferation, thus providing a molecular link between the longstanding observation that is accumulating ROS and altered Ca2+ signaling are key oncogenic drivers of cancer.

Effect of a Best-Practice Alert on the Rate of Smoking Cessation among Pregnant Women.

OBJECTIVE: This study aimed to determine if a best-practice alert (BPA) implementation increases the rate of smoking cessation during pregnancy and affects pregnancy outcomes associated with smoking. STUDY DESIGN: This was a pretest-posttest study design where a BPA was added to electronic medical records (EMR) of pregnant persons who reported active smoking. The BPA provided the 5A's method to conduct counseling on smoking cessation. The rates of smoking cessation during pregnancy were compared 1.5 years before and after implementation of the BPA. Secondary outcomes examined whether counseling on smoking cessation was done, the number of the counseling sessions during pregnancy, and obstetric outcomes associated with maternal smoking. RESULTS: After implementation of the BPA, the rate of smoking cessation in pregnancy increased from 17.5% prior to BPA implementation to 54.9% after BPA implementation (p < 0.001). The rate of counseling on smoking cessation increased from 66.6% prior to BPA implementation to 95.6% after BPA implementation, with an increase noted also in the number of smoking cessation counseling sessions. In multivariate analyses, after controlling for maternal demographic and clinical factors, BPA implementation was significantly associated with higher rates of smoking cessation (adjusted odds ratio [aOR]: 3.44, 95% confidence interval [CI]: 2.17-5.51), higher rates of documented smoking cessation counseling in the EMR (aOR: 12.44, 95% CI: 6.06-25.64), and higher odds of conducting the counseling more than once (aOR: 6.90 95% CI: 4.45-10.88). CONCLUSION: The rate of smoking cessation and number of times pregnant persons were counseled increased after implementation of a BPA. The BPA could be a useful EMR tool to increase smoking cessation rates during pregnancy. KEY POINTS: · Smoking during pregnancy is a maternal and fetal concern.. · Prenatal care offers the chance to address smoking.. · BPA increases rates of smoking counseling and cessation..

Frequent Upregulation Of HER2 Protein In Hormone Receptor-Positive HER2-Negative Breast Cancer After Short-Term Neoadjuvant Endocrine Therapy.

Background. Endocrine resistant metastatic disease develops in ~20-25% of hormone-receptor positive (HR+) breast cancer (BC) patients despite endocrine therapy (ET) use. Upregulation of HER family receptor tyrosine kinases (RTKs) represent escape mechanisms in response to ET in some HR+ tumors. Short-term neoadjuvant ET (NET) offers the opportunity to identify early endocrine escape mechanisms initiated in individual tumors. Methods. This was a single arm, interventional phase II clinical trial evaluating 4 weeks (+/-1 week) of NET in patients with early-stage HR+/HER2-negative (HER2-) BC. The primary objective was to assess NET-induced changes in HER1-4 proteins by immunohistochemistry (IHC) score. Protein upregulation was defined as an increase of ≥1 in IHC score following NET. Results. Thirty-seven patients with cT1-T3, cN0, HR+/HER2- BC were enrolled. In 35 patients with evaluable tumor HER protein after NET, HER2 was upregulated in 48.6% (17/35; p=0.025), with HER2-positive status (IHC 3+ or FISH-amplified) detected in three patients at surgery, who were recommended adjuvant trastuzumab-based therapy. Downregulation of HER3 and/or HER4 protein was detected in 54.2% of tumors, whereas HER1 protein remained low and unchanged in all cases. While no significant volumetric reduction was detected radiographically after short-term NET, significant reduction in tumor proliferation rates were observed. No significant associations were identified between any clinicopathologic covariates and changes in HER1-4 protein expression on multivariable analysis. Conclusion . Short-term NET frequently and preferentially upregulates HER2 over other HER-family RTKs in early-stage HR+/HER2- BC and may be a promising strategy to identify tumors that utilize HER2 as an early endocrine escape pathway. Trial registration number: NCT03219476 Date of registration for prospectively registered trials: July 17, 2017.

HLA antibodies in fetal and neonatal alloimmune thrombocytopenia.

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is caused by antibodies against human platelet antigens (HPA). However, in many cases that meet clinical criteria for the condition, maternal sera do not have HPA antibodies. In studies examining whether human leukocyte antigen (HLA) antibodies cause FNAIT, the results are limited and inconclusive. This study sought to examine whether clinically suspected FNAIT cases with absent maternal HPA antibodies had different HLA antibody strength and specificity compared to controls. STUDY DESIGN AND METHODS: A retrospective case-control study assessed class I HLA antibody strength and specificity in cases submitted for testing to Versiti, Wisconsin. There were 813 cases that met initial screening criteria, but written consent could only be obtained for 50. After review of medical records and expert panel review, 31 cases with clinical criteria of FNAIT and maternal HLA but not HPA antibodies were included. Each case was matched for maternal age, gestational age at delivery, parity, and race/ethnicity to two controls from unaffected pregnancies that had maternal serum HLA antibodies. RESULTS: FNAIT cases were found to have both significantly higher HLA antibody strength, measured by mean fluorescence index (MFI), and broader HLA antibody specificity at antigen epitope level, compared to matched controls (p < .001). p-values remained significant after controlling for parity and gestational age at delivery. DISCUSSION: Additional studies are needed to further examine whether the strong HLA antibodies identified in HPA-antibody-negative cases directly cause neonatal thrombocytopenia and whether prenatal treatment may be warranted in select cases to prevent recurrence.

Impact of prior gestational diabetes on long-term type 2 diabetes complications.

AIMS: While women with gestational diabetes mellitus (GDM) have a higher risk of developing type 2 diabetes mellitus (T2DM) and at a younger age, it is unknown whether T2DM following GDM is associated with worse clinical outcomes. This study aims to examine the impact of GDM on subsequent development of long-term complications of T2DM. METHODS: All women with T2DM from the National Health and Nutrition Examination Survey (NHANES), a nationally representative cross-sectional survey of US population, between 2007 and 2018 (n = 2494) were stratified into two groups: those with a history of GDM (n = 385) and those without (n = 2109). Rates of macrovascular and microvascular complications of T2DM were compared between the two groups using bivariate and multivariate analyses. RESULTS: Of 2494 participants with T2DM included in the analysis, 385 (15.4 %) had a history of GDM and 2109 (84.6 %) did not. A history of GDM was independently associated with increased risk of myocardial infarction (aOR 2.53, 95%Cl: 1.18-5.40) and likely coronary artery disease (aOR 2.15, 95 % Cl: 1.00-4.66). CONCLUSIONS: In this cohort, women with T2DM and a history of GDM had higher risk of macrovascular complications of myocardial infarction and coronary artery disease, compared to those with no history of gestational diabetes.

Tumor Derived Extracellular Vesicles Drive T Cell Exhaustion in Tumor Microenvironment through Sphingosine Mediated Signaling and Impacting Immunotherapy Outcomes in Ovarian Cancer.

SPHK1 (sphingosine kinase-1) catalyzes the phosphorylation of sphingosine to sphingosine-1-phosphate (S1P), is found to be highly expressed in solid tumors. Here, extracellular vesicles (EVs) are identified as the key transporters of SPHK1 to the tumor microenvironment. Consequently, SPHK1-packaged EVs elevate S1P levels in the tumor microenvironment, where S1P appears as an immunosuppressive agent. However, the exact mechanism of how S1P mediates its immunosuppressive effects in cancer is not understood. It is investigated that S1P can induce T cell exhaustion. S1P can also upregulate programmed death ligand-1 (PDL-1) expression through E2F1-mediated transcription. Notably, an SPHK1 inhibitor PF543 improves T cell-mediated cytotoxicity. Furthermore, combining PF543 with an anti-PD-1 antibody reduces tumor burden and metastasis more effectively than PF543 alone in vivo. These data demonstrate a previously unrecognized mechanism of how SPHK1-packaged EVs contribute to the progression of ovarian cancer and thus present the potential clinical application of inhibiting SPHK1/S1P signaling to improve immune checkpoint blockage (anti-PD-1 antibody) therapy in ovarian cancer.

Racial and Ethnic Disparities in Maternal and Neonatal Outcomes among Women with Chronic Hypertension.

OBJECTIVE: The objective of this study was to compare maternal and neonatal outcomes in women with chronic hypertension by maternal race and ethnicity. METHODS: A retrospective cohort study of women with chronic hypertension was performed from the Consortium on Safe Labor (2002-2008). Maternal self-reported race and ethnicity were analyzed as non-Hispanic White, non-Hispanic Black, and Hispanic. Maternal outcomes included cesarean birth, postpartum hemorrhage, blood transfusion, placental abruption, eclampsia, maternal intensive care unit admission, and death. Neonatal outcomes included preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA), 5-minute Apgar <7, respiratory distress syndrome, hypoxic-ischemic encephalopathy, intraventricular hemorrhage, neonatal intensive care unit admission, sepsis, and death. Univariable and multivariable analyses were performed to examine the association between maternal race and ethnicity and perinatal outcomes. RESULTS: A total of 2,729 women were included. In unadjusted analysis, non-Hispanic White women had higher rates of placental abruption and Hispanic women had higher rates of placental abruption and eclampsia. In multivariable analysis, non-Hispanic Black continued to have higher odds of placental abruption (adjusted odds ratio 4.16, 95% confidence interval 1.29-18.70), but the rest of the maternal outcomes did not differ between the groups. When comparing neonatal outcomes, PTB, SGA, and LBW were more frequent in, 5-minute Apgar <7 non-Hispanic Black and Hispanic women compared with non-Hispanic White women. In addition, 5-minute Apgar <7 and neonatal sepsis were more frequent in non-Hispanic Black neonates and neonatal death was more frequent in Hispanic neonates compared with non-Hispanic White women. In multivariable regression, neonates of non-Hispanic Black women had higher odds of PTB, SGA, LBW, 5-minute Apgar < 7, and sepsis compared with non-Hispanic White women. Similarly, neonates of Hispanic women had higher odds of SGA, LBW, and death. CONCLUSION: Significant racial and ethnic disparities were identified mainly in neonatal outcomes of women with chronic hypertension. KEY POINTS: · Non-Hispanic Black women with chronic hypertension had higher rates of placental abruption.. · Neonates of non-Hispanic Black women with chronic hypertension had higher odds of PTB, SGA, and LBW.. · Neonates of Hispanic women with chronic hypertension had higher odds of SGA, LBW, and neonatal death..

RNA-binding protein FXR1 drives cMYC translation by recruiting eIF4F complex to the translation start site.

Fragile X-related protein-1 (FXR1) gene is highly amplified in patients with ovarian cancer, and this amplification is associated with increased expression of both FXR1 mRNA and protein. FXR1 expression directly associates with the survival and proliferation of cancer cells. Surface sensing of translation (SUnSET) assay demonstrates that FXR1 enhances the overall translation in cancer cells. Reverse-phase protein array (RPPA) reveals that cMYC is the key target of FXR1. Mechanistically, FXR1 binds to the AU-rich elements (ARE) present within the 3' untranslated region (3'UTR) of cMYC and stabilizes its expression. In addition, the RGG domain in FXR1 interacts with eIF4A1 and eIF4E proteins. These two interactions of FXR1 result in the circularization of cMYC mRNA and facilitate the recruitment of eukaryotic translation initiation factors to the translation start site. In brief, we uncover a mechanism by which FXR1 promotes cMYC levels in cancer cells.

Multi-omics mapping of human papillomavirus integration sites illuminates novel cervical cancer target genes.

BACKGROUND: Integration of human papillomavirus (HPV) into the host genome is a dominant feature of invasive cervical cancer (ICC), yet the tumorigenicity of cis genomic changes at integration sites remains largely understudied. METHODS: Combining multi-omics data from The Cancer Genome Atlas with patient-matched long-read sequencing of HPV integration sites, we developed a strategy for using HPV integration events to identify and prioritise novel candidate ICC target genes (integration-detected genes (IDGs)). Four IDGs were then chosen for in vitro functional studies employing small interfering RNA-mediated knockdown in cell migration, proliferation and colony formation assays. RESULTS: PacBio data revealed 267 unique human-HPV breakpoints comprising 87 total integration events in eight tumours. Candidate IDGs were filtered based on the following criteria: (1) proximity to integration site, (2) clonal representation of integration event, (3) tumour-specific expression (Z-score) and (4) association with ICC survival. Four candidates prioritised based on their unknown function in ICC (BNC1, RSBN1, USP36 and TAOK3) exhibited oncogenic properties in cervical cancer cell lines. Further, annotation of integration events provided clues regarding potential mechanisms underlying altered IDG expression in both integrated and non-integrated ICC tumours. CONCLUSIONS: HPV integration events can guide the identification of novel IDGs for further study in cervical carcinogenesis and as putative therapeutic targets.

NSG-Pro mouse model for uncovering resistance mechanisms and unique vulnerabilities in human luminal breast cancers.

Most breast cancer deaths are caused by estrogen receptor-α­positive (ER+) disease. Preclinical progress is hampered by a shortage of therapy-naïve ER+ tumor models that recapitulate metastatic progression and clinically relevant therapy resistance. Human prolactin (hPRL) is a risk factor for primary and metastatic ER+ breast cancer. Because mouse prolactin fails to activate hPRL receptors, we developed a prolactin-humanized Nod-SCID-IL2Rγ (NSG) mouse (NSG-Pro) with physiological hPRL levels. Here, we show that NSG-Pro mice facilitate establishment of therapy-naïve, estrogen-dependent PDX tumors that progress to lethal metastatic disease. Preclinical trials provide first-in-mouse efficacy of pharmacological hPRL suppression on residual ER+ human breast cancer metastases and document divergent biology and drug responsiveness of tumors grown in NSG-Pro versus NSG mice. Oncogenomic analyses of PDX lines in NSG-Pro mice revealed clinically relevant therapy-resistance mechanisms and unexpected, potently actionable vulnerabilities such as DNA-repair aberrations. The NSG-Pro mouse unlocks previously inaccessible precision medicine approaches for ER+ breast cancers.

Residential proximity to tree canopy and preterm birth in Black women.

BACKGROUND: There are marked racial disparities in obstetrical outcomes, with the incidence of preterm birth being the highest among non-Hispanic Black women. The presence of green space, such as forests and parks, is now widely viewed as a health-promoting characteristic of residential environments. OBJECTIVE: This study aimed to examine the association between the proximity of tree canopies to a prenatal residential address and the rates of preterm birth among non-Hispanic Black women in Milwaukee, Wisconsin. STUDY DESIGN: This was a retrospective, case-control study utilizing hospital pregnancy records of self-identified non-Hispanic Black women. The addresses of the women, who delivered from 2011 to 2019, were geocoded to characterize the percentage of tree canopy surrounding the prenatal address using the National Land Cover Database. Circular residential buffers of 100, 150, 250, and 500 m were used to assess the exposure to tree canopy coverage in proximity to a prenatal address. Univariable and multivariable analyses were conducted to determine whether tree canopy percentage at 4 different proximity buffers, examined both in means and quartiles, was associated with preterm birth (birth at <37 weeks' gestation). RESULTS: Of the 2771 non-Hispanic Black women included in the study, 333 (12.0%) experienced preterm births. Less tree canopy coverage was significantly (P < .05) associated with preterm birth, irrespective of whether the coverage was quantified as a mean or by quartile. In the unadjusted and adjusted models, which adjusted for sociodemographic and clinical risk factors for preterm birth, a 10% increase in tree canopy coverage was associated with lower odds of preterm birth at all 4 buffers examined. When examining the green space by quartile, higher quartiles were associated with lower odds of preterm birth at the 100-, 150-, and 250 m buffers, but not at the 500 m buffer. CONCLUSION: A higher percentage of tree canopy coverage in close proximity to the prenatal residential address is associated with lower odds of preterm birth among non-Hispanic Black women. These findings suggest that access to neighborhood green space is an important factor associated with preterm birth.