Retraction Note: miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2.

A Retraction to this paper has been published and can be accessed via a link at the top of the paper.

Author Correction: miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2.

Change history: In this Letter, the citation to 'Fig. 4e, f' in the main text should be 'Fig. 3e, f'. This has not been corrected online.

Medicaid Dental Benefits for Pregnant People and Dental Care Use Among Very Young Children.

OBJECTIVES: The aim of this study was to examine the association between Medicaid dental benefits for pregnant people and dental care use among very young children in Medicaid. We hypothesized that children living in states with more generous dental benefits for Medicaid-enrolled pregnant people would be more likely to have a recent dental visit. METHODS: This national cross-sectional study used pooled 2017-2019 data from the National Survey of Children's Health, as well as state Medicaid policy data. The study sample included children aged 0-2 enrolled in Medicaid. Multivariable logistic regression models estimated the association between Medicaid dental benefit generosity for pregnant people and the child having a dental visit in the past year. RESULTS: Children in states with emergency-only dental coverage for pregnant people were 2.5 times as likely to have had a dental visit than children in states with extensive coverage (OR 2.48, 95% CI 1.35-4.53). In supplemental analyses excluding children living in Texas, there was no longer an association between dental coverage for pregnant people and dental utilization among young children (OR 1.52, 95% CI 0.82-2.83). CONCLUSIONS FOR PRACTICE: Young children in states that provided emergency-only dental benefits for pregnant people in Medicaid had significantly higher odds of dental utilization than young children in states with more generous dental benefits for pregnant people. This relationship disappeared after excluding the state Texas, which had the highest rate of child dental utilization in the country and provided emergency-only dental benefits for pregnant people in Medicaid.

Empathy levels among health professional students at a large midwestern public university - a cross-sectional study.

BACKGROUND: Empathic care is considered extremely important by patients and providers alike but there is still an ample need for assessing empathy among healthcare students and professionals and identifying appropriate educational interventions to improve it. This study aims to assess empathy levels and associated factors among students at different healthcare colleges at the University of Iowa. METHODS: An online survey was delivered to healthcare students, including nursing, pharmacy, dental, and medical colleges (IRB ID #202,003,636). The cross-sectional survey included background questions, probing questions, college-specific questions, and the Jefferson Scale of Empathy-Health Professionals Student version (JSPE-HPS). To examine bivariate associations, Kruskal Wallis and Wilcoxon rank sum tests were used. A linear model with no transformation was used in the multivariable analysis. RESULTS: Three hundred students responded to the survey. Overall JSPE-HPS score was 116 (± 11.7), consistent with other healthcare professional samples. There was no significant difference in JSPE-HPS score among the different colleges (P = 0.532). CONCLUSION: Controlling for other variables in the linear model, healthcare students' view of their faculty's empathy toward patients and students' self-reported empathy levels were significantly associated with students' JSPE-HPS scores.

Targeting renal cell carcinoma with a HIF-2 antagonist.

Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the von Hippel-Lindau tumour suppressor gene (VHL). Because no other gene is mutated as frequently in ccRCC and VHL mutations are truncal, VHL inactivation is regarded as the governing event. VHL loss activates the HIF-2 transcription factor, and constitutive HIF-2 activity restores tumorigenesis in VHL-reconstituted ccRCC cells. HIF-2 has been implicated in angiogenesis and multiple other processes, but angiogenesis is the main target of drugs such as the tyrosine kinase inhibitor sunitinib. HIF-2 has been regarded as undruggable. Here we use a tumourgraft/patient-derived xenograft platform to evaluate PT2399, a selective HIF-2 antagonist that was identified using a structure-based design approach. PT2399 dissociated HIF-2 (an obligatory heterodimer of HIF-2α-HIF-1ß) in human ccRCC cells and suppressed tumorigenesis in 56% (10 out of 18) of such lines. PT2399 had greater activity than sunitinib, was active in sunitinib-progressing tumours, and was better tolerated. Unexpectedly, some VHL-mutant ccRCCs were resistant to PT2399. Resistance occurred despite HIF-2 dissociation in tumours and evidence of Hif-2 inhibition in the mouse, as determined by suppression of circulating erythropoietin, a HIF-2 target and possible pharmacodynamic marker. We identified a HIF-2-dependent gene signature in sensitive tumours. Gene expression was largely unaffected by PT2399 in resistant tumours, illustrating the specificity of the drug. Sensitive tumours exhibited a distinguishing gene expression signature and generally higher levels of HIF-2α. Prolonged PT2399 treatment led to resistance. We identified binding site and second site suppressor mutations in HIF-2α and HIF-1ß, respectively. Both mutations preserved HIF-2 dimers despite treatment with PT2399. Finally, an extensively pretreated patient whose tumour had given rise to a sensitive tumourgraft showed disease control for more than 11 months when treated with a close analogue of PT2399, PT2385. We validate HIF-2 as a target in ccRCC, show that some ccRCCs are HIF-2 independent, and set the stage for biomarker-driven clinical trials.

Surgery start time and early implant failure: A case-control study.

OBJECTIVE: To evaluate the influence of surgery start time (SST) and other patient- and therapy-related variables on the risk for early implant failure (EIF) in an academic setting. MATERIAL AND METHODS: Data were extracted from the electronic health records of 61 patients who had at least one EIF and 140 age- and gender-matched, randomly selected, non-EIF controls. Bivariate and multivariable analyses were performed to identify relevant associations between EIF and different variables, such as SST. RESULTS: Incidence of EIF was not significantly associated with SST (HR: 1.9 for afternoon implant placement, 95% CI: 0.9-3.9; p = .105). Other factors that were associated with a significantly increased risk for EIF in a multivariable model were pre-placement ridge augmentation (HR: 7.5, 95% CI: 2.2-25.1; p = .001), intra-operative complications (HR: 5.9, 95% CI: 2.2-16.3; p < .001), simultaneous soft tissue grafting (HR: 5.03, 95% CI: 1.3-19.5; p = .020), simultaneous bone grafting (HR: 3.7, 95% CI: 1.6-8.8; p = .002), and placement with sedation (HR: 3.4, 95% CI: 1.5-7.5; p = .002). CONCLUSIONS: While SST was not associated with the occurrence of EIF in our cohort, other variables, such as ridge augmentation prior to implant placement, simultaneous bone or soft tissue grafting, intra-operative complications, implant placement with sedation, and number of implants in the oral cavity, were associated with an increased risk for this adverse event.

Correction: SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer.

[This corrects the article DOI: 10.1371/journal.pgen.1006650.].

miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2.

Bone-resorbing osteoclasts significantly contribute to osteoporosis and bone metastases of cancer. MicroRNAs play important roles in physiology and disease, and present tremendous therapeutic potential. Nonetheless, how microRNAs regulate skeletal biology is underexplored. Here we identify miR-34a as a novel and critical suppressor of osteoclastogenesis, bone resorption and the bone metastatic niche. miR-34a is downregulated during osteoclast differentiation. Osteoclastic miR-34a-overexpressing transgenic mice exhibit lower bone resorption and higher bone mass. Conversely, miR-34a knockout and heterozygous mice exhibit elevated bone resorption and reduced bone mass. Consequently, ovariectomy-induced osteoporosis, as well as bone metastasis of breast and skin cancers, are diminished in osteoclastic miR-34a transgenic mice, and can be effectively attenuated by miR-34a nanoparticle treatment. Mechanistically, we identify transforming growth factor-ß-induced factor 2 (Tgif2) as an essential direct miR-34a target that is pro-osteoclastogenic. Tgif2 deletion reduces bone resorption and abolishes miR-34a regulation. Together, using mouse genetic, pharmacological and disease models, we reveal miR-34a as a key osteoclast suppressor and a potential therapeutic strategy to confer skeletal protection and ameliorate bone metastasis of cancers.

SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer.

Hepatocellular carcinoma (HCC) is the fifth most common solid tumor in the world and the third leading cause of cancer-associated deaths. A Sleeping Beauty-mediated transposon mutagenesis screen previously identified mutations that cooperate with MYC to accelerate liver tumorigenesis. This revealed a tumor suppressor role for Steroid Receptor Coactivator 2/Nuclear Receptor Coactivator 2 (Src-2/Ncoa2) in liver cancer. In contrast, SRC-2 promotes survival and metastasis in prostate cancer cells, suggesting a tissue-specific and context-dependent role for SRC-2 in tumorigenesis. To determine if genetic loss of SRC-2 is sufficient to accelerate MYC-mediated liver tumorigenesis, we bred Src-2-/- mice with a MYC-induced liver tumor model and observed a significant increase in liver tumor burden. RNA sequencing of liver tumors and in vivo chromatin immunoprecipitation assays revealed a set of direct target genes that are bound by SRC-2 and exhibit downregulated expression in Src-2-/- liver tumors. We demonstrate that activation of SHP (Small Heterodimer Partner), DKK4 (Dickkopf-4), and CADM4 (Cell Adhesion Molecule 4) by SRC-2 suppresses tumorigenesis in vitro and in vivo. These studies suggest that SRC-2 may exhibit oncogenic or tumor suppressor activity depending on the target genes and nuclear receptors that are expressed in distinct tissues and illuminate the mechanisms of tumor suppression by SRC-2 in liver.

Statistical justification of expansion cohorts in phase 1 cancer trials.

BACKGROUND: Phase I cancer trials increasingly incorporate dose-expansion cohorts (DECs), reflecting a growing demand to acquire more information about investigational drugs. Protocols commonly fail to provide a sample-size justification or analysis plan for the DEC. In this study, we develop a statistical framework for the design of DECs. METHODS: We assume the maximum tolerated dose (MTD) for the investigational drug has been identified in the dose-escalation stage of the trial. We use the 80% lower confidence bound and the 90% upper confidence bound for the response and toxicity rates, respectively, as decision thresholds for the dose-expansion stage. We calculate the operating characteristics with reference to prespecified minimum effective response rates and maximum safe DLT rates. RESULTS: We apply our framework to specify a system of DEC plans. The design comprises three components: 1) the number of subjects enrolled at the MTD, 2) the minimum number of responses necessary to indicate provisional drug efficacy, and 3) the maximum number of dose-limiting toxicities (DLTs) permitted to indicate drug safety. We demonstrate our method in an application to a cancer immunotherapy trial. CONCLUSIONS: Our simple and practical tool enables creation of DEC designs that appropriately address the safety and efficacy objectives of the trial.