Self-reported strategy use and prospective memory: The roles of cue focality and task importance.

Interest in the metacognitive aspects of prospective memory (PM) is growing. Yet, the interplay between participants' metacognitive awareness of PM task demands and features that contribute to successful PM require further attention. To this aim, participants in the current study completed laboratory-based PM tasks of varying difficulty (cue focality: focal, nonfocal-category, or nonfocal-syllable) and reported their strategy use and perceptions of PM task importance. Most participants reported using a strategy regardless of cue focality. However, only under the most challenging condition (i.e., nonfocal-syllable) did participants who reported using a strategy exhibit better PM performance compared to those who did not use a strategy. Additionally, strategy use and cue focality were independently associated with greater costs to ongoing task performance: strategy users exhibited greater slowing relative to individuals who did not use a strategy, and the extent of slowing was greater as the task difficulty increased across cue focality. Finally, perceived task importance appeared to play an important role in the interactive link between cue focality and strategy use on PM performance for the more challenging, nonfocal PM tasks. Specifically, moderation analyses suggested that greater perceived task importance alone may improve the likelihood of PM success for moderately challenging PM tasks (i.e., nonfocal-category), but for the most challenging PM tasks (i.e., nonfocal-syllable), individuals' strategy use was still associated with better PM performance. The present study expands our understanding of metacognition's role in PM performance and has implications for everyday PM performance.

HE4 Overexpression by Ovarian Cancer Promotes a Suppressive Tumor Immune Microenvironment and Enhanced Tumor and Macrophage PD-L1 Expression.

Ovarian cancer is a highly fatal malignancy characterized by early chemotherapy responsiveness but the eventual development of resistance. Immune targeting therapies are changing treatment paradigms for numerous cancer types but have had minimal success in ovarian cancer. Through retrospective patient sample analysis, we have determined that high human epididymis protein 4 (HE4) production correlates with multiple markers of immune suppression in ovarian cancer, including lower CD8+ T cell infiltration, higher PD-L1 expression, and an increase in the peripheral monocyte to lymphocyte ratio. To further understand the impact that HE4 has on the immune microenvironment in ovarian cancer, we injected rats with syngeneic HE4 high- and low-expressing cancer cells and analyzed the differences in their tumor and ascites immune milieu. We found that high tumoral HE4 expression promotes an ascites cytokine profile that is rich in myeloid-recruiting and differentiation factors, with an influx of M2 macrophages and increased arginase 1 production. Additionally, CTL activation is significantly reduced in the ascites fluid, and there is a trend toward lower CTL infiltration of the tumor, whereas NK cell recruitment to the ascites and tumor is also reduced. PD-L1 expression by tumor cells and macrophages is increased by HE4 through a novel posttranscriptional mechanism. Our data have identified HE4 as a mediator of tumor-immune suppression in ovarian cancer, highlighting this molecule as a potential therapeutic target for the treatment of this devastating disease.

Concerned friends of intimate partner violence survivors: results from the myPlan randomized controlled trial on college campuses.

BACKGROUND: Nearly half of intimate partner violence (IPV) survivors experience their first abusive relationship at college age (18-24 years). Most often they disclose the violence to friends. Existing college campus "bystander" interventions training peers to safely intervene have been effective in sexual assault prevention; similar interventions have rarely been tested for IPV. Therefore, we evaluated the effectiveness of an interactive, personalized safety decision and planning tool, myPlan app, on decisional conflict, decisional preparedness, confidence in intervening, supportive safety behaviors, and IPV attitudes with concerned friends of abused college women. METHODS: We recruited college students (age 18-24, N = 293) of any gender who had a female-identified friend who had recently experienced IPV ("concerned friends") from 41 Oregon and Maryland colleges/universities. Participants were randomized to myPlan (n = 147) or control (usual web-based resources; n = 146). Outcomes included decisional conflict, decisional preparedness, confidence to intervene, safety/support behaviors, and IPV attitudes. RESULTS: At baseline, concerned friends described the abused person as a close/best friend (79.1%); 93.7% had tried at least one strategy to help. Most (89.2%) reported concerns their friend would be seriously hurt by the abuser; 22.7% reported extreme concern. Intervention participants had greater improvements in decisional conflict (specifically, understanding of their own values around the decision to intervene and help a friend) and decisional preparedness immediately after their first use of myPlan, and a significantly greater increase in confidence to talk with someone about their own relationship concerns at 12 months. At 12-month follow-up, both intervention and control groups reported increased confidence to intervene, and did not differ significantly in terms of percentage of safety/support strategies used, whether strategies were helpful, or IPV attitudes. CONCLUSIONS: A technology-based intervention, myPlan, was effective in reducing one aspect of decisional conflict (improving clarity of values to intervene) and increasing decisional preparedness to support a friend in an unsafe relationship. Information on IPV and related safety strategies delivered through the myPlan app or usual web-based resources both increased confidence to intervene with a friend. College students in the myPlan group were more likely to talk with someone about concerns about their own relationship, demonstrating potential for IPV prevention or early intervention. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT02236663, registration date 10/09/2014.

Requirement for cleavage factor IIm in the control of alternative polyadenylation in breast cancer cells.

Alternative polyadenylation (APA) determines stability, localization and translation potential of the majority of mRNA in eukaryotic cells. The heterodimeric mammalian cleavage factor II (CF IIm) is required for pre-mRNA 3' end cleavage and is composed of the RNA kinase hClp1 and the termination factor hPcf11; the latter protein binds to RNA and the RNA polymerase II carboxy-terminal domain. Here, we used siRNA mediated knockdown and poly(A) targeted RNA sequencing to analyze the role of CF IIm in gene expression and APA in estrogen receptor positive MCF7 breast cancer cells. Identified gene ontology terms link CF IIm function to regulation of growth factor activity, protein heterodimerization and the cell cycle. An overlapping requirement for hClp1 and hPcf11 suggested that CF IIm protein complex was involved in the selection of proximal poly(A) sites. In addition to APA shifts within 3' untranslated regions (3'-UTRs), we observed shifts from promoter proximal regions to the 3'-UTR facilitating synthesis of full-length mRNAs. Moreover, we show that several truncated mRNAs that resulted from APA within introns in MCF7 cells cosedimented with ribosomal components in an EDTA sensitive manner suggesting that those are translated into protein. We propose that CF IIm contributes to the regulation of mRNA function in breast cancer.

Patients Achieving 90°/45°/0° Intraoperative Stability Do Not Require Hip Precautions Following Posterior Approach Total Hip Arthroplasty: A Prospective Randomized Study.

BACKGROUND: Hip precautions are traditionally employed after posterior total hip arthroplasty (THA). The primary purpose was to investigate the necessity of hip precautions after posterior approach THA. We hypothesized that eliminating precautions in patients that achieved appropriate intraoperative stability would not increase the dislocation rate. METHODS: Randomized controlled trial of 346 consecutive eligible patients undergoing primary THA with a mean follow-up of 2.3 years (range 11 months to 3.7 years). EXCLUSION CRITERIA: lumbar fusion, scoliosis, abductor insufficiency, inability to achieve intraoperative stability with combined 90° flexion and 45° internal rotation in 0° adduction. Fisher's exact test was used to compare dislocation rates between the hip precaution (HP) control group and no hip precaution (NP) study group. In addition, Mann-Whitney U test was used to compare differences in HOOS JR scores at 2, 6, 12 weeks between groups. RESULTS: The dislocation rate was not increased in the NP (0/172: 0%) group compared to the HP group 4/174 (2.29%) (P = .418). All dislocations occurred in the precautions group, two of which required revision. There were no differences in mean HOOS Jr. scores at any 2, 6, or 12 weeks (P > .05 at all timepoints) (secondary outcome). CONCLUSION: Eliminating hip precautions in patients undergoing posterior approach THA that achieve 90°/45°/0° intraoperative stability does not increase the rate of dislocation. In fact, every dislocation occurred in patients receiving hip precautions. Short-term patient-reported outcome measures were not affected by hip precautions. Surgeons may discontinue the use of hip precautions as the standard of care in patients achieving 90°/45°/0° stability.

Analysis of serum HE4 levels in various histologic subtypes of epithelial ovarian cancer and other malignant tumors.

BACKGROUND: The measurement of serum HE4 levels has emerged as a sensitive and specific biomarker for epithelial ovarian cancers (EOCs). However, serum levels in women diagnosed with various histologic subtypes of EOC and in women with metastatic non-ovarian primary malignancies have not been widely reported. OBJECTIVE: The goal of this study was to identify how serum HE4 levels vary in women diagnosed with different histologic subtypes of EOC and non-ovarian malignancies. METHODS: Data from six prospective pelvic mass clinical trials was combined and an evaluation of serum HE4 levels in women diagnosed with a malignancy was performed. For all patients, serum was obtained prior to surgery and final pathology, including primary tumor site, histologic subtype, grade and stage, were recorded. The mean, median, standard deviation, maximum, and minimum HE4 levels were determined for each group. RESULTS: A total of 984 patients were included in this study, with the average patient age being 60 years old. There were 230 premenopausal and 754 postmenopausal patients. Serum HE4 levels were elevated (≥70.0 pMol) in 85%of EOCs, 40%of LMP tumors, 21%of non-EOCs (germ cell tumors), 25%of cervical cancers, and 47%of non-gynecologic metastatic cancers. Analysis of histologic subtypes revealed 90%(n = 391) of serous, 85%(n = 73) of endometrioid, 45%(n = 42) of mucinous, 86%(n = 51) of mixed tumors, and 69%(n = 36) of clear cell tumors had elevated serum HE4 levels. CONCLUSIONS: Serum HE4 levels are most often elevated in women with high grade serous and endometrioid EOCs, and though serum elevations are seen more often with advanced stage disease, HE4 is also often elevated in early stage disease and lower grade tumors.

Alternative polyadenylation in the regulation and dysregulation of gene expression.

Transcriptional control shapes a cell's transcriptome composition, but it is RNA processing that refines its expression. The untranslated regions (UTRs) of mRNA are hotspots for regulatory control. Features in these can impact mRNA stability, localisation and translation. Here we describe how alternative cleavage and polyadenylation can change mRNA fate by changing the length of its 3'UTR.

Comparative effectiveness of an economic empowerment program on adolescent economic assets, education and health in a humanitarian setting.

BACKGROUND: Adolescence is a critical period of human development, however, limited research on programs to improve health and well-being among younger adolescents living in conflict-affected and humanitarian settings exists. The purpose of this study was to assess the comparative effectiveness of an economic empowerment program on young adolescent outcomes in a complex humanitarian setting. METHODS: This longitudinal, mixed methods study examined the relative effectiveness of an integrated parent (Pigs for Peace, PFP) and young adolescent (Rabbits for Resilience, RFR) animal microfinance/asset transfer program (RFR + PFP) on adolescent outcomes of asset building, school attendance, mental health, experienced stigma, and food security compared to RFR only and PFP only over 24 months. A sub-sample of young adolescents completed in-depth qualitative interviews on the benefits and challenges of participating in RFR. RESULTS: Five hundred forty-two young adolescents (10-15 years) participated in three groups: RFR + PFP (N = 178), RFR only (N = 187), PFP only (N = 177). 501 (92.4%) completed baseline surveys, with 81.7% (n = 442) retention at endline. The group by time interaction (24 months) was significant for adolescent asset building (X2 = 16.54, p = .002), school attendance (X2 = 12.33, p = .015), and prosocial behavior (X2 = 10.56, p = .032). RFR + PFP (ES = 0.31, ES = 0.38) and RFR only (ES-0.39, ES = 0.14) adolescents had greater improvement in asset building and prosocial behavior compared to PFP only, respectively. The odds of missing two or more days of school in the past month were 78.4% lower in RFR only and 45.1% lower in RFR + PFP compared to PFP only. No differences between groups in change over time were found for internalizing behaviors, experienced stigma, or food security. Differences by age and gender were observed in asset building, prosocial behavior, school attendance, experienced stigma, and food security. The voices of young adolescents identified the benefits of the RFR program through their ability to pay for school fees, help their families meet basic needs, and the respect they gained from family and community. Challenges included death of rabbits and potential conflict within the household on how to use the rabbit asset. CONCLUSION: These findings underscore the potential for integrating economic empowerment programs with both parents and young adolescents to improve economic, educational, and health outcomes for young adolescents growing up in rural and complex humanitarian settings. TRIAL REGISTRATION: NCT02008695. Retrospectively registered 11 December 2013.

Successful transplantation of human hepatic stem cells with restricted localization to liver using hyaluronan grafts.

Cell therapies are potential alternatives to organ transplantation for liver failure or dysfunction but are compromised by inefficient engraftment, cell dispersal to ectopic sites, and emboli formation. Grafting strategies have been devised for transplantation of human hepatic stem cells (hHpSCs) embedded into a mix of soluble signals and extracellular matrix biomaterials (hyaluronans, type III collagen, laminin) found in stem cell niches. The hHpSCs maintain a stable stem cell phenotype under the graft conditions. The grafts were transplanted into the livers of immunocompromised murine hosts with and without carbon tetrachloride treatment to assess the effects of quiescent versus injured liver conditions. Grafted cells remained localized to the livers, resulting in a larger bolus of engrafted cells in the host livers under quiescent conditions and with potential for more rapid expansion under injured liver conditions. By contrast, transplantation by direct injection or via a vascular route resulted in inefficient engraftment and cell dispersal to ectopic sites. Transplantation by grafting is proposed as a preferred strategy for cell therapies for solid organs such as the liver.

Forchlorfenuron-Induced Mitochondrial Respiration Inhibition and Metabolic Shifts in Endometrial Cancer.

Forchlorfenuron (FCF) is a widely used plant cytokinin that enhances fruit quality and size in agriculture. It also serves as a crucial pharmacological tool for the inhibition of septins. However, the precise target of FCF has not yet been fully determined. This study reveals a novel target of FCF and elucidates its downstream signaling events. FCF significantly impairs mitochondrial respiration and mediates metabolic shift toward glycolysis, thus making cells more vulnerable to glycolysis inhibition. Interestingly, FCF's impact on mitochondrial function persists, even in cells lacking septins. Furthermore, the impaired mitochondrial function leads to the degradation of HIF-1α, facilitated by increased cellular oxygen. FCF also induces AMPK activation, suppresses Erk1/2 phosphorylation, and reduces the expression of HER2, ß-catenin, and PD-L1. Endometrial cancer is characterized by metabolic disorders such as diabetes and aberrant HER2/Ras-Erk1/2/ß-catenin signaling. Thus, FCF may hold promise as a potential therapeutic in endometrial cancer.

Dichotomous effects of IFN-γ on dendritic cell function determine the extent of IL-12-driven antitumor T cell immunity.

Sustained intratumoral delivery of IL-12 and GM-CSF can overcome tumor immune suppression and promote T cell-dependent eradication of established disease in murine tumor models. However, the antitumor effector response is transient and rapidly followed by a T suppressor cell rebound. The mechanisms that control the switch from an effector to a regulatory response in this model have not been defined. Because dendritic cells (DC) can mediate both effector and suppressor T cell priming, DC activity was monitored in the tumors and the tumor-draining lymph nodes (TDLN) of IL-12/GM-CSF-treated mice. The studies demonstrated that therapy promoted the recruitment of immunogenic DC (iDC) to tumors with subsequent migration to the TDLN within 24-48 h of treatment. Longer-term monitoring revealed that iDC converted to an IDO-positive tolerogenic phenotype in the TDLN between days 2 and 7. Specifically, day 7 DC lost the ability to prime CD8(+) T cells but preferentially induced CD4(+)Foxp3(+) T cells. The functional switch was reversible, as inhibition of IDO with 1-methyl tryptophan restored immunogenic function to tolerogenic DC. All posttherapy immunological activity was strictly associated with conventional myeloid DC, and no functional changes were observed in the plasmacytoid DC subset throughout treatment. Importantly, the initial recruitment and activation of iDC as well as the subsequent switch to tolerogenic activity were both driven by IFN-γ, revealing the dichotomous role of this cytokine in regulating IL-12-mediated antitumor T cell immunity.

Chronic chemoimmunotherapy achieves cure of spontaneous murine mammary tumors via persistent blockade of posttherapy counter-regulation.

Intratumoral delivery of IL-12 and GM-CSF induces local and systemic antitumor CD8(+) T cell activation and tumor kill. However, the effector response is transient and is rapidly countered by CD4(+) Foxp3(+) T suppressor cell expansion. To determine whether depletion of the pre-existing T suppressor cell pool prior to treatment could diminish posttherapy regulatory cell resurgence, FVBneuN mice bearing advanced spontaneous mammary tumors were treated with cyclophosphamide (CY) 1 d before IL-12/GM-CSF therapy. Administration of CY mediated a significant delay in the post-IL-12/GM-CSF T suppressor cell rebound, resulting in a 7-fold increase in the CD8(+) CTL/T suppressor cell ratio, a 3-fold enhancement of CTL cytotoxicity, and an extension of the effector window from 3 to 7 d. In long-term therapy studies, chronic chemoimmunotherapy promoted a dramatic enhancement of tumor regression, resulting in complete cure in 44% of the mice receiving CY plus IL-12/GM-CSF. Tumor eradication in the chronic therapy setting was associated with the ability to repeatedly rescue and maintain cytotoxic CD8(+) T cell activity. These findings demonstrated that chronic administration of CY in conjunction with immune therapy enhances the initial induction of antitumor T effector cells and, more importantly, sustains their cytotoxic activity over the long-term via persistent blockade of homeostatic counter-regulation.

Perceived stereotyping and seeking care for chronic vulvar pain.

OBJECTIVES: We examined stereotyping of chronic pain sufferers among women aged 18-40 years and determined whether perceived stereotyping affects seeking care for women with chronic vulvar pain. DESIGN: Cross-sectional study using a community-based survey of vulvodynia asking if "Doctors think that people with chronic pain exaggerate their pain," and if "People believe that vulvar pain is used as an excuse to avoid having sex". SETTING AND PARTICIPANTS: Twelve thousand eight hundred thirty-four women aged 18-40 years in metropolitan Minneapolis/St. Paul, Minnesota. OUTCOME MEASURES: Women were considered to have a history of chronic vulvar pain if they reported vulvar burning lasting more than 3 months or vulvar pain on contact. RESULTS: Four thousand nine hundred eighty-seven (38.9%) women reported a chronic pain condition; 1,651 had chronic vulvar pain. Women experiencing chronic pain were more likely than those without to perceive stereotyping from both doctors and others; a dose-response with the number of pain conditions existed. Women with chronic vulvar pain were more likely to believe that people think vulvar pain is an excuse to avoid intercourse. Half of the women with chronic vulvar pain did not seek medical care for it; of these, 40.4% perceived stereotyping from doctors. However, it was women who actually sought care (45.1%) who were more likely to feel stigmatized by doctors (adjusted relative risk = 1.11, 95% confidence interval: 1.01-1.23). CONCLUSIONS: Perceived negative stereotyping among chronic pain sufferers is common, particularly negative perceptions about physicians. In fact, chronic vulvar pain sufferers who felt stigmatized were more likely to have sought care than those who did not feel stigmatized.

Caregiving During the COVID-19 Pandemic: Factors Associated With Feelings of Caregiver Preparedness.

Examination of caregiver preparedness for the COVID-19 pandemic can inform efforts to support caregivers in future times of global crisis. Informal caregivers of adults with dementia or severe disabilities (n = 72, Mage = 62.82 years, 90.28% female) were recruited through Adult Day Centers across the United States. Caregivers responding to an online survey regarding their experiences and preparedness reported an increase in burden, stress, and time spent caregiving since the onset of the pandemic. Caregivers reported feeling prepared for typical caregiving responsibilities but felt less prepared for someone else to assume the role of primary caregiver. Multiple regression modeling indicated that resilience accounted for significant variance in primary caregiver preparedness, over and above burden, but only caregiver age accounted for significant variability in a component representing feeling prepared to delegate caregiving to another person. These findings have implications for research and applied efforts to promote caregiver well-being and preparedness.

The short-chain fatty acid crotonate reduces invasive growth and immune escape of Candida albicans by regulating hyphal gene expression.

Microbes are exposed to nutritional and stress challenges in their environmental and host niches. To rise to these challenges, they regulate transcriptional programs that enable cellular adaptation. For instance, metabolite concentrations regulate post-translational modifications of chromatin, such as histone acetylation. In this way, metabolic signals are integrated with transcription. Over the last decade, several histone acylations have been discovered, including histone crotonylation. Their roles in microbial biology, environmental adaptation, and microbe-host interactions are incompletely defined. Here we show that the short-chain fatty acid crotonate, which is used to study histone crotonylation, changes cell morphology and immune interactions of Candida albicans. Crotonate reduces invasive hyphal morphogenesis of C. albicans within macrophages, thereby delaying macrophage killing and pathogen escape, as well as reducing inflammatory cytokine maturation. Crotonate's ability to reduce hyphal growth is environmentally contingent and pronounced within macrophages. Moreover, crotonate is a stronger hyphal inhibitor than butyrate under the conditions that we tested. Crotonate causes increased histone crotonylation in C. albicans under hyphal growth conditions and reduces transcription of hyphae-induced genes in a manner that involves the Nrg1 repressor pathway. Increasing histone acetylation by histone deacetylase inhibition partially rescues hyphal growth and gene transcription in the presence of crotonate. These results indicate that histone crotonylation might compete with acetylation in the regulation of hyphal morphogenesis. Based on our findings, we propose that diverse acylations of histones (and likely also non-histone proteins) enable C. albicans to respond to environmental signals, which in turn regulate its cell morphology and host-pathogen interactions.IMPORTANCEMacrophages curtail the proliferation of the pathogen Candida albicans within human body niches. Within macrophages, C. albicans adapts its metabolism and switches to invasive hyphal morphology. These adaptations enable fungal growth and immune escape by triggering macrophage lysis. Transcriptional programs regulate these metabolic and morphogenetic adaptations. Here we studied the roles of chromatin in these processes and implicate lysine crotonylation, a histone mark regulated by metabolism, in hyphal morphogenesis and macrophage interactions by C. albicans. We show that the short-chain fatty acid crotonate increases histone crotonylation, reduces hyphal formation within macrophages, and slows macrophage lysis and immune escape of C. albicans. Crotonate represses hyphal gene expression, and we propose that C. albicans uses diverse acylation marks to regulate its cell morphology in host environments. Hyphal formation is a virulence property of C. albicans. Therefore, a further importance of our study stems from identifying crotonate as a hyphal inhibitor.

Why local concepts matter: Using cultural expressions of distress to explore the construct validity of research instruments to measure mental health problems among Congolese women in Nyarugusu refugee camp.

There is considerable variation in the presentation of mental health problems across cultural contexts. Most screening and assessment tools do not capture local idioms and culturally specific presentations of distress, thus introducing measurement error and overlooking meaningful variation in mental health. Before applying screening and assessment tools in a particular context, a qualitative exploration of locally salient idioms and expression of distress can help assess whether existing measures are appropriate in a specific context as well as what adaptations may improve their construct validity. We aimed to employ a mixed-methods approach to describe and measure cultural concepts of distress among female Congolese survivors of intimate partner violence in Nyarugusu refugee camp, Tanzania. This sequential study used data from 55 qualitative (free-listing and in-depth) interviews followed by 311 quantitative interviews that included assessments of symptoms of common mental disorder to explore whether the symptom constellations were consistent across these methodologies. Results from thematic analysis of qualitative data and exploratory factor analysis of quantitative data converged on three concepts of distress: huzuni (deep sadness), msongo wa mawazo (stress, too many thoughts), and hofu (fear). The psychometric properties of these constructs were comparable to those of the three original common mental disorders measured by the quantitative symptom assessment tools-anxiety, depression, and post-traumatic stress disorder-adding weight to the appropriateness of using these tools in this specific setting. This mixed-methods approach presents an innovative additional method for assessing the local "cultural fit" of globally used tools for measuring mental health in cross-cultural research.

Metastatic melanoma posing as a pelvic mass.

Pelvic metastasis of melanoma is extremely rare and may pose a diagnostic challenge. We present a case report of a female with a history of colon cancer who underwent exploratory surgery for a pelvic mass that was suspicious for ovarian malignancy. Pathology was consistent with both recurrent colon cancer as well as synchronous newly diagnosed metastatic melanoma.

Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1.

Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8+T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.

Human hepatic stem cell and maturational liver lineage biology.

Livers are comprised of maturational lineages of cells beginning extrahepatically in the hepato-pancreatic common duct near the duodenum and intrahepatically in zone 1 by the portal triads. The extrahepatic stem cell niches are the peribiliary glands deep within the walls of the bile ducts; those intrahepatically are the canals of Hering in postnatal livers and that derive from ductal plates in fetal livers. Intrahepatically, there are at least eight maturational lineage stages from the stem cells in zone 1 (periportal), through the midacinar region (zone 2), to the most mature cells and apoptotic cells found pericentrally in zone 3. Those found in the biliary tree are still being defined. Parenchymal cells are closely associated with lineages of mesenchymal cells, and their maturation is coordinated. Each lineage stage consists of parenchymal and mesenchymal cell partners distinguishable by their morphology, ploidy, antigens, biochemical traits, gene expression, and ability to divide. They are governed by changes in chromatin (e.g., methylation), gradients of paracrine signals (soluble factors and insoluble extracellular matrix components), mechanical forces, and feedback loop signals derived from late lineage cells. Feedback loop signals, secreted by late lineage stage cells into bile, flow back to the periportal area and regulate the stem cells and other early lineage stage cells in mechanisms dictating the size of the liver mass. Recognition of maturational lineage biology and its regulation by these multiple mechanisms offers new understandings of liver biology, pathologies, and strategies for regenerative medicine and treatment of liver cancers.

Comfort in discussing vulvar pain in social relationships among women with vulvodynia.

OBJECTIVE: To assess women's likelihood of feeling comfortable in discussing vulvar pain. STUDY DESIGN: Using a survey of women with self-reported clinician-diagnosed vulvodynia, we assessed the likelihood of comfort in discussing vulvar pain within four types of relationships: husband/partner, mother/sister, best friend, and other women friends. Separate multivariable models were fit for relationship type to determine whether vulvar pain characteristics (length, severity,family history) were associated with likelihood of feeling comfortable in discussing. RESULTS: A total of 67% of women with a partner were comfortable discussing their vulvar pain with that person, whereas 39% were comfortable with family and 26% were comfortable with women friends. Independent of age, the more years women had vulvodynia the less likely they would be comfortable discussing it. Compared to lower levels of vulvar pain, increasing levels (mild, moderate and severe) were associated with greater comfort in discussing their pain with friends; women were 10% more likely to be comfortable with each increase in pain level, and 12% more likely to be comfortable with other women friends. CONCLUSION: Our data suggest that vulvar pain characteristics may determine how comfortable a woman is to discuss her vulvar pain, but it varies by relationship type.