Decreased Human Immunodeficiency Virus Diagnosis Rates Among Black and Hispanic or Latino Men Who Have Sex With Men in US Jurisdictions Supported by the THRIVE Demonstration Project, 2014-2019.

BACKGROUND: Black and Hispanic/Latino men who have sex with men (MSM) are disproportionately affected by human immunodeficiency virus (HIV). In the Targeted Highly Effective Interventions to Reverse the HIV Epidemic (THRIVE) demonstration project, 7 community collaboratives were developed to provide comprehensive HIV prevention services for these populations. METHODS: We analyzed National HIV Surveillance System data to determine the number of HIV diagnoses for each year from 2014 to 2019 among Black, Hispanic/Latino, and White MSM in 7 THRIVE-eligible Metropolitan Statistical Areas (MSAs) that were awarded funding and 12 THRIVE-eligible MSAs that were not awarded funding. We used generalized linear Poisson regression models to estimate adjusted estimated annual percentage changes (EAPCs) with 95% confidence intervals for HIV diagnosis rates controlling for HIV prevalence, viral suppression, HIV testing rates, preexposure prophylaxis (PrEP) prescription rates, poverty, education, and insurance status. RESULTS: We found larger estimated decreases in HIV diagnosis rates in THRIVE jurisdictions compared with non-THRIVE jurisdictions. The adjusted EAPC among Black MSM was -8.2 (-11.7 to -4.6) in THRIVE MSAs compared with -4.2 (-7.8 to -0.4) in non-THRIVE MSAs. The adjusted EAPC among Hispanic/Latino MSM was -8.6 (-12.2 to -4.8) in THRIVE MSAs compared with -2.6 (-5.1 to -0.1)in non-THRIVE MSAs. The adjusted EAPC among White MSM was -7.6 (-12.0 to -3.1) in THRIVE MSAs compared with 5.9 (1.8-10.1) in non-THRIVE MSAs. CONCLUSIONS: The THRIVE community collaborative model was associated with a decrease in HIV diagnoses among Black and Hispanic/Latino MSM. To achieve the goals of the US Ending the HIV Epidemic initiative, effective interventions aimed to increase PrEP use need to be focused on Black and Hispanic/Latino MSM.

HIV Care Outcomes in Relation to Racial Redlining and Structural Factors Affecting Medical Care Access Among Black and White Persons with Diagnosed HIV-United States, 2017.

Black/African American (Black) versus White persons are unequally burdened by human immunodeficiency virus (HIV) in the United States. Structural factors can influence social determinants of health, key components in reducing HIV-related health inequality by race. This analysis examined HIV care outcomes among Black and White persons with diagnosed HIV (PWDH) in relation to three structural factors: racial redlining, Medicaid expansion, and Ryan White HIV/AIDS Program (RWHAP) use. Using National HIV Surveillance System, U.S. Census, and Home Mortgage Disclosure Act data, we examined linkage to HIV care and viral suppression (i.e., viral load < 200 copies/mL) in relation to the structural factors among 12,996 Black and White PWDH with HIV diagnosed in 2017/alive at year-end 2018, aged ≥ 18 years, and residing in 38 U.S. jurisdictions with complete laboratory data, geocoding, and census tract-level redlining indexes. Compared to White PWDH, a lower proportion of Black PWDH were linked to HIV care within 1 month after diagnosis and were virally suppressed in 2018. Redlining was not associated with the HIV care outcomes. A higher prevalence of PWDH residing (v. not residing) in states with Medicaid expansion were linked to HIV care ≤ 1 month after diagnosis. A higher prevalence of those residing (v. not residing) in states with > 50% of PWDH in RWHAP had viral suppression. Direct exposure to redlining was not associated with poor HIV care outcomes. Structural factors that reduce the financial burden of HIV care and improve care access like Medicaid expansion and RWHAP might improve HIV care outcomes of PWDH.

Third-order harmonic mode-locked and Q-switched Er-doped fiber laser based on a Cr2Ge2Te6 saturable absorber.

This paper reports the generation of fundamental solitons and third-order solitons in an erbium-doped fiber laser (EDFL) by a Cr2Ge2Te6-polyvinyl alcohol (CGT-PVA) saturable absorber (SA). Stable fundamental solitons at 1559.09 nm at a repetition frequency of 5.1 MHz were detected, and third-order solitons with a maximum output power of 6.807 mW and narrowest monopulse duration of 615.2 fs were obtained under a repetition frequency of 15.3 MHz by changing pump power. To the best of our knowledge, it is the first time to achieve a Q-switched pulse with a minimum pulse duration of 2.2 µs and maximum single pulse energy of 12.11 nJ in EDFL based on CGT-PVA SA after reducing the cavity length. Its repetition rate monotonically increased from 18.8 kHz to 61.8 kHz with a tuning range of about 43 kHz. The experimental results sufficiently demonstrate that CGT has enormous potential as an ultrafast photonics device.

Semi-supervised classification of fundus images combined with CNN and GCN.

PURPOSE: Diabetic retinopathy (DR) is one of the most serious complications of diabetes, which is a kind of fundus lesion with specific changes. Early diagnosis of DR can effectively reduce the visual damage caused by DR. Due to the variety and different morphology of DR lesions, automatic classification of fundus images in mass screening can greatly save clinicians' diagnosis time. To alleviate these problems, in this paper, we propose a novel framework-graph attentional convolutional neural network (GACNN). METHODS AND MATERIALS: The network consists of convolutional neural network (CNN) and graph convolutional network (GCN). The global and spatial features of fundus images are extracted by using CNN and GCN, and attention mechanism is introduced to enhance the adaptability of GCN to topology map. We adopt semi-supervised method for classification, which greatly improves the generalization ability of the network. RESULTS: In order to verify the effectiveness of the network, we conducted comparative experiments and ablation experiments. We use confusion matrix, precision, recall, kappa score, and accuracy as evaluation indexes. With the increase of the labeling rates, the classification accuracy is higher. Particularly, when the labeling rate is set to 100%, the classification accuracy of GACNN reaches 93.35%. Compared with DenseNet121, the accuracy rate is improved by 6.24%. CONCLUSIONS: Semi-supervised classification based on attention mechanism can effectively improve the classification performance of the model, and attain preferable results in classification indexes such as accuracy and recall. GACNN provides a feasible classification scheme for fundus images, which effectively reduces the screening human resources.

Trends in HIV-2 Diagnoses and Use of the HIV-1/HIV-2 Differentiation Test - United States, 2010-2017.

Since 2014, the recommended laboratory testing algorithm for diagnosing human immunodeficiency virus (HIV) infection has included a supplemental HIV-1/HIV-2 differentiation test to confirm infection type on the basis of the presence of type-specific antibodies (1). Correctly identifying HIV-1 and HIV-2 infections is vital because their epidemiology and clinical management differ. To describe the percentage of diagnoses for which an HIV-1/HIV-2 differentiation test result was reported and to categorize HIV type based on laboratory test results, 2010-2017 data from CDC's National HIV Surveillance System (NHSS) were analyzed. During 2010-2017, a substantial increase in the number of HIV-1/HIV-2 differentiation test results were reported to NHSS, consistent with implementation of the HIV laboratory-based testing algorithm recommended in 2014. However, >99.9% of all HIV infections identified in the United States were categorized as HIV-1, and the number of HIV-2 diagnoses (mono-infection or dual-infection) remained extremely low (<0.03% of all HIV infections). In addition, the overall number of false positive HIV-2 test results produced by the HIV-1/HIV-2 differentiation increased. The diagnostic value of a confirmatory antibody differentiation test in a setting with sensitive and specific screening tests and few HIV-2 infections might be limited. Evaluation and consideration of other HIV tests approved by the Food and Drug Administration (FDA) that might increase efficiencies in the CDC and Association of Public Health Laboratories-recommended HIV testing algorithm are warranted.

Racial and Ethnic Disparities in Sustained Viral Suppression and Transmission Risk Potential Among Persons Receiving HIV Care - United States, 2014.

Non-Hispanic blacks/African Americans (blacks) represent 12% of the U.S. POPULATION: * However, in 2014 an estimated 43% (471,500) of persons living with diagnosed and undiagnosed human immunodeficiency virus (HIV) infection were blacks (1). In 2016, blacks accounted for 44% of all new HIV diagnoses (2). Although antiretroviral therapy (ART) prescriptions among persons in HIV care increased overall from 89% in 2009 to 94% in 2013, fewer blacks than Hispanics or Latinos (Hispanics) and non-Hispanic whites (whites) were on ART and had a suppressed viral load (<200 HIV RNA copies/mL) in their most recent viral load test result (3). Blacks also might be less likely to have sustained viral suppression over time and to experience longer periods with viral loads >1,500 HIV RNA copies/mL, a level that increases the risk for transmitting HIV (4-7). National HIV Surveillance System (NHSS) data are among those used to monitor progress toward reaching the national goal of reducing health disparities. CDC analyzed NHSS data to describe sustained viral suppression and transmission risk potential by race/ethnicity. Among 651,811 persons with HIV infection diagnosed through 2013 and who were alive through 2014 in 38 jurisdictions with complete laboratory reporting, a lower percentage of blacks had sustained viral suppression (40.8%), than had Hispanics (50.1%) and whites (56.3%). Among persons who were in care (i.e., had at least one viral load test in 2014) and had not achieved sustained viral suppression in 2014, blacks experienced longer periods (52.1% of the 12-month period) with viral loads >1,500 copies/mL, than did Hispanics (47.2%) and white (40.8%). Blacks aged 13-24 years had the lowest prevalence of sustained viral suppression, a circumstance that might increase transmission risk potential. Strengthening interventions that improve access to ART, promote adherence, and address barriers to clinical care and supportive services for all persons with diagnosed HIV infection is important for achieving the national goal of reducing health disparities.

Zinc Finger Homeodomain Factor Zfhx3 Is Essential for Mammary Lactogenic Differentiation by Maintaining Prolactin Signaling Activity.

The zinc finger homeobox 3 (ZFHX3, also named ATBF1 for AT motif binding factor 1) is a transcription factor that suppresses prostatic carcinogenesis and induces neuronal differentiation. It also interacts with estrogen receptor α to inhibit cell proliferation and regulate pubertal mammary gland development in mice. In the present study, we examined whether and how Zfhx3 regulates lactogenic differentiation in mouse mammary glands. At different stages of mammary gland development, Zfhx3 protein was expressed at varying levels, with the highest level at lactation. In the HC11 mouse mammary epithelial cell line, an in vitro model of lactogenesis, knockdown of Zfhx3 attenuated prolactin-induced ß-casein expression and morphological changes, indicators of lactogenic differentiation. In mouse mammary tissue, knock-out of Zfhx3 interrupted lactogenesis, resulting in underdeveloped glands with much smaller and fewer alveoli, reduced ß-casein expression, accumulation of large cytoplasmic lipid droplets in luminal cells after parturition, and failure in lactation. Mechanistically, Zfhx3 maintained the expression of Prlr (prolactin receptor) and Prlr-Jak2-Stat5 signaling activity, whereas knockdown and knock-out of Zfhx3 in HC11 cells and mammary tissues, respectively, decreased Prlr expression, Stat5 phosphorylation, and the expression of Prlr-Jak2-Stat5 target genes. These findings indicate that Zfhx3 plays an essential role in proper lactogenic development in mammary glands, at least in part by maintaining Prlr expression and Prlr-Jak2-Stat5 signaling activity.

Using the Index of Concentration at the Extremes to Evaluate Associations of Economic and Hispanic/Latino-White Racial Segregation with HIV Outcomes Among Adults Aged ≥ 18 Years with Diagnosed HIV - United States, 2021.

OBJECTIVE(S): To examine associations between Index of Concentration at the Extremes (ICE) measures (proxy for structural racism) for economic and Hispanic/Latino-White racial segregation and HIV outcomes among adults in the U.S. METHODS: Census tract-level HIV diagnoses, linkage to HIV medical care within 1 month of diagnosis (linkage), and viral suppression within 6 months of diagnosis (viral suppression) data for 2021 from the National HIV Surveillance System were used. Three ICE measures were obtained from the American Community Survey: ICEincome (income segregation), ICErace (Hispanic/Latino-White racial segregation), and ICEincome + race (Hispanic/Latino-White racialized economic segregation). Rate ratios (RRs) for HIV diagnosis and prevalence ratios (PRs) for linkage and viral suppression were used to examine differences in HIV outcomes across ICE quintiles with Quintile5 (Q5: most privileged) as reference group and adjusted by selected characteristics. RESULTS: Among the 32,529 adults, diagnosis rates were highest in Quintile1 (Q1: most deprived) for ICEincome (28.7) and ICEincome + race (28.4) and Q2 for ICErace (27.0). We also observed higher RRs in HIV diagnosis and lower PRs in linkage and viral suppression (except for ICErace for linkage) in Q1 compared to Q5. Higher RRs and lower PRs in ICE measures were observed among males (diagnosis), adults aged 18‒34 (diagnosis and linkage) and aged ≥ 45 (viral suppression), and among adults in the South (all 3 HIV outcomes). CONCLUSIONS: Barriers in access to care/treatment in more Hispanic/Latino-White racialized economic segregated communities perpetuate the disproportionate impact of HIV on the population. Removing barriers to HIV care/treatment created by systemic racism/segregation may improve HIV outcomes and reduce disparities.

Compounds identification and mechanism prediction of YuXueBi capsule in the treatment of arthritis by integrating UPLC/IM-QTOF-MS and network pharmacology.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that seriously affects the life quality of patients. As a patent medicine of Chinese traditional medicine, YuXueBi capsule (YXBC) is widely used for treating RA with significant effects. However, its active compounds and therapeutic mechanisms are not fully illuminated, encumbering the satisfactory clinical application. In this study, we developed a method for identifying the chemical compounds of YXBC and the absorbed compounds into blood of rats using ultra performance liquid chromatography/ion mobility-quadrupole time-of-flight mass spectrometry (UPLC/IM-QTOF-MS) combined with UNIFI analysis software. A total of 58 compounds in YXBC were unambiguously or tentatively identified, 16 compounds from which were found in serum of rats after administration of YXBC. By network pharmacology, these prototype compounds identified in serum were predicted to regulate 30 main pathways (including HIF-1 signaling pathway, neuroactive ligand-receptor interaction, IL-17 signaling pathway, and so on) through 146 targets, resulting in promoting blood circulation and removing blood stasis, analgesia, and anti-inflammatory activities. This study provides a scientific basis for the clinical efficacy of YXBC in the treatment of RA.

A difficulty-aware and task-augmentation method based on meta-learning model for few-shot diabetic retinopathy classification.

Background: Accurate classification techniques are essential for the early diagnosis and treatment of patients with diabetic retinopathy (DR). However, the limited amount of annotated DR data poses a challenge for existing deep-learning models. This article proposes a difficulty-aware and task-augmentation method based on meta-learning (DaTa-ML) model for few-shot DR classification with fundus images. Methods: The difficulty-aware (Da) method operates by dynamically modifying the cross-entropy loss function applied to learning tasks. This methodology has the ability to intelligently down-weight simpler tasks, while simultaneously prioritizing more challenging tasks. These adjustments occur automatically and aim to optimize the learning process. Additionally, the task-augmentation (Ta) method is used to enhance the meta-training process by augmenting the number of tasks through image rotation and improving the feature-extraction capability. To implement the expansion of the meta-training tasks, various task instances can be sampled during the meta-training stage. Ultimately, the proposed Ta method was introduced to optimize the initialization parameters and enhance the meta-generalization performance of the model. The DaTa-ML model showed promising results by effectively addressing the challenges associated with few-shot DR classification. Results: The Asia Pacific Tele-Ophthalmology Society (APTOS) 2019 blindness detection data set was used to evaluate the DaTa-ML model. The results showed that with only 1% of the training data (5-way, 20-shot) and a single update step (training time reduced by 90%), the DaTa-ML model had an accuracy rate of 89.6% on the test data, which is a 1.7% improvement over the transfer-learning method [i.e., residual neural network (ResNet)50 pre-trained on ImageNet], and a 16.8% improvement over scratch-built models (i.e., ResNet50 without pre-trained weights), despite having fewer trainable parameters (the parameters used by the DaTa-ML model are only 0.47% of the ResNet50 parameters). Conclusions: The DaTa-ML model provides a more efficient DR classification solution with little annotated data and has significant advantages over state-of-the-art methods. Thus, it could be used to guide and assist ophthalmologists to determine the severity of DR.

Role of ERRF, a novel ER-related nuclear factor, in the growth control of ER-positive human breast cancer cells.

Whereas estrogen-estrogen receptor α (ER) signaling plays an important role in breast cancer growth, it is also necessary for the differentiation of normal breast epithelial cells. How this functional conversion occurs, however, remains unknown. Based on a genome-wide sequencing study that identified mutations in several breast cancer genes, we examined some of the genes for mutations, expression levels, and functional effects on cell proliferation and tumorigenesis. We present the data for C1orf64 or ER-related factor (ERRF) from 31 cell lines and 367 primary breast cancer tumors. Whereas mutation of ERRF was infrequent (1 of 79 or 1.3%), its expression was up-regulated in breast cancer, and the up-regulation was more common in lower-stage tumors. In addition, increased ERRF expression was significantly associated with ER and/or progesterone receptor (PR) positivity, which was still valid in human epidermal growth factor receptor 2 (HER2)-negative tumors. In ER-positive tumors, ERRF expression was inversely correlated with HER2 status. Furthermore, higher ERRF protein expression was significantly associated with better disease-free survival and overall survival, particularly in ER- and/or PR-positive and HER2-negative tumors (luminal A subtype). Functionally, knockdown of ERRF in two ER-positive breast cancer cell lines, T-47D and MDA-MB-361, suppressed cell growth in vitro and tumorigenesis in xenograft models. These results suggest that ERRF plays a role in estrogen-ER-mediated growth of breast cancer cells and could, thus, be a potential therapeutic target.

Oestrogen causes ATBF1 protein degradation through the oestrogen-responsive E3 ubiquitin ligase EFP.

We reported previously that the tumour suppressor ATBF1 (AT motif-binding factor 1) formed an autoregulatory feedback loop with oestrogen-ERα (oestrogen receptor α) signalling to regulate oestrogen-dependent cell proliferation in breast cancer cells. In this loop ATBF1 inhibits the function of oestrogen-ERα signalling, whereas ATBF1 protein levels are fine-tuned by oestrogen-induced transcriptional up-regulation as well as UPP (ubiquitin-proteasome pathway)-mediated protein degradation. In the present study we show that EFP (oestrogen-responsive finger protein) is an E3 ubiquitin ligase mediating oestrogen-induced ATBF1 protein degradation. Knockdown of EFP increases ATBF1 protein levels, whereas overexpression of EFP decreases ATBF1 protein levels. EFP interacts with and ubiquitinates ATBF1 protein. Furthermore, we show that EFP is an important factor in oestrogen-induced ATBF1 protein degradation in which some other factors are also involved. In human primary breast tumours the levels of ATBF1 protein are positively correlated with the levels of EFP protein, as both are directly up-regulated ERα target gene products. However, the ratio of ATBF1 protein to EFP protein is negatively correlated with EFP protein levels. Functionally, ATBF1 antagonizes EFP-mediated cell proliferation. These findings not only establish EFP as the E3 ubiquitin ligase for oestrogen-induced ATBF1 protein degradation, but further support the autoregulatory feedback loop between ATBF1 and oestrogen-ERα signalling and thus implicate ATBF1 in oestrogen-dependent breast development and carcinogenesis.

Estrogen up-regulates ATBF1 transcription but causes its protein degradation in estrogen receptor-alpha-positive breast cancer cells.

The proper level of estrogen-estrogen receptor (ER) signaling is important for the maintenance of epithelial homeostasis in the breast. In a previous study we demonstrated that ATBF1, which has been suggested as a tumor suppressor in breast cancer, inhibited estrogen-mediated cell proliferation by selectively competing with AIB1 for binding to the ER. However, the expression of ATBF1 mRNA was shown to positively correlate with ER in breast cancer specimens. We, therefore, examined whether estrogen regulates ATBF1. We demonstrated that estrogen up-regulated the transcription of ATBF1, which was mediated by the direct binding of the ER onto the ATBF1 promoter, and that a half-estrogen-responsive element in the ATBF1 promoter was essential for ER direct binding. Furthermore, we found that estrogen at lower levels increased, but at higher levels decreased the expression of ATBF1 protein, which involved the degradation of ATBF1 protein by the estrogen-responsive proteasome system. ATBF1 protein levels fluctuate with estrogen levels. Although lower levels of estrogen increased ATBF1 protein expression, ATBF1 still inhibited cell proliferation caused by lower levels of estrogen. These findings not only reveal an autoregulatory feedback loop between ATBF1 and estrogen-ER signaling but also suggest that ATBF1 plays a role in both the maintenance of breast epithelial homeostasis and breast tumorigenesis caused by elevated estrogen levels.

Oestrogen causes degradation of KLF5 by inducing the E3 ubiquitin ligase EFP in ER-positive breast cancer cells.

KLF5 (Krüppel-like factor 5) is a multifunctional transcription factor involved in cell proliferation, differentiation and carcinogenesis. In addition to frequent inactivation in different types of human cancers, including breast cancer, KLF5 has been identified as an essential co-factor for the TGF-ß (transforming growth factor ß) tumour suppressor. In our previous study demonstrating a negative regulation of ER (oestrogen receptor α) function by KLF5 in breast cancer cells [Guo, Dong, Zhao, Sun, Li and Dong (2010) Int. J. Cancer 126, 81-89], we noticed that oestrogen reduced the protein level of KLF5. In the present study, we have tested whether and how oestrogen/ER signalling regulates KLF5 protein. We found that oestrogen caused the degradation of KLF5 protein, and the degradation was sensitive to proteasome inhibitors, but not other inhibitors. The oestrogen-inducible E3 ligase EFP (oestrogen-responsive finger protein) was identified as a key player in oestrogen-mediated degradation of KLF5, as knockdown and overexpression of EFP increased and decreased KLF5 protein levels respectively, and the decrease continued even when protein synthesis was blocked. EFP-mediated degradation impaired the function of KLF5 in gene transcription. Although only unubiquitinated EFP interacted with KLF5, overexpression of EFP appeared to prevent the ubiquitination of KLF5, while resulting in heavy ubiquitination of the E3 itself. Furthermore, ubiquitination of EFP interrupted its interaction with KLF5. Although the mechanism for how EFP degrades KLF5 remains to be determined, the results of the present study suggest that oestrogen causes the degradation of KLF5 protein by inducing the expression of EFP in ER-positive breast cancer cells.

ATBF1 inhibits estrogen receptor (ER) function by selectively competing with AIB1 for binding to the ER in ER-positive breast cancer cells.

Loss of the q22 band of chromosome 16 is a frequent genetic event in breast cancer, and the candidate tumor suppressor gene, ATBF1, has been implicated in breast cancer by genomic deletion, transcriptional down-regulation, and association with better prognostic parameters. In addition, estrogen receptor (ER)-positive breast cancer expresses a higher level of ATBF1, suggesting a role of ATBF1 in ER-positive breast cancer. In this study, we examined whether and how ATBF1 affects the ER function in breast cancer cells. We found that ATBF1 inhibited ER-mediated gene transcription, cell growth, and proliferation in ER-positive breast cancer cells. In vitro and in vivo immunoprecipitation experiments revealed that ATBF1 interacted physically with the ER and that multiple domains in both ATBF1 and ER proteins mediated the interaction. Furthermore, we demonstrated that ATBF1 inhibited ER function by selectively competing with the steroid receptor coactivator AIB1 but not GRIP1 or SRC1 for binding to the ER. These findings not only support the concept that ATBF1 plays a tumor-suppressive role in breast cancer, they also provide a mechanism for how ATBF1 functions as a tumor suppressor in breast cancer.

Acetylation of KLF5 alters the assembly of p15 transcription factors in transforming growth factor-beta-mediated induction in epithelial cells.

KLF5 plays important roles in a variety of cellular processes including proliferation and differentiation. Recently KLF5 was shown to reverse its function in proliferative and p15 regulation upon transforming growth factor-beta (TGFbeta)-mediated acetylation. To understand how KLF5 acetylation functions in TGFbeta-induced p15 transcription, we characterized the interactions of KLF5 with other transcription factors and promoter DNA elements in the context of TGFbeta. KLF5 interacted with Smad2-4 and Miz-1 in a TGFbeta-independent manner, but interacted with Myc only when TGFbeta was activated, and at least some of the interactions had an additive effect on TGFbeta-induced p15 transcription. Oligo pulldown assays showed that binding of Myc to the Inr element was KLF5-dependent, and TGFbeta could enhance the binding when more KLF5 was available. Furthermore, TGFbeta induced an interaction between KLF5 and the p300 acetylase, and acetylation of KLF5 was necessary for Smad4 to associate with p300. Failure in KLF5 acetylation not only prevented p300-assembled Smad4-KLF5 complex formation on p15 promoter but also affected the binding of Smad4 and FOXO3 on the p15 promoter in vivo. These findings suggest that without TGFbeta, some KLF5 associates with Smads in the nucleus and other KLF5 associates with Miz-1 on the p15 promoter to repress its transcription. Activation of TGFbeta recruits p300 to the KLF5-Smad complex to acetylate KLF5, and the complex with acetylated KLF5 binds to the Smad binding element and alters the binding of other factors to p15 promoter to induce its transcription.

Opposing effects of KLF5 on the transcription of MYC in epithelial proliferation in the context of transforming growth factor beta.

The proto-oncogene MYC plays a critical role in cell proliferation and tumorigenesis, and its down-regulation by transforming growth factor beta (TGFbeta) signaling is necessary for TGFbeta to inhibit cell proliferation. KLF5, on the other hand, is a pro-proliferative basic transcription factor that reverses function to become an anti-proliferative TGFbeta cofactor upon TGFbeta stimulation in epithelial homeostasis. In this study we investigated whether KLF5 directly regulates MYC transcription in epithelial cells in the context of TGFbeta. Knockdown of KLF5 significantly reduced MYC expression in the HaCaT epidermal epithelial cells. When TGFbeta was applied, however, whereas MYC expression was significantly inhibited, knockdown of KLF5 increased MYC expression. Furthermore, re-expression of KLF5 restored the inhibitory effect of TGFbeta on MYC expression in two cancer cell lines. Chromatin immunoprecipitation and oligo pulldown experiments demonstrated that whereas binding of KLF5 to both KLF5 binding element (KBE) and TGFbeta inhibitory element (TIE) DNA elements was necessary for MYC transcription, binding to KBE was decreased by TGFbeta, and binding to TIE was increased by TGFbeta. These results suggest that KLF5 is not only essential for MYC transcription in proliferating epithelial cells but also mediates the inhibitory effect of TGFbeta on MYC transcription. Furthermore, different binding sites mediate different effects of KLF5 in the context of TGFbeta.

Estrogen-induced interaction between KLF5 and estrogen receptor (ER) suppresses the function of ER in ER-positive breast cancer cells.

Kruppel-like factor 5 (KLF5) is implicated in human breast cancer by frequent genomic deletion and expressional deregulation, but the molecular mechanisms by which KLF5 affects breast tumorigenesis are still unknown. This study was conducted to examine whether and how KLF5 affects the function of estrogen receptor (ER) in breast cancer cells. Using different cell lines, we found that restored expression of KLF5 inhibited estrogen-promoted cell proliferation in ER-positive MCF-7 and T-47D cell lines but had no effect on ER-negative SK-BR-3 cells. Transcriptional activity of ER was also suppressed by KLF5, as detected by using estrogen-stimulated ER responsive element-mediated reporter assay and expression analysis of ER target genes including c-MYC and Cathepsin D (CSTD). Chromatin immunoprecipitation assays showed that KLF5 inhibited ERalpha binding to the promoter of c-myc and CSTD. Furthermore, estrogen induced an interaction between KLF5 and ERalpha. These results suggest that KLF5 inhibits the function of ERalpha in gene regulation and cell proliferation through protein interaction that interrupts the binding of ERalpha to target gene promoters to prevent target gene induction.

SnoRNA U50 is a candidate tumor-suppressor gene at 6q14.3 with a mutation associated with clinically significant prostate cancer.

Deletion of chromosome 6q14-q22 is common in multiple human cancers including prostate cancer, and chromosome 6 transferred into cancer cells induces senescence and reduces cell growth, tumorigenicity and metastasis, indicating the existence of one or more tumor-suppressor genes in 6q. To identify the 6q tumor-suppressor gene, we first narrowed the common region of deletion to a 2.5 Mb interval at 6q14-15. Of the 11 genes located in this minimal deletion region and expressed in normal prostates, only snoRNA U50 was mutated, demonstrated transcriptional downregulation and inhibited colony formation in prostate cancer cells. The mutation, a homozygous 2 bp (TT) deletion, was found in two of 30 prostate cancer cell lines/xenografts and nine of 89 localized prostate cancers (eleven of 119 or 9% cancers). Two of 89 (2%) patients with prostate cancer also showed the same mutation in their germline DNA, but none of 104 cancer-free control men did. The homozygous deletion abolished U50 function in a colony formation assay. Analysis of 1371 prostate cancer cases and 1371 matched control men from a case-control study nested in a prospective cohort showed that, although a germline heterozygous genotype of the deletion was detected in both patients and controls at similar frequencies, the homozygosity of the deletion was significantly associated with clinically significant prostate cancer (odds ratio 2.9; 95% confidence interval 1.17-7.21). These findings establish snoRNA U50 as a reasonable candidate for the 6q tumor-suppressor gene in prostate cancer and likely in other types of cancers.

Brief Report: Racial and Ethnic Disparities in Sustained Viral Suppression and Transmission Risk Potential Among Persons Aged 13-29 Years Living With Diagnosed HIV Infection, United States, 2016.

BACKGROUND: In 2016, persons aged 13-29 years represented 23.1% of the US population, yet accounted for 41.7% of HIV diagnoses. Racial/ethnic minorities are disproportionally affected by HIV. Sustaining viral suppression helps persons living with diagnosed HIV infection (PLWDH) stay healthy and reduces the risk of transmitting HIV. We examined racial/ethnic disparities in sustained viral suppression and transmission risk potential among PLWDH aged 13-29 years. METHODS: We analyzed data from the National HIV Surveillance System reported through December 2018 from 42 jurisdictions with complete laboratory reporting. We included persons aged 13-29 years who received an HIV diagnosis by December 31, 2015, most recently resided in one of the 42 jurisdictions, and were alive at the end of 2016. Sustained viral suppression was defined as viral load <200 copies/mL for all tests in 2016. Transmission risk potential was estimated using the number of days with viral loads >1500 copies/mL. RESULTS: Of the 90,812 PLWDH aged 13-29 years included in the analysis, 41.5% had sustained viral suppression in 2016. Across age, sex, and most transmission categories, blacks had the lowest prevalence of sustained viral suppression. Among the 28,154 who were in care but without sustained viral suppression, the average number of days with viral load >1500 copies/mL was 206 days (56.4% of the 12-month period). CONCLUSIONS: Sustained viral suppression was suboptimal and transmission risk potential was high for PLWDH aged 13-29 years. Racial/ethnic disparities were apparent, calling for strengthening tailored interventions to improve care outcomes.