data-tracker/#variant-proportions Vaccine type/Period † Aggregate weekly count of residents No. of cases Vaccine effectiveness, % (95% CI) p-value** Unadjusted § Adjusted ¶ Any mRNA vaccine

During epithelial homeostasis, stem cells divide to produce progenitor cells, which not only proliferate to generate the cell mass but also respond to cellular signaling to transition from a proliferative state to a differentiation state. Such a transition involves functional alterations of transcriptional factors, yet the underlying molecular mechanisms are poorly understood. Recent studies have implicated Kruppel-like factors (KLFs) including KLF5 in the renewal and maintenance of stem/progenitor cells. Here we demonstrate that the pro-proliferative factor KLF5 becomes anti-proliferative upon TGF␤-mediated acetylation in an in vitro model of epithelial homeostasis. In the HaCaT epidermal cell line treated with or without TGF␤, we found that KLF5 was not only essential for cell proliferation, it was also indispensable for TGF␤-induced anti-proliferation in these cells. KLF5 inhibited the expression of p15 (CDKN2B), a cell cycle inhibitor, without TGF␤, but became a coactivator in TGF␤-induced p15 expression in the same cells. Mechanistically, TGF␤ recruited acetylase p300 to acetylate KLF5, and acetylation in turn altered the binding of KLF5 to p15 promoter, resulting in the reversal of KLF5 function. These studies not only demonstrate that a basic transcription factor can be both pro-proliferation and anti-proliferation in epithelial homeostasis, they also present a unique mechanism for how transcriptional regulation changes during the transition from proliferation to inhibition of proliferation. Furthermore, they establish KLF5 as an essential cofactor for TGF␤ signaling.Epithelia constitute the surface and lining of many solid tissues and have essential functions in different tissues. They are maintained through epithelial homeostasis, which involves the proliferation of stem/progenitor cells and the differentiation of their daughter cells. Epithelial homeostasis constantly occurs in vivo, and its disruption causes different diseases including cancer (1). At the molecular level, signaling from stroma compartment in a tissue such as transforming growth factor ␤ (TGF␤) 2 signaling regulates epithelial homeostasis through a transcriptional network, but the molecular details are not well understood.The basic transcription factor KLF5 is ubiquitously expressed in many tissues including the breast, colon, intestine, lung, prostate, etc (2-5). KLF5 is highly expressed in proliferating epithelial cells such as immortal but untransformed epithelial cell lines and proliferating primary cultures of epithelial cells, which mostly represent progenitor cells (2, 3, 6, 7). In normal intestine, KLF5 is expressed at a higher level in basal rapidly proliferating cells, but at a lower level in mature and differentiated cells (8) and knock-out of one KLF5 allele significantly reduced the size of villi in mouse intestine (8). In vivo overexpression of KLF5 in epidermis causes hyperplasia of basal cells but lack of mature skin (9), further indicating a proproliferative role of KLF5 in epithelial homeostasis. Recently a combinatio...

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.

Deletion of chromosome 6q is frequent in breast cancer, and the deletion often involves a region in 6q14-q16. At present, however, the underlying tumor suppressor gene has not been established. Based on a recent study identifying snoRNA U50 as a candidate for the 6q14-16 tumor suppressor gene in prostate cancer, we investigated whether U50 is also involved in breast cancer. PCR-based approaches showed that U50 underwent frequent genomic deletion and transcriptional downregulation in cell lines derived from breast cancer. Mutation screening identified the same 2-bp deletion of U50 as in prostate cancer in both cell lines and primary tumors from breast cancer, and the deletion was both somatic and in germline. Genotyping of a cohort of breast cancer cases and controls for the mutation demonstrated that, while homozygous genotype of the mutation was rare, its heterozygous genotype occurred more frequently in women with breast cancer. Functionally, re-expression of U50 resulted in the inhibition of colony formation in breast cancer cell lines. These results suggest that noncoding snoRNA U50 plays a role in the development and/or progression of breast cancer.

Rationale Low circulating progenitor cell (PC) numbers and activity may reflect impaired intrinsic regenerative/reparative potential, but it remains uncertain whether this translates into a worse prognosis. Objectives To investigate whether low numbers of PCs associate with a greater risk of mortality in a population at high cardiovascular risk. Methods & Results Patients undergoing coronary angiography were recruited into two cohorts (1, n=502 and 2, n=403) over separate time periods. PCs were enumerated by flow cytometry as CD45med+ blood mononuclear cells expressing CD34, with additional quantification of subsets co-expressing CD133, VEGFR2 and CXCR4. Coefficient of variation for CD34 cells was 2.9% and 4.8%, 21.6% and 6.5% for the respective subsets. Each cohort was followed for a mean of 2.7 and 1.2 years, respectively, for the primary endpoint of all-cause death. There was an inverse association between CD34+ and CD34+/CD133+ cell counts and risk of death in Cohort 1 (β=−0.92, p=0.043 and β=−1.64, p=0.019, respectively) that was confirmed in Cohort 2 (β=−1.25, p=0.020 and β=−1.81, p=0.015, respectively). Covariate adjusted HRs in the pooled cohort (n=905) were 3.54 (1.67-7.50) and 2.46 (1.18-5.13), respectively. CD34+/CD133+ cell counts improved risk prediction metrics beyond standard risk factors. Conclusion Reduced circulating PC counts, identified primarily as CD34+ mononuclear cells or its subset expressing CD133 are associated with risk of death in individuals with coronary artery disease, suggesting that impaired endogenous regenerative capacity is associated with increased mortality. These findings have implications for biological understanding, risk prediction and cell selection for cell based therapies.

On January 8, 2021, this report was posted as an MMWR Early Release on the MMWR website (https://www.cdc.gov/mmwr).During the beginning of the coronavirus disease 2019 (COVID-19) pandemic, nursing homes were identified as congregate settings at high risk for outbreaks of 2). Their residents also are at higher risk than the general population for morbidity and mortality associated with infection with SARS-CoV-2, the virus that causes COVID-19, in light of the association of severe outcomes with older age and certain underlying medical conditions (1,3). CDC's National Healthcare Safety Network (NHSN) launched nationwide, facility-level COVID-19 nursing home surveillance on April 26, 2020. A federal mandate issued by the Centers for Medicare & Medicaid Services (CMS), required nursing homes to commence enrollment and routine reporting of COVID-19 cases among residents and staff members by May 25, 2020. This report uses the NHSN nursing home COVID-19 data reported during May 25-November 22, 2020, to describe COVID-19 rates among nursing home residents and staff members and compares these with rates in surrounding communities by corresponding U.S. Department of Health and Human Services (HHS) region.* COVID-19 cases among nursing home residents increased during June and July 2020, reaching 11.5 cases per 1,000 resident-weeks (calculated as the total number of occupied beds on the day that weekly data were reported) (week of July 26). By mid-September, rates had declined to 6.3 per 1,000 resident-weeks (week of September 13) before increasing again, reaching 23.2 cases per 1,000 residentweeks by late November (week of November 22). COVID-19 cases among nursing home staff members also increased during June and July (week of July 26 = 10.9 cases per 1,000 resident-weeks) before declining during August-September (week of September 13 = 6.3 per 1,000 resident-weeks); rates increased by late November (week of November 22 = 21.3 cases per 1,000 resident-weeks). Rates of COVID-19 in the surrounding communities followed similar trends. Increases in community rates might be associated with increases in nursing home COVID-19 incidence, and nursing home mitigation strategies need to include a comprehensive plan to monitor local SARS-CoV-2 transmission and minimize highrisk exposures within facilities.

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.

The proto-oncogene MYC plays a critical role in cell proliferation and tumorigenesis, and its down-regulation by transforming growth factor ␤ (TGF␤) signaling is necessary for TGF␤ to inhibit cell proliferation. KLF5, on the other hand, is a pro-proliferative basic transcription factor that reverses function to become an anti-proliferative TGF␤ cofactor upon TGF␤ stimulation in epithelial homeostasis. In this study we investigated whether KLF5 directly regulates MYC transcription in epithelial cells in the context of TGF␤. Knockdown of KLF5 significantly reduced MYC expression in the HaCaT epidermal epithelial cells. When TGF␤ 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 TGF␤ 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 TGF␤ inhibitory element (TIE) DNA elements was necessary for MYC transcription, binding to KBE was decreased by TGF␤, and binding to TIE was increased by TGF␤. These results suggest that KLF5 is not only essential for MYC transcription in proliferating epithelial cells but also mediates the inhibitory effect of TGF␤ on MYC transcription. Furthermore, different binding sites mediate different effects of KLF5 in the context of TGF␤.The c-myc (MYC) gene encodes a short-lived transcription factor (MYC) which heterodimerizes with Max. MYC/Max heterodimers activate or repress two distinct pools of target genes that elicit a variety of biological responses, including cell cycle progression, cellular growth, differentiation, and apoptosis/survival (1-3). Physiologically, MYC is broadly expressed during embryogenesis and in the compartments of adult tissues that possess high proliferative capacity, including skin epidermis and gut, and its role in the regulation of cell proliferation, differentiation, and apoptosis has been demonstrated (3). In epithelial homeostasis, MYC has a positive function in cell proliferation which involves its interaction with the zinc finger protein Miz-1 and Smads to repress the cyclin-dependent kinase inhibitor p15Ink4b (4, 5). More specifically, MYC appears to promote the switch from stem cell to transit amplifying cell (6 -9), and ectopic expression of MYC disrupts terminal differentiation of epithelial cells (7). During TGF␤ 2 -induced epithelial differentiation, MYC is rapidly down-regulated, and its down-regulation is necessary for TGF␤ to induce cyclin-dependent kinase inhibitors p15 Ink4b and p21Cip1 and to inhibit cell cycle progression from G 1 to S phase (10, 11). Although the down-regulation of MYC involves a number of transcription factors including Smads and E2F4/5 (12-15), regulation of MYC in proliferating cells is not well understood.Human Krüppel-like factor 5 (KLF5, also named IKLF or BTEB2) belongs to the Sp/KLF zinc finger transcription factor family, which is composed of about 2...