Intestinal epithelial stem cell identity and location has been the matter of substantial research. Cells in the +4 niche are slow-cycling and label retaining, while a distinct stem cell niche located at the crypt base is occupied by crypt base columnar (CBC) cells. CBCs are distinct from +4 cells, and the relationship between them is unknown, though both give rise to all intestinal epithelial lineages. We demonstrate that Hopx, an atypical homeobox protein, is a novel and specific marker of +4 cells. Hopx-expressing cells give rise to CBCs and all mature intestinal epithelial lineages. Conversely, CBCs can give rise to +4 Hopx positive cells. These findings demonstrate a bi-directional lineage relationship between active and quiescent stem cells in their niches.

Summary Epidermal and hair follicle development from surface ectodermal progenitor cells require coordinated changes in gene expression. Histone deacetylases alter gene expression programs through modification of chromatin and transcription factors. We find that deletion of ectodermal Hdac1 and Hdac2 results in dramatic failure of hair follicle specification and epidermal proliferation and stratification, phenocopying loss of the key ectodermal transcription factor p63. While expression of p63 and its positively regulated basal cell targets is maintained in Hdac1/2 deficient ectoderm, targets of p63-mediated repression, including p21, 14-3-3σ and p16/INK4a, are ectopically expressed, and HDACs bind and are active at their promoter regions in normal undifferentiated keratinocytes. Mutant embryos display increased levels of acetylated p53, which opposes p63 functions, and p53 is required for HDAC inhibitor-mediated p21 expression in keratinocytes. Our data identify critical requirements for HDAC1/2 in epidermal development, and indicate that HDAC1/2 directly mediate repressive functions of p63, and suppress p53 activity.

SUMMARYThe mammalian hair follicle relies on adult resident stem cells and their progeny to fuel and maintain hair growth throughout the life of an organism. The cyclical and initially synchronous nature of hair growth makes the hair follicle an ideal system with which to define homeostatic mechanisms of an adult stem cell population. Recently, we demonstrated that Hopx is a specific marker of intestinal stem cells. Here, we show that Hopx specifically labels long-lived hair follicle stem cells residing in the telogen basal bulge. Hopx + cells contribute to all lineages of the mature hair follicle and to the interfollicular epidermis upon epidermal wounding.Unexpectedly, our analysis identifies a previously unappreciated progenitor population that resides in the lower hair bulb of anagenphase follicles and expresses Hopx. These cells co-express Lgr5, do not express Shh and escape catagen-induced apoptosis. They ultimately differentiate into the cytokeratin 6-positive (K6) inner bulge cells in telogen, which regulate the quiescence of adjacent hair follicle stem cells. Although previous studies have suggested that K6 + cells arise from Lgr5-expressing lower outer root sheath cells in anagen, our studies indicate an alternative origin, and a novel role for Hopx-expressing lower hair bulb progenitor cells in contributing to stem cell homeostasis.

There was no correlation between pain severity and disease severity by sinus CT scan as graded by the Lund-McKay, Harvard, or Kennedy staging system. Facial pain and headache, although frequent complaints of patients with rhinosinusitis, are not useful predictors of sinus disease severity. There appears to be a difference in pain perception between the two North American populations.

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Successful treatment of solid cancers relies on complete surgical excision of the tumor either for definitive treatment or before adjuvant therapy. Radial sectioning of the resected tumor and surrounding tissue is the most common form of intra-operative and post-operative margin assessment. However, this technique samples only a tiny fraction of the available tissue and therefore may result in incomplete excision of the tumor, increasing the risk of recurrence and distant metastasis and decreasing survival. Repeat procedures, chemotherapy, and other resulting treatments pose significant morbidity, mortality, and fiscal costs for our healthcare system. Mohs Micrographic Surgery (MMS) is used for the removal of basal cell and squamous cell carcinoma utilizing frozen sections for real-time margin assessment while assessing 100% of the peripheral and deep margins, resulting in a recurrence rate of less than one percent. Real-time assessment in many tumor types is constrained by tissue size and complexity and the time to process tissue and evaluate slides while a patient is under general anesthesia. In this study, we developed an artificial intelligence (AI) platform, ArcticAI, which augments the surgical workflow to improve efficiency by reducing rate-limiting steps in tissue preprocessing and histological assessment through automated mapping and orientation of tumor to the surgical specimen. Using basal cell carcinoma (BCC) as a model system, the results demonstrate that ArcticAI can provide effective grossing recommendations, accurately identify tumor on histological sections, map tumor back onto the surgical resection map, and automate pathology report generation resulting in seamless communication between the surgical pathology laboratory and surgeon. AI-augmented-surgical excision workflows may make real-time margin assessment for the excision of more complex and challenging tumor types more accessible, leading to more streamlined and accurate tumor removal while increasing healthcare delivery efficiency.

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