Conditional telomerase induction causes proliferation of hair follicle stem cells.

TERT, the protein component of telomerase, serves to maintain telomere function through the de novo addition of telomere repeats to chromosome ends, and is reactivated in 90% of human cancers. In normal tissues, TERT is expressed in stem cells and in progenitor cells, but its role in these compartments is not fully understood. Here we show that conditional transgenic induction of TERT in mouse skin epithelium causes a rapid transition from telogen (the resting phase of the hair follicle cycle) to anagen (the active phase), thereby facilitating robust hair growth. TERT overexpression promotes this developmental transition by causing proliferation of quiescent, multipotent stem cells in the hair follicle bulge region. This new function for TERT does not require the telomerase RNA component, which encodes the template for telomere addition, and therefore operates through a mechanism independent of its activity in synthesizing telomere repeats. These data indicate that, in addition to its established role in extending telomeres, TERT can promote proliferation of resting stem cells through a non-canonical pathway.

TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program.

Telomerase serves a critical role in stem cell function and tissue homeostasis. This role depends on its ability to synthesize telomere repeats in a manner dependent on the reverse transcriptase (RT) function of its protein component telomerase RT (TERT), as well as on a novel pathway whose mechanism is poorly understood. Here, we use a TERT mutant lacking RT function (TERT(ci)) to study the mechanism of TERT action in mammalian skin, an ideal tissue for studying progenitor cell biology. We show that TERT(ci) retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis. To understand the nature of this RT-independent function for TERT, we studied the genome-wide transcriptional response to acute changes in TERT levels in mouse skin. We find that TERT facilitates activation of progenitor cells in the skin and hair follicle by triggering a rapid change in gene expression that significantly overlaps the program controlling natural hair follicle cycling in wild-type mice. Statistical comparisons to other microarray gene sets using pattern-matching algorithms revealed that the TERT transcriptional response strongly resembles those mediated by Myc and Wnt, two proteins intimately associated with stem cell function and cancer. These data show that TERT controls tissue progenitor cells via transcriptional regulation of a developmental program converging on the Myc and Wnt pathways.

Reinvigorating the clinical examination for the 21st century.

At its most fundamental level, the clinical encounter between a patient and their doctor seeks to solve a mystery. Clinicians uncover clues through the history, physical examination, and ancillary tests to arrive at a diagnosis and develop a management plan. Despite advances in technology, the majority of clinical diagnoses are still reached through the history and physical examination without the use of laboratory and imaging tests. However, in the modern American hospital, clinicians spend as little as 12% of their time in direct contact with patients and their families. This has led to a decline in clinical examination skills and contributes to diagnostic error. There is a growing movement to return clinicians and trainees back to the bedside. In 2017, we formed the Society of Bedside Medicine to encourage innovation, education, and research on the role of the clinical encounter in 21st century medicine. Over the last 3 years, we have embraced the following 6 strategies to reinvigorate the practice of the clinical examination: 1) be present with the patient; 2) practice an evidence­based approach to the physical exam; 3) create opportunities for intentional practice of the physical exam; 4) recognize the power of the physical examination beyond diagnosis; 5) use point­of­care technology to aid in diagnosis and reinforce skills; and 6) seek and provide specific feedback on physical examination skills. By employing these strategies in both teaching and practice, clinicians can maximize the value of time spent with patients and renew the importance of the clinical examination in 21st century practice.

The Outpatient Physical Examination.

The physical examination in the outpatient setting is a valuable tool. Even in settings where there is lack of evidence, such as the annual physical examination of an asymptomatic adult, the physical examination is beneficial for the physician-patient relationship. When a patient has specific symptoms, the physical examination-in addition to a thorough history-can help narrow down, or in many cases establish, a diagnosis. In a time where imaging and laboratory tests are easily available, but are expensive and can be invasive, a skilled physical examination remains an important component of patient evaluation.