Dysregulation of the thyroid hormone receptor (TR)β is common in human cancers. Restoration of functional TRβ delays tumor progression in models of thyroid and breast cancers implicating TRβ as a tumor suppressor. Conversely, aberrant expression of the runt-related transcription factor 2 (Runx2) is established in the progression and metastasis of thyroid, breast, and other cancers. Silencing of Runx2 diminishes tumor invasive characteristics. With TRβ as a tumor suppressor and Runx2 as a tumor promoter, a compelling question is whether there is a functional relationship between these regulatory factors in thyroid tumorigenesis. Here, we demonstrated that these proteins are reciprocally expressed in normal and malignant thyroid cells; TRβ is high in normal cells, and Runx2 is high in malignant cells. T3 induced a time- and concentration-dependent decrease in Runx2 expression. Silencing of TRβ by small interfering RNA knockdown resulted in a corresponding increase in Runx2 and Runx2-regulated genes, indicating that TRβ levels directly impact Runx2 expression and associated epithelial to mesenchymal transition molecules. TRβ specifically bound to 3 putative thyroid hormone-response element motifs within the Runx2-P1 promoter ((-)105/(+)133) as detected by EMSA and chromatin immunoprecipitation. TRβ suppressed Runx2 transcriptional activities, thus confirming TRβ regulation of Runx2 at functional thyroid hormone-response elements. Significantly, these findings indicate that a ratio of the tumor-suppressor TRβ and tumor-promoting Runx2 may reflect tumor aggression and serve as biomarkers in biopsy tissues. The discovery of this TRβ-Runx2 signaling supports the emerging role of TRβ as a tumor suppressor and reveals a novel pathway for intervention.

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Background: The femoral intercondylar notch type and the alpha angle (the angle between the femoral notch roof and the long axis of the femur) are easily measured in clinical settings; however, their associations with anterior cruciate ligament (ACL) injury remain unclear. Hypothesis/Purpose: The purpose was to determine if the alpha angle and the femoral notch type are associated with noncontact ACL injury univariately and in combination with previously identified knee geometric risk factors. We hypothesized that the alpha angle and the femoral notch type are associated with noncontact ACL injury and that the association differs between men and women. Study Design: Case control study; Level of evidence, 3. Methods: The alpha angle and the femoral notch type were measured via 3T magnetic resonance imaging (MRI) acquired from 61 women and 25 men with a first-time noncontact ACL injury. Each injured patient was matched with a control participant based on age, sex, and participation on the same sports team. A conditional logistic regression was used to assess univariate associations with ACL injury as well as multivariate associations using MRI-based risk factors of knee geometry identified in previous analyses: femoral intercondylar notch width at the anterior outlet, femoral intercondylar notch anteromedial ridge thickness, volume of the ACL, tibial plateau lateral compartment subchondral bone slope, lateral compartment middle articular cartilage slope, lateral compartment meniscus-cartilage height, lateral compartment meniscus-bone angle, and medial tibial spine volume. Results: For female athletes, the alpha angle (odds ratio, [OR], 1.82 per 1-degree increase; P = .001), the tibial lateral compartment articular cartilage slope (OR, 1.25 per 1-degree increase in the posterior-inferior directed slope; P = .022), and the femoral notch anteromedial ridge thickness (OR, 3.36 per 1-mm increase; P = .027) were independently associated with ACL disruption. For men, no other variables entered the models after the alpha angle was inputted as the first step (OR, 2.19 per 1-degree increase; P = .010). Conclusion: For women, ACL injury was most strongly associated with increased alpha angle, increased tibial plateau slope, and increased femoral notch ridge thickness. For men, increased alpha angle was the most significant factor associated with ACL injury. The mechanism of injury might be associated with a combination of impingement of the ACL against the bone and increased ligament loading.

Metastatic breast cancer is refractory to conventional therapies and is an end-stage disease. RUNX2 is a transcription factor that becomes oncogenic when aberrantly expressed in multiple tumor types, including breast cancer, supporting tumor progression and metastases. Our previous work demonstrated that the thyroid hormone receptor beta (TRβ) inhibits RUNX2 expression and tumorigenic characteristics in thyroid cells. As TRβ is a tumor suppressor, we investigated the compelling question whether TRβ also regulates RUNX2 in breast cancer. The Cancer Genome Atlas indicates that TRβ expression is decreased in the most aggressive basal-like subtype of breast cancer. We established that modulated levels of TRβ results in corresponding changes in the high levels of RUNX2 expression in metastatic, basal-like breast cells. The MDA-MB-231 triple-negative breast cancer cell line exhibits low expression of TRβ and high levels of RUNX2. Increased expression of TRβ decreased RUNX2 levels. The thyroid hormone-mediated suppression of RUNX2 is TRβ specific as TRα overexpression failed to alter RUNX2 expression. Consistent with these findings, knockdown of TRβ in non-tumor MCF10A mammary epithelial-like cells results in an increase in RUNX2 and RUNX2 target genes. Mechanistically, TRβ directly interacts with the proximal promoter of RUNX2 through a thyroid hormone response element to reduce promoter activity. The TRβ suppression of the oncogene RUNX2 is a signaling pathway shared by thyroid and breast cancers. Our findings provide a novel mechanism for TRβ-mediated tumor suppression in breast cancers. This pathway may be common to many solid tumors and impact treatment for metastatic cancers.

Introduction The impact of the COVID-19 pandemic on non‐COVID-19 pathologies has been experienced worldwide. While people appropriately avoided social interactions, many also avoided essential medical care for acute and chronic conditions. This delay in seeking care has been associated with increased morbidity and mortality in several conditions, including life-threatening infections such as necrotizing fasciitis. Methods We retrospectively reviewed the records of patients that presented to the University of Vermont Medical Center for necrotizing fasciitis during the 1-year period following the declaration of a global pandemic on March 11, 2020. We subsequently compared this data with that of the previous 4 years. Results During the period of March 12, 2020 to March 12, 2021, there were 17 cases of newly diagnosed necrotizing fasciitis. Compared with an average per year of 8 cases over the previous 4 years, this represents a 113% percent increase in cases of necrotizing fasciitis during the study period ( P = .071861). Out of the 17 cases, 4 patients died during their admission, producing a case-fatality rate of 23.5%. This represents a statistically significant increase from previous years ( P = .003248), where the average case-fatality rate was 6.3%. Conclusion Our study demonstrates a substantial increase in cases of necrotizing fasciitis following the onset of the coronavirus pandemic. A significant increase in the case-fatality rate was also observed. Given the growing body of literature describing the negative impact of the pandemic on non-COVID-19 morbidity and mortality, our study posits necrotizing fasciitis as one of many affected pathologies. Level of Evidence Level IV. Epidemiological