Topical GZ21T Inhibits the Growth of Actinic Keratoses in a UVB-Induced Model of Skin Carcinogenesis.

Actinic keratoses (AKs) are premalignant intraepidermal neoplasms that occur as a result of cumulative sun damage. AKs commonly relapse, and up to 16% undergo malignant transformation into cutaneous squamous cell carcinoma. There is a need for novel therapies that reduce the quantity and surface area of AKs as well as prevent malignant transformation to cutaneous squamous cell carcinomas. We recently showed that GZ17-6.02, an anticancer agent composed of curcumin, haramine, and isovanillin, inhibited the growth of H297.T cells. This study evaluated the efficacy of a topical formulation of GZ17-6.02, known as GZ21T, in a murine model of AK generated by exposing SKH1 mice to UVR. Treatment of mice with topical GZ21T inhibited the growth of AKs by decreasing both lesion count (P = 0.012) and surface area occupied by tumor (P = 0.002). GZ21T also suppressed the progression of AKs to cutaneous squamous cell carcinoma by decreasing the count (P = 0.047) and surface area (P = 0.049) of lesions more likely to represent cutaneous squamous cell carcinoma. RNA sequencing and proteomic analyses revealed that GZ21T suppressed several pathways, including MAPK (P = 0.025), phosphoinositide 3-kinase-protein kinase B (P = 0.04), HIF-1α (P = 0.016), Wnt (P = 0.025), insulin (P = 0.018), and ERBB (P = 0.016) signaling. GZ21T also upregulated the autophagy-promoting protein AMPK while suppressing proteins such as PD-L1, glutaminase, pAkt1 S473, and eEF2K.

Differential Response of Mycosis Fungoides Cells to Vorinostat.

Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL) and is characterized by epidermotrophism of malignant CD4+ T-lymphocytes. When MF advances to a recurrent stage, patients require treatment with systemic therapies such as vorinostat, a histone deacetylase inhibitor. While vorinostat has been shown to exhibit anti-tumor activity in MF, its exact molecular mechanism has yet to be fully discerned. In the present study, we examined the transcriptomic and proteomic profiles of vorinostat treatment in two MF cell lines, Myla 2059 and HH. We find that vorinostat downregulates CTLA-4, CXCR4, and CCR7 in both cell lines, but its effect on several key pathways differs between the two MF cell lines. For example, vorinostat upregulates CCL5, CCR5, and CXCL10 expression in Myla cells but downregulates CCL5 and CXCL10 expression in HH cells. Furthermore, vorinostat upregulates IFN-γ and IL-23 signaling and downregulates IL-6, IL-7, and IL-15 signaling in Myla cells but does not affect these pathways in HH cells. Although Myla and HH represent established MF cell lines, their distinct tumor origin from separate patients demonstrates that inherent phenotypic variations within the disease persist, underscoring the importance of using a variety of MF cells in the preclinical development of MF therapeutics.

The Tibiofibular Line: A Reliable Method of Syndesmosis Assessment in Certain Fibula Morphologies.

Background The tibiofibular line (TFL) technique was initially proposed to assess syndesmosis reduction. Clinical utility was limited by low observer reliability when applied to all fibulas. This study aimed to refine this technique by describing TFL's applicability to various fibula morphologies. Methods Three observers reviewed 52 ankle CT scans. Observer consistencies for TFL measurement, anterolateral fibula contact length, and fibula morphology were assessed using intraclass correlation (ICC) and Fleiss' Kappa. Results TFL measurement and fibula contact length intra-observer and inter-observer consistencies were excellent (minimum ICC, 0.87). Fibula shape categorization intra-observer consistency was substantial to almost perfect (Fleiss' Kappa, 0.73 to 0.97). Six to 10 mm of fibula contact length corresponded to excellent TFL distance consistency (ICC, 0.80 to 0.98). Conclusion The TFL technique appears best for patients with 6 mm to 10 mm of straight anterolateral fibula. Sixty-one percent (61%) of fibulas featured this morphology, indicating most patients may be amenable to this technique.

Reliability of the "Clinical Tibiofibular Line" Technique for Open Syndesmosis Reduction Assessment.

BACKGROUND: When intraoperative computed tomography (CT) is unavailable, open syndesmosis assessment is a universally available, safe alternative that is more accurate than radiographic assessment. However, it has a documented malreduction rate of up to 16%. This may be improved upon with a validated technique for assessing the accuracy of open syndesmosis reductions. The "tibiofibular line" (TFL) is a CT-based technique found to be sensitive for malreduction. The purpose of this study was to assess the feasibility of adapting the CT-TFL method into a reliable intraoperative open technique by refining the methodology of previous work exploring the clinical TFL technique. METHODS: Three observers were instructed to clinically simulate the TFL on cadaveric lower limbs. For each specimen, observers repeated and recorded 3 clinical TFL measurements for each of 4 measurement series representing different degrees of fibula reduction. Intraclass correlation was used to assess intra- and interobserver reliabilities. RESULTS: Mean intraobserver reliability was .88. Mean interobserver reliability was .75. Both intra- and interobserver reliabilities were highest for anatomic syndesmosis reduction. CONCLUSION: The findings of excellent to near perfect intraobserver and good to excellent interobserver reliability indicate the feasibility of translating the CT-TFL into a reliable open technique. LEVELS OF EVIDENCE: Level III: Diagnostic study.

Computed Tomographic Validation of the Center-Center Radiographic Technique for Syndesmosis Fixation Axis Alignment in Normal Ankles.

BACKGROUND: Ankle syndesmotic ligament injury is an important factor affecting clinical outcome after lower extremity injury with as little as 2 mm of syndesmotic displacement leading to worse clinical outcome. One important factor is the appropriate placement of clamps and fixation across the syndesmosis. When not ideally aligned, these can result in malalignment of the fibula in the incisura. This study sought to provide computer validation of using the center-center technique to identify an ideal centroid axis for placement of syndesmotic implants. METHODS: Thirty computed tomography (CT) scans of patients from July 1, 2016, to June 30, 2018, with normal syndesmoses were evaluated. Center-center and centroid measurements were drawn and compared on the axial CT images at 10, 20, and 30 mm superior to the tibial plafond. Three observers recorded measurements for the same 50 patients in order to compare interobserver reliability. RESULTS: The difference between the centroid and center-center axis at each height level was a mean 0.4 degrees (range, 0.3-0.5 degrees). The center-center and centroid axis change by externally rotating as the height increases away from the tibial plafond with mean, 3 degrees (range, 0-6.1 degrees). Intraclass correlation coefficients (ICCs) were measured at 0.98, thus demonstrating excellent intraobserver and interobserver reliability on these measurements. CONCLUSION: The center-center technique can be used to identify the centroid axis within an acceptable degree of rotation at heights above the tibial plafond that are relevant to an operating surgeon placing syndesmotic fixation. CLINICAL RELEVANCE: Theoretically, this aligns the centroids of the fibula and tibia, which achieves the same ideal patient-specific alignment and raises the question as to the extent to which the centroid and center-center axes correlate in the general population. If present, a strong correlation has potentially high clinical importance when planning syndesmotic fixation.