Krüppel-like Factors 4 and 5 in Colorectal Tumorigenesis.

Krüppel-like factors (KLFs) are transcription factors regulating various biological processes such as proliferation, differentiation, migration, invasion, and homeostasis. Importantly, they participate in disease development and progression. KLFs are expressed in multiple tissues, and their role is tissue- and context-dependent. KLF4 and KLF5 are two fascinating members of this family that regulate crucial stages of cellular identity from embryogenesis through differentiation and, finally, during tumorigenesis. They maintain homeostasis of various tissues and regulate inflammation, response to injury, regeneration, and development and progression of multiple cancers such as colorectal, breast, ovarian, pancreatic, lung, and prostate, to name a few. Recent studies broaden our understanding of their function and demonstrate their opposing roles in regulating gene expression, cellular function, and tumorigenesis. This review will focus on the roles KLF4 and KLF5 play in colorectal cancer. Understanding the context-dependent functions of KLF4 and KLF5 and the mechanisms through which they exert their effects will be extremely helpful in developing targeted cancer therapy.

5-FU-miR-15a Inhibits Activation of Pancreatic Stellate Cells by Reducing YAP1 and BCL-2 Levels In Vitro.

Chronic pancreatitis is characterized by chronic inflammation and fibrosis, processes heightened by activated pancreatic stellate cells (PSCs). Recent publications have demonstrated that miR-15a, which targets YAP1 and BCL-2, is significantly downregulated in patients with chronic pancreatitis compared to healthy controls. We have utilized a miRNA modification strategy to enhance the therapeutic efficacy of miR-15a by replacing uracil with 5-fluorouracil (5-FU). We demonstrated increased levels of YAP1 and BCL-2 (both targets of miR-15a) in pancreatic tissues obtained from Ptf1aCreERTM and Ptf1aCreERTM;LSL-KrasG12D mice after chronic pancreatitis induction as compared to controls. In vitro studies showed that delivery of 5-FU-miR-15a significantly decreased viability, proliferation, and migration of PSCs over six days compared to 5-FU, TGFß1, control miR, and miR-15a. In addition, treatment of PSCs with 5-FU-miR-15a in the context of TGFß1 treatment exerted a more substantial effect than TGFß1 alone or when combined with other miRs. Conditioned medium obtained from PSC cells treated with 5-FU-miR-15a significantly inhibits the invasion of pancreatic cancer cells compared to controls. Importantly, we demonstrated that treatment with 5-FU-miR-15a reduced the levels of YAP1 and BCL-2 observed in PSCs. Our results strongly suggest that ectopic delivery of miR mimetics is a promising therapeutic approach for pancreatic fibrosis and that 5-FU-miR-15a shows specific promise.

Chemotherapeutic Drug Resistance Associated with Differential miRNA Expression of miR-375 and miR-27 among Oral Cancer Cell Lines.

Recent advances have suggested that non-coding miRNAs (such as miR-21, miR-27, miR-145, miR-155, miR-365, miR-375 and miR-494) may be involved in multiple aspects of oral cancer chemotherapeutic responsiveness. This study evaluated whether these specific miRNAs are correlated with oral cancer responsiveness to chemotherapies, including Paclitaxel, Cisplatin and Fluorouracil (5FU). Commercially available and well-characterized oral squamous cell carcinoma cell lines (SCC4, SCC9, SCC15, SCC25 and CAL27) revealed differing resistance and chemosensitivity to these agents-with SCC9 and SCC25 demonstrating the most resistance to all chemotherapeutic agents. SCC9 and SCC25 were also the only cell lines that expressed miR-375, and were the only cell lines that did not express miR-27. In addition, the expression of miR-375 was associated with the upregulation of Rearranged L-myc fusion (RLF) and the downregulation of Centriolar protein B (POC1), whereas lack of miR-27 expression was associated with Nucleophosmin 1 (NPM1) expression. These data have revealed important regulatory pathways and mechanisms associated with oral cancer proliferation and resistance that must be explored in future studies of potential therapeutic interventions.

Clinical Feasibility of Multi-Acquisition Variable-Resonance Image Combination-Based T2 Mapping near Hip Arthroplasty.

Background: Hip arthroplasty is increasingly prevalent, and early detection of complications can improve outcomes. Quantitative magnetic resonance imaging (qMRI) methods using multi-acquisition variable-resonance image combination (MAVRIC) may allow for the assessment of soft tissues in close proximity to hip arthroplasty devices. Question/Purposes: We sought to determine the clinical feasibility of MAVRIC-based T2 mapping as a qMRI approach for assessing synovial reactions in patients with a hip arthroplasty device. We hypothesized that there would be differences in T2 metrics by synovial type, clinical impression, and clinical findings related to synovitis. Methods: We conducted a cross-sectional study of 141 subjects with 171 hip arthroplasties with greater than 1 year post-implantation. We enrolled subjects who had had a primary total hip arthroplasty or hip resurfacing arthroplasty between May 2019 and March 2020, excluding those with a revision hip arthroplasty and those with standard safety contraindications for receiving an MRI. Institutional standard 2D fast spin echo (FSE), short-tau inversion recovery (STIR), and susceptibility-reduced MAVRIC morphological MR images were acquired for each hip and followed by a dual-echo acquisition MAVRIC T2 mapping sequence. Results: While 131 subjects (81%) were classified as having a "normal" synovial reaction, significantly longer T2 values were found for fluid synovial reactions compared with mixed reactions. In addition, subjects with synovial dehiscence and decompression present had T2 prolongation. Larger synovial volumes were found in subjects with low-signal intensity deposits. Conclusions: MAVRIC-based T2 mapping is clinically feasible and there are significant quantitative differences based on type of synovial reaction. Patients undergoing hip arthroscopy revision surgery will warrant comparison of T2 values with direct histologic assessment of a tissue sample obtained intraoperatively. The approach used in this study may be used for a quantitative evaluation and monitoring of soft tissues around metal implants.

Efficacy, Safety, and Practicality of Tacrolimus Monitoring after Bone Marrow Transplant: Assessment of a Change in Practice.

BACKGROUND: Currently, there is no standardized approach to the frequency of monitoring tacrolimus levels in patients who have undergone hematopoietic stem cell transplant (HSCT). Previously, the practice at the study hospital was to monitor tacrolimus levels daily throughout a patient's admission. A recent institutional study suggested that measurement of tacrolimus level is more frequent than needed to achieve consistent time in the therapeutic range (TTR), particularly after the first 7 days. As a result, tacrolimus monitoring was changed to daily measurement for the initial week of therapy, followed by measurements on Monday, Wednesday, and Friday in subsequent weeks. OBJECTIVE: To confirm the safety and efficacy of the recent practice change. METHODS: This retrospective chart review of HSCT patients admitted to The Ottawa Hospital involved 68 patients in the pre-practice change group and 43 patients in the post-practice change group. Data on tacrolimus measurement were collected for up to 21 days after initiation of this medication. The proportion of TTR was compared between the 2 groups. Differences in the incidence and severity of renal dysfunction and the incidence of acute graft versus host disease (GVHD) were determined and described. RESULTS: In the pre-practice change cohort, the median proportion of TTR for tacrolimus was 40.5% for days 1-7, 65.1% for days 8-14, and 78.9% for days 15-21, similar to the values for the post-practice change group (46.6% [p = 0.09], 62.9% [p = 0.93], and 70.0% [p = 0.22], respectively, for the same periods). The incidence of acute GVHD within 100 days after HSCT was 24% and 33% for the pre- and post-practice change cohorts, respectively. The incidence and severity of renal dysfunction were similar between the 2 groups. CONCLUSION: The proportion of TTR for tacrolimus was not significantly affected by the recent practice change. Similarly, the incidence and severity of renal dysfunction and the incidence of acute GVHD did not appear to differ between the pre- and post-practice change groups.

CONTEXTE: Il n'existe actuellement aucune approche standardisée portant sur la fréquence des contrôles des valeurs du tacrolimus pour les patients ayant subi une greffe de cellules souches hématopoïétiques (GCSH). Dans le passé, la pratique à l'hôpital où s'est déroulée l'étude consistait à les contrôler quotidiennement durant tout le séjour du patient. Une récente étude institutionnelle a laissé entendre que cette mesure était plus fréquente que nécessaire pour obtenir une marge thérapeutique régulière (TTR), particulièrement après les sept premiers jours. Par conséquent, une modification du contrôle des valeurs du tacrolimus préconise désormais des mesures quotidiennes pendant la première semaine de la thérapie, suivies de mesures le lundi, le mercredi et le vendredi au cours des semaines suivantes. OBJECTIF: Confirmer la sécurité et l'efficacité du récent changement apporté à la pratique. MÉTHODE: Cet examen rétrospectif des dossiers des patients GCSH admis à l'Hôpital d'Ottawa concernait 68 patients du groupe « avant le changement de pratique ¼ et 43 du groupe « après le changement de pratique ¼. Les données relatives aux mesures des valeurs du tacrolimus ont été recueillies pendant les 21 premiers jours après le début de l'administration de ce médicament. La comparaison entre les deux groupes portait sur la proportion de TTR. Les différences d'incidence et de gravité du dysfonctionnement rénal et l'apparition de réaction aiguë du greffon contre l'hôte (GVHD) ont été définies et décrites. RÉSULTATS: Dans la cohorte « avant le changement de pratique ¼, la proportion moyenne de TTR du tacrolimus était de 40,5 % du 1er au 7e jour; de 65,1 % du 8e au 14e jour et de 78,9 % du 15e au 21e jour. Ces valeurs sont similaires à celles du groupe « après le changement de pratique ¼ (respectivement 46,6 % [p = 0,09], 62,9 % [p = 0,93] et 70,0 % [p = 0,22] pendant les mêmes périodes). L'incidence de réaction aiguë du greffon contre l'hôte dans les 100 jours après la GCSH se montait respectivement à 24 % et à 33 % dans les cohortes « avant et après le changement de pratique ¼. L'incidence et la gravité du dysfonctionnement rénal étaient similaires dans les deux groupes. CONCLUSION: La proportion de TTR relative au tacrolimus n'a pas été modifiée de manière significative par le changement récent de pratique. De même, l'incidence et la gravité du dysfonctionnement rénal et l'incidence de réaction aiguë du greffon contre l'hôte ne semblaient pas différer entre les groupes avant et après le changement de pratique.