Assessing antiviral treatment efficacy and risk factors for severe COVID-19 in kidney transplant recipients during the Omicron subvariant-dominant period: a retrospective study.

BACKGROUND: Kidney transplant recipients (KTRs) are at risk of severe coronavirus disease 2019 (COVID-19), and even now that Omicron subvariants have become dominant, cases of severe disease are certain to occur. The aims of this retrospective study were to evaluate the efficacy of antiviral treatment for COVID-19 and to identify risk factors for severe disease in KTRs during Omicron subvariant-dominant periods. METHODS: A total of 65 KTRs diagnosed with COVID-19 who received antiviral treatment between July 2022 and September 2023 were analyzed. Mild cases received oral molnupiravir (MP) as outpatient therapy, while moderate or worse cases received intravenous remdesivir (RDV) as inpatient therapy. In principle, mycophenolate mofetil was withdrawn and switched to everolimus. We investigated the efficacy of antiviral treatment and compared the clinical parameters of mild/moderate and severe/critical cases to identify risk factors for severe COVID-19. RESULTS: Among 65 cases, 49 were mild, 6 were moderate, 9 were severe, and 1 was of critical severity. MP was administered to 57 cases; 49 (86%) improved and 8 (14%) progressed. RDV was administered to 16 cases; 14 (87%) improved and 2 (13%) progressed. Seventeen (26%) cases required hospitalization, and none died. Comparisons of the severe/critical group (n = 10) with the mild/moderate group (n = 55) demonstrated that the severe/critical group had a significantly higher median age (64 vs. 53 years, respectively; p = 0.0252), prevalence of diabetes (70% vs. 22%, respectively; p = 0.0047) and overweight/obesity (40% vs. 11%, respectively; p = 0.0393), as well as a significantly longer median time from symptom onset to initial antiviral therapy (3 days vs. 1 day, respectively; p = 0.0026). Multivariate analysis showed that a longer time from symptom onset to initial antiviral treatment was an independent risk factor for severe COVID-19 (p = 0.0196, odds ratio 1.625, 95% confidence interval 1.081-2.441). CONCLUSION: These findings suggest that a longer time from symptom onset to initial antiviral treatment is associated with a higher risk of severe COVID-19 in KTRs. Initiating antiviral treatment as early as possible is crucial for preventing severe outcomes; this represents a valuable insight into COVID-19 management in KTRs.

Low dose tacrolimus exposure and early steroid withdrawal with strict body weight control can improve post kidney transplant glucose tolerance in Japanese patients.

The development of diabetes mellitus (DM) after living donor kidney transplantation (KT) is a risk factor for worsening transplant kidney function, cardiac disease, and cerebrovascular disease, which may affect prognosis after KT. At our institution, all patients' glucose tolerance is evaluated perioperatively by oral glucose tolerance tests (OGTTs) at pre-KT, and 3, 6, and 12 month (mo.) after KT. We analyzed the insulinogenic index (ISI) and homeostasis model assessment beta cell (HOMA-ß) based on the immunoreactive insulin (IRI) levels to determine how glucose tolerance changed after KT in 214 patients who had not been diagnosed with DM before KT. In addition, we analyzed the body mass index (BMI) which may also influence glucose tolerance after KT. The concentration of tacrolimus (TAC) in blood was also measured as the area under the curve (AUC) to examine its effects at each sampling point. The preoperative-OGTTs showed that DM was newly diagnosed in 22 of 214 patients (10.3%) who had not been given a diagnosis of DM by the pre-KT fasting blood sugar (FBS) tests. The glucose tolerance was improved in 15 of 22 DM patients at 12 mo. after KT. ISI and IRI deteriorated only at 3 mo. after KT but improved over time. There was a trend of an inverse correlation between HOMA-ß and TAC-AUC. We also found inverse correlations between IRI and an increase in BMI from 3 to 12 mo. after KT. Early corticosteroid withdrawal or the steroid minimization protocol with tacrolimus to maintain a low level of diabetogenic tacrolimus and BMI decrease after KT used by our hospital individualizes lifestyle interventions for each patient might contribute to an improvement in post-KT glucose tolerance.

Characterization and treatment of gemcitabine- and cisplatin-resistant bladder cancer cells with a pan-RAS inhibitor.

Combination chemotherapy with gemcitabine and cisplatin (GC) is recommended as the primary treatment for advanced bladder cancer (BC). However, the benefits of this approach are limited owing to the acquisition of drug resistance. Here, we found that gemcitabine-resistant and cisplatin-resistant BCs do not exhibit cross-resistance, and that these BCs exhibit different mRNA patterns, as revealed using RNA sequence analysis. To overcome drug resistance, we used the newly developed pan-RAS inhibitor Compound 3144. Compound 3144 inhibited cell viability through suppression of RAS-dependent signaling in gemcitabine- and cisplatin-resistant BCs. RNA sequencing revealed that several genes and pathways, particularly those related to the cell cycle, were significantly downregulated in Compound 3144-treated BCs. These findings provide insights into potential therapeutic strategies for treating BC.

Laparoscopic Surgery for Pheochromocytoma in Hemodialysis Patients.

Objectives: We analyzed the clinical outcomes of laparoscopic adrenalectomy for pheochromocytomas in hemodialysis compared with nonhemodialysis patients. Methods: Fifty-seven patients (7 hemodialysis and 50 nonhemodialysis) were included in the study. We analyzed the differences in clinical parameters and outcomes between the hemodialysis patient groups and nonhemodialysis patient groups as well as identified predictors for an intraoperative hypertensive spike. Results: The increasing intravascular volume before surgery in hemodialysis patients made perioperative hemodynamic management safer. No significant difference in clinical parameters between the two groups was observed except for the length of hospitalization that was significantly longer in the hemodialysis patients (9 vs. 6 days, P=0.005). An increase in systolic blood pressure at CO2 insufflation was an independent predictor of a hypertensive spike with a cutoff value of 22.5 mmHg (odds ratio 1.038, 95% confidence interval 1.012-1.078). Conclusion: Laparoscopic adrenalectomy for pheochromocytomas in hemodialysis was safe and feasible. An increase in systolic blood pressure at CO2 insufflation was a predictor of the intraoperative hypertensive spike. The research in this manuscript is not registered. This is a retrospective study.

Targeting of the glutamine transporter SLC1A5 induces cellular senescence in clear cell renal cell carcinoma.

In recent years, cancer metabolism has attracted attention as a therapeutic target, and glutamine metabolism is considered one of the most important metabolic processes in cancer. Solute carrier family 1 member 5 (SLC1A5) is a sodium channel that functions as a glutamine transporter. In various cancer types, SLC1A5 gene expression is enhanced, and cancer cell growth is suppressed by inhibition of SLC1A5. However, the involvement of SLC1A5 in clear cell renal cell carcinoma (ccRCC) is unclear. Therefore, in this study, we evaluated the clinical importance of SLC1A5 in ccRCC using The Cancer Genome Atlas database. Our findings confirmed that SLC1A5 was a prognosis factor for poor survival in ccRCC. Furthermore, loss-of-function assays using small interfering RNAs or an SLC1A5 inhibitor (V9302) in human ccRCC cell lines (A498 and Caki1) showed that inhibition of SLC1A5 significantly suppressed tumor growth, invasion, and migration. Additionally, inhibition of SLC1A5 by V9302 in vivo significantly suppressed tumor growth, and the antitumor effects of SLC1A5 inhibition were related to cellular senescence. Our findings may improve our understanding of ccRCC and the development of new treatment strategies for ccRCC.

Evaluation of subscapularis tendon tears of the anterosuperior aspect using radial-sequence magnetic resonance imaging.

BACKGROUND: Magnetic resonance imaging (MRI) is widely used to diagnose subscapularis tendon tears; however, it is difficult to assess the anterosuperior aspect of these tears. Radial-sequence MRI can reveal the fiber components of the anterosuperior aspect, from perpendicular, by overcoming the partial volume effect. We aimed to classify the insertion of subscapularis tendon tears on radial-sequence MRI and determine the effectiveness of radial-sequence MRI for subscapularis tendon tear assessments. METHODS: We retrospectively investigated 196 patients (mean age, 66.7 ± 9.0 years; 118 men, 78 women) who underwent 1.5 T MRI before arthroscopic rotator cuff repair. Radial-sequence MRI findings of the anterosuperior aspect insertion of the subscapularis tendon were classified into five grades, and intraoperative findings compared with preoperative conventional MRI and radial-sequence MRI. We calculated sensitivity, specificity, accuracy, and positive and negative predictive values. Interobserver and intraobserver reliability for radial-sequence MRI classification was calculated using kappa (κ). RESULTS: Conventional MRI sensitivity of subscapularis tendon tears was 45.3%; specificity, 95.8%; accuracy, 82.1%; positive predictive value, 80.0%; and negative predictive value, 82.5%. Radial-sequence MRI sensitivity was 92.5%; specificity, 88.1%; accuracy, 89.3%; positive predictive value, 74.2%; and negative predictive value, 96.9%. Sensitivity (P < .001), accuracy (P = .04), specificity (P = .02), and negative predictive values (P < .001) in radial-sequence MRI were significantly higher than those in conventional MRI. Intraobserver and interobserver reliabilities for radial-sequence MRI classification were κ = 0.78 and 0.65, respectively, corresponding to high reproducibility, and defined as good. CONCLUSION: We provide evidence that radial-sequence MRI is an effective tool to evaluate subscapularis tendon tears, especially before surgery.

Shoulder ranges of motion and humeral torsions of injured baseball players have different characteristics depending on their pitching sides.

BACKGROUND: Right- and left-side throwers in baseball may have different shoulder conditions and throwing biomechanics. This study aimed to compare the passive range of motion, humeral torsion, and clinical findings between right- and left-handed throwers who sustained throwing shoulder injuries and confirm the differences in the characteristics between throwing sides. METHODS: A total of 52 pitchers diagnosed with throwing shoulder injuries were included in this study: 27 patients were right-side throwers (R group), and 25 were left-side throwers (L group). We measured the bilateral passive external and internal rotation angles in abduction position (ABIR) and total arc at their first visit. To assess posterior shoulder tightness, the internal rotation angles in forward flexion (FIR), and the abduction angle (AA) and horizontal flexion angle (HFA) without scapula motion were measured. The bilateral humeral torsion angles were also measured using ultrasonography. These values were compared between the participants' throwing and non-throwing sides and between the R and L groups' throwing sides. Furthermore, several physical findings in the shoulders were assessed, and the positive ratio was compared between the R and L groups. RESULTS: On comparing the throwing and non-throwing sides, the R group had significantly greater external rotation angles in the abduction position and humeral torsion angle, and smaller ABIR, total arc, FIR, AA, and HFA in the throwing side, while the L group showed no significant differences, except for a smaller ABIR and larger HFA in the throwing side. On comparing the throwing side between the R and L groups, the R group had a smaller FIR, AA, and FHA than the L group. Regarding the physical findings, the posterior jerk test, Kim test, anterior and posterior drawer sign, sulcus sign, and scapular winging in the L group were significantly more positive than in the R group. CONCLUSION: The range of motion and humeral torsions differed between the left- and right-side throwers, as did the pathology between their throwing sides. Clinicians should consider the possibility that the pathological condition differs between left- and right-side throwers.

Effectiveness of measuring tension during arthroscopic rotator cuff repair.

PURPOSE: Arthroscopic rotator cuff repair (ARCR) for relatively small rotator cuff tears (RCTs) has shown promising results; however, such surgery for larger tears often results in failure and poor clinical outcomes. One cause of failure is over-tension at the repair site that will be covered with the tendon stump. Reports on the clinical outcomes using ARCR with tension ≤ 30 N are lacking. This study aimed to evaluate ARCR outcomes and failure rates using less tension (30 N) and to assess the prognostic factors for failure. METHODS: Our study group comprised of 118 patients who underwent ARCR for full-thickness RCTs with full tendon stump coverage of the footprint with a tension of ≤ 30 N, measured using a tension meter; no additional procedures, such as margin convergence or footprint medialisation, were performed. The failure rate was calculated, and the prognostic factor for failure was assessed using multivariate regression analyses. RESULTS: There were seven cases of failure in the study group. Postoperatively, flexion and internal rotation ranges of motion, acromiohumeral interval, muscle strength, and clinical results improved significantly. Using multivariate regression analyses, intraoperative concomitant subscapularis tendon lesion and pre-operative infraspinatus tendon retraction, assessed using radial-sequence magnetic resonance imaging, were significantly correlated with post-ARCR failure using less tension (p = 0.030 and p = 0.031, respectively). CONCLUSION: ARCR is likely to succeed for RCTs that can be extracted using tension ≤ 30 N. However, cases with more severe subscapularis tendon lesions and those with high infraspinatus tendon retraction may show surgical failure. LEVEL OF EVIDENCE: LEVEL IV Retrospective case series.

The Benefit of Minced Cartilage Over Isolated Chondrocytes in Atelocollagen Gel on Chondrocyte Proliferation and Migration.

OBJECTIVE: Autologous chondrocyte implantation is a necessary procedure for the repair of articular cartilage defects; however, isolated chondrocyte implantation requires a 2-step procedure (for harvesting and implantation) and is limited by cytotoxicity due to enzymatic digestion. Therefore, in this in vitro study, we evaluated the possible benefit of using minced cartilage embedded in a 3-dimensional culture scaffold and fixed with fibrin glue, in comparison with isolated chondrocytes in atelocollagen, to induce cell migration, proliferation, and matrix production, using cartilage from patients with knee joint osteoarthritis. DESIGN: Cartilage fragments were obtained from 7 female patients with knee osteoarthritis (OA) and embedded in atelocollagen gels. As a control, chondrocytes were isolated and embedded in gels in the same manner. These composites were cultured for 3 weeks, and cell proliferation and matrix production were evaluated using histology and immunochemistry. RESULTS: Histologically, minced cartilage showed cell migration from the cartilage fragments into the gel, with the Bern score and cell count in the minced cartilage group being significantly higher than those in the control group. Immunohistochemistry revealed that the number of Ki67-positive cells, the expression of LECT-1 and TGF-ß, and the glycosaminoglycan content were significantly higher in the minced cartilage than in the control group. Minced cartilage exhibited superior cell migration, proliferation, and glycosaminoglycan content than isolated chondrocytes. CONCLUSION: Our findings support that minced cartilage has a favorable potential for cell proliferation and matrix production compared with the isolated chondrocytes after enzymatic treatment.

Arthroscopic Rotator Cuff Repair With Muscle Advancement and Artificial Biodegradable Sheet Reinforcement for Massive Rotator Cuff Tears.

BACKGROUND: Because high failure rates have frequently been reported after arthroscopic rotator cuff repair (ARCR) of massive rotator cuff tears (mRCTs), we introduced the technique of ARCR with supraspinatus and infraspinatus muscle advancement (MA). However, for cases where the original footprint cannot be completely covered, additional surgery using an approved artificial biomaterial is performed. PURPOSE: To investigate the postoperative clinical outcomes and failure rate after MA-ARCR, with and without our reinforcement technique. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 74 patients (mean ± SD age, 68.7 ± 7.7 years) diagnosed with mRCT with a minimum postoperative follow-up of 2 years were included in the current study. Of these patients, 47 underwent MA-ARCR with polyglycolic acid (PGA) sheet reinforcement (study group), and 27 patients underwent MA-ARCR alone (control group). PGA reinforcement was performed when full coverage of the footprint could not be achieved by MA alone, but where the latter was possible, reinforcement was not required. Thus, the study group had significantly worse muscle quality than the control group (P < .05). The pre- and postoperative range of motion (ROM), isometric muscle strength, acromiohumeral interval, and clinical outcomes were evaluated and compared between these 2 groups. Cuff integrity during the last follow-up period was assessed with magnetic resonance imaging, and the failure rate was calculated. In addition, the postoperative foreign body reaction was investigated in the study group. RESULTS: In both groups, significant postoperative improvements were seen in acromiohumeral interval, clinical scores, ROM in anterior flexion, and isometric muscle strength in abduction, external rotation, and internal rotation (P < .001 for all). The failure rate of the study group was 12.8% (6 patients) and that of the control group was 25.9% (7 patients). No significant differences were noted between the 2 groups on any of the data findings, even regarding the failure rate. Foreign body reactions in the early period were found in 3 patients, although these spontaneously disappeared within 3 months. CONCLUSION: Patients who underwent PGA patch reinforcement for MA-ARCR when the footprint could not be completely covered had clinical results similar to isolated MA-ARCR when the footprint could be covered. Both procedures resulted in significant improvement in symptoms and function compared with preoperatively.

Repair of an Osteochondral Defect With Minced Cartilage Embedded in Atelocollagen Gel: A Rabbit Model.

BACKGROUND: Autologous chondrocyte implantation (ACI) is often performed for large cartilage defects. Because this technique has several disadvantages, including the need for second-stage surgery, cartilage repair using minced cartilage has been suggested. However, this technique could be improved using 3-dimensional scaffolds. PURPOSE: To examine the ability of chondrocyte migration and proliferation from minced cartilage in atelocollagen gel in vitro and evaluate the repairable potential of minced cartilage embedded in atelocollagen gel covered with a periosteal flap in a rabbit model. STUDY DESIGN: Controlled laboratory study. METHODS: Minced cartilage or isolated chondrocytes from rabbits were embedded in atelocollagen gel and cultured for 3 weeks. Chondrocyte proliferation and matrix production were evaluated in vitro. An osteochondral defect at the trochlear groove was created in 56 rabbits, which were divided into 4 groups. The defect was left empty (defect group), filled with allogenic minced cartilage (minced cartilage group), filled with isolated allogenic chondrocytes embedded in atelocollagen gel (ACI group), or filled with atelocollagen gel (atelocollagen with periosteal flap group). At 4, 12, and 24 weeks after surgery, repair of the defect was evaluated in these 4 groups. RESULTS: In vitro, the number of chondrocytes and abundant matrix on the surface of the gel significantly increased in the minced cartilage group compared with the ACI group (P < .05). In vivo, the minced cartilage and ACI groups showed good cartilage repair compared with the empty defect and atelocollagen/periosteal flap groups (P < .05); there was no significant difference in the Pineda score between the minced cartilage and ACI groups. CONCLUSION: Minced cartilage in atelocollagen gel had good chondrocyte migration and proliferation abilities in vitro, and osteochondral defects were well repaired by implanting minced cartilage embedded in the atelocollagen gel in vivo. Implantation of minced cartilage embedded in atelocollagen gel showed good cartilage repair equivalent to ACI. CLINICAL RELEVANCE: Implantation of minced cartilage embedded in atelocollagen gel as a 1-step procedure has outcomes similar to those of ACI but is cheaper and more convenient than ACI.

Tumor­suppressive microRNA­223 targets WDR62 directly in bladder cancer.

miRNA­223 (miR­223) has been reported to function not only as a tumor suppressor, but also as an oncogenic microRNA (miRNA or miR) in various cancer cells. Therefore, the functional role of miR­223 has not been elucidated to date, at least to the best of our knowledge. We previously performed the deep sequencing analysis of clinical bladder cancer (BC) specimens. It was revealed that miR­223 expression was significantly downregulated in BC, suggesting that miR­223 functions as a tumor suppressor miRNA in BC. The aim of this study was to investigate the functional roles of miR­223 and to identify its targets in BC. The expression levels of miR­223 were significantly decreased in our clinical BC specimens. The Cancer Genome Atlas (TCGA) database indicated that miR­223 expression was related to lymphovascular invasion and distant metastasis. The restoration of miR­223 expression significantly inhibited tumor aggressiveness and induced apoptosis via caspase­3/7 activation in BC cells. WD repeat domain 62 (WDR62), a candidate target of miR­223 according to in silico analyses, has been previously proposed to play a role in neurodevelopment. Direct binding between WDR62 and miR­223 was confirmed by luciferase assay. The TCGA database revealed positive associations between WDR62 mRNA expression and a higher tumor grade and stage in BC. The knockdown of WDR62 significantly inhibited tumor aggressiveness and induced the apoptosis of BC cells. On the whole, the findings of this study reveal a novel miR­223 target, oncogenic WDR62, and provided insight into the oncogenesis of BC.

Regulation of ITGA3 by the dual-stranded microRNA-199 family as a potential prognostic marker in bladder cancer.

This corrects the article DOI: 10.1038/bjc.2017.43.

Regulation of ITGA3 by the dual-stranded microRNA-199 family as a potential prognostic marker in bladder cancer.

BACKGROUND: Based on the microRNA (miRNA) signature of bladder cancer (BC) by deep sequencing, we recently found that several double-stranded mature miRNAs derived from the same pre-miRNAs were sufficiently expressed and acted as tumour suppressors by regulating common target genes in BC. Our deep-sequencing signature of BC showed that all miR-199 family members (miR-199a-3p/-5p and miR-199b-3p/-5p) were also downregulated. We hypothesised that these miRNAs may function as tumour suppressors by regulating common target genes. METHODS: Functional assays of BC cells were performed using transfection of mature miRNA. In silico analyses and luciferase reporter analyses were applied to identify target genes of these miRNAs. The overall survival of patients with BC in The Cancer Genome Atlas (TCGA) database was evaluated by the Kaplan-Meier method. RESULTS: Restoration of these miRNAs significantly inhibited cell migration and invasion in BC cells. Integrin α3 (ITGA3) was directly regulated by these miRNAs. The Cancer Genome Atlas database showed that patients with low pre-miR-199 family (miR-199a-1/-2 and miR-199b) expression exhibited significantly poorer overall survival compared with patients with high pre-miR-199 family expression. CONCLUSIONS: miR-199 family miRNAs functioned as tumour suppressors in BC cells by targeting ITGA3 and might be good prognostic markers for predicting survival in patients with BC.

Regulation of metastasis-promoting LOXL2 gene expression by antitumor microRNAs in prostate cancer.

Our recent studies of microRNA (miRNA) expression signatures of prostate cancer (PCa) showed that six miRNAs (specifically, miR-26a, miR-26b, miR-29a, miR-29b, miR-29c and miR-218) were markedly reduced in cancer tissues. Moreover, ectopic expression of these miRNAs suppressed PCa cell aggressiveness, indicating that these miRNAs acted in concert to regulate genes that promoted metastasis. Genome-wide gene expression analysis and in silico database analysis identified a total of 35 candidate genes that promoted metastasis and were targeted by these 6 miRNAs. Using luciferase reporter assays, we showed that the lysyl oxidase-like 2 (LOXL2) gene was directly controlled by these tumor-suppressive miRNAs in PCa cells. Overexpression of LOXL2 was confirmed in PCa tissues and knockdown of the LOXL2 gene markedly inhibited the migration and invasion of PCa cells. Aberrant expression of LOXL2 enhanced migration and invasion of PCa cells. Downregulation of antitumor miRNAs might disrupt the tightly controlled RNA networks found in normal cells. New insights into the novel molecular mechanisms of PCa pathogenesis was revealed by antitumor miRNA-regulated RNA networks.

Dual-receptor (EGFR and c-MET) inhibition by tumor-suppressive miR-1 and miR-206 in head and neck squamous cell carcinoma.

Our studies of microRNA (miRNA) expression signatures have shown that microRNA-1 (miR-1) and microRNA-206 (miR-206) were downregulated in head and neck squamous cell carcinoma (HNSCC) clinical specimens. The seed sequences of these miRNAs are identical, suggesting that the identification of the molecular targets regulated by miR-1 and miR-206 will provide new insights into novel mechanisms of HNSCC pathogenesis. Our present data showed that restoration of miR-1 and miR-206 significantly inhibited HNSCC cells' aggressiveness. A combination of gene expression data and in silico analysis revealed that several pathways ('pathway in cancer', 'focal adhesion pathway', 'MAPK signaling pathway', 'regulation of actin cytoskeleton pathway' and 'ECM-receptor interaction pathway') were regulated by miR-1 and miR-206. Among them, we found that two growth factor receptors, epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-MET), were directly regulated by both miR-1 and miR-206 in HNSCC cells. Also, downstream oncogenic signaling of these receptors was reduced by restoration of miR-1 or miR-206 expression. Moreover, overexpression of EGFR and c-MET was observed in HNSCC clinical specimens. The identification of targets modulated by tumor-suppressive miR-1 and miR-206 may lead to a better understanding of molecular pathogenesis of HNSCC.

The tumor-suppressive microRNA-23b/27b cluster regulates the MET oncogene in oral squamous cell carcinoma.

Our recent studies of microRNA (miRNA) expression signatures in human cancers revealed that two clustered miRNAs, microRNA-23b (miR-23b) and microRNA-27b (miR­27b), were significantly reduced in cancer tissues. Few reports have provided functional analyses of these clustered miRNAs in oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the functional significance of miR-23b and miR-27b in OSCC and to identify novel miR-23b/27b-mediated cancer pathways and target genes involved in OSCC oncogenesis and metastasis. Expression levels of miR-23b and miR-27b were significantly reduced in OSCC specimens. Restoration of miR-23b or miR-27b in cancer cells revealed that both miRNAs significantly inhibited cancer cell migration and invasion. Our in silico analyses and luciferase reporter assays showed that the receptor tyrosine kinase MET, was directly regulated by these miRNAs. Moreover, downregulating the MET gene by use of siRNA significantly inhibited cell migration and invasion by OSCC cells. The identification of novel molecular pathways regulated by miR-23b and miR-27b may lead to a better understanding of the oncogenesis and metastasis of this disease.

The microRNA signature of patients with sunitinib failure: regulation of UHRF1 pathways by microRNA-101 in renal cell carcinoma.

Molecular targeted therapy is a standard treatment for patients with advanced renal cell carcinoma (RCC). Sunitinib is one of the most common molecular-targeted drugs for metastatic RCC. Molecular mechanisms of sunitinib resistance in RCC cells is still ambiguous. The microRNA (miRNA) expression signature of patients with sunitinib failure in RCC was constructed using a polymerase chain reaction (PCR)-based array. Several miRNAs that were aberrantly expressed in RCC tissues from patients treated with sunitinib were identified in this analysis. MicroRNA-101 (miR- 101) was markedly suppressed in sunitinib treated RCC tissues. Restoration of miR-101 significantly inhibited cell migration and invasion in Caki-1 and 786-O cells. Ubiquitin-like with PHD and ring finger domains 1 (UHRF1) was directly suppressed by miR-101 in RCC cells, and overexpression of UHRF1 was confirmed in sunitinib-treated RCC tissues. The pathways of nucleotide excision repair and mismatch repair were significantly suppressed by knockdown of UHRF1. Our findings showed that antitumor miR-101- mediated UHRF1 pathways may be suppressed by sunitinib treatment.

Dual tumor-suppressors miR-139-5p and miR-139-3p targeting matrix metalloprotease 11 in bladder cancer.

Our recent study of the microRNA (miRNA) expression signature of bladder cancer (BC) by deep-sequencing revealed that two miRNA, microRNA-139-5p/microRNA-139-3p were significantly downregulated in BC tissues. The aim of this study was to investigate the functional roles of these miRNA and their modulation of cancer networks in BC cells. Functional assays of BC cells were performed using transfection of mature miRNA or small interfering RNA (siRNA). Genome-wide gene expression analysis, in silico analysis and dual-luciferase reporter assays were applied to identify miRNA targets. The associations between the expression of miRNA and its targets and overall survival were estimated by the Kaplan-Meier method. Gain-of-function studies showed that miR-139-5p and miR-139-3p significantly inhibited cell migration and invasion by BC cells. The matrix metalloprotease 11 gene (MMP11) was identified as a direct target of miR-139-5p and miR-139-3p. Kaplan-Meier survival curves showed that higher expression of MMP11 predicted shorter survival of BC patients (P = 0.029). Downregulated miR-139-5p or miR-139-3p enhanced BC cell migration and invasion in BC cells. MMP11 was directly regulated by these miRNA and might be a good prognostic marker for survival of BC patients.

The role of microRNAs in bladder cancer.

Bladder cancer (BC) is the fifth most common cancer worldwide and is associated with significant morbidity and mortality. The prognosis of muscle invasive BC is poor, and recurrence is common after radical surgery or chemotherapy. Therefore, new diagnostic methods and treatment modalities are critical. MicroRNAs (miRNAs), a class of small noncoding RNAs, regulate the expression of protein-coding genes by repressing translation or cleaving RNA transcripts in a sequence-specific manner. miRNAs have important roles in the regulation of genes involved in cancer development, progression, and metastasis. The availability of genomewide miRNA expression profiles by deep sequencing technology has facilitated rapid and precise identification of aberrant miRNA expression in BC. Indeed, several miRNAs that are either upregulated or downregulated have been shown to have associations with significant cancer pathways. Furthermore, many miRNAs, including those that can be detected in urine and blood, have been studied as potential noninvasive tumor markers for diagnostic and prognostic purposes. Here, we searched PubMed for publications describing the role of miRNAs in BC by using the keywords "bladder cancer" and "microRNA" on March 1, 2016. We found 374 papers and selected articles written in English in which the level of scientific detail and reporting were sufficient and in which novel findings were demonstrated. In this review, we summarize these studies from the point of view of miRNA-related molecular networks (specific miRNAs and their targets) and miRNAs as tumor markers in BC. We also discuss future directions of miRNA studies in the context of therapeutic modalities.