Reconstruction of High-Grade Trochlea Dysplasia in a Young Female with Recurrent Patella Dislocation: A Case Report.

The patellofemoral joint involves a combination of bony structures and soft tissues to maintain stability. Patella instability is a disabling condition, and the cause is multifactorial. The main risk factors include patella alta, trochlea dysplasia, excessive tibial tuberosity to trochlea grove (TT-TG) distance, and excessive lateral patella tilt. In this case report, we highlight the thinking process of diagnosis and method for selecting the optimal treatment in accordance with the guidelines by Dejour et al. when we are presented with a patient with patella instability. A 20-year-old Asian woman without underlying medical conditions, presented with recurrent (>3 episodes) right patella dislocation for 7 years. Investigations revealed a type D trochlea dysplasia, increased TT-TG distance, and excessive lateral tilt angle. She underwent trochlea sulcus deepening, sulcus lateralization and lateral facet elevation, lateral retinacular release, and medial quadriceps tendon-femoral ligament (MQTFL) reconstruction. Due to the complexity behind the anatomy and biomechanics of patella instability, an easy-to-follow treatment algorithm is essential for the treating surgeon to provide effective and efficient treatment. MQTFL reconstruction is recommended for recurrent patella dislocation due to satisfactory clinical and patient reported outcomes and a reduced risk of iatrogenic patella fracture. Controversies for surgical indication in lateral retinacular release, and whether the sulcus angle is an accurate parameter for diagnosis of trochlea dysplasia, remain, and further research is required.

Kinome-Wide siRNA Screening Identifies DYRK1B as a Potential Therapeutic Target for Triple-Negative Breast Cancer Cells.

AIMS: The selective molecules for targeted therapy of triple-negative breast cancer (TNBC) are limited. Several kinases play pivotal roles in cancer development and malignancy. The study aims to determine if any kinases confer to malignancy of TNBC cells, which could serve as a theranostic target for TNBC. METHODS: Kinome siRNA library was used to screen selective genes required for the proliferation of TNBC cells. The involvement of DYRK1B in cancer malignancy was evaluated with migration, invasion assays, and spheroid culture. The expression of DYRK1B was confirmed with quantitative PCR and immunoblotting. The clinical correlation of DYRK1B in TNBC patients was examined with tissue microarray and The Cancer Genome Atlas (TCGA) database. RESULTS: Our results showed that silencing DYRK1B significantly suppressed cell viability in DYRK1B-high expressed TNBC cells, likely by arresting the cell cycle at the G1 phase. Nevertheless, silencing DYRK1B had marginal effects on DYRK1B-low expressed TNBC cells. Similarly, the knockdown of DYRK1B decreased tumorsphere formation and increased cell death of the tumorsphere. Moreover, inactivation of DYRK1B by either specific inhibitor or ectopic expressing catalytic mutant of DYRK1B inhibited cell viability and metastatic characteristics, including migration and invasion. In addition, DYRK1B protein expression was elevated in tumor tissues compared to that in adjacent normal tissues of TNBC patients. Further, DYRK1B gene expression was highly correlated with CCDC97 or ZNF581 genes in TNBC cells and patients. High co-expression of DYRK1B with CCDC97 or ZNF581 was significantly associated with unfavorable overall survival and disease-free survival of TNBC patients. CONCLUSIONS: our results suggest DYRK1B might be essential for promoting tumor progression and could be a theranostic target for TNBC. Silencing or inactivation of DYRK1B might be a potential targeted therapy for TNBC.

Kinome-Wide siRNA Screening Identifies Src-Enhanced Resistance of Chemotherapeutic Drugs in Triple-Negative Breast Cancer Cells.

Background: Chemotherapy is the main treatment for triple-negative breast cancer (TNBC), which lack molecular markers for diagnosis and therapy. Cancer cells activate chemoresistant pathways and lead to therapeutic failure for patients with TNBC. Several kinases have been identified as chemoresistant genes. However, the involvement of kinases in the chemoresistance in TNBC cells is not fully understood. Methods: We employed a kinome siRNA library to screen whether targeting any kinases could increase the chemosensitivity of TNBC cell lines. The effects of kinase on cell viability in various breast cancer cells were validated with ATP level and colony formation. Protein expression and phosphorylation were determined by immunoblotting. The Cancer Genome Atlas (TCGA) dataset was collected to analyze the correlation of Src expression with prognosis of TNBC patients. Results: Primary screening and validation for the initial hits showed that Src kinase was a potential doxorubicin-resistant kinase in the TNBC cell lines MDA-MB-231 and Hs578T. Both siRNA against Src and the Src inhibitor dasatinib enhanced the cytotoxic effects of doxorubicin in TNBC cells. Moreover, phosphorylation of AKT and signal transducer and activator of transcription 3 (STAT3), downstream effectors of Src, were accordingly decreased in Src-silenced or -inhibited TNBC cells. Additionally, TCGA data analysis indicated that Src expression levels in tumor tissues were higher than those in tumor-adjacent normal tissues in patients with TNBC. High co-expression level of Src and STAT3 was also significantly correlated with poor prognosis in patients. Conclusion: Our results showed that Src-STAT3 axis might be involved in chemoresistance of TNBC cells.

Drug Repurposing Screening Identifies Tioconazole as an ATG4 Inhibitor that Suppresses Autophagy and Sensitizes Cancer Cells to Chemotherapy.

Background: Tumor cells require proficient autophagy to meet high metabolic demands and resist chemotherapy, which suggests that reducing autophagic flux might be an attractive route for cancer therapy. However, this theory in clinical cancer research remains controversial due to the limited number of drugs that specifically inhibit autophagy-related (ATG) proteins. Methods: We screened FDA-approved drugs using a novel platform that integrates computational docking and simulations as well as biochemical and cellular reporter assays to identify potential drugs that inhibit autophagy-required cysteine proteases of the ATG4 family. The effects of ATG4 inhibitors on autophagy and tumor suppression were examined using cell culture and a tumor xenograft mouse model. Results: Tioconazole was found to inhibit activities of ATG4A and ATG4B with an IC50 of 1.3 µM and 1.8 µM, respectively. Further studies based on docking and molecular dynamics (MD) simulations supported that tioconazole can stably occupy the active site of ATG4 in its open form and transiently interact with the allosteric regulation site in LC3, which explained the experimentally observed obstruction of substrate binding and reduced autophagic flux in cells in the presence of tioconazole. Moreover, tioconazole diminished tumor cell viability and sensitized cancer cells to autophagy-inducing conditions, including starvation and treatment with chemotherapeutic agents. Conclusion: Tioconazole inhibited ATG4 and autophagy to enhance chemotherapeutic drug-induced cytotoxicity in cancer cell culture and tumor xenografts. These results suggest that the antifungal drug tioconazole might be repositioned as an anticancer drug or chemosensitizer.

Feasibility and safety of laparoendoscopic single-site surgery of total extraperitoneal inguinal hernia repair after previous open groin hernia repair: a comparative study.

BACKGROUND: This study is aimed at evaluating the feasibility and safety of laparoendoscopic single-site surgery (LESS) for totally extraperitoneal (TEP) endoscopic hernia surgery after previous open groin hernia repair that may hamper preperitoneal dissection. METHODS: This prospective cohort study included 213 consecutive patients undergoing LESS TEP hernia repair between January 2009 and December 2013. The study group consisted of 36 patients with a history of previous open inguinal hernia repair before undergoing LESS TEP hernia repair. The study enrolled the other 177 patients who underwent LESS TEP during the same period and were enrolled as the control group. We obtained perioperative data for all patients including demographic data, operation time, length of hospital stay, narcotic dose, conversions, and complications. RESULTS: A total of 213 patients with inguinal hernia underwent LESS TEP repair. One case in the control group (0.56 %) required conversion to LESS transabdominal preperitoneal hernia repair, while no cases in the study group required conversion. We observed no differences between the two groups in terms of operative time, analgesic use, hospital stay, and postoperative complications. CONCLUSIONS: LESS TEP hernia repair for patients with previous open inguinal hernia repair can be performed safely by experienced surgeons. Operative outcomes were comparable between both the primary inguinal and recurrent hernia groups.

Selective cytotoxic effects of low-power laser irradiation on human oral cancer cells.

BACKGROUND AND OBJECTIVES: Low-power laser irradiation (LPLI) is known to regulate cell proliferation and migration in clinical use. Recent studies have shown that LPLI induces cell death in some certain types of cancer cell lines. However, the cytotoxic selectivity of LPLI for cancer cells is not fully understood. The aim of this study was to compare the cytotoxic effects of LPLI in both human oral cancer OC2 cells and normal human gingival fibroblast (HGF) cells. MATERIALS AND METHODS: LPLI at 810 nm with an energy density from 10 to 60 J/cm(2) was used to irradiate human oral cancer OC2 cells and normal HGF cells. RESULTS: We found that LPLI significantly diminished cell viability of human oral cancer OC2 cells due to cell cycle arrest at the G1 phase and the induction of cell death but that it had no or little effects on cell cycle progression and death in normal HGF cells. Moreover, the production of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential (MMP) were elevated in human oral cancer OC2 cells compared with the un-irradiated cells. In contrast, these effects remained unchanged in normal HGF cells after exposure to LPLI. LPLI also induced apoptosis in caspase-3 dependent manner in human oral cancer OC2 cells, a mode of action that could be mediated by ROS and mitochondrial damage. CONCLUSION: Our findings imply LPLI might be a potential therapy for oral cancers.

12 GHz passive harmonic mode-locking in a 1.06 µm semiconductor optical amplifier-based fiber laser with figure-eight cavity configuration.

We report the generation of passively harmonic mode-locked pulses using a 1.06 µm semiconductor optical amplifier (SOA) in a figure-eight laser configuration operated in the all-normal-dispersion regime. Different orders of harmonic mode-locking can be obtained from 30 MHz to 12.02 GHz by changing the injection current of the SOA from 80 to 660 mA together with the adjustment of polarization controllers. The highest pulse repetition rate increases almost linearly with the SOA current. As SOA current is set to 660 mA, we obtain the intracavity power of 46 mW at the highest repetition rate of 12.02 GHz, corresponding to the 1202th harmonic of the fundamental mode-locking frequency. To our best knowledge, this is the lowest intracavity power to generate the highest repetition rate with a passively mode-locked laser in the all-normal-dispersion regime.

WWOX protein expression varies among RCC histotypes and downregulation of WWOX protein correlates with less-favorable prognosis in clear RCC.

BACKGROUND: WWOX has been shown to be a candidate tumor suppressor gene in numerous human cancers. The objective of this study is to determine the expression of WWOX in human renal cell carcinoma tumor cells and its possible correlation with clinical outcome. METHODS: The WWOX protein expressions of human renal cell carcinoma (RCC) tumor and of matched normal renal parenchyma were examined, and its correlation with clinical cancer-specific survival was investigated. RESULTS: Downregulation of WWOX only in clear cell type RCC was demonstrated in our results including immunohistochemistry, Western blot, and RT-PCR assay. For the remnant cell types of RCC, sample sizes were insufficient to draw any conclusion of WWOX protein expression. The decreased expression of WWOX in clear cell RCC tumor compared with matched normal renal parenchyma was also correlated with clinical cancer-specific survival (Kaplan-Meier, p=0.0482). CONCLUSIONS: We proved that the expression level of WWOX is downregulated in human clear cell RCC. Moreover, the decreased expression of WWOX in clear cell RCC tumor compared with matched normal renal parenchyma was also correlated with clinical cancer-specific survival. Since clear cell RCC is a special human cancer using unique molecular pathogenesis, further investigation will provide more linking intracellular signaling of WWOX and novel therapeutic targets of human renal cell carcinoma.