Realignment Surgery for Failed Osteochondral Autologous Transplantation in Osteochondral Lesions of the Talus Associated With Malalignment.

BACKGROUND: While osteochondral autologous transplantation (OAT) offers favorable results in most patients with osteochondral lesions of the talus (OLT), some patients continue to experience persistent pain following the procedure. Information regarding the etiology of this pain and outcomes of revision surgery are limited. This study aimed to report results of revision surgery with realignment procedures in patients with failed OAT who demonstrated concomitant malalignment at the distal tibia or hindfoot. METHODS: Eight patients (8 ankles), who had been experiencing persistent pain for more than 1 year following OAT, underwent realignment procedures during revision surgery. All patients underwent primary OAT for the treatment of medial OLTs. Patients were divided into 2 groups based on the main location of deformity: the supramalleolar realignment group (SRG, 5 ankles) and the hindfoot realignment group (HRG, 3 ankles). No direct procedure was performed on the osteochondral lesion at the time of revision surgery. Ankle and hindfoot alignment were evaluated using 6 parameters in weightbearing radiographs. Computed tomography (CT) was used to assess for medial gutter narrowing, spur formation, and cyst volume around transplanted osteochondral plug preoperatively and postoperatively. Clinical outcomes were assessed using Foot Function Index and Visual Analogue Scale. RESULTS: All patients had medial gutter narrowing or spur formation, which are early signs of ankle arthritis. The SRG had varus distal tibial alignment with a median medial distal tibial angle of 85.7 degrees (interquartile range [IQR], 3.2). The HRG had valgus hindfoot alignment and a lower medial longitudinal arch with a median hindfoot moment arm of 8.4 mm (IQR, 6.1) and a median Meary's angle of 11.8 degrees (IQR, 1.4). Spontaneous restoration of the osteochondral lesion was observed after realignment surgery, with cyst volume decreasing from 0.2592 to 0.0873 cm3 (P < .05). Clinical scores improved in all patients. CONCLUSION: The current study demonstrates the effectiveness of realignment surgery in a selected patient group who experienced persistent pain and showed radiographic evidence of malalignment after primary OAT. Our study provides evidence supporting the use of realignment procedures in these cases, with results indicating improved patient-reported outcomes and spontaneous restoration of osteochondral lesions. LEVELS OF EVIDENCE: Level IV: Case series.

Lower limb alignment in patients with primary valgus ankle arthritis: A comparative analysis with patients with varus ankle arthritis and healthy controls.

BACKGROUND: While it is commonly acknowledged that the combined effect of lower limb orientation and ankle and hindfoot alignment play a fundamental role in ankle arthritis, supramalleolar/lower limb alignment has received less attention in valgus ankle arthritis. The purpose of this study was to analyze the lower limb alignment of patients with valgus ankle arthritis with primary origin, compared to that of varus ankle arthritis and normal controls. We hypothesized that patients with valgus ankle arthritis would have the opposite pattern of lower limb alignment as those with varus ankle arthritis. METHODS: A retrospective radiographic analysis was performed on 61 patients (62 ankles, mean age, 59.3 ± 12 years) with primary valgus ankle arthritis. On preoperative radiographs, seven parameters, including talar tilt angle, medial distal tibial angle (MDTA), talar center migration, anterior distal tibial angle, talo-first metatarsal (Meary's) angle, hindfoot moment arm (HMA), and mechanical axis deviation (MAD), were measured and compared to those of primary varus ankle arthritis (n = 55; mean age, 59.7 ± 8.1 years) and control patients (n = 59; mean age, 29.3 ± 7.3 years). RESULTS: The valgus group had a significantly lower mean MDTA than the control group (p < 0.0001), indicating a varus distal tibial plafond in comparison to the control group. Meary's angle and HMA were significantly lower in the valgus group compared to the varus group (p < 0.05 and p < 0.0001, respectively), indicating a lower medial longitudinal arch and valgus hindfoot alignment. On whole limb radiographs, the valgus group showed a greater MAD than the control group, indicating varus lower limb alignment (p < 0.05). However, the MAD did not differ significantly between the valgus and varus groups (p = 0.7031). CONCLUSION: Our findings indicate that a significant proportion of ankles with primary valgus arthritis have a varus tibial plafond and a varus lower limb mechanical axis. This study contributes to our understanding of primary valgus ankle arthritis and suggests that lower limb alignment should be analyzed and considered throughout valgus ankle arthritis realignment procedures.

PKR-Mediated Phosphorylation of eIF2a and CHK1 Is Associated with Doxorubicin-Mediated Apoptosis in HCC1143 Triple-Negative Breast Cancer Cells.

Triple-negative breast cancer is more aggressive than other types of breast cancer. Protein kinase R (PKR), which is activated by dsRNA, is known to play a role in doxorubicin-mediated apoptosis; however, its role in DNA damage-mediated apoptosis is not well understood. In this study, we investigated the roles of PKR and its downstream players in doxorubicin-treated HCC1143 triple-negative breast cancer cells. Doxorubicin treatment induces DNA damage and apoptosis. Interestingly, doxorubicin treatment induced the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) via PKR, whereas the inhibition of PKR with inhibitor C16 reduced eIF2α phosphorylation. Under these conditions, doxorubicin-mediated DNA fragmentation, cell death, and poly(ADP ribose) polymerase and caspase 7 levels were recovered. In addition, phosphorylation of checkpoint kinase 1 (CHK1), which is known to be involved in doxorubicin-mediated DNA damage, was increased by doxorubicin treatment, but blocked by PKR inhibition. Protein translation was downregulated by doxorubicin treatment and upregulated by blocking PKR phosphorylation. These results suggest that PKR activation induces apoptosis by increasing the phosphorylation of eIF2α and CHK1 and decreasing the global protein translation in doxorubicin-treated HCC1143 triple-negative breast cancer cells.

Dome Supramalleolar Osteotomies for the Treatment of Ankle Pain with Opposing Coronal Plane Deformities Between Ankle and the Lower Limb.

BACKGROUND: The dome-type osteotomy is a powerful technique for deformity correction of the limb. However, there is limited information about the utility of dome supramalleolar osteotomy (SMO) in ankle joint preservation surgery. This study aimed to describe the technique and indications for dome SMO in distal tibial malalignment. METHODS: Twenty-three patients (23 ankles) who underwent dome SMO with a 2-year follow-up were reviewed. Dome SMO was indicated when there were opposing deformities in the ankle and lower limb mechanical axis (ie, varus ankle deformity with valgus lower limb alignment and vice versa) where inherent translation following conventional wedge-type osteotomies could worsen the deformity of the entire lower limb. Patients were divided into 2 groups based on preoperative ankle alignment: the varus ankle group (n = 11) and the valgus ankle group (n = 12). The radiographic correction was assessed using 6 parameters from weightbearing ankle and hindfoot alignment views. In addition, the lower limb mechanical axis was assessed with ankle center deviation (ACD) from the hip-knee (HK) line on the whole limb radiograph, and the weightbearing line (WBL) point was measured to identify changes in the weightbearing load within the ankle joint. RESULTS: Preoperatively, the varus ankle group had varus ankle deformity (tibiotalar angle [TTA], 76.5 ± 5.8 degrees) with valgus lower limb mechanical axis, whereas the valgus ankle group had valgus ankle deformity (TTA, 99.1 ± 4.5 degrees) with varus lower limb mechanical axis alignment. Postoperatively, a significant improvement in the ankle alignment and the lower limb mechanical axis was observed in both groups. The ACD significantly changed toward the HK line, suggesting an improved lower limb mechanical axis, and the WBL point showed a significant shift of the weightbearing axis toward the uninvolved area within the ankle joint. CONCLUSION: Dome SMO demonstrated a successful correction of local deformity while simultaneously realigning the hip-knee-ankle axis toward neutral. Additionally, an effective load shifting toward an uninvolved area within the ankle joint was observed. LEVEL OF EVIDENCE: Level IV, case series.

Repositional Subtalar Arthrodesis Combined With Supramalleolar Osteotomy for Late-Stage Varus Ankle Arthritis With Hindfoot Valgus.

BACKGROUND: Late-stage varus ankle arthritis is thought to be associated with varus of the tibial plafond and hindfoot. However, some late-stage varus arthritis show hindfoot valgus, which can be explained by subtalar subluxation with opposite directional motion between the talus and calcaneus. We hypothesized that late-stage varus ankle arthritis with hindfoot valgus could improve with repositional subtalar arthrodesis and supramalleolar osteotomy (SMO). The purpose of this study was to investigate the clinical and radiographic results of the repositional subtalar arthrodesis combined with SMO for late-stage varus ankle arthritis with hindfoot valgus. METHODS: This study includes 16 consecutive patients (16 ankles) with late-stage varus ankle arthritis of Takakura stage 3-b and hindfoot valgus who were treated using repositional subtalar arthrodesis combined with SMO and followed for a minimum of 2 years. Clinical results were assessed with the visual analog scale (VAS) and the Foot Function Index (FFI). Radiographic results were assessed with standard parameters measured on weightbearing foot and ankle radiographs. Clinical and radiographic results were evaluated preoperatively and at the last follow-up. RESULTS: VAS and FFI significantly improved after surgery. Mean talar tilt angle improved from 12.8 ± 2.8 degrees to 3.9 ± 3.1 degrees (P < .001). Talus center migration and Meary angle significantly improved after surgery. Medial distal tibial angle, lateral talocalcaneal angle, hindfoot moment arm, and talonavicular coverage angle significantly changed after surgery. Radiographic stage improved in 15 ankles (93.8%) after surgery. CONCLUSION: In this series with minimum 2-year follow-up, we found that late-stage (Takakura stage 3-b) varus ankle arthritis with hindfoot valgus clinically and radiographically improved with repositional subtalar arthrodesis combined with SMO. LEVEL OF EVIDENCE: Level IV, prognostic.

Joint Preservation Surgery for Varus Ankle Arthritis with Large Talar Tilt.

BACKGROUND: Varus ankle arthritis with large talar tilt (TT) is a challenging condition when considering joint preservation surgery. Three-dimensional deformity of the talus has been demonstrated with weightbearing computed tomography in varus ankle arthritis with large TT. The aim of this study was to investigate the clinical and radiographic results of posterior tibial tendon (PTT) transfer generally combined with bony realignment for varus ankle arthritis with large TT in nonparalytic ankle arthritis and to determine the indications for PTT transfer. METHODS: This study includes 23 ankles with varus arthritis and TT larger than 7.5 degrees. Patients were categorized into improved (19 ankles) and unimproved (4 ankles) groups according to the postoperative clinical results at the last follow-up. Clinical and radiographic results were compared between the groups. A cut-off point for preoperative TT that indicated a borderline between improved and unimproved groups was determined to suggest the appropriate indication for joint preservation surgery. RESULTS: In the improved group, TT, radiographic stage, Meary angle, and hindfoot alignment significantly improved at 6 months after surgery and were maintained at the last follow-up. In the unimproved group, the radiographic parameters mentioned above did not improve at 6 months after surgery, and TT decreased to 0.8 degrees as radiographic stage had progressed to end-stage arthritis at the last follow-up. In this small series, the cut-off point for predicting failure of surgery was 14.3 degrees of preoperative TT. CONCLUSION: PTT transfer often combined with bony realignment procedures may be a reasonable option for treating painful varus ankle arthritis with TT less than 14 degrees and hindfoot varus. LEVEL OF EVIDENCE: Level IV, case series.

Clinical and Radiographic Results of Ankle Joint Preservation Surgery in Posterior Ankle Arthritis.

BACKGROUND: Little information is available about how to manage ankles with eccentric arthritis in the sagittal plane. This study aimed to report clinical and radiographic outcomes following joint preservation surgery for ankles with eccentric arthritis at the posterior tibiotalar joint and a plantarflexed talus in the sagittal plane, which we named posterior ankle arthritis. METHODS: Ten ankles with posterior ankle arthritis were treated with realignment surgery between 2017 and 2018. Posterior ankle arthritis was defined as having both (1) eccentric narrowing of the joint space at the posterior aspect of the tibiotalar joint on weightbearing lateral radiographs and (2) coronal talar tilt angle less than 4 degrees on weightbearing anteroposterior radiographs. Flatfoot reconstruction with a hindfoot arthrodesis procedure was performed in all patients (subtalar arthrodesis, n = 9; triple arthrodesis, n = 1), and a supramalleolar osteotomy was added in patients with varus distal tibial alignment (n = 6). Pain, functional outcome (foot function index [FFI]), radiographic arthritis stage (stage I to IV), and 9 radiographic parameters, including lateral talar center migration (LTCM), were evaluated on pre- and postoperative weightbearing radiographs. All patients completed a minimum 2-year follow-up. RESULTS: Preoperative radiographic evaluation demonstrated that ankles with posterior arthritis had a lower medial longitudinal arch, forefoot abduction, and valgus hindfoot alignment. Postoperatively, sagittal tibiotalar alignment was restored, as evidenced by an improved median LTCM from -3.3 to -0.3 mm (P < .001). The radiographic arthritis stage improved in 7 (70%) patients, whereas 3 (30%) remain unchanged in the same stage. The median score for pain (visual analog scale) decreased significantly from 8 to 2, and the median FFI improved significantly from 67.8 to 23.4 (P < .001). None of the patients underwent conversion to joint-sacrificing procedures at the latest follow-up. CONCLUSION: The study results suggest a possible relationship between posterior ankle arthritis and the plantarflexion of the talus, which can be seen in the setting of a flatfoot deformity. Reconstruction of the flatfoot deformity using subtalar arthrodesis restored the tibiotalar relationship in the sagittal plane and resulted in clinical improvements at an average 2.3-year follow-up in this 10-ankle case series. LEVEL OF EVIDENCE: Level IV, case series.

Outcomes of Joint Preservation Surgery in Valgus Ankle Arthritis Without Deltoid Ligament Insufficiency.

BACKGROUND: To date, information about the role of proximal alignment correction in treating nontraumatic valgus ankle arthritis is limited. This study aimed to report outcomes of realignment surgery, including supramalleolar correction in valgus arthritic ankles without evidence of deltoid ligament insufficiency. METHODS: Thirteen patients (13 ankles) who underwent joint preservation surgery for valgus ankle arthritis without evidence of deltoid ligament insufficiency were reviewed. Medial opening wedge supramalleolar osteotomy (n = 11) and varization supramalleolar dome osteotomy (n = 2) were performed to realign the hip-knee-ankle-hindfoot axis. Concomitant hindfoot correction was accompanied with either medial displacement calcaneal osteotomy (n = 8) or subtalar arthrodesis (n = 5). Pain, functional outcome (Foot Function Index [FFI]), radiographic arthritis grade (grades 0-4), 9 plain radiographic parameters, and 2 weightbearing computed tomography parameters were evaluated pre- and postoperatively. All patients completed a minimum 2-year follow-up. RESULTS: Preoperatively, 10 ankles (77%) demonstrated a varus tibial plafond, and 3 ankles (23%) demonstrated a valgus or neutral tibial plafond. Postoperatively, radiographic arthritis grade improved in all except 1 patient, and the mean talar tilt angle improved from 5.5 to 1.7 degrees. The mean pain score (visual analog scale) decreased significantly from 7.3 to 2.5 (P < .05), and the mean FFI improved significantly from 57.7 to 18.6 (P < .001). None of the patients underwent conversion to joint-sacrificing procedures at the latest follow-up. CONCLUSION: This study demonstrated a possible relationship between lower limb malalignment and valgus ankle arthritis. Realignment surgery, including supramalleolar osteotomies, which straightens the mechanical axis and decreases the slope of the tibial plafond, may be a reasonable approach in joint preservation of valgus ankle arthritis without deltoid ligament insufficiency. LEVEL OF EVIDENCE: Level IV, case series.

Dynamic medial column stabilization using flexor hallucis longus tendon transfer in the surgical reconstruction of flatfoot deformity in adults.

BACKGROUND: A common challenge in flatfoot reconstruction arises when there are multiple locations of collapse within the medial column. An extension of arthrodesis may lead to complications such as stiffness or adjacent joint arthritis. The purpose of this study was to report outcomes of flatfoot reconstruction using the dynamic medial column stabilization (DMCS) technique, which transfers the flexor hallucis longus (FHL) tendon to the first metatarsal base to support the entire medial column. METHODS: We retrospectively reviewed 14 consecutive patients (14 feet) who underwent DMCS as an adjunct to flatfoot reconstruction. In all cases, a medial displacement calcaneal osteotomy and gastrocnemius recession were performed to address hindfoot valgus deformity and heel cord tightness, respectively. Deformity correction was assessed using preoperative and postoperative weightbearing radiographs. The newly defined metatarsal-cuneiform articular angle (MCAA) and naviculo-cuneiform articular angle (NCAA) were measured to assess correction at each medial column joints. Clinical outcomes included the FFI and VAS scores. Any complications related to the surgery were investigated. RESULTS: All radiographic parameters significantly improved postoperatively. The sagittal plane correction occurred at all three joints within the medial column. Clinically, both FFI and VAS improved significantly at the final follow-up. One patient developed plantar pain under the first metatarsal head that may have been associated with the overtightening of the transferred tendon. CONCLUSION: DMCS using FHL tendon transfer to the first metatarsal base was a useful technique for restoring the medial arch and correcting three planar deformities in the setting of flatfoot deformity.

Characteristics of medial gutter arthritis on weightbearing CT and plain radiograph.

OBJECTIVE: An ankle arthritis with medial gutter obliteration is known to have good results after joint preservation surgery. However, the diagnosis is often missed on radiographs. The aims of this study were to investigate sensitivity of radiographs in the identification of medial gutter arthritis, incidence and direction of the talar tilt on weightbearing CT (WBCT), and to assess radiographic alignment of the medial gutter arthritis. MATERIALS AND METHODS: Radiographic data was retrospectively evaluated in 102 ankles which were diagnosed medial gutter arthritis by using the WBCT at our clinic between January 2017 and June 2019. Among the 102 ankles, proportion of ankles which showed medial gutter arthritis on plain radiograph was obtained. The presence and direction of talar tilt were assessed on three coronal WBCT images at the anterior, middle, and posterior aspect of the ankle. Plain radiographic parameters were compared between the 102 ankles and control group. RESULTS: Plain radiograph showed medial gutter arthritis only in 63 ankles (62%) among the 102 ankles. Most of the ankles with medial gutter arthritis showed talar tilt on WBCT, and about half of all ankles showed valgus talar tilt at the anterior aspect of ankle on WBCT. In ankles with medial gutter arthritis, the mechanical axis of the lower extremity and the tibial plafond were varus angulated and the talus was medially translated compared to the control group. CONCLUSION: Radiographs were less sensitive than WBCT in demonstrating medial gutter arthritis. Anterior aspect of ankles with medial gutter arthritis often showed valgus direction of talar tilt. Varus mechanical axis deviation and varus tibial plafond are commonly associated with the medial gutter arthritis.

Eccentric ankle arthritis in the sagittal plane: a novel description of anterior and posterior ankle arthritis.

BACKGROUND: To report radiographic characteristics of anterior and posterior ankle arthritis, which demonstrates the eccentric narrowing of either aspect of the tibiotalar joint in the sagittal plane. METHODS: Radiographic analysis of 19 ankles with anterior arthritis and 16 ankles with posterior arthritis was performed, which were defined as having both (1) eccentric narrowing of the anterior or posterior tibiotalar joint space on lateral radiographs and (2) talar tilt angle less than 4 degrees on anteroposterior radiographs. Measured radiographic parameters were: Talar tilt angle, medial distal tibial angle (MDTA), talar center migration (TCM), anterior distal tibial angle (ADTA), tibial axis-to-talus ratio (TT ratio), talo-first metatarsal (Meary) angle, hindfoot alignment angle (HAA), hindfoot moment arm, and mechanical axis deviation (MAD). An Intergroup comparison analysis, including a normal control group, was also performed. RESULTS: The TT ratio was significantly different between each group, indicating a distinct talus position in the sagittal plane. The anterior group had a significantly larger TCM than the control group and lower ADTA compared to other groups, indicating medial translation of the talus and anterior opening of the tibial plafond. The posterior group demonstrated a significantly higher Meary angle and lower HAA compared to other groups and lower MDTA compared to the control group, indicating lower medial longitudinal arch, valgus heel alignment, and varus tibial plafond. The MAD was significantly higher in both the anterior and posterior groups than the control group, indicating varus lower limb alignment. CONCLUSION: Anterior ankle arthritis demonstrated anteromedial translation of the talus and anterior opening of the tibial plafond. Posterior ankle arthritis was associated with the lower medial longitudinal arch and hindfoot valgus, indicating an association with flatfoot deformity. Both anterior and posterior ankle arthritis were associated with varus lower limb alignment.

Radiographic characteristics and outcomes of simple resection for naviculo-medial cuneiform coalition in adults.

BACKGROUND: This study aimed to report the outcomes of coalition resection in adults with naviculo-medial cuneiform (NC) coalition. METHODS: Seventeen adults (20 feet) who underwent NC coalition resection were identified. The location and morphology of coalitions and five angular parameters, including medial arch sag angle (MASA), were assessed on weightbearing radiographs. Pre- and postoperative visual analogue scale and foot function index were evaluated for clinical outcomes. RESULTS: Most feet (19 out of 20) had a coalition at the plantar-medial aspect, and there was no radiographic evidence of residual NC joint space compromise. There was no radiographic evidence of medial arch sag (MASA, p = 0.749) or recurrence at the final follow-up (21.7 months, range 12 to 48). Clinical scores improved significantly in all patients. CONCLUSIONS: Resection of NC coalition in adults can be successful and provides an option to arthrodesis when conservative treatments have failed.

Detection of 8-oxoguanine and apurinic/apyrimidinic sites using a fluorophore-labeled probe with cell-penetrating ability.

BACKGROUND: Reactive oxygen species (ROS) produce different lesions in DNA by ROS-induced DNA damage. Detection and quantification of 8-oxo-7,8-dihydroguanine (8-oxoG) within cells are important for study. Human ribosomal protein S3 (hRpS3) has a high binding affinity to 8-oxoG. In this study, we developed an imaging probe to detect 8-oxoG using a specific peptide from hRpS3. Transactivator (TAT) proteins are known to have cell-penetrating properties. Therefore, we developed a TAT-S3 probe by attaching a TAT peptide to our imaging probe. RESULTS: A DNA binding assay was conducted to confirm that our probe bound to 8-oxoG and apurinic/apyrimidinic (AP) sites. We confirmed that the TAT-S3 probe localized in the mitochondria, without permeabilization, and fluoresced in H2O2-treated HeLa cells and zebrafish embryos. Treatment with Mitoquinone (MitoQ), a mitochondria-targeted antioxidant, reduced TAT-S3 probe fluorescence. Additionally, treatment with O8, an inhibitor of OGG1, increased probe fluorescence. A competition assay was conducted with an aldehyde reaction probe (ARP) and methoxyamine (MX) to confirm binding of TAT-S3 to the AP sites. The TAT-S3 probe showed competitive binding to AP sites with ARP and MX. CONCLUSIONS: These results revealed that the TAT-S3 probe successfully detected the presence of 8-oxoG and AP sites in damaged cells. The TAT-S3 probe may have applications for the detection of diseases caused by reactive oxygen species.

G-Protein-Coupled Receptor 120 Mediates DHA-Induced Apoptosis by Regulating IP3R, ROS and, ER Stress Levels in Cisplatin-Resistant Cancer Cells.

The omega-3 fatty acid docosahexaenoic acid (DHA) is known to induce apoptosis and cell cycle arrest via the induction of reactive oxygen species (ROS) production and endoplasmic reticulum (ER) stress in many types of cancers. However, the roles of DHA in drug-resistant cancer cells have not been elucidated. In this study, we investigated the effects of DHA in cisplatin-resistant gastric cancer SNU-601/cis2 cells. DHA was found to induce ROS-dependent apoptosis in these cells. The inositol 1,4,5-triphosphate receptor (IP3R) blocker 2-aminoethyl diphenylboninate (2-APB) reduced DHA-induced ROS production, consequently reducing apoptosis. We also found that G-protein-coupled receptor 120 (GPR120), a receptor of long-chain fatty acids, is expressed in SNU-601/cis2 cells, and the knockdown of GPR120 using specific shRNAs alleviated DHA-mediated ROS production and apoptosis. GPR120 knockdown reduced the expression of ER stress response genes, similar to the case for the pre-treatment of the cells with N-acetyl-L-cysteine (NAC), an ROS scavenger, or 2-APB. Indeed, the knockdown of C/EBP homologous protein (CHOP), a transcription factor that functions under ER stress conditions, markedly reduced DHA-mediated apoptosis, indicating that CHOP plays an essential role in the anti-cancer activity of DHA. These results suggest that GPR120 mediates DHA-induced apoptosis by regulating IP3R, ROS, and ER stress levels in cisplatin-resistant cancer cells, and that GPR120 is an effective chemotherapeutic target for cisplatin resistance.

Angelica gigas Nakai Has Synergetic Effects on Doxorubicin-Induced Apoptosis.

Natural products are valuable sources for drug discovery because they have a wide variety of useful chemical components and biological properties. A quick reevaluation of the potential therapeutic properties of established natural products was made possible by the recent development of the methodology and improvement in the accuracy of an automated high-throughput screening system. In this study, we screened natural product libraries to detect compounds with anticancer effects using HeLa cells. Of the 420 plant extracts screened, the extract of Angelica gigas Nakai (AGN) was the most effective in reducing cell viability of HeLa cells. Markers of apoptosis, such as exposure of phosphatidylserine and cleavage of caspase-7 and PARP, were increased by treatment with the AGN extract. Treatment of the AGN extract increased expression of PKR as well as ATF4 and CHOP, the unfolded protein response genes. In addition, cotreatment of doxorubicin and the AGN extract significantly increased doxorubicin-induced apoptosis in HeLa cells. Decursin and decursinol angelate, which were known to have anticancer effects, were the main components of the AGN extract. These results suggest that the extract of AGN containing, decursin and decursinol angelate, increases doxorubicin susceptibility.

Apoptotic and Anti-Inflammatory Effects of Eupatorium japonicum Thunb. in Rheumatoid Arthritis Fibroblast-Like Synoviocytes.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by synovitis, hyperplasia, and the destruction of bone and cartilage. A variety of immunosuppressive biological agents have been developed because the pathogenesis of RA is related predominantly to the inflammatory response. However, rheumatoid arthritis fibroblast-like synovial cells (RAFLS), which are known to play an important role in RA progression, exhibit resistance to immunosuppressants through cancer-like properties. In this study, we identified a novel therapeutic compound for RA, which reduced inflammation and the abnormal proliferation of RAFLS in natural product library made from Korean native plants. Eupatorium japonicum Thunb. (EJT) extract, a component of the natural product library, most effectively reduced viability through the induction of ROS-mediated apoptosis in a dose-dependent manner. In addition, the increased ROS induced the expression of ATF4 and CHOP, key players in ER stress-mediated apoptosis. Interestingly, EJT extract treatment dose-dependently reduced the expression of IL-1ß and the transcription of MMP-9, which were induced by TNF-α treatment, through the inhibition of NF-κB and p38 activation. Collectively, we found that EJT extract exerted apoptotic effects through increases in ROS production and CHOP expression and exerted anti-inflammatory effects through the suppression of NF-κB activation, IL-1ß expression, and MMP-9 transcription.

Weight-bearing computed tomography findings in varus ankle osteoarthritis: abnormal internal rotation of the talus in the axial plane.

OBJECTIVES: To assess the incidence of abnormal internal rotation of the talus in the axial plane in patients with varus ankle osteoarthritis, and to determine whether this incidence differs from the severity of varus ankle osteoarthritis (moderate versus severe). MATERIALS AND METHODS: We retrospectively evaluated weight-bearing computed tomography (CT) and plain radiographs of 52 ankles with no abnormalities (control group) and 96 ankles with varus osteoarthritis (varus-OA group), which were further stratified into a moderate-OA subgroup (50 ankles) and a severe-OA subgroup (46 ankles). A new radiographic parameter on weight-bearing CT, the talus rotation ratio, was used to assess the rotation of the talus in the axial plane. The normal range of the talus rotation ratio was defined as the 95% prediction interval for talus rotation ratio values in the control group. Abnormal internal rotation of the talus was defined for talus rotation ratio values above the normal range. We determined the incidence of abnormal internal rotation of the talus in the varus-OA group, moderate-OA subgroup, and severe-OA subgroup. RESULTS: In the varus-OA group, the incidence of abnormal internal rotation of the talus was 45% (43 ankles), which corresponded to an incidence of 32% (16 ankles) in the moderate-OA subgroup and 59% (27 ankles) in the severe-OA subgroup (p = 0.013). CONCLUSION: Our study demonstrates that abnormal internal rotation of the talus occurs in patients with varus ankle osteoarthritis, and is more frequently noted in severe than in moderate varus ankle osteoarthritis.

Change in Talar Translation in the Coronal Plane After Mobile-Bearing Total Ankle Replacement and Its Association with Lower-Limb and Hindfoot Alignment.

BACKGROUND: Mobile-bearing total ankle replacement (TAR) enables motion at the tibial implant-polyethylene insert interface. This motion could lead to coronal translation of the talus relative to the tibia and may affect radiographic outcome. We aimed to assess the translation of the talus before and after mobile-bearing TAR to determine whether translation of the talus after TAR is associated with coronal plane alignment of the lower limb and hindfoot as well as to investigate the complications associated with talar translation. METHODS: In this retrospective cohort study, we enrolled 153 patients (159 ankles) with a minimum follow-up of 3 years who underwent mobile-bearing TAR. The location of the talus in the coronal plane was quantified with use of talar center migration (TCM) on anteroposterior radiographs both preoperatively and at postoperative intervals, and the relationship between them was investigated. Radiographic parameters in the coronal plane-including mechanical axis deviation (MAD), lateral distal tibial angle (LDTA), hindfoot alignment angle, and hindfoot moment arm-were measured. The relationship between TCM and radiographic parameters in the coronal plane was assessed in each group. The complications associated with talar translation were examined during the same period. RESULTS: During the 36-month follow-up period, the postoperative TCM showed a strong relationship with the preoperative TCM. Moreover, MAD, LDTA, and hindfoot alignment were significantly related to talar translation (p < 0.01). Complications included medial malleolar impingement in 5 cases (including delayed medial malleolar fracture due to medial impingement in 2 cases), insert dislocation in 1 case, and edge-loading in 2 cases; all of the cases with complications demonstrated implant overhang with talar translation. CONCLUSIONS: Talar translation in the coronal plane after mobile-bearing TAR correlates with the preoperative talar translation. Talar translation arises from deformities of MAD, LDTA, and hindfoot alignment, and it may be accompanied by various complications, as observed on coronal radiography. Therefore, additional realignment procedures for coronal malalignment should be considered to prevent talar translation after mobile-bearing TAR. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Demineralized Bone Matrix Injection in Consolidation Phase Enhances Bone Regeneration in Distraction Osteogenesis via Endochondral Bone Formation.

BACKGROUND: Distraction osteogenesis (DO) is a promising tool for bone and tissue regeneration. However, prolonged healing time remains a major problem. Various materials including cells, cytokines, and growth factors have been used in an attempt to enhance bone formation. We examined the effect of percutaneous injection of demineralized bone matrix (DBM) during the consolidation phase on bone regeneration after distraction. METHODS: The immature rabbit tibial DO model (20 mm length-gain) was used. Twenty-eight animals received DBM 100 mg percutaneously at the end of distraction. Another 22 animals were left without further procedure (control). Plain radiographs were taken every week. Postmortem bone dual-energy X-ray absorptiometry and micro-computed tomography (micro-CT) studies were performed at the third and sixth weeks of the consolidation period and histological analysis was performed. RESULTS: The regenerate bone mineral density was higher in the DBM group when compared with that in the saline injection control group at the third week postdistraction. Quantitative analysis using micro-CT revealed larger trabecular bone volume, higher trabecular number, and less trabecular separation in the DBM group than in the saline injection control group. Cross-sectional area and cortical thickness at the sixth week postdistraction, assessed using micro-CT, were greater in the regenerates of the DBM group compared with the control group. Histological evaluation revealed higher trabecular bone volume and trabecular number in the regenerate of the DBM group. New bone formation was apparently enhanced, via endochondral ossification, at the site and in the vicinity of the injected DBM. DBM was absorbed slowly, but it remained until the sixth postoperative week after injection. CONCLUSIONS: DBM administration into the distraction gap at the end of the distraction period resulted in a significantly greater regenerate bone area, trabecular number, and cortical thickness in the rabbit tibial DO model. These data suggest that percutaneous DBM administration at the end of the distraction period or in the early consolidation period may stimulate regenerate bone formation and consolidation in a clinical situation with delayed bone healing during DO.

Long-Term Outcomes of Endoscopic Versus Surgical Resection of Superficial Submucosal Colorectal Cancer.

BACKGROUND: The long-term outcomes of endoscopic resection of superficial submucosal colorectal cancer (CRC) had not been adequately compared with those of surgical resection. AIMS: We aimed to compare the long-term clinical outcomes of endoscopic resection of superficial submucosal CRC to those of surgical resection. METHODS: Submucosal CRC patients with a tumor depth of sm1 or less than 1 mm from the muscularis mucosa were enrolled. Patients with unfavorable histology, such as poorly differentiated cancer or lymphovascular invasion, were excluded. Recurrence-free survival and overall survival were investigated in 87 patients who underwent endoscopic resection and in 171 patients who underwent surgical resection. RESULTS: The mean ages of the endoscopic and surgical resection groups were 59.7 and 59.8 years, respectively. Hospital stay was shorter in the endoscopic resection group (1.7 ± 1.6 vs. 8.6 ± 3.8 days; p < 0.001). The 3- and 5-year recurrence-free survival rates were 98.7 and 96.7 % in the endoscopic resection group and 98.7 and 97.5 % in the surgical resection group, respectively (p = 0.837). The 3- and 5-year overall survival rates were 100.0 and 95.2 % in the endoscopic resection group and 98.7 and 92.8 % in the surgical resection group, respectively (p = 0.928). Recurred cases showed an unfavorable histology that was overlooked at the time of initial resection. CONCLUSIONS: Long-term outcomes after endoscopic resection of superficial submucosal CRC are comparable to those after surgical resection. Thorough initial histopathological evaluations are needed to guarantee the correct indication for endoscopic resection of submucosal CRC.