Regulation of PD-L1: a novel role of pro-survival signalling in cancer.

Evasion of immune system is a hallmark of cancer, which enables cancer cells to escape the attack from immune cells. Cancer cells can express many immune inhibitory signalling proteins to cause immune cell dysfunction and apoptosis. One of these inhibitory molecules is programmed death-ligand-1 (PD-L1), which binds to programmed death-1 (PD-1) expressed on T-cells, B-cells, dendritic cells and natural killer T-cells to suppress anti-cancer immunity. Therefore, anti-PD-L1 and anti-PD-1 antibodies have been used for the treatment of cancer, showing promising outcomes. However, only a proportion of patients respond to the treatments. Further understanding of the regulation of PD-L1 expression could be helpful for the improvement of anti-PD-L1 and anti-PD-1 treatments. Studies have shown that PD-L1 expression is regulated by signalling pathways, transcriptional factors and epigenetic factors. In this review, we summarise the recent progress of the regulation of PD-L1 expression in cancer cells and propose a regulatory model for unified explanation. Both PI3K and MAPK pathways are involved in PD-L1 regulation but the downstream molecules that control PD-L1 and cell proliferation may differ. Transcriptional factors hypoxia-inducible factor-1α and signal transducer and activation of transcription-3 act on the promoter of PD-L1 to regulate its expression. In addition, microRNAs including miR-570, miR-513, miR-197, miR-34a and miR-200 negatively regulate PD-L1. Clinically, it could increase treatment efficacy of targeted therapy by choosing those molecules that control both PD-L1 expression and cell proliferation.

Clinical feasibility of a novel biphasic osteochondral composite for matrix-associated autologous chondrocyte implantation.

OBJECTIVE: Matrix-associated autologous chondrocyte implantation has been used to treat cartilage defects. We developed a biphasic cylindrical osteochondral composite construct for such use, and conducted this study to determine its feasibility for treating osteochondral lesions in human knees. METHOD: Ten patients with symptomatic osteochondral lesions at femoral condyles were treated by replacing pathological tissue with the construct of dl-poly-lactide-co-glycolide, whose lower body was impregnated with ß-tricalcium phosphate and served as osseous phase. The construct had a chamber to load double-minced autologous cartilage, serving as source of chondrocytes. Osteochondral lesion was drill-fashioned a pit of identical dimension as the construct. Chondrocyte-laden construct was press-fit to fill the pit. Postoperative outcome was evaluated using Knee Injury and Osteoarthritis Outcome Score (KOOS) scale up to 24 months. Magnetic resonance image was taken, and sample tissue was collected with second-look arthroscopic needle biopsy at 12 months. Outcome parameters were primarily safety of surgery, and secondarily postoperative change in KOOS and regeneration of hyaline cartilage and cancellous bone. RESULTS: No patient experienced serious adverse events. Postoperative mean KOOS in "symptoms" subscale had not changed significantly from pre-operation until 24 months; whereas those in the other four subscales were significantly higher than pre-operation at 12 and 24 months. Second-look arthroscopy showed completely filled grafted sites, with regenerate cartilaginous surfaces flushed with surrounding native joint surface. Microscopically, regenerated cartilage appeared hyaline. CONCLUSION: This novel construct for chondrocyte implantation is safe for surgical application in knee. It repairs osteochondral lesions of femoral condyles by successful regeneration of hyaline cartilage.

The modulation function and realizing method of holographic functional screen.

The modulation function of holographic functional screen (HFS) in the real-time, large-size full-color (RLF), three-dimensional (3D) display system is derived from angular spectrum analysis. The directional laser speckle (DLS) method to realize the HFS is proposed. A HFS by the DLS method was fabricated and used in the experiment. Experimental results show that the HFS is valid in the RLF 3D display, and that the derived modulation function is valuable for the design of the HFS. The research results are important to realize the RLF 3D display system which will find many applications such as holographic video.

Tetranectin and apolipoprotein A-I in cerebrospinal fluid as potential biomarkers for Parkinson's disease.

OBJECTIVE: The application of biomarkers may potentially improve the efficiency of the diagnosis for Parkinson's disease (PD). However, no reliable biomarker has been identified to date. This study is aimed to identify proteins that might serve as potential biomarkers for PD diagnosis or pathogenesis. MATERIALS AND METHODS: Two-dimensional difference gel electrophoresis (2D DIGE) technique, in combination with matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS), was used to determine the differentially expressed cerebrospinal fluid (CSF) proteins in PD patients (n = 3) compared with normal controls (n = 3). Selected proteins were further confirmed by Western blotting analysis in the CSF of PD patients (n = 8), Alzheimer's disease (AD) patients (n = 6) and normal control subjects (n = 7). RESULTS: Eight proteins were identified after MS and protein database interrogation. In the CSF of PD patients, the expression levels of one isoform of apolipoprotein A-I (apoA-I), tetranectin, myosin phosphatase target subunit 1 (MYPT1), and two unknown proteins were down-regulated, whereas the expression levels of another apoA-I isoform, proapolipoprotein, and lipoprotein were up-regulated. Western blotting indicates that the expression of tetranectin was reduced in the CSF from PD patients and elevated in AD, while the expression of apoA-I was changed only in the CSF from PD patients. CONCLUSION: Our preliminary results suggest that tetranectin and apoA-I may serve as potential biomarkers for PD, though further validation is needed.

Association of fine-particulate and acidic-gas air pollution with premenstrual syndrome risk.

OBJECTIVE: Air pollution had been reported to be associated with the reproductive health of women. However, the association of particulate matter (PM) and acid gases air pollution with premenstrual syndrome (PMS) warrants investigation. This study investigated the effects of air pollution on PMS risk. POPULATION: We combined data from the Taiwan Air Quality-Monitoring Database and the Longitudinal Health Insurance Database. In total, an observational cohort of 85 078 Taiwanese women not diagnosed as having PMS. METHODS: Air pollutant concentrations were grouped into four levels based on the concentration quartiles of several types of air pollutants. MAIN OUTCOME MEASURES: We then applied univariable and multivariable Cox proportional hazard regression models to assess PMS risk in association with each pollutant type. RESULTS: Women exposed to Q4-level SO2 exhibited a 7.77 times higher PMS risk compared with those to Q1-level SO2 (95% confidence interval [CI] = 6.22-9.71). Women exposed to Q4-level NOx exhibited a 2.86 times higher PMS risk compared with those exposed to Q1-level NOx (95% CI = 2.39-3.43). Women exposed to Q4-level NO exhibited a 3.17 times higher PMS risk compared with women exposed to Q1-level NO (95% CI = 2.68-3.75). Finally, women exposed to Q4-level PM with a ≤2.5-µm diameter (PM2.5) exhibited a 3.41 times higher PMS risk compared with those exposed to Q1-level PM2.5 (95% CI = 2.88-4.04). CONCLUSIONS: High incidences of PMS were noted in women who lived in areas with higher concentrations of SO2, NOx, NO, NO2 and PM2.5.

Demonstration of a large-size real-time full-color three-dimensional display.

A large-size and full-color three-dimensional (3D) display system without the need for special eyeglasses is demonstrated. With a specially fabricated holographic functional screen with a size of 1.8x1.3 m(2), the system including optimally designed camera-projector arrays and a video server can display the fully continuous, natural 3D scene with more than 1 m image depth in real time. We explain the operating principle and present experimental results.

MicroRNA-645 is an oncogenic regulator in colon cancer.

Despite advances in early diagnosis and the development of molecularly targeted therapy, curative treatment of colon cancer once it has metastasized is yet to be accomplished. This is closely associated with deregulated CRC cell proliferation and resistance to apoptosis. Here we reveal that upregulation of microRNA-645 (miR-645) through DNA copy number gain is responsible for enhanced proliferation and resistance to apoptosis in colon cancer. MiR-645 was upregulated in most colon cancer tissues related to adjacent normal mucosa. This appeared to be associated with amplification of a section of chromosome 20q13.13, where miR-645 is located. Inhibition of miR-645 reduced proliferation and enhanced sensitivity to apoptosis triggered by the chemotherapeutic drugs 5-fluorouracil and cisplatin in CRC cells, and retarded colon cancer xenograft growth. Conversely, overexpression of miR-645 in normal colon epithelial cells enhanced proliferation and triggered anchorage-independent cell growth. Although SRY-related HMG-box 30 (SOX30) was identified as a miR-645 target, its expression was only partially affected by miR-645, suggesting that miR-645 is a fine-tuning mechanism of SOX30 expression. Moreover, overexpression of SOX30 only moderately inhibited promotion of CRC cell proliferation by miR-645, indicating that miR-645 may have more targets that contribute to its pro-proliferation effect in colon cancer. Together, this study reveals that miR-645 can regulate oncogenesis in colon cancer with SOX30 being one of its targets.

INPP4B is an oncogenic regulator in human colon cancer.

Inositol polyphosphate 4-phosphatase type II (INPP4B) negatively regulates phosphatidylinositol 3-kinase signaling and is a tumor suppressor in some types of cancers. However, we have found that it is frequently upregulated in human colon cancer cells. Here we show that silencing of INPP4B blocks activation of Akt and serum- and glucocorticoid-regulated kinase 3 (SGK3), inhibits colon cancer cell proliferation and retards colon cancer xenograft growth. Conversely, overexpression of INPP4B increases proliferation and triggers anchorage-independent growth of normal colon epithelial cells. Moreover, we demonstrate that the effect of INPP4B on Akt and SGK3 is associated with inactivation of phosphate and tensin homolog through its protein phosphatase activity and that the increase in INPP4B is due to Ets-1-mediated transcriptional upregulation in colon cancer cells. Collectively, these results suggest that INPP4B may function as an oncogenic driver in colon cancer, with potential implications for targeting INPP4B as a novel approach to treat this disease.

Note: A new regulation method of stable operation of high power cathode ion source.

The hot cathode ion source will tend to be unstable when operated with high power and long pulse. In order to achieve stable operation, a new regulation method based on the arc power (discharge power) feedback control was designed and tested on the hot cathode ion source test bed with arc discharge and beam extraction. The results show that the new regulation method can achieve stable arc discharge and beam extraction. It verifies the success of feedback control of arc source with arc power.

Changes in the moment arms of the rotator cuff and deltoid muscles with abduction and rotation.

The behavior of the moment arms of the rotator cuff and deltoid muscles was studied during simple and combine movements of abduction and rotation about the glenohumeral joint. This was done by experimental measurement of excursions of the muscles in an in vitro cadaver model and by use of a multiple-regression analysis to delineate the changes in the moment arms as a function of abduction and rotation. The results demonstrated the potential of some rotator cuff muscles to contribute to both abduction and rotation, the sensitivity of the abductor moment-arm lengths to internal and external rotation and of the rotator moment-arm lengths to the degree of abduction, and the capacity of the abductor moment-arm lengths of the deltoid to increase with increasing abduction. Characterization of this behavior resulted in an increased understanding of the complex role of the rotator cuff and deltoid muscles about the gleno-humeral joint and provided quantitative descriptions of functional relationships. This study demonstrates the capacity of the infraspinatus and subscapularis muscles to contribute not only to external and internal rotation, respectively, but also to elevation of the arm in the plane of the scapula, a role for which these muscles have been given little or no consideration. Furthermore, it demonstrates that the contribution of the infraspinatus to abduction is enhanced with internal rotation while that of the subscapularis is enhanced with external rotation. Thus, dysfunction of the supraspinatus muscle need not preclude good elevation of the arm, and rehabilitation to reprogram and strengthen the remaining muscles becomes an important consideration.

Vibration arthrometry in the patients with failed total knee replacement.

This is a preliminary research on the vibration arthrometry of artificial knee joint in vivo. Analyzing the vibration signals measured from the accelerometer on patella, there are two speed protocols in knee kinematics: 1) 2 degrees/s, the signal is called "physiological patellofemoral crepitus (PPC)", and 2) 67 degrees/s, the signal is called "vibration signal in rapid knee motion". The study has collected 14 patients who had revision total knee arthroplasty due to prosthetic wear or malalignment represent the failed total knee replacement (FTKR), and 12 patients who had just undergone the primary total knee arthroplasty in the past two to six months and have currently no knee pain represent the normal total knee replacement (NTKR). FTKR is clinically divided into three categories: metal wear, polyethylene wear of the patellar component, and no wear but with prosthesis malalignment. In PPC, the value of root mean square (rms) is used as a parameter; in vibration signals in rapid knee motion, autoregressive modeling is used for adaptive segmentation and extracting the dominant pole of each signal segment to calculate the spectral power ratios in f < 100 Hz and f > 500 Hz. It was found that in the case of metal wear, the rms value of PPC signal is far greater than a knee joint with polyethylene wear and without wear, i.e., PPC signal appears only in metal wear. As for vibration signals in rapid knee motion, prominent time-domain vibration signals could be found in the FTKR patients with either polyethylene or metal wear of the patellar component. We also found that for normal knee joint, the spectral power ratio of dominant poles has nearly 80% distribution in f < 100 Hz, is between 50% and 70% for knee with polyethylene wear and below 30% for metal wear, whereas in f > 500 Hz, spectral power ratio of dominant poles has over 30% distribution in metal wear but only nonsignificant distribution in polyethylene wear, no wear, and normal knee. The results show that vibration signals in rapid knee motion can be used for effectively detecting polyethylene wear of the patellar component in the early stage, while PPC signals can only be used to detect prosthetic metal wear in the late stage.

Vibration arthrometry in patients with knee joint disorders.

Physiological patellofemoral crepitus (PPC) is the vibration signal produced by the knee joint during slow motion (less than 5 degrees per second), which can be measured by vibration arthrometry (VAM). By using the autoregressive (AR) model for the PPC signals of patients with knee osteoarthritis, the study analyzes the PPC signals to evaluate the condition of patellar-femoral joint cartilage. Accordingly, we can divide osteoarthritis into three types, type 1: the cartilage of patellar-femoral joint is intact, the osteoarthritis found in the femoral-tibial joint surface; type 2: degeneration occurs in the surface cartilage of both the femoral-tibial joint and the femoral trochlea, but not on the patellar surface; type 3: both patellar-femoral and femoral-tibial joints have osteoarthritis. For the analysis, the intraclass distance of AR coefficients and spectral power ratio of dominant poles are adopted. Based on the proposed method, two cases of type 1, six of type 2, and 28 of type 3 were found in 36 cases of knee osteoarthritis. This is in agreement with the operative findings. For comparison, the PPC signals of 10 subjects with normal knees (without pain or wound history) were also measured. The results of analysis of the 10 normal subjects were consistent and clearly differentiable from those of the osteoarthritis patients. Therefore, the proposed method is efficient for the analysis of the condition of patellar-femoral joint cartilage and VAM may become an alternative way of noninvasive diagnosis of knee osteoarthritis.

Modified Bankart procedure for recurrent anterior shoulder dislocation.

BACKGROUND AND PURPOSE: Recurrent anterior shoulder dislocation is a serious condition, for which the Bankart procedure is a standard treatment. Having made three modifications to the original procedure, we examined the efficacy of this modified Bankart procedure in the treatment of patients with recurrent anterior shoulder dislocation. PATIENTS AND METHODS: The medical records of 21 patients who received a modified Bankart procedure for recurrent anterior shoulder dislocation during the period from 1989 through 1998 were retrospectively analyzed. The average age at initial dislocation was 22 +/- 5 years. The average postoperative follow-up period was 41 +/- 16 months. Three of the patients complained of mild shoulder pain before their operation. RESULTS: The postoperative loss of external rotation and abduction compared with the nonoperated side was 9 +/- 4 degrees and 5 +/- 4 degrees, respectively. There were no limitations in daily activities during follow-up. No patient had shoulder pain after surgery. Redislocation occurred in one patient during the follow-up period. Patient satisfaction was rated as excellent by 20 (96%) patients and poor by one. CONCLUSION: This modified Bankart procedure is a technically easy operation with a low complication rate, a high rate of patient satisfaction, and a low redislocation rate. It is a procedure of choice for the management of traumatic recurrent anterior shoulder dislocation.

Effect of external load on isokinetic torque production by the knee in anterior cruciate ligament deficient patients.

The purpose of this study was to examine the effect of an external load on the isokinetic torque production of the knee directly from the anterior cruciate ligament (ACL) of deficient patients. Ten surgically proven ACL deficient patients were included in this study. Each patient was preoperatively studied using a Biodex isokinetic dynamometer. Isokinetic contraction of the quadriceps muscle and hamstring muscles were performed in five repetitions with an angular velocity of 45 degrees per second with proximal and distal pad placement, respectively. The results demonstrated that the ratio of torque production of the ACL deficient knee to the contralateral normal knee was greater in proximal pad placement than in distal placement and that the ratio of torque production of the knee in proximal pad placement to that of the knee in distal pad placement was greater in the ACL deficient knee than in the contralateral normal knee. Similar results were found for both extension and flexion of the knee. The results showed that ACL deficient patients felt more confident doing isokinetic contractions of the knee with proximal pad placement.

Evaluation of critical postoperative situations in orthopedic patients.

Most orthopedic surgery is elective. Even in the severely traumatized patient, orthopedic surgery is carried out after the patient's general condition stabilizes. Critical postoperative situations are still problems in orthopedic surgery. From November 1992 through May 1995, 7,325 patients were admitted to the orthopedic ward at the National Taiwan University Hospital and underwent surgery. We present a retrospective study of 78 postoperative orthopedic patients who were admitted to a surgical intensive care unit (ICU) during this period. Fourteen of these became vegetative or died. The patients admitted to an ICU were categorized into four groups, based on the type of surgery: arthroplasty (13 patients), spinal surgery (50), fracture other than spine (13), and others (2). The causes of ICU admission in each group were analyzed. The following operations were found to carry a high risk of postoperative complications: revisional total hip arthroplasty (one of four ICU-admitted patients died); debridement for infected total hip arthroplasty (two of two died); bilateral total knee arthroplasty (two of four died); and debridement of spinal infection (three of five died). The associated risk factors for ICU admission were: old age, underlying medical disease, pulmonary embolism in multiple fracture, respiratory compromise in spinal surgery, and massive blood loss. Great care should be taken when performing orthopedic surgery on patients with these risk factors.

Correlation between MRI and operative findings of the rotator cuff tear.

Rotator cuff disease is one of the most common causes of shoulder pain. Various methods have been used to evaluate this problem. In this study, we determine the accuracy of magnetic resonance imaging (MRI) of the shoulder in diagnosing the rotator cuff tear based on operative findings. Ten patients with a painful shoulder requiring operation received an MRI of the shoulder before surgery. A GE 1.5 Tesla MR scanner with a five-inch planar surface coil was applied and the diagnosis was confirmed by an experienced radiologist in the field of musculoskeletal MRI. All patients underwent surgery within two weeks of MRI examination. Nine of the 10 patients were shown to have rotator cuff tear by MRI. Among the nine MRI positive patients, eight were proven to have such lesions on operation (two massive tears, four moderate complete tears, and two bursal side tears). One false-positive result was found to be an adhesive capsulitis and supraspinatus tendinitis at operation. The remaining case, diagnosed as tendinitis by MRI, turned out to be a small incomplete tear on operation. Therefore, the sensitivity of MRI for rotator cuff tear in this study was 0.89. The overall accuracy was 80%. We concluded that MRI has a high accuracy in detecting the rotator cuff tear. False-positive and false-negative diagnoses were attributed to a severe tendinitis and an incomplete tear, respectively.

Patellar thickness in total knee replacement.

The question of patellar thickness after total knee replacement (TKR) is an important issue. From November 1989 to June 1993, a total of 294 TKR were performed on 219 patients (34 males, 185 females) with an average age of 67 years. Tricon-M prostheses were used in TKRs performed before October 1992, and PCA prostheses were used after that date. In each TKR, all polyethylene patellar components used on patellar resurfacing were cemented in place. The average preoperative patellar thickness was 21.2 +/- 1.8 mm. The thickness was preserved in 106 knees, while for 53 knees, a slight increase in thickness (mean, 1.5 +/- 0.9 mm) was recorded, and for 120 knees, a slight decrease in thickness (mean, 1.5 +/- 0.8 mm) was recorded. Lateral retinacular release was performed in 96 knees (40%) of the 238 TKR with a Tricon-M prosthesis, but in only seven knees (17%) among the 41 TKR using the PCA prosthesis. Patellar subluxation and dislocation after TKR occurred in 13 knees of 11 patients (10 females, one male, mean body weight 63.5 kg) with the Tricon-M prosthesis. The mean time from arthroplasty to occurrence of patellar instability was eight months. Six knees were treated by proximal realignment procedure while seven knees were given conservative treatment, with good results and no recurrence reported. The use of a patellar cutting jig allows better control of patellar thickness when performing patellar resurfacing for small patella. No complications such as patellar fracture, infection or patellar component-loosening were encountered in the 294 TKRs performed.

Posterior slope angle of the medial tibial plateau.

The overall average of the posterior slope of the medial plateau of the tibia as determined from the lateral radiography of the knee was 10 degrees +/- 4 degrees, with a range from 0 degrees to 20 degrees. This value was independent of age and gender and was unaffected by arthrosis as long as the arcuate contours of the medial socket were not eroded and could be identified by lateral radiography. While the average value of this posterior slope was similar to that of a cadaveric study, the range was much greater. The current practice of neglecting the preoperative posterior tibial slope and arbitrarily setting the tibial component at a predetermined posterior tilt angle failed to take into account the wide variation in posterior tibial slope.

Regional nerve block for total knee arthroplasty.

Femoral and sciatic nerve blocks have been used occasionally for unilateral total knee arthroplasty (TKA). In order to evaluate the effectiveness of this technique, combined femoral 3-in-1 and sciatic nerve blocks were performed in 20 cases of TKA, by the same surgeon. This surgeon also performed unilateral TKA under spinal anesthesia in another 20 cases. The anesthetic effectiveness of the two types of anesthesia was compared in terms of the time needed to complete the surgery, amount of intraoperative blood loss, and time interval until the first dose of analgesic. The results showed that the two types of anesthesia had comparable anesthetic effects. Ten of the 20 patients who had spinal anesthesia complained of postoperative urinary retention, while none of those who had nerve block had this complaint. Neither group experienced postpunctural headache, neurovascular damage, or drug-over-dose toxicity. We conclude that combined femoral 3-in-1 and sciatic nerve block is an effective anesthetic alternative for unilateral TKA.

Factors affecting knee motion after total knee arthroplasty: a cadaveric study of the collateral ligament.

Many of the factors affecting postoperative knee motion are related to collateral ligament imbalance. In a cadaveric knee model, the center of origin of either the medial or lateral collateral ligament was found to be located at the center of the quarter circle of the posterior femoral condyle. Two distances were identified: OD (from the center of origin of the collateral ligament to the distal tibiofemoral articulation) and OP (from the center of origin of the collateral ligament to the posterior tibiofemoral articulation). The effect of the collateral ligaments on knee motion was demonstrated by stimulating joint line elevation and ligamentous stretching in a cadaveric knee model. In the knee with an elevated joint line without concomitant anterior displacement (OD reduced, OP unchanged), the flexion limit was reduced. When the collateral ligaments were stretched in a knee with constant OD and OP, both the flexion and extension limits were reduced. A correct joint level can be achieved by measuring the OD, OP and the tension of the collateral ligaments during total knee arthroplasty.