A Prediction Rule for the Dystonic Spread of Blepharospasm: A 4-Year Prospective Cohort Study.

OBJECTIVE: Blepharospasm (BSP), focal dystonia with the highest risk of spread, lacks clear understanding of early spreading risk factors and objective prognostic indicators. We aimed to identify these risk factors through clinical and electrophysiological assessments, and to establish a predictive model for dystonic spread in BSP. METHODS: We prospectively followed BSP patients for 4 years, collecting data on dystonic spread, and conducting electrophysiological evaluations. The blink reflex, masseter inhibitory reflex, and trigeminal somatosensory evoked potential were assessed. Univariable and multivariable Cox proportional hazard regression models were used to assess clinical characteristics associated with BSP dystonic spread. A predictive model was constructed using a nomogram, and performance of the model was evaluated using the area under the receiver operating characteristic curve. RESULTS: A total of 136 enrolled participants (mean age 56.34 years) completed a 4-year follow-up. Among them, 62 patients (45.6%) showed spread to other body regions. Multivariable Cox regression analysis showed that a high Hamilton Anxiety Scale score (hazard ratio 1.19, 95% confidence interval 1.13-1.25, p < 0.001), prolonged trigeminal somatosensory evoked potential mandibular branch P1-N2 peak interval (hazard ratio 1.11, 95% confidence interval 1.02-1.21, p = 0.017), and elevated trigeminal somatosensory evoked potential mandibular branch P1-N2 peak amplitude (hazard ratio 1.26, 95% confidence interval 1.12-1.41, p < 0.001) were independent risk factors for BSP dystonic spread within 4 years. Combining these factors, the predictive models demonstrated excellent discriminative ability, with the receiver operating characteristic curve score being 0.797, 0.790, 0.847, and 0.820 at 1, 2, 3 and 4 years after enrollment, respectively. INTERPRETATION: We established a predictive model with significant value for anticipating dystonic spread in BSP, offering crucial evidence. These findings contribute essential insights into the early clinical identification of the development and evolution of BSP diseases. ANN NEUROL 2024.

Stronger stimulus triggers synaptic transmission faster through earlier started action potential.

Synaptic transmission plays an important and time-sensitive role in the nervous system. Although the amplitude of neurotransmission is positively related to the intensity of external stimulus, whether stronger stimulus could trigger synaptic transmission faster remains unsolved. Our present work in the primary sensory system shows that besides the known effect of larger amplitude, stronger stimulus triggers the synaptic transmission faster, which is regulated by the earlier started action potential (AP), independent of the AP's amplitude. More importantly, this model is further extended from the sensory system to the hippocampus, implying broad applicability in the nervous system. Together, we found that stronger stimulus induces AP faster, which suggests to trigger the neurotransmission faster, implying that the occurrence time of neurotransmission, as well as the amplitude, plays an important role in the timely and effective response of nervous system.

Kinect-based objective assessment of the acute levodopa challenge test in parkinsonism: a feasibility study.

INTRODUCTION: The acute levodopa challenge test (ALCT) is an important and valuable examination but there are still some shortcomings with it. We aimed to objectively assess ALCT based on a depth camera and filter out the best indicators. METHODS: Fifty-nine individuals with parkinsonism completed ALCT and the improvement rate (IR, which indicates the change in value before and after levodopa administration) of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) was calculated. The kinematic features of the patients' movements in both the OFF and ON states were collected with an Azure Kinect depth camera. RESULTS: The IR of MDS-UPDRS III was significantly correlated with the IRs of many kinematic features for arising from a chair, pronation-supination movements of the hand, finger tapping, toe tapping, leg agility, and gait (rs = - 0.277 ~ - 0.672, P < 0.05). Moderate to high discriminative values were found in the selected features in identifying a clinically significant response to levodopa with sensitivity, specificity, and area under the curve (AUC) in the range of 50-100%, 47.22%-97.22%, and 0.673-0.915, respectively. The resulting classifier combining kinematic features of toe tapping showed an excellent performance with an AUC of 0.966 (95% CI = 0.922-1.000, P < 0.001). The optimal cut-off value was 21.24% with sensitivity and specificity of 94.44% and 87.18%, respectively. CONCLUSION: This study demonstrated the feasibility of measuring the effect of levodopa and objectively assessing ALCT based on kinematic data derived from an Azure Kinect-based system.

Correlation between spherical equivalent and biometry parameters in adult Cynomolgus macaque.

PURPOSE: To characterize the distribution of refractive and ocular biometry parameters and analyze the effect factors of the refractive status in cynomolgus monkey colonies. METHODS: A Population-based cross-sectional study was conducted in adult cynomolgus macaque colonies. Animals were anesthetized with Zoletil 50. Intraocular pressure was measured using the Icare tonometer. Cycloplegic refraction (three drops of 1% tropicamide) and corneal radius of curvature (CRC) were measured using an autorefractor. The spherical equivalent (SE) was calculated. Biometric measurements, including the anterior chamber depth (ACD), lens thickness (LT), and axial length (AL), were obtained by A-scan ultrasonography. The AL-to-CR ratio (AL/CRC) was calculated. Central corneal thickness (CCT) and choroidal thickness (ChT) were measured using the Heidelberg Spectralis HRA OCT. Multiple regression analysis was performed to explore the association between refraction and ocular biometry. RESULTS: Among 263 cynomolgus monkeys (aged 5-26 years), which consisted of 520 eyes, 29.42% had hyperopia, 27.12% had emmetropia, 33.27% had mild-to-moderate myopia and 10.19% had high myopia. The mean SE was -1.27 ± 3.44 Diopters (D). The mean CRC, CCT, AL, and ChT was 5.70 ± 0.22 mm, 454.30 ± 32.40 µm, 18.76 ± 0.89 mm and 188.96 ± 38.19 µm, respectively. The LT was the thickest in the hyperopic eyes. CRC was the lowest, and CCT was the thickest in high myopic eyes. AL increased, while ChT decreased as SE decreased. For the SE variance, AL alone explained 40.5%; age, AL, and CRC together explained 57.5%. CONCLUSIONS: The refractive characteristics and biometry parameters of cynomolgus monkeys are highly comparable to those of humans. AL, CRC, and ChT showed the similar variation tendency in cynomolguses when compared to humans. Cynomolgus monkeys with naturally-occurring refractive errors may be a good animal model for refractive studies.

Multi-threshold splitting tree algorithm to reduce the number of filters in programmable hyperspectral imaging for fast multi-target classification.

Programmable hyperspectral imaging is a promising and efficient technique for fast target classification by coding hyperspectral post-processing algorithms as spectral transmittances, which enables such post-processing to be directly performed by special optical dispersive element during the process of optical imaging. Compared with conventional hyperspectral imaging and post-processing techniques, it shows significant advantages of fast image acquisition, post-processing free, and a much lower load of data transmission and storage. However, when multi-target classification tasks are encountered, the speed would decrease seriously due to the requirement of a large number of filters. In this study, a novel splitting strategy is proposed to reduce the number of filters in programmable hyperspectral imaging for fast multi-target classification while maintaining the classification performance. Numerical simulation experiments were performed on six publicly available hyperspectral data sets. Compared with the conventional splitting strategies, the proposed splitting strategy can reduce the number of filters by 25% to 80% and achieve similar classification performance, which is of great significance to improve the speed of multi-target classification with programmable hyperspectral imaging technique.

Automated and accurate assessment for postural abnormalities in patients with Parkinson's disease based on Kinect and machine learning.

BACKGROUND: Automated and accurate assessment for postural abnormalities is necessary to monitor the clinical progress of Parkinson's disease (PD). The combination of depth camera and machine learning makes this purpose possible. METHODS: Kinect was used to collect the postural images from 70 PD patients. The collected images were processed to extract three-dimensional body joints, which were then converted to two-dimensional body joints to obtain eight quantified coronal and sagittal features (F1-F8) of the trunk. The decision tree classifier was carried out over a data set established by the collected features and the corresponding doctors' MDS-UPDRS-III 3.13 (the 13th item of the third part of Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale) scores. An objective function was implanted to further improve the human-machine consistency. RESULTS: The automated grading of postural abnormalities for PD patients was realized with only six selected features. The intraclass correlation coefficient (ICC) between the machine's and doctors' score was 0.940 (95%CI, 0.905-0.962), meaning the machine was highly consistent with the doctors' judgement. Besides, the decision tree classifier performed outstandingly, reaching 90.0% of accuracy, 95.7% of specificity and 89.1% of sensitivity in rating postural severity. CONCLUSIONS: We developed an intelligent evaluation system to provide accurate and automated assessment of trunk postural abnormalities in PD patients. This study demonstrates the practicability of our proposed method in the clinical scenario to help making the medical decision about PD.

Regulatory role of primary cilia in oral and maxillofacial development and disease.

Primary cilia have versatile functions, such as receiving signals from the extracellular microenvironment, mediating signaling transduction, and transporting ciliary substances, in tissue and organ development and clinical disease pathogenesis. During early development (embryos within 10 weeks) in the oral and maxillofacial region, defects in the structure and function of primary cilia can result in severe craniofacial malformations. For example, mice with mutations in the cilia-related genes Kif3a and IFT88 exhibit midline expansion and cleft lip/palate, which occur due to abnormalities in the fusion of the single frontonasal prominence and maxillary prominences. In the subsequent development of the oral and maxillofacial region, we discussed the regulatory role of primary cilia in the development of the maxilla, mandible, Meckel cartilage, condylar cartilage, lip, tongue, and tooth, among others. Moreover, primary cilia are promising regulators in some oral and maxillofacial diseases, such as tumors and malocclusion. We also summarize the regulatory mechanisms of primary cilia in oral and maxillofacial development and related diseases, including their role in various signaling transduction pathways. For example, aplasia of submandibular glands in the Kif3a mutant mice is associated with a decrease in SHH signaling within the glands. This review summarizes the similarities and specificities of the role of primary cilia in tissue and organ development and disease progression in the oral and maxillofacial region, which is expected to contribute several ideas for the treatment of primary cilia-related diseases.

Sex-specific association of circulating Isthmin-1 with isolated post-challenge hyperglycemia.

Introduction: To explore the distribution of Isthmin-1 (ISM1) level and its association with isolated post-challenge hyperglycemia (IPH). Methods: A total of 522 participants without a history of diabetes were invited to attend a standard 75g 2-h oral glucose tolerance test (OGTT), and 71 subjects were further invited for a 3-h oral minimal model test. Insulin sensitivity and ß-cell function were evaluated using both HOMA and estimated from OGTT. Circulating ISM1 levels were determined by a commercially available ELISA kit. Results: A total of 76 (14.6%) participants were diagnosed as IPH, accounting for 61.3% of the newly diagnosed diabetes. ISM1 levels were significantly higher in men than in women (1.74 ng/mL versus 0.88 ng/mL). The inverse correlation between ISM1 and ß-cell function and IPH was only significant in men. After multivariate adjustment, per unit increment in ISM1 was associated with 0.68-fold (95% CI: 0.49-0.90) reduced odds ratio (OR) of IPH in men. Compared to men with the lowest ISM1 levels, the adjusted OR of IPH with the highest ISM1 levels decreased by 73% (95% CI: 0.11-0.61). Moreover, incorporation of ISM1 into the New Chinese Diabetes Risk Score (NCDRS) model yielded a substantial improvement in net reclassification improvement of 58% (95% CI: 27%-89%) and integrated discrimination improvement of 6.4% (95% CI: 2.7%-10.2%) for IPH. Conclusions: ISM1 was significantly and independently associated with IPH, and serves as a feasible biomarker for the early identification of men with high risk of IPH.

Scaled-Up Synthesis of Freestanding Molybdenum Disulfide Membranes for Nanopore Sensing.

2D materials are ideal for nanopores with optimal detection sensitivity and resolution. Among these, molybdenum disulfide (MoS2 ) has gained traction as a less hydrophobic material than graphene. However, experiments using 2D nanopores remain challenging due to the lack of scalable methods for high-quality freestanding membranes. Herein, a site-directed, scaled-up synthesis of MoS2 membranes on predrilled nanoapertures on 4-inch wafer substrates with 75% yields is reported. Chemical vapor deposition (CVD), which introduces sulfur and molybdenum dioxide vapors across the sub-100 nm nanoapertures results in exclusive formation of freestanding membranes that seal the apertures. Nucleation and growth near the nanoaperture edges is followed by nanoaperture decoration with MoS2 , which proceeds until a critical flake curvature is achieved, after which fully spanning freestanding membranes form. Intentional blocking of reagent flow through the apertures inhibits MoS2 nucleation around the nanoapertures, promoting the formation of large-crystal monolayer MoS2 membranes. The in situ grown membranes along with facile membrane wetting and nanopore formation using dielectric breakdown enables the recording of dsDNA translocation events at an unprecedentedly high 1 MHz bandwidth. The methods presented here are important steps toward the development of scalable single-layer membrane manufacture for 2D nanofluidics and nanopore applications.

Seroprevalence rates in children aged 3-6 years after implementing a two-dose varicella vaccination: A observational study.

The study evaluates the outcomes of including varicella vaccines (VarV) in the local expanded programme on immunization (EPI) on the seropositivity rates and corresponding protective effects for children aged 3-6 years in Suzhou. The study is observational. Varicella prevalence in children was assessed based on data from the China Information System for Disease Control and Prevention (CISDCP) and the Jiangsu Province Vaccination Integrated Service Management Information System (JPVISMIS). Seropositivity was determined using the enzyme-linked immunosorbent assay (ELISA). A total of 2,873 children aged 3-6 years were enrolled in this study. The seropositivity rates were 95.31% and 86.89% for children with and without the strategy, respectively. The difference in seropositivity rate in children using the different strategies was statistically significant (Trend χ2 = 0.397, P = .255). It is therefore suggested that Suzhou had a high rate of occult infection before the inclusion of varicella vaccine in the EPI. The difference in seroprevalence rate between children with no history of varicella vaccination and those with a history of varicella vaccination was statistically different (χ2 = 51.362, P < .001). The positive rates of antibodies increased with increasing doses of vaccination (χ2 = 56.252, P < .001). For the protective effect of one-dose and two-dose, it was found that the protection rates of one-dose were 72.98% and 100.00%, respectively. The varicella vaccine is an effective method to prevent varicella disease, which can increase serum seroprevalence levels and block the transmission of varicella disease.

Evaluation of vaccination status of children with special health care needs in Suzhou, China, 2020-2022: A retrospective survey study.

Children with special health care needs (CSHCNs) are at an increased risk of vaccine-preventable infections (VPDs), but they also face the dilemma of vaccine hesitancy. We obtained information on pediatric visits from the Referral and Assessment Information System for Vaccination (RAISV) and information on vaccination from the Jiangsu Province Immunization Information System (JSIIS). We followed the occurrence of Adverse Events Following Immunization (AEFIs) and VPDs by actively calling and querying the China Information System for Disease Control and Prevention (CISDCP). The Poisson test was used to compare the incidence of AEFIs between groups. A total of 5,037 children who visited a vaccination assessment clinic were followed-up in this study. The majority were children with developmental anomalies (28.5%), certain conditions originating in the perinatal period (12.1%), and nervous system disorders (9.0%). Most CSHCNs (66.9%) were advised to have all vaccines according to routine practice, 29.0% were advised to have partial vaccination, and 4.1% were advised to delay all vaccines and wait for future assessment. A total of 201 (4.0%) CSHCNs were not vaccinated, although they were assessed to be eligible for vaccination. By querying the immunization planning module in CISDCP, we observed 55 AEFI cases, which amounted to an incidence rate of 1.2 per 1,000, and the occurrence of abnormal reactions was not significantly different compared with the general population. The vaccination program following the designed workflow for CSHCNs was safe and could be recommended in other areas.

A digital nanoplasmonic microarray immunosensor for multiplexed cytokine monitoring during CAR T-cell therapy from a leukemia tumor microenvironment model.

The release of cytokines by chimeric antigen receptor (CAR) T-cells and tumor resident immune cells defines a significant part of CAR T-cell functional activity and patient immune responses during CAR T-cell therapy. However, few studies have so far precisely characterized the cytokine secretion dynamics in the tumor niche during CAR T-cell therapy, which requires multiplexed, and timely biosensing platforms and integration with biomimetic tumor microenvironment. Herein, we implemented a digital nanoplasmonic microarray immunosensor with a microfluidic biomimetic Leukemia-on-a-Chip model to monitor cytokine secretion dynamics during CD19 CAR T-cell therapy against precursor B-cell acute lymphocytic leukemia (B-ALL). The integrated nanoplasmonic biosensors achieved precise multiplexed cytokine measurements with low operating sample volume, short assay time, heightened sensitivity, and negligible sensor crosstalk. Using the digital nanoplasmonic biosensing approach, we measured the concentrations of six cytokines (TNF-α, IFN-γ, MCP-1, GM-CSF, IL-1ß, and IL-6) during first 5 days of CAR T-cell treatment in the microfluidic Leukemia-on-a-Chip model. Our results revealed a heterogeneous secretion profile of various cytokines during CAR T-cell therapy and confirmed a correlation between the cytokine secretion profile and the CAR T-cell cytotoxic activity. The capability to monitor immune cell cytokine secretion dynamics in a biomimetic tumor microenvironment could further help in study of cytokine release syndrome during CAR T-cell therapy and in development of more efficient and safer immunotherapies.

Prevalence and human papillomavirus (HPV) genotype distribution in Suzhou, China.

Persistent infection with high-risk human papillomavirus (HR-HPV) is a known pathogenic factor of cervical cancer. To develop scientific guidance for cervical cancer screening and HPV vaccination, we analyzed HPV genotypes in Suzhou City, China. This study utilized data from the cervical cancer screening project in Suzhou from 2016 to 2021. A total of 444,471 female residents who voluntarily underwent HPV testing were included in the study. The overall HR-HPV prevalence was 10.2%. The three most common HR-HPV genotypes were HPV52 (2.81%), HPV58 (1.64%), and HPV16 (1.46%). The rate of HPV infection increased with age. Having a junior school education or higher was a protective factor compared to having an education level below junior school. The overall HPV infection rate showed a downwards trend from 2016 to 2021. HPV16 exhibited the fastest annual decline rate, followed by HPV18. As the severity of cervical intraepithelial neoplasia increases, the detection rate of HPV infection significantly increased. In conclusion, in addition to cervical cancer screening, it is important to pay attention to health promotion and education for low-educated women aged 45-59. Considering the distribution of HPV genotypes, prioritizing the administration of high-valency HPV vaccines to local seventh-grade female students is recommended.

Kinect-based objective evaluation of bradykinesia in patients with Parkinson's disease.

Objective: To quantify bradykinesia in Parkinson's disease (PD) with a Kinect depth camera-based motion analysis system and to compare PD and healthy control (HC) subjects. Methods: Fifty PD patients and twenty-five HCs were recruited. The Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) was used to evaluate the motor symptoms of PD. Kinematic features of five bradykinesia-related motor tasks were collected using Kinect depth camera. Then, kinematic features were correlated with the clinical scales and compared between groups. Results: Significant correlations were found between kinematic features and clinical scales (P < 0.05). Compared with HCs, PD patients exhibited a significant decrease in the frequency of finger tapping (P < 0.001), hand movement (P < 0.001), hand pronation-supination movements (P = 0.005), and leg agility (P = 0.003). Meanwhile, PD patients had a significant decrease in the speed of hand movements (P = 0.003) and toe tapping (P < 0.001) compared with HCs. Several kinematic features exhibited potential diagnostic value in distinguishing PD from HCs with area under the curve (AUC) ranging from 0.684-0.894 (P < 0.05). Furthermore, the combination of motor tasks exhibited the best diagnostic value with the highest AUC of 0.955 (95% CI = 0.913-0.997, P < 0.001). Conclusion: The Kinect-based motion analysis system can be applied to evaluate bradykinesia in PD. Kinematic features can be used to differentiate PD patients from HCs and combining kinematic features from different motor tasks can significantly improve the diagnostic value.

A Computational Model of Cytokine Release Syndrome during CAR T-cell Therapy.

Cytokine release syndrome (CRS) is a lethal adverse event in chimeric antigen receptor (CAR) T-cell therapy, hindering this promising therapy for cancers, such as B-cell acute lymphoblastic leukemia (B-ALL). Clinical management of CRS requires a better understanding of its underlying mechanisms. In this study, a computational model of CRS during CAR T-cell therapy is built to depict how the cellular interactions among CAR T-cells, B-ALL cells, and bystander monocytes, as well as the accompanying molecular interactions among various inflammatory cytokines, influence the severity of CRS. The model successfully defines the factors related to severe CRS and studied the effects of immunomodulatory therapy on CRS. The use of the model is also demonstrated as a precision medicine tool to optimize the treatment scheme, including personalized choice of CAR T-cell products and control of switchable CAR T-cell activity, for a more efficient and safer immunotherapy. This new computational oncology model can serve as a precision medicine tool to guide the clinical management of CRS during CAR T cell therapy.

Effects of Repetitive Transcranial Magnetic Stimulation on Motor Symptoms in Parkinson's Disease: A Meta-Analysis.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique that has been closely examined as a possible treatment for Parkinson's disease (PD). Owing to various rTMS protocols and results, the optimal mode and suitable PD symptoms have yet to be established. OBJECTIVES: This study intends to systematically evaluate the efficacy of rTMS intervention and identify optimal stimulation protocol of rTMS for specific motor symptoms. METHODS: PubMed and web of Science databases were searched before January 2022. Eligible studies included sham-controlled and randomized clinical trials of rTMS intervention for motor dysfunction in patients with PD. Standard mean difference (SMD) was calculated with random-effects models. The effects of rTMS on motor symptoms were mainly estimated by the UPDRS-III. RESULTS: A total of 1172 articles were identified, of which 32 articles met the inclusion criteria for meta-analysis. The pooled evidence suggested that rTMS relieves motor symptoms of patients with PD (SMD 0.64, 95%CI [0.47, 0.80]). High frequency stimulation on M1 is the most effective mode of intervention (SMD 0.79, 95%CI [0.52, 1.07]). HF rTMS has significant therapeutic effects on limbs motor function (SMD 1.93, 95%CI [0.73, 3.12] for upper limb function and SMD 0.88, 95%CI [0.43, 1.33] for lower limb function), akinesia (SMD 1.17, 95%CI [0.43, 1.92), rigidity (SMD 1.02, 95%CI [0.12, 1.92]) and tremor(SMD 0.91, 95%CI [0.15, 1.67]). CONCLUSION: rTMS therapy is an effective treatment for motor symptoms of PD and the individualized stimulation protocols for different symptoms would further improve its clinical efficacy.

Piezo1 and IFT88 synergistically regulate mandibular condylar chondrocyte differentiation under cyclic tensile strain.

OBJECTIVE(S): Mandibular condyle chondrocytes (MCCs) are exposed to various mechanical environments. Primary cilia, as a carrier for ion channels, can sense mechanical signals. Intraflagellar transport protein 88 (IFT88) is crucial for the assembly and function of primary cilia. Piezo1 is a mechanically activated ion channel that mediates mechanical signal transduction. This study aimed to identify the possible synergistic effect between Piezo1 and IFT88 in MCC differentiation during mechanical conduction. MATERIALS AND METHODS: Confocal immunofluorescence staining was used to reveal the Piezo1 localization. Small interfering RNA (siRNA) technology was used to knock down the expression levels of Piezo1 and IFT88. The chondrogenic differentiation ability of MCCs was evaluated by Alcian blue staining, and the early differentiation ability was evaluated by Western blot of SOX9 and COL2A1. RESULTS: Confocal immunofluorescence results showed that Piezo1 localized in the root of primary cilia. Without cyclic tensile strain (CTS) stimuli, Alcian blue staining showed that Piezo1 knockdown had a marginal effect on the chondrogenic differentiation of MCCs, while IFT88 knockdown inhibited the chondrogenic differentiation. The protein levels of SOX9 and COL2A1 decreased significantly with CTS stimuli. However, these protein levels were restored when Piezo1 was knocked down. In addition, IFT88 knockdown decreased the protein level of Piezo1 with or without CTS. CONCLUSION: Piezo1 and IFT88 might play a synergistic role in regulating MCC differentiation under CTS stimuli.

Intraflagellar transport protein 88 interacts with polycystin 2 to regulate mechanosensitive hedgehog signaling in mandibular condylar chondrocytes.

OBJECTIVE: This study aimed to explore whether intraflagellar transport protein 88 (IFT88) was associated with polycystin 2 during mechanotransduction of mandibular condylar chondrocytes. METHODS: Rat mandibular condylar chondrocytes isolated from the condylar bone-cartilage junction were subjected to cyclic tensile strain (0.1 Hz, 10% elongation). Overexpression of IFT88 was achieved by lentiviral vector-mediated transfection. Knockdown of IFT88 and polycystin 2 was achieved by small interfering RNA (siRNA). The prevalence and length of cilia were reflected by immunofluorescence staining. The activities of hedgehog signaling were evaluated by western blot analysis. The interaction between polycystin 2 and IFT88 was evaluated by conducting a co-immunoprecipitation (co-IP) assay. RESULTS: Overexpression of IFT88 increased the length of cilia. Protein levels of polycystin 2, Indian hedgehog (Ihh), Patched 1 (Ptch1), Smoothened (Smo), and Glioma-associated oncogene homolog 1 (Gli1) were elevated in IFT88-overexpressing mandibular condylar chondrocytes under cyclic tensile strain. Knockdown of the protein level of IFT88 reduced the prevalence and length of cilia, and protein levels of polycystin 2, Ihh, Ptch1, Smo, and Gli1. A co-IP assay showed that IFT88 formed a complex with polycystin 2 under cyclic tensile strain. Knockdown of polycystin 2 decreased the protein levels of IFT88, Ihh, Ptch1, Smo, and Gli1 in mandibular condylar chondrocytes following cyclic tensile strain. CONCLUSION: These findings highlight the vital role of an interaction between IFT88 and polycystin 2 in mechanosensitive hedgehog signaling in mandibular condylar chondrocytes following cyclic tensile strain, which suggest that therapies regulating polycystin 2 may be considered for the disorders of temporomandibular joints.

Computational model of CAR T-cell immunotherapy dissects and predicts leukemia patient responses at remission, resistance, and relapse.

BACKGROUND: Adaptive CD19-targeted chimeric antigen receptor (CAR) T-cell transfer has become a promising treatment for leukemia. Although patient responses vary across different clinical trials, reliable methods to dissect and predict patient responses to novel therapies are currently lacking. Recently, the depiction of patient responses has been achieved using in silico computational models, with prediction application being limited. METHODS: We established a computational model of CAR T-cell therapy to recapitulate key cellular mechanisms and dynamics during treatment with responses of continuous remission (CR), non-response (NR), and CD19-positive (CD19+) and CD19-negative (CD19-) relapse. Real-time CAR T-cell and tumor burden data of 209 patients were collected from clinical studies and standardized with unified units in bone marrow. Parameter estimation was conducted using the stochastic approximation expectation maximization algorithm for nonlinear mixed-effect modeling. RESULTS: We revealed critical determinants related to patient responses at remission, resistance, and relapse. For CR, NR, and CD19+ relapse, the overall functionality of CAR T-cell led to various outcomes, whereas loss of the CD19+ antigen and the bystander killing effect of CAR T-cells may partly explain the progression of CD19- relapse. Furthermore, we predicted patient responses by combining the peak and accumulated values of CAR T-cells or by inputting early-stage CAR T-cell dynamics. A clinical trial simulation using virtual patient cohorts generated based on real clinical patient datasets was conducted to further validate the prediction. CONCLUSIONS: Our model dissected the mechanism behind distinct responses of leukemia to CAR T-cell therapy. This patient-based computational immuno-oncology model can predict late responses and may be informative in clinical treatment and management.

Prediction of the postoperative prognosis in patients with non-muscle-invasive bladder cancer based on preoperative serum surface-enhanced Raman spectroscopy.

Non-muscle-invasive bladder cancer (NMIBC) is a common urinary tumor and has a high recurrence rate due to improper or inadequate conservative treatment. The early and accurate prediction of its recurrence can be helpful to implement timely and rational treatment. In this study, we explored a preoperative serum surface-enhanced Raman spectroscopy based prognostic protocol to predict the postoperative prognosis for NMIBC patients at the time even before treatment. The biochemical analysis results suggested that biomolecules related to DNA/RNA, protein substances, trehalose and collagen are expected to be potential prognostic markers, which further compared with several routine clinically used immunohistochemistry expressions with prognostic values. In addition, high prognostic accuracies of 87.01% and 89.47% were achieved by using the proposed prognostic models to predict the future postoperative recurrence and recurrent type, respectively. Therefore, we believe that the proposed method has great potential in the early and accurate prediction of postoperative prognosis in patients with NMIBC, which is with important clinical significance to guide the treatment and further improve the recurrence rate and survival time.