Impact of ARID1A and TP53 mutations in pediatric refractory or relapsed mature B-Cell lymphoma treated with CAR-T cell therapy.

BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy has been used to treat pediatric refractory or relapsed mature B-cell non-Hodgkin lymphoma (r/r MB-NHL) with significantly improved outcomes, but a proportion of patients display no response or experience relapse after treatment. To investigate whether tumor-intrinsic somatic genetic alterations have an impact on CAR-T cell treatment, the genetic features and treatment outcomes of 89 children with MB-NHL were analyzed. METHODS: 89 pediatric patients treated at multiple clinical centers of the China Net Childhood Lymphoma (CNCL) were included in this study. Targeted next-generation sequencing for a panel of lymphoma-related genes was performed on tumor samples. Survival rates and relapse by genetic features and clinical factors were analyzed. Survival curves were calculated using a log-rank (Mantel-Cox) test. The Wilcox sum-rank test and Fisher's exact test were applied to test for group differences. RESULTS: A total of 89 driver genes with somatic mutations were identified. The most frequently mutated genes were TP53 (66%), ID3 (55%), and ARID1A (31%). The incidence of ARID1A mutation and co-mutation of TP53 and ARID1A was high in patients with r/r MB-NHL (P = 0.006; P = 0.018, respectively). CAR-T cell treatment significantly improved survival in r/r MB-NHL patients (P = 0.00081), but patients with ARID1A or ARID1A and TP53 co-mutation had poor survival compared to those without such mutations. CONCLUSION: These results indicate that children with MB-NHL harboring ARID1A or TP53 and ARID1A co-mutation are insensitive to initial conventional chemotherapy and subsequent CAR-T cell treatment. Examination of ARID1A and TP53 mutation status at baseline might have prognostic value, and risk-adapted or more effective therapies should be considered for patients with these high-risk genetic alterations.

Homoharringtonine-Based Induction Regimen Improved the Remission Rate and Survival Rate in Chinese Childhood AML: A Report From the CCLG-AML 2015 Protocol Study.

PURPOSE: Homoharringtonine (HHT) is commonly used for the treatment of Chinese adult AML, and all-trans retinoic acid (ATRA) has been verified in acute promyelocytic leukemia (APL). However, the efficacy and safety of HHT-based induction therapy have not been confirmed for childhood AML, and ATRA-based treatment has not been evaluated among patients with non-APL AML. PATIENTS AND METHODS: This open-label, multicenter, randomized Chinese Children's Leukemia Group-AML 2015 study was performed across 35 centers in China. Patients with newly diagnosed childhood AML were first randomly assigned to receive an HHT-based (H arm) or etoposide-based (E arm) induction regimen and then randomly allocated to receive cytarabine-based (AC arm) or ATRA-based (AT arm) maintenance therapy. The primary end points were the complete remission (CR) rate after induction therapy, and the secondary end points were the overall survival (OS) and event-free survival (EFS) at 3 years. RESULTS: We enrolled 1,258 patients, of whom 1,253 were included in the intent-to-treat analysis. The overall CR rate was significantly higher in the H arm than in the E arm (79.9% v 73.9%, P = .014). According to the intention-to-treat analysis, the 3-year OS was 69.2% (95% CI, 65.1 to 72.9) in the H arm and 62.8% (95% CI, 58.7 to 66.6) in the E arm (P = .025); the 3-year EFS was 61.1% (95% CI, 56.8 to 65.0) in the H arm and 53.4% (95% CI, 49.2 to 57.3) in the E arm (P = .022). Among the per-protocol population, who received maintenance therapy, the 3-year EFS did not differ significantly across the four arms (H + AT arm: 70.7%, 95% CI, 61.1 to 78.3; H + AC arm: 74.8%, 95% CI, 67.0 to 81.0, P = .933; E + AC arm: 72.9%, 95% CI, 65.1 to 79.2, P = .789; E + AT arm: 66.2%, 95% CI, 56.8 to 74.0, P = .336). CONCLUSION: HHT is an alternative combination regimen for childhood AML. The effects of ATRA-based maintenance are comparable with those of cytarabine-based maintenance therapy.

Multimodal Assessment of Schizophrenia Symptom Severity From Linguistic, Acoustic and Visual Cues.

Assessing the condition of every schizophrenia patient correctly normally requires lengthy and frequent interviews with professionally trained doctors. To alleviate the time and manual burden on those mental health professionals, this paper proposes a multimodal assessment model that predicts the severity level of each symptom defined in Scale for the Assessment of Thought, Language, and Communication (TLC) and Positive and Negative Syndrome Scale (PANSS) based on the patient's linguistic, acoustic, and visual behavior. The proposed deep-learning model consists of a multimodal fusion framework and four unimodal transformer-based backbone networks. The second-stage pre-training is introduced to make each off-the-shelf pre-trained model learn the pattern of schizophrenia data more effectively. It learns to extract the desired features from the view of its modality. Next, the pre-trained parameters are frozen, and the light-weight trainable unimodal modules are inserted and fine-tuned to keep the number of parameters low while maintaining the superb performance simultaneously. Finally, the four adapted unimodal modules are fused into a final multimodal assessment model through the proposed multimodal fusion framework. For the purpose of validation, we train and evaluate the proposed model on schizophrenia patients recruited from National Taiwan University Hospital, whose performance achieves 0.534/0.685 in MAE/MSE, outperforming the related works in the literature. Through the experimental results and ablation studies, as well as the comparison with other related multimodal assessment works, our approach not only demonstrates the superiority of our performance but also the effectiveness of our approach to extract and integrate information from multiple modalities.

Influencing factors for thyroid function among radiation workers in Wuhan City / 预防医学

Objective@# To investigate the thyroid functions and influencing factors among radiation workers in Wuhan City, so as to provide insights into occupational health monitoring among radiation workers.@*Methods @#Radiation workers receiving physical examinations in Wuhan Prevention and Treatment Center for Occupational Diseases from January to October 2022 were enrolled, and participants' gender, age, smoking, alcohol consumption, medical history, medication use, types of occupational radiation and work duration were collected. Triiodothyronine (TT3), thyroxine (TT4), free thyroxine (FT4), free triiodothyronine (FT3) and thyroid stimulating hormone (TSH) were measured using a magnetic microparticle-based chemiluminescence immunoassay. Personnel dose equivalent was monitored using thermoluminescent dosimetry, and annual cumulative radiation dose was estimated. Factors affecting thyroid function were identified using a multivariable linear regression model.@*Results@#Totally 978 radiation workers were recruited, with a median age of 32.00 (interquartile range, 10.00) years, and including 782 men (79.96%) and 196 women (20.04%). There were 246 smokers (25.15%), 257 workers with alcohol consumption (26.28%) and 489 with a history of radiation work (50.00%). The median annual cumulative radiation dose was 0.20 (interquartile range, 0.24) mSv. The percentage of abnormal thyroid function was 14.72%. Multivariable logistic regression analysis showed that women (OR=1.925, 95%CI: 1.061-3.490), history of radiation work (OR=2.810, 95%CI: 1.119-7.057) and involving in medical application (OR=1.915, 95%CI: 1.101-3.332) were associated with abnormal thyroid function.@*Conclusions@#The percentage of abnormal thyroid function was 14.72% among radiation workers in Wuhan City. History of exposure to ionizing radiation, types of occupational radiation and gender were main factors affecting thyroid function.

Mental Status Detection for Schizophrenia Patients via Deep Visual Perception.

Schizophrenia is a mental disorder that will progressively change a person's mental state and cause serious social problems. Symptoms of schizophrenia are highly correlated to emotional status, especially depression. We are thus motivated to design a mental status detection system for schizophrenia patients in order to provide an assessment tool for mental health professionals. Our system consists of two phases, including model learning and status detection. For the learning phase, we propose a multi-task learning framework to infer the patient's mental state, including emotion and depression severity. Unlike previous studies inferring emotional status mainly by facial analysis, in the learning phase, we adopted a Cross-Modality Graph Convolutional Network (CMGCN) to effectively integrate visual features from different modalities, including the face and context. We also designed task-aware objective functions to realize better model convergence for multi-task learning, i.e., emotion recognition and depression estimation. Further, we followed the correlation between depression and emotion to design the Emotion Passer module, to transfer the prior knowledge on emotion to the depression model. For the detection phase, we drew on characteristics of schizophrenia to detect the mental status. In the experiments, we performed a series of experiments on several benchmark datasets, and the results show that the proposed learning framework boosts state-of-the-art (SOTA) methods significantly. In addition, we take a trial on schizophrenia patients, and our system can achieve 69.52 in mAP in a real situation.

Evaluation of left atrial function and mechanical dispersion in breast cancer patients after chemotherapy.

BACKGROUND: Left atrial (LA) function and mechanical dispersion changes in breast cancer patients treated with chemotherapy remain unclear. HYPOTHESIS: LA function and LA mechanical dispersion in breast cancer patients would be impaired after chemotherapy. METHODS: This single-center retrospective study included 91 consecutive breast cancer patients treated with chemotherapy and 30 controls. Patients were examined by echocardiography three times at intervals. Conventional parameters, left ventricular strain, LA strain, and LA mechanical dispersion were evaluated and compared. RESULTS: LA strain during reservoir phase (LASr), conduit phase (LAScd), and contraction phase (LASct) all decreased markedly after chemotherapy and were lower than those of the controls (all p < .01). The standard deviation of time to peak positive strain during LA reservoir phase corrected by R-R interval (LA SD-TPSr) was significantly increased after chemotherapy and was higher than that of the controls (p < .001). The change of LA function was expressed as Δ. Multivariate linear regression analyses showed that LAVIp (0.399, 95% confidence interval [CI]: 0.610, 1.756, p = .000) was independently associated with ΔLASr, LAPEF (-0.325, 95% CI: -45.123, -10.676, p = .002) and age (0.227, 95% CI: 0.021, 0.350, p = .027) were independently associated with ΔLAScd, and LAVImax (0.341, 95% CI: 0.192, 0.723, p = .001) was independently associated with ΔLASct. LAVImax (0.505, 95% CI: 0.000, 0.001, p = .039) and mitral E (-0.256, 95% CI: 0.000, 0.000, p = .024）were independently associated with ΔLA SD-TPSr. CONCLUSIONS: Mechanical function of LA declined after chemotherapy in breast cancer patients. With the decrease of LA mechanical function, LA mechanical dispersion assessed by two-dimensional speckle-tracking echocardiography increased significantly, and its clinical value needs to be further studied.

Arsenic Combined With All-Trans Retinoic Acid for Pediatric Acute Promyelocytic Leukemia: Report From the CCLG-APL2016 Protocol Study.

PURPOSE: Arsenic combined with all-trans retinoic acid (ATRA) is the standard of care for adult acute promyelocytic leukemia (APL). However, the safety and effectiveness of this treatment in pediatric patients with APL have not been reported on the basis of larger sample sizes. METHODS: We conducted a multicenter trial at 38 hospitals in China. Patients with newly diagnosed APL were stratified into two risk groups according to baseline WBC count and FLT3-ITD mutation. ATRA plus arsenic trioxide or oral arsenic without chemotherapy were administered to the standard-risk group, whereas ATRA, arsenic trioxide, or oral arsenic plus reduced-dose anthracycline were administered to the high-risk group. Primary end points were event-free survival and overall survival at 2 years. RESULTS: We enrolled 193 patients with APL. After a median follow-up of 28.9 months, the 2-year overall survival rate was 99% (95% CI, 97 to 100) in the standard-risk group and 95% (95% CI, 90 to 100) in the high-risk group (P = .088). The 2-year event-free survival was 97% (95% CI, 93 to 100) in the standard-risk group and 90% (95% CI, 83 to 96) in the high-risk group (P = .252). The plasma levels of arsenic were significantly elevated after treatment, with a stable effective level ranging from 42.9 to 63.2 ng/mL during treatment. In addition, plasma, urine, hair, and nail arsenic levels rapidly decreased to normal 6 months after the end of treatment. CONCLUSION: Arsenic combined with ATRA is effective and safe in pediatric patients with APL, although long-term follow-up is still needed.

Posaconazole and fluconazole prophylaxis during induction therapy for pediatric acute lymphoblastic leukemia.

PURPOSE: To assess and compare the efficacy and safety of posaconazole with fluconazole for the prevention of invasive fungal infections in children who were undergoing induction therapy for acute lymphoblastic leukemia (ALL). To develop an approach to predict invasive fungal infections in ALL patients who accepted posaconazole prophylaxis. METHODS: This was a single-center, retrospective cohort study of patients with newly diagnosed ALL, comparing invasive fungal infections in patients who received no prophylaxis, posaconazole prophylaxis, or fluconazole prophylaxis during induction therapy. A propensity score-weighted logistic regression model was used to adjust for confounders. Hepatotoxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria. RESULTS: Out of the 155 ALL patients, 60 received no prophylaxis, 70 received posaconazole prophylaxis, and 25 received fluconazole prophylaxis. Posaconazole prophylaxis reduced the odds of invasive fungal infections by > 60%, prolonged infection-free survival significantly, and did not increase the risk of hepatotoxicity. Additionally, we found that the combination of age at diagnosis, clinically documented bacterial infection in the first 15 days of induction therapy, and absolute neutrophil count (ANC) curve enabled significant prediction of the susceptibility to infections after receiving posaconazole prophylaxis. CONCLUSIONS: Our findings supported using targeted prophylaxis with posaconazole in ALL children undergoing induction chemotherapy. Age, clinically documented bacterial infection and ANC are important predictors of invasive fungal infections in patients with posaconazole prophylaxis.

Percutaneous closure of the left atrial appendage: The value of real time 3D transesophageal echocardiography and the intraoperative change in the size of the left atrial appendage.

OBJECTIVE: The aim of this study was to investigate the value of real time three-dimensional transesophageal echocardiography (RT3DTEE) in percutaneous closure of the left atrial appendage (LAAC). In addition, this study also explored the change in the size of the left atrial appendage (LAA) from 24 hours before the operation to just before implantation during the operation. METHODS AND RESULTS: In a retrospective study, 32 patients underwent two-dimensional transesophageal echocardiography (2DTEE) and RT3DTEE 24 hours prior to operation and during operation. The maximal LAA orifice diameter (by 2DTEE, 22.7 ± 2.7 vs 24.6 ± 2.2 mm, P < 0.01; by RT3DTEE, 24.2 ± 2.9 vs 25.8 ± 2.7 mm, P < 0.01), the maximal landing zone diameter (by 2DTEE, 19.0 ± 2.8 vs 20.4 ± 2.8 mm, P < 0.01; by RT3DTEE, 20.4 ± 2.7 vs 22.6 ± 3.0 mm, P < 0.01), and the maximal depth diameter (by 2DTEE, 25.2 ± 3.2 vs 26.5 ± 3.0 mm, P < 0.01; by RT3DTEE, 26.4 ± 3.2 vs 27.5 ± 3.7 mm, P < 0.01) all increased significantly during the operation. The highest correlation (R) between the maximal landing zone diameter and the compressed occluder diameter was determined for RT3DTEE measurements during the operation (R = 0.90), whereas the landing zone diameter (R = 0.80) measured by 2DTEE was less correlated. In addition, our study showed that RT3DTEE was of great value in discriminating the LAA orifice shape, allowing differentiation of the LAA morphology and identification of the number of LAA lobes. CONCLUSIONS: A certain amount of intravenous rehydration just before and during operation increased the LAA size significantly. The measurements by RT3DTEE showed a closer correlation to LAA occluder size than those by 2DTEE. The LAA displayed by RT3DTEE was more visible than that by 2DTEE.

[Construction of expression vector of ALAg and immune protection of its recombinant protein induced in mice].

OBJECTIVE: To determine the candidate genes for engineering vaccine of Ascaris lumbricoides. METHODS: pMD18-T-ALAg and plasmid expression vector pET-28a(+) were digested with BamH I and EcoR I and linked to each other. The resultant plasmid pET-28a(+)-ALAg was transferred into E. coli BL21 (DE3) and its expression was induced with IPTG, and the recombinant ALAg(rALAg) was purified. A total of 30 mice were equally divided into 3 groups, the mice in each group were injected with rALAg-FCA, FCA and PBS respectively, then they were attacked by infectious eggs of Ascaris (3 600 per mouse). The IgG levels in sera of mice in each group were detected by indirect ELASA. RESULTS: rALAg was recognized by the sera from repeatedly Ascaris lumbricoides inoculated rabbits. The numbers of larvae of Ascaris lumbricoides from liver and lung of mice were 25.30 +/- 4.55 in the rALAg-FCA group and 57.60 +/- 5.76 in the PBS group, respectively, the former being the reducing rate of 69.26%, and the difference among the 3 groups showed statistical significances (P < 0.01). The IgG levels (A450 value) of the rALAg-FCA, FCA and PBS groups were 0.858 +/- 0.003, 0.149 +/- 0.004 and 0.134 +/- 0.004, respectively, there were statistical differences among them (P < 0.01). CONCLUSION: ALAg can be used as a candidate gene of genetic engineering vaccine of Ascaris lumbricoides.

Silicon-on-insulator eight-channel optical multiplexer based on a cascade of asymmetric Mach-Zehnder interferometers.

A monolithically integrated eight-channel optical multiplexer (Mux) with a 400 GHz channel spacing ~1550 nm is presented based on a silicon-on-insulator rib waveguide and an asymmetric Mach-Zehnder interferometer. All channels were optimized independently with integrated heaters. The fully tuned Mux shows an adjacent channel isolation of ~13 dB, an excess loss of ~2.6 dB, and a channel uniformity of ~1.5 dB over a 25 nm wavelength span. In addition, the phase tuning efficiency for different interlevel dielectric layer thicknesses and thermal crosstalk were investigated.

High-speed optical modulation based on carrier depletion in a silicon waveguide.

We present a high-speed and highly scalable silicon optical modulator based on the free carrier plasma dispersion effect. The fast refractive index modulation of the device is due to electric-field-induced carrier depletion in a Silicon-on-Insulator waveguide containing a reverse biased pn junction. To achieve high-speed performance, a travelling-wave design is used to allow co-propagation of electrical and optical signals along the waveguide. We demonstrate high-frequency modulator optical response with 3 dB bandwidth of ~20 GHz and data transmission up to 30 Gb/s. Such high-speed data transmission capability will enable silicon modulators to be one of the key building blocks for integrated silicon photonic chips for next generation communication networks as well as future high performance computing applications.

High efficiency wavelength conversion of 10 Gb/s data in silicon waveguides.

Efficient wavelength conversion via four-wave-mixing in silicon-on-isolator p-i-n waveguides has been realized. By reverse biasing the p-i-n diode structure formed along the silicon rib waveguide, the nonlinear absorption due to two photon absorption induced free carrier absorption is significantly reduced, and a wavelength conversion efficiency of -8.5 dB has been achieved in an 8 cm long waveguide at a pump intensity of 40 MW/cm2. A high-speed pseudo-random bit sequence data at 10 Gb/s rate is converted to a new wavelength channel in the C-band with clear open eye diagram and no waveform distortion. Conversion efficiency as functions of pump power, wavelength detuning, and bias voltages, have been investigated. For shorter waveguides of 1.6 cm long, a conversion bandwidth of > 30 nm was achieved.

Monolithic integrated Raman silicon laser.

We present a monolithic integrated Raman silicon laser based on silicon-on-insulator (SOI) rib waveguide race-track ring resonator with an integrated p-i-n diode structure. Under reverse biasing, we achieved stable, single mode, continuous-wave (CW) lasing with output power exceeding 30mW and 10% slope efficiency. The laser emission has high spectral purity with a measured side mode suppression exceeding 70dB and laser linewidth of <100 kHz. This laser architecture allows for on-chip integration with other silicon photonics components to provide a highly integrated and scaleable monolithic device.

A continuous-wave Raman silicon laser.

Achieving optical gain and/or lasing in silicon has been one of the most challenging goals in silicon-based photonics because bulk silicon is an indirect bandgap semiconductor and therefore has a very low light emission efficiency. Recently, stimulated Raman scattering has been used to demonstrate light amplification and lasing in silicon. However, because of the nonlinear optical loss associated with two-photon absorption (TPA)-induced free carrier absorption (FCA), until now lasing has been limited to pulsed operation. Here we demonstrate a continuous-wave silicon Raman laser. Specifically, we show that TPA-induced FCA in silicon can be significantly reduced by introducing a reverse-biased p-i-n diode embedded in a silicon waveguide. The laser cavity is formed by coating the facets of the silicon waveguide with multilayer dielectric films. We have demonstrated stable single mode laser output with side-mode suppression of over 55 dB and linewidth of less than 80 MHz. The lasing threshold depends on the p-i-n reverse bias voltage and the laser wavelength can be tuned by adjusting the wavelength of the pump laser. The demonstration of a continuous-wave silicon laser represents a significant milestone for silicon-based optoelectronic devices.

An all-silicon Raman laser.

The possibility of light generation and/or amplification in silicon has attracted a great deal of attention for silicon-based optoelectronic applications owing to the potential for forming inexpensive, monolithic integrated optical components. Because of its indirect bandgap, bulk silicon shows very inefficient band-to-band radiative electron-hole recombination. Light emission in silicon has thus focused on the use of silicon engineered materials such as nanocrystals, Si/SiO2 superlattices, erbium-doped silicon-rich oxides, surface-textured bulk silicon and Si/SiGe quantum cascade structures. Stimulated Raman scattering (SRS) has recently been demonstrated as a mechanism to generate optical gain in planar silicon waveguide structures. In fact, net optical gain in the range 2-11 dB due to SRS has been reported in centimetre-sized silicon waveguides using pulsed pumping. Recently, a lasing experiment involving silicon as the gain medium by way of SRS was reported, where the ring laser cavity was formed by an 8-m-long optical fibre. Here we report the experimental demonstration of Raman lasing in a compact, all-silicon, waveguide cavity on a single silicon chip. This demonstration represents an important step towards producing practical continuous-wave optical amplifiers and lasers that could be integrated with other optoelectronic components onto CMOS-compatible silicon chips.

Net continuous wave optical gain in a low loss silicon-on-insulator waveguide by stimulated Raman scattering.

We observe for the first time net continuous wave optical gain in a low loss silicon-on-insulator waveguide based on stimulated Raman scattering. We show that nonlinear optical loss due to two-photon absorption induced free carrier absorption can be significantly reduced by introducing a reverse biased p-i-n diode in the waveguide. For a 4.8 cm long waveguide with an effective core area of ~1.6 microm2, we obtain a net CW Raman gain of > 3dB with a pump power of ~700mW inside the waveguide.

Lossless optical modulation in a silicon waveguide using stimulated Raman scattering.

In this paper we describe a new modulation scheme using stimulated Raman scattering in conjunction with a reverse biased p-i-n diode embedded in a silicon waveguide. We show optical modulation of a weak probe beam by modulating the reverse bias voltage of the silicon waveguide excited by a strong pump beam. The probe beam modulation is due to the two-photon absorption-induced carrier density modulation in the waveguide. By tuning the probe wavelength to the Stokes wavelength, we demonstrate for the first time a lossless optical modulator in silicon with modulation speeds up to 80-MHz.