The optimal threshold of PD-L1 combined positive score to predict the benefit of PD-1 antibody plus chemotherapy for patients with HER2-negative gastric adenocarcinoma: a meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) combined with chemotherapy have become the first-line treatment of metastatic gastric and gastroesophageal adenocarcinomas (GEACs). This study aims to figure out the optimal combined positive score (CPS) cutoff value. METHODS: We searched for randomized phase III trials to investigate the efficacy of ICIs plus chemotherapy for metastatic GEACs compared with chemotherapy alone. Pooled analyses of hazard ratios (HRs) based on PD-L1 expression were performed. RESULTS: A total of six trials (KEYNOTE-062, KEYNOTE-590, KEYNOTE-859, ATTRACTION-04, CheckMate 649, and ORIENT-16) were included, comprising 5,242 patients. ICIs plus chemotherapy significantly improved OS (HR: 0.79, 95% CI 0.72-0.86 in global patients; HR: 0.75, 95% CI 0.57-0.98 in Asian patients) and PFS (HR: 0.74, 95% CI 0.68-0.82 in global patients; HR: 0.64, 95% CI 0.56-0.73 in Asian patients) compared with chemotherapy alone. The differences in OS (ratio of HR: 1.05, 95% CI 0.79-1.40; predictive value: - 5.1%) and PFS (ratio of HR: 1.16, 95% CI 0.98-1.36; predictive value: - 13.5%) were not statistically significant between the global and Asian patients. Subgroup analyses indicated that the optimal CPS threshold was at ≥ 5 for OS and ≥ 10 for PFS with the highest predictive values. CONCLUSIONS: The benefit derived from ICIs plus chemotherapy is similar between Asian and global GEAC patients. However, those with a PD-L1 CPS < 5 or CPS < 10 may not have significant benefits from ICIs therapy. Therefore, it is advisable to routinely assess PD-L1 expression in GEAC patients considered for ICIs treatment.

Potential roles of hydroxybenzoate paralytic shellfish toxins in modulating toxin biokinetics in scallops.

Paralytic shellfish toxins (PSTs) produced by some marine dinoflagellates can cause severe human intoxication via vectors like bivalves. Toxic dinoflagellate Gymnodinium catenatum produce a novel group of hydroxybenzoate PSTs named GC toxins, but their biokinetics in bivalves haven't been well examined. In this experiment, we analyzed PSTs in bay scallops Argopecten irradians exposed to G. catenatum (strain MEL11) to determine their accumulation, elimination, anatomical distribution, and biotransformation. To our surprise, up to 30% of the PSTs were accumulated in the adductor muscle of scallops at the end of the experiment, and the toxicity of adductor muscle exceeded the regulatory limit of 800 µg STXeq/kg in only 6 days. High concentration of toxins in the adductor muscle are likely linked to the rapid transfer of GC toxins from viscera to other tissues. Moreover, most GC toxins in scallops were found rapidly transformed to decarbamoyl toxins through enzyme-mediated hydrolysis, which was further supported by the in vitro incubation experiments. Our study demonstrates that GC toxins actively participate in toxin distribution and transformation in scallops, which may increase the risks of food poisoning associated with the consumption of scallop adductor muscle. ENVIRONMENTAL IMPLICATION: The negative impacts of harmful algal blooms (HABs) have become a global environmental concern under the joint effects of cultural eutrophication and climate change. Our study, targeted on the biokinetics of paralytic shellfish toxins in scallops exposed to Gymnodinium catenatum producing unique GC toxins, aims to elucidate potential risks of seafood poisoning associated with GC toxins. The findings of this study will help us to understand the roles of GC toxins in seafood poisoning, and to develop effective management strategies against toxic algal blooms and phycotoxins.

Sono-anatomy of the middle cervical sympathetic ganglion verified with pathology.

Objectives: Cervical discomfort and other symptoms may be attributable to the middle cervical sympathetic ganglion. The aim of this study was to explore the sonographic features of this ganglion in anatomical specimens and cadavers and evaluate the feasibility of its visualization using high-resolution ultrasonography. Methods: We examined three cervical sympathetic-ganglion specimens and two fresh cadavers using high-resolution ultrasound to explore the sonographic features of this ganglion. Basic imaging characteristics examined included the shape, echo intensity, and location of the ganglion. Core-needle biopsy was performed to examine the suspected middle cervical sympathetic ganglion in the two fresh cadavers and verify the accuracy of the sonographic identification via pathological examination. Results: The middle cervical sympathetic ganglion appeared on high-resolution ultrasonography as an oval-shaped hypoechoic structure, with at least one continuous hypoechoic line connected to each ending in the anatomical specimens and fresh cadavers, and it was distinctly different from the adjacent lymph nodes. Discussion: Based on an adequate understanding of both its location and sonographic features, the direct visualization of the middle cervical sympathetic ganglion using high-resolution ultrasonography is feasible.

Toripalimab plus capecitabine in the treatment of patients with residual nasopharyngeal carcinoma: a single-arm phase 2 trial.

Patients with residual nasopharyngeal carcinoma after receiving definitive treatment have poor prognoses. Although immune checkpoint therapies have achieved breakthroughs for treating recurrent and metastatic nasopharyngeal carcinoma, none of these strategies have been assessed for treating residual nasopharyngeal carcinoma. In this single-arm, phase 2 trial, we aimed to evaluate the antitumor efficacy and safety of toripalimab (anti-PD1 antibody) plus capecitabine in patients with residual nasopharyngeal carcinoma after definitive treatment (ChiCTR1900023710). Primary endpoint of this trial was the objective response rate assessed according to RECIST (version 1.1). Secondary endpoints included complete response rate, disease control rate, duration of response, progression-free survival, safety profile, and treatment compliance. Between June 1, 2020, and May 31, 2021, 23 patients were recruited and received six cycles of toripalimab plus capecitabine every 3 weeks. In efficacy analyses, 13 patients (56.5%) had complete response, and 9 patients (39.1%) had partial response, with an objective response rate of 95.7% (95% CI 78.1-99.9). The trial met its prespecified primary endpoint. In safety analyses, 21 of (91.3%) 23 patients had treatment-related adverse events. The most frequently reported adverse event was hand-foot syndrome (11 patients [47.8%]). The most common grade 3 adverse event was hand-foot syndrome (two patients [8.7%]). No grades 4-5 treatment-related adverse events were recorded. This phase 2 trial shows that combining toripalimab with capecitabine has promising antitumour activity and a manageable safety profile for patients with residual nasopharyngeal carcinoma.

Transient vacuolar changes of the crystalline lens in patients using a dispersive ophthalmic viscosurgical device.

AIM: To report the clinical prognosis and pathological findings of accidental lens vacuolar changes in eyes with intraoperative exposure to a dispersive ophthalmic viscosurgical device (OVD). METHODS: Two patients who developed transient lens vacuolar changes during uneventful persistent pupillary membrane (PPM) removal surgery were presented and followed up. This event was speculated to be associated with an intraoperative dispersive OVD DisCoVisc (hyaluronic acid 1.6%-chondroitin sulfate 4.0%) exposure. Then, to provide the pathological basis for our speculation, another four cataract patients were randomly exposed to different OVDs, and their anterior lens capsules were investigated with transmission electron microscopy (TEM). RESULTS: After months, the subcapsular vacuoles in both PPM cases were gradually disappeared without visual deterioration. For the cataract patients, similar lens changes were observed intraoperatively in those exposed to a dispersive DisCoVisc but not a cohesive OVD IVIZ (sodium hyaluronate gel 1.0%). In addition, marked ultrastructural changes, including chromatin condensation, extensive cytoplasmic vacuoles, and obvious intercellular space between lens epithelial cells in the anterior lens capsules of all eyes exposed to DisCoVisc, were observed by TEM. CONCLUSION: The lens vacuolar changes may be associated with a dispersive OVD exposure. Therefore, it is not preferable to use dispersive OVDs in patients with transparent lenses or without the intention of lens extraction. In addition, close follow-ups instead of immediate lens extraction are recommended for the occurrence of similar lens lesions.

Carotid-cavernous fistula following mechanical thrombectomy of the tortuous internal carotid artery: A case report.

BACKGROUND: A carotid-cavernous fistula (CCF) is an abnormal connection between the internal carotid artery (ICA) and the cavernous sinus. Although direct CCFs typically result from trauma or as an iatrogenic complication of neuroendovascular procedures, they can occur as surgery-related complications after mechanical thrombectomy (MT). With the widespread use of MT in patients with acute ischemic stroke complicated with large vessel occlusion, it is important to document CCF following MT and how to avoid them. In this study, we present a case of a patient who developed a CCF following MT and describe in detail the characteristics of ICA tortuosity in this case. CASE SUMMARY: A 60-year-old woman experienced weakness in the left upper and lower limbs as well as difficulty speaking for 4 h. The neurological examination revealed left central facial paralysis and left hemiplegia, with a National Institutes of Health Stroke Scale score of 9. Head magnetic resonance imaging revealed an acute cerebral infarction in the right basal ganglia and radial crown. Magnetic resonance angiography demonstrated an occlusion of the right ICA and middle cerebral artery. Digital subtraction angiography demonstrated distal occlusion of the cervical segment of the right ICA. We performed suction combined with stent thrombectomy. Then, postoperative angiography was performed, which showed a right CCF. One month later, CCF embolization was performed, and the patient's clinical symptoms have significantly improved 5 mo after the operation. CONCLUSION: Although a CCF is a rare complication after MT, it should be considered. Understanding the tortuosity of the internal carotid-cavernous sinus may help predict the complexity of MT and avoid this complication.

Dietary magnesium is able to influence the relationship between vitamin C and estimated glomerular filtration rate: A cross-sectional study.

The estimated glomerular filtration rate (eGFR) is a comprehensive index that is widely used to assess renal function. Although studies have confirmed a correlation between eGFR and dietary vitamin C, the impact of varying levels of vitamin C on eGFR remains unclear. Additionally, the interaction between dietary magnesium intake and vitamin C concentration on eGFR is not well understood. As such, the objective of this study was to investigate the relationship between dietary magnesium intake and vitamin C in relation to eGFR. This study analyzed the data of consecutive NHANES from 2005 to 2018. We included 17,633 participants aged 20 or older and used multiple linear regression analysis to evaluate the relationship between dietary vitamin C and eGFR. Dietary Mg intake from experimental data was dichotomized into a low dietary Mg intake group (≤254 mg/day) and a normal dietary Mg intake group (>254 mg/day). To evaluate the impact of dietary magnesium intake on eGFR, a multivariable linear regression was conducted utilizing an interaction test between dietary vitamin C and eGFR. We discovered a positive association between dietary vitamin C content and eGFR. The relationship between dietary vitamin C levels and eGFR differed between individuals with low Mg intake and those with normal Mg intake (ß: 2.96 95% CI:1.63 ~ 4.29 vs. ß: 1.05 95% CI: -0.15 to 2.25), and the positive association of high dietary vitamin C content with eGFR was stronger in the low Mg intake group. Furthermore, we observed that dietary magnesium intake significantly altered the positive association between dietary vitamin C and eGFR (interaction value of 0.020). Our experimental study revealed that the interaction between dietary magnesium and dietary vitamin C can significantly impact eGFR. This finding carries significant implications for the treatment of diseases resulting from abnormal eGFR, as well as the selection of clinically relevant drugs.

Bestrophin3 Deficiency in Vascular Smooth Muscle Cells Activates MEKK2/3-MAPK Signaling to Trigger Spontaneous Aortic Dissection.

BACKGROUND: Aortic dissection (AD) is a fatal cardiovascular disorder without effective medications due to unclear pathogenic mechanisms. Bestrophin3 (Best3), the predominant isoform of bestrophin family in vessels, has emerged as critical for vascular pathological processes. However, the contribution of Best3 to vascular diseases remains elusive. METHODS: Smooth muscle cell-specific and endothelial cell-specific Best3 knockout mice (Best3SMKO and Best3ECKO, respectively) were engineered to investigate the role of Best3 in vascular pathophysiology. Functional studies, single-cell RNA sequencing, proteomics analysis, and coimmunoprecipitation coupled with mass spectrometry were performed to evaluate the function of Best3 in vessels. RESULTS: Best3 expression in aortas of human AD samples and mouse AD models was decreased. Best3SMKO but not Best3ECKO mice spontaneously developed AD with age, and the incidence reached 48% at 72 weeks of age. Reanalysis of single-cell transcriptome data revealed that reduction of fibromyocytes, a fibroblast-like smooth muscle cell cluster, was a typical feature of human ascending AD and aneurysm. Consistently, Best3 deficiency in smooth muscle cells decreased the number of fibromyocytes. Mechanistically, Best3 interacted with both MEKK2 and MEKK3, and this interaction inhibited phosphorylation of MEKK2 at serine153 and MEKK3 at serine61. Best3 deficiency induced phosphorylation-dependent inhibition of ubiquitination and protein turnover of MEKK2/3, thereby activating the downstream mitogen-activated protein kinase signaling cascade. Furthermore, restoration of Best3 or inhibition of MEKK2/3 prevented AD progression in angiotensin II-infused Best3SMKO and ApoE-/- mice. CONCLUSIONS: These findings unveil a critical role of Best3 in regulating smooth muscle cell phenotypic switch and aortic structural integrity through controlling MEKK2/3 degradation. Best3-MEKK2/3 signaling represents a novel therapeutic target for AD.

Risk factors for postoperative acute kidney injury in overweight patients with acute type A aortic dissection.

OBJECTIVE: To analyze the clinical characteristics of patients with overweight acute type A aortic dissection, and to explore the risk factors of acute kidney injury in patients with overweight acute type A aortic dissection. METHODS: From March 2019 to February 2022, the clinical data of 71 patients with acute type a aortic dissection diagnosed by CTA and undergoing surgical treatment with BMI > 24 in the First People's Hospital of Yunnan Province were retrospectively analyzed, and analyzed by univariate and logistic multivariate analysis methods. RESULTS: The mean BMI of all included patients was 27.23, The mean surface area of all included human populations was 1.833. The mean age of all patients was (52.06 ± 10.71) years old, and 35 patients developed acute kidney injury after surgery. Multi-factor Logistics regression analysis confirmed the risk factors for postoperative acute kidney injury in overweight patients with acute type A aortic dissection, including gender, CPB transit time and intraoperative infusion of suspended red blood cells. Seven patients in the AKI group died in hospital after surgery and two patients died in the non-AKI group. CONCLUSIONS: Among patients with overweight acute Type A aortic dissection, the incidence of AKI is 49.30%. According to multi-factor Logistics regression analysis, gender, CPB transit time and intraoperative suspended red blood cell volume are independent risk factors for postoperative acute kidney injury in patients with overweight acute Type A aortic dissection.

High-throughput Pore-C reveals the single-allele topology and cell type-specificity of 3D genome folding.

Canonical three-dimensional (3D) genome structures represent the ensemble average of pairwise chromatin interactions but not the single-allele topologies in populations of cells. Recently developed Pore-C can capture multiway chromatin contacts that reflect regional topologies of single chromosomes. By carrying out high-throughput Pore-C, we reveal extensive but regionally restricted clusters of single-allele topologies that aggregate into canonical 3D genome structures in two human cell types. We show that fragments in multi-contact reads generally coexist in the same TAD. In contrast, a concurrent significant proportion of multi-contact reads span multiple compartments of the same chromatin type over megabase distances. Synergistic chromatin looping between multiple sites in multi-contact reads is rare compared to pairwise interactions. Interestingly, the single-allele topology clusters are cell type-specific even inside highly conserved TADs in different types of cells. In summary, HiPore-C enables global characterization of single-allele topologies at an unprecedented depth to reveal elusive genome folding principles.

Effects of acupuncture on microglial polarization and the TLR4/TRIF/MyD88 pathway in a rat model of traumatic brain injury.

OBJECTIVE: Neuroinflammation caused by traumatic brain injury (TBI) can lead to neurological deficits. Acupuncture can inhibit neuroinflammation and promote nerve repair; however, the specific mechanism is still unclear. The purpose of this study was to explore whether acupuncture could modulate the M1 and M2 phenotypic polarization of microglia in a rat model of TBI via the toll-like receptor 4 (TLR4)/intracellular toll-interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon-ß (TRIF)/myeloid differentiation factor 88 (MyD88) pathway. METHODS: A total of 90 adult male Sprague-Dawley (SD) rats, SPF grade, were randomly divided into a normal group, model group and acupuncture group. Each group was further divided into three subgroups (first, third, and fifth day groups) according to the treatment time (n = 10 rats/subgroup). We used the modified neurological severity score (mNSS) method to quantify neurological deficits before and after modeling. We used Nissl staining to observe the pathological changes in brain tissue, flow cytometry to detect the proportion of M1 and M2 polarized microglia in the injured area on the first, third and fifth day, and co-immunoprecipitation (Co-IP) to examine TLR4/TRIF/MyD88 expression in microglia on the first, third and fifth day, as well as expression of the amount of binding of TLR4 with TRIF and MyD88. RESULTS: Compared to the model group, mNSS in the acupuncture group gradually decreased and pathological morphology improved. The proportion of CD11b/CD86 positive cells was decreased, while that of CD11b/CD206 was increased in the acupuncture group. Expression of IP TLR4, IP TRIF and IP MyD88 also decreased in the acupuncture group. CONCLUSION: The results of this study demonstrate that one of the mechanisms through which acupuncture mitigates neuroinflammation and promotes nerve repair in TBI rats may be inhibition of M1 phenotypic polarization and promotion of M2 phenotypic polarization through inhibition of the TLR4/TRIF/MyD88 signaling pathway.

Reflexes of training in the abdominal core on students' physical coordination / Reflexos do treino no centro abdominal sobre a coordenação física de alunos / Reflejos del entrenamiento en el núcleo abdominal en la coordinación física de los alumnos

ABSTRACT Introduction Currently, the physical quality of college students has been declining, contrary to China's goal of building a strong and competitive country for sports. Therefore, developing certain plans to improve students' physical quality and coordination ability is necessary. Objective Study the reflection of muscle strength training in the abdominal core by aerobic gymnastics on students' physical coordination ability. Methods 36 volunteers were randomly divided into experimental and control groups. The explosive strength of the central regions and the body coordination and balance ability of the two groups of students were measured before and after the experiment, and the data were classified. Results In the experimental group, the value of supine, incline, right side, left side, jump 360 °, and single foot rotation 360 ° were improved. The evolution of the experimental group was much higher than the control group. Conclusion Muscular strength training in the abdominal core with aerobic gymnastics can effectively regulate students' physical quality and movement coordination, thus establishing a good physical basis for daily work, studies, and routine. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução Atualmente, a qualidade física dos estudantes universitários vem diminuindo, o que contraria o objetivo da China em construir um país forte e competitivo para o esporte. Portanto, é necessário apresentar certos planos para melhorar a qualidade física e a capacidade de coordenação dos estudantes. Objetivo Estudar o reflexo do treinamento da força muscular no centro abdominal por ginástica aeróbica na capacidade de coordenação física dos estudantes. Métodos 36 voluntários foram divididos aleatoriamente em grupo experimental e grupo de controle. A força explosiva das regiões centrais e a capacidade de coordenação e equilíbrio corporal dos dois grupos de estudantes foram medidas antes e depois do experimento, sendo os dados classificados. Resultados No grupo experimental, o valor de supino, inclinado, lado direito, lado esquerdo, salto 360° e rotação de um único pé 360° foram melhorados. A evolução do grupo experimental foi muito maior do que a do grupo de controle. Conclusão O treinamento de força muscular no centro abdominal com ginástica aeróbica pode efetivamente regular a qualidade física e a coordenação de movimentos dos alunos, estabelecendo assim uma boa base física para o trabalho diário, estudos e rotina. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción En la actualidad, la calidad física de los estudiantes universitarios ha ido disminuyendo, lo que va en contra del objetivo de China de construir un país fuerte y competitivo para el deporte. Por lo tanto, es necesario idear ciertos planes para mejorar la calidad física y la capacidad de coordinación de los alumnos. Objetivo Estudiar el reflejo del entrenamiento de la fuerza muscular en el núcleo abdominal mediante la gimnasia aeróbica en la capacidad de coordinación física de los alumnos. Métodos 36 voluntarios fueron divididos aleatoriamente en grupo experimental y grupo de control. Se midió la fuerza explosiva de las regiones centrales y la coordinación corporal y la capacidad de equilibrio de los dos grupos de estudiantes antes y después del experimento, y se clasificaron los datos. Resultados En el grupo experimental, se mejoró el valor de la posición supina, la inclinación, el lado derecho, el lado izquierdo, el salto de 360° y la rotación de un solo pie de 360°. La evolución del grupo experimental fue muy superior a la del grupo de control. Conclusión El entrenamiento de la fuerza muscular en el núcleo abdominal con gimnasia aeróbica puede regular eficazmente la calidad física y la coordinación de los movimientos de los alumnos, estableciendo así una buena base física para el trabajo diario, los estudios y la rutina. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

An investigation on bloom dynamics of Alexandrium catenella and A. pacificum and toxin accumulation in shellfish along the coast of Qinhuangdao, China.

The dinoflagellate genus Alexandrium comprises most of the toxic bloom-forming species producing paralytic shellfish toxins (PSTs) in the sea. Recently, repeated paralytic shellfish poisoning episodes have been recorded in Qinhuangdao located at the west coast of the Bohai Sea. To elucidate the relationship between toxic Alexandrium blooms and the poisoning episodes, a year-round investigation was carried out in this region from July 2020 to July 2021. Two qPCR assays were used to detect A. catenella and A. pacificum, and LC-MS/MS was applied to analyze PSTs in phytoplankton and shellfish samples. The blooms of A. catenella and A. pacificum were found in April and July, respectively, and PST content in three bivalves exhibited notable increase following the bloom of A. catenella. The results revealed bloom dynamics of the two toxic Alexandrium species in the Bohai Sea for the first time, and further confirmed A. catenella as the causative agent of poisoning episodes.

A cost-effectiveness analysis of capecitabine maintenance therapy versus routine follow-up for early-stage triple-negative breast cancer patients after standard treatment from a perspective of Chinese society.

BACKGROUND: Capecitabine maintenance therapy is safe and efficacious for early-stage triple-negative breast cancer (TNBC) patients, but the cost-effectiveness of its long-term use has not been investigated. Here, we evaluated the cost-effectiveness of capecitabine maintenance therapy, compared with routine follow-up, in early-stage TNBC patients after standard treatment from a perspective of Chinese society. METHODS: A three-state Markov model based on the data from the SYSUCC-001 trial was constructed to estimate the cost-effectiveness of capecitabine maintenance therapy in a month cycle over a period of 30-year time horizon. A 5% annual discount rate was set for all costs and benefits. One-way and probabilistic sensitivity analyses were performed to explore the model uncertainties. The main outcomes include quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER), and the number needed to treat (NNT) to prevent one additional event. RESULTS: Compared with routine follow-up, 1-year capecitabine maintenance therapy yielded an additional 1.29 quality-adjusted life years (QALYs) at an additional cost of $3391.70, with an ICER of $2630.53 (95% CI: $1159.81-$5090.12) per QALY gained. The ICER was considerably lower than the recommended willingness-to-pay (WTP) threshold (i.e., $28,130.00 per QALY). The results were sensitive to the discount rate, drug cost, and treatment cost after relapse. Further, the NNT to prevent one additional relapse case was 29.2 (95% CI: 13.2-196.6), 16.7 (95% CI: 8.4-111.6), and 12.0 (95% CI: 5.7-82.6) at 1, 2, and 5 years, respectively. CONCLUSIONS: One-year capecitabine maintenance therapy for early-stage TNBC after standard treatment, compared with routine follow-up, was found to be highly cost-effective with promising clinical benefits and acceptable increased costs. Real-world studies are warranted to validate our findings in the future.

Water Quality Prediction Based on SSA-MIC-SMBO-ESN.

Water pollution threatens the safety of human production and life. To quickly respond to water pollution, it is important for water management staff to predict water quality changes in advance. Drawing on the temporality of water quality data, the leaky integrator echo state network (ESN) was introduced to construct the water quality prediction models for dissolved oxygen (DO), permanganate index (CODMn), and total phosphorus (TP), respectively. First, the missing values were filled by the linear trend method of adjacent points, and the outliers were detected and corrected by the Z-score method and the linear trend method. Second, the singular spectrum analysis (SSA) was performed to denoise the original monitoring data, such that the predicted data catch up with the real data, and the model accuracy is not affected by the hidden noise in the data. Third, the correlation between water quality indices was measured by the maximum information coefficient (MIC), and the strongly correlated indices were imported to the prediction model. Finally, according to these strong correlation indicators, the water quality prediction models based on multiple features were constructed, respectively, using the offline and online learning algorithms of the ESN. The hyperparameters of the models were optimized through the sequential model-based optimization (SMBO). Experimental results show that the proposed water quality prediction models, namely, SSA-MIC-SMBO-Offline ESN and SSA-MIC-SMBO-Online ESN, predicted DO, CODMn, and TP accurately, providing suitable tools for practical applications.

Add-on individualizing prediction of nasopharyngeal carcinoma using deep-learning based on MRI: A multicentre, validation study.

In nasopharyngeal carcinoma, deep-learning extracted signatures on MR images might be correlated with survival. In this study, we sought to develop an individualizing model using deep-learning MRI signatures and clinical data to predict survival and to estimate the benefit of induction chemotherapy on survivals of patients with nasopharyngeal carcinoma. Two thousand ninety-seven patients from three independent hospitals were identified and randomly assigned. When the deep-learning signatures of the primary tumor and clinically involved gross cervical lymph nodes extracted from MR images were added to the clinical data and TNM staging for the progression-free survival prediction model, the combined model achieved better prediction performance. Its application is among patients deciding on treatment regimens. Under the same conditions, with the increasing MRI signatures, the survival benefits achieved by induction chemotherapy are increased. In nasopharyngeal carcinoma, these prediction models are the first to provide an individualized estimation of survivals and model the benefit of induction chemotherapy on survivals.

Rare and potential pathogenic mutations of LMNA and LAMA4 associated with familial arrhythmogenic right ventricular cardiomyopathy/dysplasia with right ventricular heart failure, cerebral thromboembolism and hereditary electrocardiogram abnormality.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is associated with ventricular arrhythmia, heart failure (HF), and sudden death. Thromboembolism is also an important and serious complication of ARVC/D. However, the etiology of ARVC/D and thromboembolism and their association with genetic mutations are unclear. METHODS: Genomic DNA samples of peripheral blood were conducted for whole-exome sequencing (WES) and Sanger sequencing in the ARVC/D family. Then, we performed bioinformatics analysis for genes susceptible to cardiomyopathies and arrhythmias. Further, we analyzed how the potential pathogenic mutations were affecting the hydrophobicity and phosphorylation of amino acids and their joint pathogenicity by ProtScale, NetPhos and ORVAL algorisms. RESULTS: We discovered a Chinese Han family of ARVC/D with right ventricular HF (RVHF), cerebral thromboembolism, arrhythmias (atrial fibrillation, atrial standstill, multifocal ventricular premature, complete right bundle block and third-degree atrioventricular block) and sudden death. Based on the WES data, the variants of LMNA p.A242V, LAMA4 p.A225P and RYR2 p.T858M are highly conserved and predicated as "deleterious" by SIFT and MetaSVM algorithms. Their CADD predicting scores are 33, 27.4 and 25.8, respectively. These variants increase the hydrophobicity of their corresponding amino acid residues and their nearby sequences by 0.378, 0.266 and 0.289, respectively. The LAMA4 and RYR2 variants lead to changes in protein phosphorylation at or near their corresponding amino acid sites. There were high risks of joint pathogenicity for cardiomyopathy among these three variants. Cosegregation analysis indicated that LMNA p.A242V might be an important risk factor for ARVC/D, electrocardiogram abnormality and cerebral thromboembolism, while LAMA4 p.A225P may be a pathogenic etiology of ARVC/D and hereditary electrocardiogram abnormality. CONCLUSIONS: The LMNA p.A242V may participate in the pathogenesis of familial ARVC/D with RVHF and cerebral thromboembolism, while LAMA4 p.A225P may be associated with ARVC/D and hereditary electrocardiogram abnormality.

Tumor Suppressor Role and Clinical Significance of the FEV Gene in Prostate Cancer.

Background: In our previous research, we developed a 32-gene risk index model that may be utilized as a robust prognostic method for predicting prostate cancer (PCa) recurrence after surgery. Among the 32 genes, the Fifth Ewing Variant (FEV) gene was one of the top downregulated genes in relapsed PCa. However, current understanding of the FEV gene and its involvement in PCa is limited. Methods: FEV mRNA expression was analyzed and correlated to clinical outcomes in PCa patients who underwent prostatectomy at the Massachusetts General Hospital. Specimens from tissue microarray (TMA) including 102 prostate cancer patients were analysis for the expression of FEV. Meanwhile, FEV expression profiles were also assessed in PCa cell lines and in BPH-1 prostate epithelial cells using western blotting and quantitative reverse transcription-PCR (qRT-PCR). Furthermore, we transfected LNCaP and PC-3 cells with either an empty vector or full-length FEV gene and performed in vitro cell functional assays. The part FEV plays in tumor xenograft growth was also assessed in vivo. Results: Of the 191 patients included in this study base on the DASL dataset, 77 (40.3%) and 24 (13.6%), respectively, developed prostate-specific antigen (PSA) relapse and metastasis postradical prostatectomy. Significant FEV downregulation was observed in PCa patients showing PSA failure and metastasis. The protein expression of FEV was significantly negatively correlated with the Gleason score and pathological stage in prostate cancer tissues. Similarly, FEV expression significantly decreased in all PCa cell lines relative to BPH-1 (all P < 0.05). Functional assays revealed that FEV expression markedly inhibited PCa cell growth, migration, and invasion, which in turn significantly repressed the growth of tumor xenografts in vivo. Conclusion: The results of this study suggest an association between downregulated FEV expression and PSA relapse in PCa patients. In addition, FEV may act as a tumor suppressor in PCa.

Establishment and Validation of a Peroxisome-related Gene Signature for Prognostic Prediction and Immune Distinction in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, which makes the prognostic prediction challenging. Abnormal peroxisomes can promote the development of cancers. This study aimed to construct a prognostic model based on peroxisome-related genes and identify its prognostic prediction and immune distinction abilities in HCC. Methods: The prognostic model was constructed based on The Cancer Genome Atlas (TCGA) and The International Cancer Genome Consortium (ICGC). Kaplan-Meier curve, time-dependent receiver operating characteristic curve and Cox analysis were used to evaluate the model. The immune status, tumor microenvironment, drug sensitivity and expression levels of the mRNA and protein between HCC and adjacent non-tumorous tissues were analyzed and compared. Results: A prognostic model of 9 peroxisome-related genes was established and validated. Overall survival was markedly higher in the low-risk group relative to the high-risk group. The risk score was an independent prognostic factor. Tumor-related pathways were enriched in the high-risk group and the HCC patients in high-risk group showed depleted immune status. Furthermore, immune checkpoint-related genes, cell cycle-related genes, and multidrug resistance-related genes were overexpressed in the high-risk group. The expression levels of prognostic genes were negatively related to the anti-tumor drugs sensitivity. In addition, the expression level of each prognostic gene in HCC tissues was higher than that in adjacent non-tumorous tissues in an independent sample cohort and the similar results were found in most cancer types. Conclusion: A signature based on the nine peroxisome-related genes is a promising biomarker of HCC and is beneficial to the realization of individualized treatment.