Loss-of-function mutation in DDX53 associated with hereditary spastic paraplegia-like disorder.

DEAD-box helicase 53 (DDX53) is a member of the DEAD-box protein family of RNA helicases. Unlike other family members that are responsible for RNA metabolism, the biological function of DDX53 and its impact on the human condition are unclear. Herein, we found a full-length DDX53 deletion mutation in a hereditary spastic paraplegia-like (HSP-like) patient with lower extremity spasticity, walking disorder, visual impairment, and lateral ventricular white matter lesions. Bioinformatic analysis revealed that DDX53 was mainly expressed in the cerebellar cortex and may function as a tissue-specific RNA helicase. Transcriptome analysis showed that the expression of multiple brain-associated genes involved in synapse organization, neuron function, and neuromuscular junctions was affected by DDX53 depletion. Moreover, RNA immunoprecipitation sequencing (RIP-seq) analysis showed that DDX53 interacted with 176 genes, and 96 of these genes were associated with the execution of neurofunction, particularly in the regulation of cell projection organization and nervous system development. Collectively, although a more specified cell or animal model is required to fully understand the functional role of DDX53 in the human brain, we report for the first time that the patient with DDX53 defects exhibits HSP-like symptoms and that DDX53 is essential for maintaining neuronal function, with loss-of-function mutation in DDX53 potentially leading to HSP due to impaired RNA metabolism in the nervous system. KEY MESSAGES: DDX53 deficiency was first reported to be associated with HSP disorder. DDX53 exhibited minimal impact on mitochondrial function. DDX53 impaired RNA metabolism in the nervous system.

Dual rare genetic diseases in five pediatric patients: insights from next-generation diagnostic methods.

BACKGROUND: Clinicians traditionally aim to identify a singular explanation for the clinical presentation of a patient; however, in some cases, the diagnosis may remain elusive or fail to comprehensively explain the clinical findings. In recent years, advancements in next-generation sequencing, including whole-exome sequencing, have led to the incidental identification of dual diagnoses in patients. Herein we present the cases of five pediatric patients diagnosed with dual rare genetic diseases. Their natural history and diagnostic process were explored, and lessons learned from utilizing next-generation diagnostic technologies have been reported. RESULTS: Five pediatric cases (3 boys, 2 girls) with dual diagnoses were reported. The age at diagnosis was from 3 months to 10 years. The main clinical presentations were psychomotor retardation and increased muscular tension, some accompanied with liver dysfunction, abnormal appearance, precocious puberty, dorsiflexion restriction and varus of both feet, etc. After whole-exome sequencing, nine diseases were confirmed in these patients: Angelman syndrome and Krabbe disease in case 1, Citrin deficiency and Kabuki syndrome in case 2, Homocysteinemia type 2 and Copy number variant in case 3, Isolated methylmalonic acidemia and Niemann-Pick disease type B in case 4, Isolated methylmalonic acidemia and 21-hydroxylase deficiency in case 5. Fifteen gene mutations and 2 CNVs were identified. Four novel mutations were observed, including c.15292de1A in KMT2D, c.159_164inv and c.1427G > A in SLC25A13, and c.591 C > G in MTHFR. CONCLUSIONS: Our findings underscore the importance of clinicians being vigilant about the significance of historical and physical examination. Comprehensive clinical experience is crucial for identifying atypical clinical features, particularly in cases involving dual rare genetic diseases.

Three-dimensional Analysis of the Temporal Bone Morphology in Patients with Craniofacial Microsomia.

OBJECTIVE: To characterise the morphology of temporal bone in patients with craniofacial microsomia (CFM). DESIGN: A retrospective study. SETTING: A craniofacial centre. PATIENTS: Ninety-four patients with unilateral craniofacial microsomia. INTERVENTIONS: Mimics 21.0 (Materialise Inc., Belgium) was used to locate temporal bone landmarks on preoperative computed tomography data. The spatial Cartesian coordinate system was established in 3-matic 13.0 (Materialise Inc., Belgium). The coordinates of each landmark and the distances and angles between the landmarks were calculated. A classification system was used to quantify the severity of the zygomatic arch deformity. MAIN OUTCOME MEASURE(S): The bilateral differences in coordinates, linear and angular measurements, and the severity of temporal bone deformity (TTL δ, Psag δ, Paxiδ, and Tsag δ) among the groups were compared using the paired t-test and Kruskal-Wallis test, respectively. RESULTS: Compared to those of the unaffected side, the landmarks of the inner ear and petrous part on the affected side showed a decrease in the Z-coordinate or an increase in the X-coordinate. A superolateral rotation tendency of the temporal bone on the affected side was found. There were no significant differences in the linear and angular measurements between the groups. The degree of zygomatic arch deformation was lower in the mild group; however, no significant difference was found between the moderate and severe groups. CONCLUSIONS: In patients with CFM, asymmetry of the temporal bone and its inner organs (vestibulocochlear organ, facial nerve, and vessels) exists in multiple dimensions; its severity is not completely consistent with the degree of mandibular involvement.

Multi-imaging platform for rhizosphere studies: Phosphorus and oxygen fluxes.

Rhizosphere is a soil volume of high spatio-temporal heterogeneity and intensive plant-soil-microbial interactions, for which visualization and process quantification is of highest scientific and applied relevance, but still very challenging. A novel methodology for quick assessment of two-dimensional distribution of available phosphorus (P) in rhizosphere was suggested, tested, and development up to the application platform. Available P was firstly trapped by an in-situ diffusive gradients in thin-films (DGT) sampler with precipitated zirconia as the binding gel, and subsequently, the loaded gel was analyzed with an optimized colorimetric imaging densitometry (CID). The imaging platform was established linking: i) DGT, ii) planar optode, and iii) soil zymography techniques to simultaneously determine available P, oxygen, and acid phosphatase in rhizosphere at sub-millimeter spatial scales. The DGT identified available P level in rice rhizosphere were spatially overlapping to the localized redox hotspots and phosphatase activity. The spatial relationship between available P and acid phosphatase activity was dependent on root development. The root radial oxygen loss (ROL) remained active during the experimental observations (2-3 days), while a flux of available P of 10 pg cm-2 s-1 was visualized within 2-3 mm of roots, confirming the correlative response of rice roots to oxygen secretion and P uptake. Summarizing, the established imaging platform is suitable to capture spatial heterogeneity and temporal dynamics of root activities, nutrient bioavailability, ROL and enzyme activities in rhizosphere.

High-resolution chemical imaging to understand Cd activation in rice rhizosphere of karstic soils.

Cadmium (Cd) activation, especially at a high spatial resolution, in paddy soils with a high geogenic Cd background is yet to be understood. To investigate the temporal and spatial patterns of Cd activation in rice rhizosphere, pot and rhizotron experiments were conducted using four paddy soils with high geogenic Cd (0.11-3.70 mg kg-1) from Guangxi, southwestern China. The pot experiment results showed that porewater Cd concentrations initially decreased and then increased over the complete rice growth period, reaching its lowest value during the late-tillering and early-filling stages. Besides, correlation analysis identified organic matter and root manganese (Mn) content as the main factors affecting rice Cd uptake, with Mn having a negative effect and organic matter having a positive effect. Sub-millimeter two-dimensional chemical imaging revealed that the distribution of labile Cd in the rhizosphere (by diffusive gradients in thin-films, or DGT) was influenced by the root system and soil properties, such as pH (by planar optode) and acid phosphatase activity (by soil zymography). Soil acid phosphatase activity increased under Cd stress. The overall pH at rice rhizosphere decreased. Moreover, a close relationship was found between the spatial distributions of soil labile Mn and Cd at the rhizosphere, with higher Mn being associated with lower Cd lability. This study highlights Mn as a key element in regulating rice Cd uptake and enlightens future Mn-based strategies for addressing Cd pollution in rice paddy soils, especially in karst areas with high geochemical background.

Condylar resorption post mandibular distraction osteogenesis in craniofacial microsomia: A retrospective study.

The aim of this study was to investigate the characteristics of condylar resorption in craniofacial microsomia (CFM) patients following mandibular distraction osteogenesis (MDO). Patients with unilateral type-IIa and type-IIb CFM, who had completed MDO and mandibular distractor extraction (MDE), were recruited. The height and volume of the condyle were measured on three-dimension models created by the analysis of computed tomography (CT) data. Normality analysis was performed using the Shapiro-Wilk test. Data for the affected and unaffected sides were compared using the paired t-test or Wilcoxon signed-rank test. Data for both type-IIa and type-IIb CFM were compared using the independent-samples t-test or Mann-Whitney U test. The Pearson or Spearman correlation was used to determine the correlations of condylar resorption rate with related measurements. In total, 48 type-IIa and 48 type-IIb CFM patients were included. The condylar resorption rate in type-IIa CFM (0.35 ± 0.32) was significantly associated with the height of the condyle (r = 0.776, p < 0.001) and distraction distance (r = 0.447, p = 0.001), while the condylar resorption rate in type-IIb CFM (0.49 ± 0.46) was significantly associated with the height of the condyle (r = 0.924, p < 0.001). However, there was no significant difference in condylar resorption rate between type-IIa and type-IIb CFM (p = 0.075). In addition to occlusal changes, no other negative symptoms of the TMJ were observed with condylar resorption. Condylar resorption was evident in CFM patients following mandibular distraction osteogenesis, and the condylar resorption rate showed a relationship with distraction distance and condylar height.

Impact of Nosocomial Infection on in-Hospital Mortality Rate in Adult Patients Under Venoarterial Extracorporeal Membrane Oxygenation After Cardiac Surgery.

Objective: There was no consensus on the impact of nosocomial infection on In-hospital mortality rate in patients receiving ECMO. This study aimed to investigate the impact of nosocomial infection (NI) on In-hospital mortality rate in adult patients receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO) after cardiac surgery. Materials and Methods: This retrospective study included 503 adult patients who underwent VA-ECMO after cardiac surgery. The impact of time-dependent NIs on In-hospital mortality rate within 28 days of ECMO initiation was investigated using a Cox regression model. The cumulative incidence function for death was compared between patients with NIs and those without NIs using a competing risk model. Results: Within 28 days after ECMO initiation, 206 (41.0%) patients developed NIs, and 220 (43.7%) patients died. The prevalence rates of NIs were 27.8% and 20.3% during and after ECMO therapy, respectively. The incidence rates of NIs during and after ECMO therapy were 49‰ and 25‰, respectively. Time-dependent NI was an independent risk factor for predicting death (hazard ratio = 1.05, 95% confidence interval = 1.00-1.11). The cumulative incidence of death in patients with NI was significantly higher than that in patients without NI at each time point within 28 days of ECMO initiation. (Z = 5.816, P = 0.0159). Conclusion: NI was a common complication in adult patients who received VA-ECMO after cardiac surgery, and time-dependent NI was an independent risk factor for predicting mortality in these patients. Using a competing risk model, we confirmed that NIs increased the risk of In-hospital mortality rate in these patients.

Modified staging system of positive lymph nodes based nomogram in intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) presents the similar trend and prevalence of lymph node metastasis to other biliary tract cancer. There is still a necessity and possibility for the current classification of lymph node in the 8th TNM of iCCA, which is the same as the criteria of hepatoma carcinoma (HCC), to further improve the prognostic capacity. We aim to explore the optimal positive lymph nodes cutoff value that could predict the survival outcomes of patients with iCCA and further establish a prognostic nomogram. METHOD: Clinical characteristics were retrospectively collected in 292 patients with iCCA from Sun Yat-sen University Cancer Center (SYSUCC) for preliminary analysis. A retrospective analysis of 107 patients with iCCA in the First Hospital of Dalian Medical University (FHDMU) was performed for verification. R software was used to determine the optimal cutoff value of positive lymph nodes (PLN) and further establish the nomogram with the Cox regression model in the primary cohort. RESULTS: In those patients who were graded into the N1 stage in 8th TNM staging system, the patients with PLN between 1 and 3 showed significantly better overall survival than those patients with more than 4 PLN (P < 0.0001). Moreover, there was a significant correlation between the new PLN classification and adverse clinical characteristic including Micro Invasion (P = 0.001), Lymph Vessel Invasion (P = 0.040), Satellite Sites (P < 0.001), and Tumor Size (P = 0.005). The PLN and ELN were both independent prognostic factors for survival outcomes in the multivariate analysis, and further showed large contribution to the nomogram. The nomogram achieved a satisfied C-index of 0.813 for overall survival (OS), 0.869 for progression-free survival (PFS) in the primary cohort, and 0.787 for OS, 0.762 for PFS in the validation cohort. CONCLUSION: The modified classification of PLN in iCCA could accurately stratify the N1 stage patients in 8th TNM staging system into two groups with significantly different overall survival. The development of this nomogram can offer new evidence to precisely post-operative management of iCCA patients.

Treatment outcomes of mucosal melanoma of the head and neck: Analysis of 190 cases from a single institution.

Objectives: To analyze the treatment outcomes and prognostic factors of mucosal melanoma of the head and neck (MMHN) from a single institution. Methods: From December 1989 to November 2018, 190 patients diagnosed with MMHN were included. Survival analysis was performed using the Kaplan-Meier method for univariate analysis with a log-rank test for significance and Cox regression for multivariate analysis. Results: With a median follow-up time of 43.5 months, 126 (68.5%) patients died. The median DSS was 35 months. The 3- and 5-year disease-specific survival (DSS) rates were 48.1% and 33.7%, respectively. The median overall survival (OS) was 34 months. The 3- and 5-year OS rates were 47.0% and 32.9%, respectively. In univariate analysis, the T3 stage, received surgery, R0 resection, and combined therapy (surgery+biotherapy/biochemotherapy) were significantly associated with better survival. Multivariable Cox regression analysis revealed that the T4 stage (HR = 1.692; 95% CI, 1.175-2.438; p = .005) and the N1 stage (HR = 1.600; 95% CI, 1.023-2.504; p = .039) were strong prognostic factors for poor survival, and that combined therapy (surgery+biotherapy/biochemotherapy) was a strong prognostic factor for better survival outcome (HR = 0.563; 95% CI, 0.354-0.896; p = .015). Conclusion: The prognosis of MMHN remains poor. Systemic treatment is warranted to reduce MMHN progression. Surgery combined with biotherapy may improve survival.

Fine-tuning Bacterial Cyclic di-AMP Production for Durable Antitumor Effects Through the Activation of the STING Pathway.

The stimulator of interferon genes (STING) protein is an important and promising innate immune target for tumor therapy. However, the instability of the agonists of STING and their tendency to cause systemic immune activation is a hurdle. The STING activator, cyclic di-adenosine monophosphate (CDA), produced by the modified Escherichia coli Nissle 1917, shows high antitumor activity and effectively reduces the systemic effects of the "off-target" caused by the activation of the STING pathway. In this study, we used synthetic biological approaches to optimize the translation levels of the diadenylate cyclase that catalyzes CDA synthesis in vitro. We developed 2 engineered strains, CIBT4523 and CIBT4712, for producing high levels of CDA while keeping their concentrations within a range that did not compromise the growth. Although CIBT4712 exhibited stronger induction of the STING pathway corresponding to in vitro CDA levels, it had lower antitumor activity than CIBT4523 in an allograft tumor model, which might be related to the stability of the surviving bacteria in the tumor tissue. CIBT4523 exhibited complete tumor regression, prolonged survival of mice, and rejection of rechallenged tumors, thus, offering new possibilities for more effective tumor therapy. We showed that the appropriate production of CDA in engineered bacterial strains is essential for balancing antitumor efficacy and self-toxicity.

Morphologic Changes of the Temporomandibular Joint in Pruzansky-Kaban Type IIa Hemifacial Microsomia Postmandibular Distraction Osteogenesis.

OBJECTIVE: Mandibular distraction osteogenesis (MDO) is a powerful tool for the correction of hemifacial microsomia (HFM). The temporomandibular joint (TMJ) is the focus of attention in the diagnosis and treatment of HFM. This observational retrospective cross-sectional study aimed to investigate morphologic changes in TMJ post-MDO in type IIa HFM. METHODS: We recruited 48 patients with unilateral type IIa HFM who had completed MDO and mandibular distractor extraction (MDE). Data relating to the length, distance, angle, and volume of the TMJ were measured on 3-dimension models created by the analysis of computed tomography data. Normality analysis was performed by using the Shapiro-Wilk test. Data were compared with the paired t test and Wilcoxon signed-ranks test. RESULTS: The spaces between the affected condyle and the affected glenoid fossa before MDO were all significantly larger than before MDE (P<0.05). The breadth of the affected glenoid fossa before MDO was significantly longer than before MDE (P<0.001). The height of the affected condyle before MDO was significantly longer than before MDE (P<0.001). The volume of the affected condyle before MDO was significantly larger than before MDE (P<0.001). The ratio between the volume of the affected condyle and unaffected condyle before MDO was 0.20±0.13. The ratio between the volume of the affected condyle before MDE and MDO was 0.65±0.32. The resorption rate of the affected condyle post-MDO was 0.35±0.32. CONCLUSION: Herein, we characterized anatomic changes of the TMJ in type- IIa HFM post-MDO. Condylar resorption and the compression of space between the condyle and the glenoid fossa on the affected side were 2 typical manifestations. Our findings enhanced the understanding of the application of MDO on HFM.

Bone Density of the Condyle of Children with Craniofacial Microsomia and its Correlation with Condylar Resorption After Mandible Distraction Osteogenesis.

OBJECTIVE: To investigate condylar bone density (BD) in children with craniofacial microsomia (CFM) and identify factors that contribute to early stage condylar resorption (CR) after mandibular distraction osteogenesis (MDO). DESIGN: Retrospective study. SETTING: Craniofacial department of a plastic surgery hospital. PATIENTS: Fifty-one children with CFM classified as Pruzansky IIa based on complete pre-(T0) and post-MDO (T1) computed tomography (CT) data. INTERVENTION AND MAIN OUTCOME MEASUREMENTS: Mimic 21.0 (Materialise Inc., Belgium) was used to measure bilateral BD and condylar height (CH) and volume (CV) of affected side. Children were split into groups based on either affected side BD or the distraction length (DL,25 mm as cutoff) .Bilateral BD was compared using a paired t-test in each group. The CH and CV of affected side at T0 and T1 were compared. The relative values of the CH and CV (CH ratio) and the volume (CV ratio) of the affected side were compared across the groups. RESULTS: The BD was lower on affected side than on unaffected side. Regarding BD, CH and CV decreased after MDO in group I, while the CH ratio and CV ratio of group I was lower than that of groups II and III. Regarding DL, the CV ratio was lower in Group L than Group S. CONCLUSIONS: The condylar bone quality on affected side is compromised in type IIa CFM. A low BD in combination with a larger distraction distance may increase the risk of CR; therefore, MDO in patients with such characteristics should be postponed.

Synthesis of hierarchically structured Fe3C/CNTs composites in a FeNC matrix for use as efficient ORR electrocatalysts.

Fe-N-C has a high number of FeN x active sites and has thus been regarded as a high-performance oxygen reduction reaction (ORR) catalyst, and combining Fe3C with Fe-N-C typically boosts ORR activity. However, the catalytic mechanism remains unknown, limiting further research and development. In this study, a precipitation-solvothermal process was used in conjunction with pyrolysis to produce a series of Fe-N-C catalysts derived from a zeolitic imidazolate framework (ZIF) that was composited with Fe3C. The prepared catalysts had a multiscale structure of ZIF-like carbon particles and rod-like structures, as well as bamboo-like carbon nanotubes (CNTs) and carbon layers wrapped with Fe3C particles while a series of studies revealed the origin of the rod-like structures and Fe3C phase. The hierarchical structure was beneficial to the enhanced electrocatalytic performance of catalysts for ORR. The optimal sample had the highest half-wave potential of 0.878 V vs. RHE, which was higher than that of commercial Pt/C (0.861 V vs. RHE). The ECSA of the optimal sample was 1.08 cm2 µg-1, with an electron transfer number close to 4, and functioning kinetics. The optimal sample exhibited high durability and methanol tolerance for the ORR. Finally, blocking different Fe active sites with coordination ions demonstrated that Fe(ii) was the main active site, indicating that Fe3C primarily served as a cocatalyst to optimize the electron structure of Fe-N-C, thereby synergistically improving the ORR activity.

Bioinformatics Analysis of Hub Genes Involved in Alcohol-Related Hemifacial Microsomia Pathogenesis.

OBJECTIVE: Alcohol is a recognized teratogen, and alcohol exposure increases the risk for hemifacial microsomia (HFM) of the fetus during maternal pregnancy. The present study aimed to explore potential mechanisms and verify hub genes of HFM associated with alcohol by bioinformatics methods. METHODS: First, HFM and alcohol pathogenic genes were obtained. Thereafter, a protein-protein interactional (PPI) network was constructed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses and molecular complex detection were performed by Metascape. Finally, we used the cytoHubba plugin to screen the hub genes. RESULTS: A total of 43 HFM genes and 50 optimal alcohol candidate genes were selected. The PPI networks for pathogenic genes contained 93 nodes and 503 edges. Functional enrichment analysis largely focused on tissue formation and development. Two modules were identified from the PPI network, and 10 hub genes were screened out. The genes most relevant to alcohol-induced HFM pathogenesis included CTNNB1, TP53, MYC, HDAC1, and SOX2. CONCLUSIONS: This study identified some significant hub genes, pathways, and modules of HFM related to alcohol by bioinformatics analyses. Our results suggest that the CTNNB1, TP53, MYC, HDAC1, and SOX B1 gene subfamilies may have played a major role in alcohol-induced HFM.

A nomogram to predict nosocomial infection in patients on venoarterial extracorporeal membrane oxygenation after cardiac surgery.

INTRODUCTION: After cardiac surgery, patients on venoarterial extracorporeal membrane oxygenation (VA-ECMO) have a higher risk of nosocomial infection in the intensive care unit (ICU). We aimed to establish an intuitive nomogram to predict the probability of nosocomial infection in patients on VA-ECMO after cardiac surgery. METHODS: We included patients on VA-ECMO after cardiac surgery between January 2011 and December 2020 at a single center. We developed a nomogram based on independent predictors identified using univariate and multivariate logistic regression analyses. We selected the optimal model and assessed its performance through internal validation and decision-curve analyses. RESULTS: Overall, 503 patients were included; 363 and 140 patients were randomly divided into development and validation sets, respectively. Independent predictors derived from the development set to predict nosocomial infection included older age, white blood cell (WBC) count abnormality, ECMO environment in the ICU, and mechanical ventilation (MV) duration, which were entered into the model to create the nomogram. The model showed good discrimination, with areas under the curve (95% confidence interval) of 0.743 (0.692-0.794) in the development set and 0.732 (0.643-0.820) in the validation set. The optimal cutoff probability of the model was 0.457 in the development set (sensitivity, 0.683; specificity, 0.719). The model showed qualified calibration in both the development and validation sets (Hosmer-Lemeshow test, p > .05). The threshold probabilities ranged from 0.20 to 0.70. CONCLUSIONS: For adult patients receiving VA-ECMO treatment after cardiac surgery, a nomogram-monitoring tool could be used in clinical practice to identify patients with high-risk nosocomial infections and provide an early warning.

Postoperative radiotherapy to the neck for pN1 status HNSCC patients after neck dissection.

The significance of postoperative radiotherapy (PORT) to the neck for pN1 status head and neck squamous cell carcinomas (HNSCC) after neck dissection is unclear. A total of 208 patients with pN1 status HNSCC treated from January 1, 2001, to December 31, 2014, were enrolled in the current study. The 5-year regional recurrence-free survival (RRFS), overall survival (OS) and distant metastasis-free survival (DMFS) were compared between patients with or without PORT to the dissected neck. Moreover, the stratified Cox proportional hazards models were used to assess the association between PORT to the neck and survival before and after propensity score matching. Seventy-nine patients received PORT to the neck, while 129 did not. All patients were followed for over 5 years, with a median follow-up duration of 64.6 months. The PORT group did not show better survival results than the group without PORT to the neck in RRFS, OS or DMFS. Moreover, no evidence showed that PORT to the neck was independently associated with 5-year survival. PORT to the neck for pN1 status HNSCC after neck dissection did not lead to better survival. However, it is necessary to conduct prospective randomized clinical trials to confirm these results.

Structure-Activity relationship study of benzothiophene oxobutanoic acid analogues leading to novel stimulator of interferon gene (STING) agonists.

Pharmacological activation of stimulator of interferon genes (STING) by agonists has emerged as a new modality of cancer immunotherapy. However, current available STING agonists remain in early developmental stage or failed in clinic trials due to limited efficacy in humans. In this report, we performed a structure-activity relationship study based on the benzothiophene oxobutanoic acid scaffold of MSA-2, a well-documented STING agonist by Merck, leading to a series of N-substituted acyloxyamino derivatives with potent STING activating effect. Among them, compounds 57 and 60 displayed the most potent activity specifically targeting both h- and m-STING. Particularly, 57 displayed more potent and rapid activation of the STING signaling pathway than ADU-S100 in THP1-Dual cells. In vivo anti-tumor efficacy of 57 by intratumoral or oral administration was also demonstrated in several mouse tumor models. Intriguingly, treatment with 57 eradicated all the CT26 tumor without further recurrence in all treated mice, which could also reject the same tumor re-inoculation, indicating an induction of immune memory by 57. Taken together, acyloxyamino derivative 57 represents a new chemotype of STING agonist with well-demonstrated in vivo anti-tumor activity, which is deserved for further investigation.

[Factors affecting phenotypes in the patients with MMACHC gene c.609G>A homozygous variant cblC type methylmalonic acidemia combined with homocysteinuria].

OBJECTIVE: To investigate the factors affecting phenotypes in the patients of methylmalonic acidemia combined with homocysteinemia cblC type with MMACHC c.609G>A homologous variant. METHODS: A retrospective study on the clinical manifestations, complications, treatment, and outcome in 164 patients of cblC type with MMACHC c.609G>A homologous variant was conducted. The patients were diagnosed by biochemical and genetic analysis from January 1998 to December 2020. RESULTS: Among the 164 patients, 2 cases were prenatally diagnosed and began treatment after birth. They are 3 and 12 years old with normal physical and mental development. Twenty-one cases were diagnosed by newborn screening. Among them, 15 cases had with normal development. They were treated from the age of two weeks at the asymptomatic period. Six cases began treatment aged 1 to 3 months after onset. Their development was delayed. One hundred and forty-one cases were clinically diagnosed. Their onset age ranges from a few minutes after birth to 6 years old. 110 cases had early-onset (78.0%). 31 cases had late-onset (22.0%). Five of them died. 24 patients lost to follow-up. Of the 141 clinically diagnosed patients, 130 (92.2%) with psychomotor retardation, 69 (48.9%) with epilepsy, 39 (27.7%) with anemia, 30 (21.3%) had visual impairment, 27 (19.1%) had hydrocephalus, 26 (18.4%) had feeding difficulties, 7 (5.0%) with liver damage, and 5 (3.5%) with metabolic syndrome. The frequency of hydrocephalus and seizures was significantly higher in the early-onset group. The urinary methylmalonic acid increased significantly in the patients with epilepsy. During the long-term follow-up, the level of plasma total homocysteine in the seizure-uncontrolled group was significantly higher than that in the seizure-controlled group, the difference had a statistical significance (P<0.05). CONCLUSION: Most of the patients with MMACHC c.609G>A homozygous variant had early-onset disease, with a high mortality and disability rate. If not treated in time, it will lead to neurological damage, resulting in epilepsy, mental retardation, hydrocephalus, and multiple organ damage. Pre-symptomatic diagnosis and treatment are crucial to prevent irreversible neurological damage. Neonatal screening and prenatal diagnosis are important to improve the outcome of the patients.

Outcome and Clinical Characteristics of Nosocomial Infection in Adult Patients Undergoing Extracorporeal Membrane Oxygenation: A Systematic Review and Meta-Analysis.

Objective: This study conducts a meta-analysis of clinical outcomes of nosocomial infection in adult patients receiving extracorporeal membrane oxygenation (ECMO) and systematically evaluates clinical epidemiological characteristics. Methods: Document retrieval strategies were determined, and all adult patients treated by ECMO were included. The prevalence, incidence, mortality, ECMO use time, intensive care unit (ICU) stay time, hospital stay time, and risk factors of nosocomial infection were systematically evaluated. Subsequently, a meta-analysis of the impact of nosocomial infection on risk of in-hospital mortality was conducted. Results: A total of 25 retrospective studies were included, and 19 studies were included in the meta-analysis. The prevalence of nosocomial infection was 8.8-64.0%, incidence was 1.7-85.4‰ (per 1,000 ECMO days), and in-hospital mortality was 31.5-75.4%. The duration of ECMO usage and length of ICU stay were longer for infected patients. Compared with non-infected patients, the meta-analysis revealed that nosocomial infection increased the relative risk of death of adult patients receiving ECMO by 32%. The risk factors included the duration of ECMO usage and disease severity score. Conclusions: Adult patients treated by ECMO have high prevalence of nosocomial infection. In addition, their ECMO use time and ICU stays are longer. Nosocomial infection significantly increases the relative risk of in-hospital mortality.

A Positive Feedback Loop between Inactive VHL-Triggered Histone Lactylation and PDGFRß Signaling Drives Clear Cell Renal Cell Carcinoma Progression.

Inactive von Hippel-Lindau (VHL) is linked to metabolic reprogramming and plays pivotal roles in the pathogenesis of clear cell renal cell carcinoma (ccRCC). Here, we identify a previously unknown oncogenic role for inactive VHL in actively triggering histone lactylation to promote ccRCC progression. In patients with ccRCC, inactive VHL positively correlates with the presence of histone lactylation, and high levels of histone lactylation indicates poor patient prognosis. Inactive VHL-triggered histone lactylation contributes to ccRCC progression by activating the transcription of platelet-derived growth factor receptor ß (PDGFRß). In turn, PDGFRß signaling is shown to stimulate histone lactylation, thereby forming an oncogenic positive feedback loop in ccRCC. Target correction of aberrant histone lactylation represses the growth and metastasis of ccRCC in vivo. More importantly, the combined inhibition of histone lactylation and PDGFRß significantly reinforces the therapeutic efficacy. This work underscores the importance of histone lactylation in facilitating ccRCC progression and suggests targeting the positive feedback loop between histone lactylation and PDGFRß signaling might provide a promising therapeutic strategy for ccRCC patients.