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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Identification of Hub Genes in Hemifacial Microsomia: Evidence From Bioinformatic Analysis.

OBJECTIVE: This thesis addresses a neglected aspect of bioinformatics research of hemifacial microsomia (HFM). Existing research stops short of prediction based on big data. This study combines multiple databases to explore underlying pathogenesis using bioinformatic approach. METHODS: The research consisted of multiple bioinformatic methods, included pathogenic genes analyses, protein-protein interaction network construction, functional enrichment, and mining target genes related miRNA, for studying pathogenic genes of HFM. RESULTS: Total of 140 genes were identified as potential genes in the study. The protein-protein interaction networks for pathogenic genes were constructed, which contained 138 nodes and 243 edges with RAF1, MAP2K1, MAP2K2, MAPK3, MAPK1, EGFR, BRAF, LMNA, ESPR1, and SFN as the hub genes. These genes were discovered significantly enriched in MAPK pathway. Besides, the whole of interactions between miRNAs and the top 5 hub genes were revealed. CONCLUSIONS: Our results indicated that occurrence of HFM is attributed to a variety of genes. Furthermore, the interactions of pathogenic genes were further elucidated by using bioinformatics approach. It reveals the MAPK pathway play an essential role in its pathogenesis. It may provide a novel perspective on better understanding the pathogenesis and more accurate early screening of HFM.

Single-cell transcriptomics reveal the intratumoral landscape of infiltrated T-cell subpopulations in oral squamous cell carcinoma.

Systematic analysis of tumor-infiltrating lymphocytes is essential for the development of new cancer treatments and the prediction of clinical responses to immunotherapy. Immunomodulatory drugs are used for the treatment of oral squamous cell carcinoma (OSCC), depending on immune infiltration profiles of the tumor microenvironment. In this study, we isolated 11,866 single T cells from tumors and paired adjacent normal tissues of three patients with OSCC. Using single-cell RNA sequencing, we identified 14 distinct T-cell subpopulations within the tumors and 5 T-cell subpopulations in the adjacent normal tissues and delineated their developmental trajectories. Exhausted CD8+ T cells and regulatory CD4+ T cells (CD4+ Tregs) were enriched in OSCC tumors, potentially linked to tumor immunosuppression. Programmed death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4) were identified as marker genes in exhausted CD8+ T cells, whereas forkhead box P3 (FOXP3) and CTLA4 were identified as markers of CD4+ Tregs. Furthermore, our data revealed that thymocyte selection-associated high-mobility group box (TOX) may be a key regulator of T-cell dysfunction in the OSCC microenvironment. Overexpression of TOX upregulated expression of genes related to T-cell dysfunction. In vitro experiments demonstrated that cytotoxic activity and proliferation efficiency of CD8+ T cells overexpressing PD-1 or TOX were reduced. Notable, the transcription factor PRDM1 was found to transactivate TOX expression via a binding motif in the TOX promoter. Our findings provide valuable insight into the functional states and heterogeneity of T-cell populations in OSCC that could advance the development of novel therapeutic strategies.

Variable phenotypes and outcomes associated with the MMACHC c.609G>A homologous mutation: long term follow-up in a large cohort of cases.

BACKGROUND: Cobalamin C deficiency (cblC) caused by the MMACHC mutations is the most common type of the disorders of intracellular cobalamin metabolism. While the c.609G > A mutation is most frequent in Chinese cblC patients, its correlation with phenotype has not been delineated. Here we aim to investigate the factors affecting variable phenotypes and outcomes associated with the MMACHC c.609G > A homologous mutation in 149 Chinese cases to have implications for treatment and prevention. METHODS: We assessed 149 cblC patients caused by MMACHC c.609G > A homozygous mutation. The clinical manifestations, complications, treatment, and outcomes were evaluated; 120 patients were followed-up till December 2019. RESULTS: Two patients (1.3%) were prenatally diagnosed, treated after birth and consequently showed normal development. In 15 patients (10.1%) detected by newborn screening, 10 were treated at the age of 2 weeks and showed normal development, while the other 5 were treated after onset and showed neurologic disorders. All 132 clinically diagnosed patients (88.6%) developed symptoms at age from few minutes after birth to 72 months. Among them, 101 (76.5%) had early-onset (before the age of 12 months) and 31 (23.5%) had late-onset (after the age of 12 months). Totally 5 patients died and 24 were lost to follow-up. Of the 132 clinical diagnosed patients, 92 (69.7%) presented with developmental delay, 65 (49.2%) had seizures, 37 (28.0%) had anemia, 24 (18.2%) had feeding difficulty, 23 (17.4%) had ocular problems, and 22 (16.7%) had hydrocephalus. Compared with the non-developmental delay group, the onset age, the age at treatment initiation and the time from onset to treatment initiation were later in the developmental delay group. Seizure group showed significantly higher urinary methylmalonic acid concentration. During long-term follow-up, plasma total homocysteine (tHcy) levels were significantly higher in patients in the uncontrolled group than those in the seizure-free group. CONCLUSIONS: Most cblC patients caused by MMACHC c.609G > A homozygous mutation showed early-onset. The clinically diagnosed patients usually showed the presence of irreversible brain disorders. Patients treated from the pre-symptomatic stage showed favorable outcomes. Therefore, newborn screening, prenatal diagnosis and early treatment are crucial and the c.609G > A mutant allele should be listed in the pre-pregnancy carrier screening panel in China.

Epidemiology of mental health problems among patients with cancer during COVID-19 pandemic.

The current study aimed to explore mental health problems in patients diagnosed with cancer during the COVID-19 pandemic. A cluster sampling, cross-sectional survey with 6213 cancer patients was conducted in one of the largest cancer centers in China. The socio-demographic and clinical characteristics, psychosomatic conditions, interpersonal relationships and social support, COVID-19 infection-related psychological stress, and mental health status were measured. Medical conditions were extracted from patients' electronic healthcare records. Among the 6213 cancer patients, 23.4% had depression, 17.7% had anxiety, 9.3% had PTSD, and 13.5% had hostility. Hierarchical liner regression models showed that having a history of mental disorder, excessive alcohol consumption, having a higher frequency of worrying about cancer management due to COVID-19, having a higher frequency feeling of overwhelming psychological pressure from COVID-19, and having a higher level of fatigue and pain were the predominant risk factors for mental health problems in cancer patients. However, there were only 1.6% of them were seeking psychological counseling during COVID-19. We also revealed the protective factors associated with lower risk of mental health problems among cancer patients. The present study revealed a high prevalence of mental health problems and gaps in mental health services for cancer patients, which also indicated high distress from COVID-19-elevated risks. We call for systematic screening of mental health status for all cancer patients, and developing specific psychological interventions for this vulnerable population.

High SOX8 expression promotes tumor growth and predicts poor prognosis through GOLPH3 signaling in tongue squamous cell carcinoma.

According to our previous study, GOLPH3 is markedly up-expressed in tongue squamous cell carcinoma (TSCC), which is also associated with poor survival. However, it remains unclear about key upstream and downstream mechanisms of GOLPH3. This study aimed to illuminate new mechanisms modulating GOLPH3 upregulation and promoting TSCC development at the molecular level. Using mass spectrometry and agarose-streptavidin-biotin pull-down analyses, SOX8 (SRY-Box 8) was identified to be the new protein to bind the GOLPH3 promoter within TSCC cells, which was further verified to be the regulator of GOLPH3 upregulation. The knockdown of SOX8 suppressed the promoter activity of GOLPH3, while secondarily inhibiting TSCC cell proliferation both in vivo and in vitro. Interestingly, GOLPH3 overexpression rescued the SOX8 knockdown-mediated suppression on TSCC proliferation. Additionally, exogenous over-expression of SOX8 also activated the activity of promoter as well as GOLPH3 expression, in the meantime of promoting TSCC development. Moreover it was discovered that SOX8 regulated GOLPH3 expression through interacting with TFAP2A. Moreover our results suggested that the SOX8 level was increased within tumor tissue compared with that in para-cancer normal counterpart, which showed positive correlation with the GOLPH3 level. According to Kaplan-Meier analyses, TSCC cases having higher SOX8 and GOLPH3 expression were associated with poorer prognostic outcomes. Taken together, this study reveals that SOX8 enhances the TSCC cell growth via the direct transcriptional activation of GOLPH3, which also indicates the potential to use SOX8/GOLPH3 pathway as the treatment target among TSCC patients.

Somatic variants in new candidate genes identified in focal cortical dysplasia type II.

OBJECTIVE: Focal cortical dysplasia type II (FCDII) is a malformation of cortex development commonly found in children with drug-resistant epilepsy. FCDII has been associated with somatic mutations in mammalian target of rapamycin (mTOR)-related pathway genes and an upregulation of mTOR. Somatic mutations were found in 10%-63% of FCDII samples; the frequency of the mutant allele was 0.93%-33.5%. This study aimed to find new candidate genes involved in FCDII. METHODS: We collected resected FCD lesions, perilesional brain tissues, and peripheral blood from 17 children with pathologically confirmed FCDII. We performed whole exome sequencing and followed a set of screening and analysis strategies to identify potentially deleterious somatic variants (PDSVs) in brain-expressed genes. We performed site-specific amplicon sequencing to validate the results. We also performed an in vitro functional study on an IRS1 variant. RESULTS: In six of 17 samples, we identified seven PDSVs in seven genes, including two frameshift variants and five missense variants. The frequencies of the variant allele were 1.29%-5.50%. The genes were MTOR, TSC2, IRS1, RAB6B, RALA, HTR6, and ZNF337. PDSVs in IRS1, RAB6B, ZNF337, RALA, and HTR6 had not been previously associated with FCD. In one lesion, two PDSVs were found in two genes. In a transfected cell line, we demonstrated that the c.1791dupG (identified in FCDII from Patient 1) led to a truncated IRS1 and significant mTOR hyperactivation compared to cells that carried wild-type IRS1. mTOR was also activated in FCDII tissue from Patient 1. SIGNIFICANCE: Seven PDSVs were identified in FCDII lesions in six of 17 children. Five variant genes had not been previously associated with cortical malformations. We demonstrated that the IRS1 variant led to mTOR hyperactivation in vitro. Although functional experiments are needed, the results provide evidence for novel candidate genes in the pathogenesis of FCDII.