Minor Spliceosomal 65K/RNPC3 Interacts with ANKRD11 and Mediates HDAC3-Regulated Histone Deacetylation and Transcription.

RNA splicing is crucial in the multilayer regulatory networks for gene expression, making functional interactions with DNA- and other RNA-processing machineries in the nucleus. However, these established couplings are all major spliceosome-related; whether the minor spliceosome is involved remains unclear. Here, through affinity purification using Drosophila lysates, an interaction is identified between the minor spliceosomal 65K/RNPC3 and ANKRD11, a cofactor of histone deacetylase 3 (HDAC3). Using a CRISPR/Cas9 system, Deletion strains are constructed and found that both Dm65KΔ/Δ and Dmankrd11Δ/Δ mutants have reduced histone deacetylation at Lys9 of histone H3 (H3K9) and Lys5 of histone H4 (H4K5) in their heads, exhibiting various neural-related defects. The 65K-ANKRD11 interaction is also conserved in human cells, and the HsANKRD11 middle-uncharacterized domain mediates Hs65K association with HDAC3. Cleavage under targets and tagmentation (CUT&Tag) assays revealed that HsANKRD11 is a bridging factor, which facilitates the synergistic common chromatin-binding of HDAC3 and Hs65K. Knockdown (KD) of HsANKRD11 simultaneously decreased their common binding, resulting in reduced deacetylation of nearby H3K9. Ultimately, this study demonstrates that expression changes of many genes caused by HsANKRD11-KD are due to the decreased common chromatin-binding of HDAC3 and Hs65K and subsequently reduced deacetylation of H3K9, illustrating a novel and conserved coupling mechanism that links the histone deacetylation with minor spliceosome for the regulation of gene expression.

Microinvasion in hepatocellular carcinoma: predictive factor and application for definition of clinical target volume for radiotherapy.

BACKGROUND: To investigate the correlation between microinvasion and various features of hepatocellular carcinoma (HCC), and to clarify the microinvasion distance from visible HCC lesions to subclinical lesions, so as to provide clinical basis for the expandable boundary of clinical target volume (CTV) from gross tumor volume (GTV) in the radiotherapy of HCC. METHODS: HCC patients underwent hepatectomy of liver cancer in our hospital between July 2019 and November 2021 were enrolled. Data on various features and tumor microinvasion distance were collected. The distribution characteristics of microinvasion distance were analyzed to investigate its potential correlation with various features. Tumor size compared between radiographic and pathologic samples was analyzed to clarify the application of pathologic microinvasion to identify subclinical lesions of radiographic imaging. RESULTS: The average microinvasion distance was 0.6 mm, with 95% patients exhibiting microinvasion distance less than 3.0 mm, and the maximum microinvasion distance was 4.0 mm. A significant correlation was found between microinvasion and liver cirrhosis (P = 0.036), serum albumin level (P = 0.049). Multivariate logistic regression analysis revealed that HCC patients with cirrhosis had a significantly lower risk of microinvasion (OR = 0.09, 95%CI = 0.02 ~ 0.50, P = 0.006). Tumor size was overestimated by 1.6 mm (95%CI=-12.8 ~ 16.0 mm) on radiographic size compared to pathologic size, with a mean %Δsize of 2.96% (95%CI=-0.57%~6.50%). The %Δsize ranged from - 29.03% to 34.78%. CONCLUSIONS: CTV expanding by 5.4 mm from radiographic GTV could include all pathologic microinvasive lesions in the radiotherapy of HCC. Liver cirrhosis was correlated with microinvasion and were independent predictive factor of microinvasion in HCC.

Associations Between Serum Selenium and Bone Mineral Density in 8-19-year-old children and adolescents: NHANES 2013-2018.

The peak bone mass (PBM) in puberty has been proven to be a critical determinant of osteoporosis and brittle fractures in the elderly. Selenium is an essential trace element that could influence bone metabolism in our bodies. However, no study has investigated the impact of selenium status on bone mineral density (BMD) among children and adolescents. This was a cross-section study from National Health and Nutrition Examination Survey (NHANES) in the USA involving participants aged 8-19 years. We conducted multiple linear regression models to assess the relationship between selenium status and BMD among children and adolescents, and then stratified analyses were performed according to genders and races. Smooth curve fits and two-piecewise linear regression models were conducted to explore their nonlinear relationship. A total of 4570 participants (2338 boys and 2232 girls) were included in the present study, with a mean age of 13.57 ± 3.41 years. In the multivariable adjustment model, serum selenium was positively associated with lumbar spine BMD (ß = 0.021 95% CI: 0.008, 0.034, P = 0.001). The dose-response analyses indicated a non-linear inverted U-shaped relationship between serum selenium and lumbar spine BMD. Lower and higher selenium concentrations were related to decreased BMD, and the inflection point of serum selenium was 2.60 umol/L. The inverted U-shaped association was also observed in females (inflection point: 2.49 umol/L), males (inflection point: 2.65 umol/L), Non-Hispanic White (inflection point: 2.50 umol/L), Non-Hispanic Black (inflection point: 2.50 umol/L), and other races (Including multi-racial) (inflection point: 2.81 umol/L). Our study first shows a non-linear inversed U-shaped association between selenium status and BMD among children and adolescents. The proper selenium status will benefit bone health in children and adolescents. More research is still required to verify our findings and their potential mechanisms.

Prognostic Value of Lymph Node Necrosis at Different N Stages in Patients with Nasopharyngeal Carcinoma.

Background: Lymph node necrosis (LNN), including retropharyngeal nodal necrosis and cervical nodal necrosis, which is related to radiotherapy/ chemotherapy resistance, is a common phenomenon in nasopharyngeal carcinoma (NPC). This study was to assess the prognostic value of LNN at different N stages in NPC patients. Materials and Methods: In total, 1,665 newly diagnosed NPC patients at stage TxN1-3M0 from two centers were enrolled. Univariate and multivariate models were constructed to assess the association between LNN and long-term survival outcomes. The propensity score matching method was performed to balance treatment groups for baseline characteristics. Results: Of the 1,665, 540 patients (540/1665, 32.4%) were diagnosed with LNN, of which 54.1% (292/540) patients were at stage N1, 31.3% (169/540) at stage N2, and 14.6% (79/540) at stage N3. Univariate and multivariate analyses indicated LNN as an independent predictor for progression­free survival (PFS), overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS) in stage N1-3 patients (all P<0.001). When patients were analyzed according to stage, similar findings were observed for N1 patients (all P<0.001); for N2 patients, LNN independently predicted PFS (P=0.003), OS (P=0.011), and DMFS (P=0.004), and for stage N3, LNN only independently predicted LRRFS (P=0.019). 123 pairs of patients who received induction chemotherapy plus concurrent chemoradiotherapy or only concurrent chemoradiotherapy were matched, adding induction chemotherapy improved 5-year OS, PFS and LRFFS, but the results were not statistically significant. Conclusions: In NPC patients, LNN could independently predict poor prognosis at all N1-3 stages and at each N stage (N1 to N3). The value of adding induction chemotherapy to concurrent chemoradiotherapy in patients with LNN still requires further prospective studies.

Prognostic value of MR-detected mandibular nerve involvement: potential indication for future individual induction chemotherapy in T4 nasopharyngeal carcinoma.

PURPOSE: To investigate the prognostic significance of MR-detected mandibular nerve involvement (MNI) and its value for induction chemotherapy (IC) administration in patients with nasopharyngeal carcinoma (NPC) and T4 disease. METHODS: This retrospective study enrolled 792 non-metastatic, biopsy-proven NPC patients. Univariate and multivariate analysis were used to evaluate potential prognosticators. The inter-observer agreement was assessed by the kappa values. RESULTS: MR-detected MNI was observed in 141 (72.3%) patients among 195 patients with T4 disease, with excellent agreement between the readers (kappa = 0.926). Patients with MR-detected MNI presented better 5-year overall survival (OS) (hazard ratio [HR], 0.40; P = 0.006) than those with MR-negative MNI. Of these patients, IC treatment was verified as an independent factor (HR: 0.35; P = 0.014) with preferable effect on OS. CONCLUSION: MR-detected MNI could serve as an independent favorable prognostic predictor for OS in NPC patients with stage T4, which should be considered for stratifying these patients for IC administration.

RuleFit-Based Nomogram Using Inflammatory Indicators for Predicting Survival in Nasopharyngeal Carcinoma, a Bi-Center Study.

Purpose: Traditional prognostic studies utilized different cut-off values, without evaluating potential information contained in inflammation-related hematological indicators. Using the interpretable machine-learning algorithm RuleFit, this study aimed to explore valuable inflammatory rules reflecting prognosis in nasopharyngeal carcinoma (NPC) patients. Patients and Methods: In total, 1706 biopsy-proven NPC patients treated in two independent hospitals (1320 and 386) between January 2010 and March 2014 were included. RuleFit was used to develop risk-predictive rules using hematological indicators with no distributive difference between the two centers. Time-event-dependent hematological rules were further selected by stepwise multivariate Cox analysis. Combining high-efficiency hematological rules and clinical predictors, a final model was established. Models based on other algorithms (AutoML, Lasso) and clinical predictors were built for comparison, as well as a reported nomogram. Area under the receiver operating characteristic curve (AUROC) and concordance index (C-index) were used to verify the predictive precision of different models. A site-based app was established for convenience. Results: RuleFit identified 22 combined baseline hematological rules, achieving AUROCs of 0.69 and 0.64 in the training and validation cohorts, respectively. By contrast, the AUROCs of the optimal contrast model based on AutoML were 1.00 and 0.58. For overall survival, the final model had a much higher C-index than the base model using TN staging in two cohorts (0.769 vs 0.717, P<0.001; 0.752 vs 0.688, P<0.001), and showing great generalizability in training and validation cohorts. The two models based on RuleFit rules performed best, compared with other models. As for other endpoints, the final model showed a similar trend. Kaplan-Meier curve exhibited 22.9% (390/1706) patients were "misclassified" by AJCC staging, but the final model could assess risk classification accurately. Conclusion: The proposed final models based on inflammation-related rules based on RuleFit showed significantly elevated predictive performance.

Emerging Novel Reassortant Influenza A(H5N6) Viruses in Poultry and Humans, China, 2021.

A novel highly pathogenic avian influenza A(H5N6) clade 2.3.4.4b virus was isolated from a poultry market in China that a person with a confirmed case had visited. Most genes of the avian and human H5N6 isolates were closely related. The virus also exhibited distinct antigenicity to the Re-11 vaccine strain.

Morphological Characteristics of the Posterior Wall Associated with Complex Acetabular Fractures: A Radiological Study Using 3D Software and Fracture Mapping Technique.

Background: The aim of the study was to compare the morphological distinctions of the posterior wall (PW) in different complex acetabular fractures using 3D software and fracture mapping technique and ultimately to provide for improved clinical treatment. Methods: One hundred and fourteen patients with complex acetabular fracture associated with PW were recruited. All patients were divided into two groups according to the injury mechanism of the PW: Group A (both-column and PW) and Group B (including posterior column and PW; T shape and PW; and transverse and PW). Fracture mapping was generated on the intra- and extrasurface of a standard template. The radiological parameters including spatial displacement, articular surface area, articular range, marginal impaction, and multifragments of the two groups were compared. Results: The spatial displacement, intra-/extra-articular surface area, and start and end point in Group A were 10.9 mm (IQR, 8.4-15.2), 8.2 ± 2.6 cm2, 17.9 ± 5.3 cm2, 0.8° (IQR, -6.0-16.2), and 107.5° (IQR, 97.2-116.9), respectively. The results in Group B were 30.4 mm (IQR, 16.8-48.7), 4.1 ± 2.0 cm2, 10.6 ± 4.4 cm2, 29.5° (IQR, 19.2-38.0), and 117.5° (IQR, 98.2-127.2), respectively. Marginal impaction was defined by Letournel et al. All the differences between two groups were significant (P < 0.05). The fracture map in Group A showed an "L"-shaped pattern and a "cusp" on the ilium, and the PW was located at 1/5 to 1/4 of the posterosuperior part of the acetabulum. The fracture maps in Group B were scattered and lacked consistency, and the PWs were confined to 1/10 to 1/8 of the posterior acetabulum. Conclusions: Quantitative measurements and fracture mapping represented the differences in morphological characteristics of PWs associated with complex acetabular fractures.

Expression Profiles and Prognostic Value of Multiple Inhibitory Checkpoints in Head and Neck Lymphoepithelioma-Like Carcinoma.

Background: Inhibitory checkpoints are promising antitumor targets and predictive biomarkers in a variety of cancers. We aimed to identify the expression levels and prognostic value of multiple inhibitory checkpoints supported by preclinical and clinical evidence in head and neck lymphoepithelioma-like carcinoma (HNLELC). Methods: The expression of seven inhibitory checkpoints were evaluated in the tumor nest (TN) and tumor stroma (TS) of 102 HNLELC specimens using immunohistochemistry and digital pathology, and an inhibitory checkpoint-based signature (ICS) was subsequently constructed using the LASSO Cox regression model. Results: PD-L1, B7H3, and IDO-1 were mostly expressed in the TN, with median H-score of TN vs TS: 63.6 vs 14.6; 8.1 vs 1.0; 61.5 vs 34.7 (all P < 0.001), whereas PD-1, TIM-3, LAG-3, and VISTA were mainly observed in the TS, with median H-score of TN vs TS: 0.2 vs 12.4, 3.4 vs 7.1, 6.2 vs 11.9, 16.4 vs 47.2 (all P < 0.001), respectively. The most common simultaneously expressed combinations consisted of PD-L1 + B7H3 + IDO-1 + TIM-3 + LAG-3 + VISTA and B7H3 + IDO-1 + TIM-3 + LAG-3 in the TN (both occurring in 8.8% of patients) and PD-L1 + B7H3 + IDO-1 in the TS (4.9%). In addition, high-ICS patients had shorter 5-year disease-free (40.6% vs 81.7%; P < 0.001), regional recurrence-free (63.5% vs 88.2%; P = 0.003), and overall survival (73.5% vs 92.9%; P = 0.006) than low-ICS patients. Multivariate analysis revealed that ICS represented an independent predictor, which could significantly complement the predictive performance of TNM stage for 3-year (AUC 0.724 vs 0.619, P = 0.014), 5-year (AUC 0.727 vs 0.640, P = 0.056), and 10-year disease-free survival (AUC 0.815 vs 0.709, P = 0.023). Conclusions: The expression of inhibitory checkpoints and ICS classifier may increase the prognostic value of the TNM staging system and guide the rational design of personalized inhibitory checkpoint blockade therapy in HNLELC.

Systematic construction and external validation of an immune-related prognostic model for nasopharyngeal carcinoma.

BACKGROUND: We attempted to identify the most reliable immune-related index for predicting nasopharyngeal carcinoma (NPC) prognosis and to reveal its precise and integrated relationship with NPC progression. METHOD: One thousand seven hundred and six patients with newly diagnosed NPC (1320 from the primary cohort and 386 from the validated cohort) from January 2010 to March 2014 were enrolled. Clinical features and 12 immune-related variables were analyzed. RESULTS: A high absolute lymphocyte count (ALC; >3.2 × 109 /L) correlated with a poor prognosis of patients with NPC. Significant OS differences were discovered between patients with high ALC and no ALC elevation (p < 0.05, in primary cohort), showing similar prognostic risk to patients with advanced NPC (p > 0.05, in validated cohort). ALC improved the predictive performance of the basic tumor-node-metastasis prognostic model (p = 0.025), which was reliably validated in the external independent cohort. CONCLUSION: High ALC is a surrogate marker for improved prognostic risk stratification in NPC.

CT-Based Classification Systems for Intra-Articular Calcaneal Fractures: The Inter- and Intraobserver Variations as well as Integrality.

The aim of this study was to measure the inter- and intraobserver variations as well as integrality of the Zwipp, Crosby-Fitzgibbons, Sanders, and Eastwood-Atkins classification systems based on more accurate CT scans. Five hundred and forty-nine patients with intra-articular calcaneal fractures from January 2018 to December 2019 taken from a database in our level-I trauma center (3 affiliated hospitals) were included. For each case, normative CT (1 mm slices) scans were available. Four different observers reviewed all CT scans 2 times according to these 4 most prevalent fracture classification systems (FCSs) within a 2-month interval. For these 4 FCSs, the kappa [κ] coefficient was used to evaluate interobserver reliability and intraobserver reproducibility, and the percentage that can be classified was used to indicate integrality. The κ values were measured for Zwipp (κ = 0.38 interobserver, κ = 0.61 intraobserver), Crosby-Fitzgibbons (κ = 0.48 interobserver, κ = 0.79 intraobserver), Sanders (κ = 0.40 interobserver, κ = 0.57 intraobserver), and Eastwood-Atkins (κ = 0.44 interobserver, κ = 0.72 intraobserver). Furthermore, the integralities were calculated for Zwipp (100%), Crosby-Fitzgibbons (100%), Sanders (92%) as well as Eastwood-Atkins (89.6%). Compared with previous literatures, CT scanning with higher accuracy can significantly improve intraobserver reproducibility of Zwipp and Eastwood-Atkins FCSs, but it has no positive effect on variability of Sanders FCS and interobserver reliability of Crosby-Fitzgibbons FCS. In terms of integrality, Zwipp and Crosby-Fitzgibbons FCSs appear to be superior to the other 2 FCSs.

Is Plating Fixation Through the Kocher-Langenbeck Approach for Associated Posterior Wall Fragment Indispensable in Both-Column Acetabular Fractures?

OBJECTIVE: The treatment methods for posterior wall (PW) in both-column acetabular fractures are controversial. The purpose of this study was to compare reduction quality, clinical outcomes, and complications of nonfixation for posterior wall fragment and plating via the Kocher-Langenbeck (KL) approach after anterior surgical procedures in both-column acetabular fractures. METHODS: Forty-nine patients with both-column acetabular fractures associated with PW fixed via iliac fossa and Stoppa approaches from October 2012 to October 2017 were recruited into this study and were divided into two groups: Nonfix group (nonfixation for PW) and KL group (PW plating through the KL approach). Operation duration, intraoperative blood loss, reduction quality, fracture healing, and relevant complications of patients were reviewed. Merle d'Aubigné scores were used for assessing functional outcome. RESULTS: The mean blood loss and operation durations were lower in Nonfix group than in KL group (both p < 0.05). The mean hospital stay durations were (18.54 ± 6.42) days and (21.17 ± 7.32) days in groups Nonfix and KL, respectively (p = 0.186). All fractures healed well with no significant difference in union time between the two groups (p = 0.210). The rates of satisfactory reduction were 84.62% (22/26) in Nonfix group and 86.96% (20/23) in KL group (p = 1.000). The mean Merle d'Aubigné scores were 15.62 ± 2.28 in Nonfix group and 16.17 ± 2.19 in KL group (p = 0.388). The complication rates were 7.69% (2/26) in Nonfix group and 34.78% (8/23) in KL group (p = 0.046). CONCLUSIONS: For both-column acetabular fractures associated with PW fragment, although fixation of PW was not performed after anterior surgical procedures, satisfactory outcomes could also be obtained. However, nonfixation was a less invasive choice with a lower complication rate.

MRI of nasopharyngeal carcinoma: parapharyngeal subspace involvement has prognostic value and influences T-staging in the IMRT era.

OBJECTIVES: To identify the prognosis of parapharyngeal space involvement (PPSI) based on the number of subspaces involved (pre-styloid space, carotid space (CS), areas outside the CS) and explore its significance for current T-staging in patients with nasopharyngeal carcinoma (NPC). METHODS: PPSI was retrospectively identified in 1224 patients with non-disseminated NPC at two centers on MRI and separated into four invasion patterns: pattern A (only post-styloid space), pattern B (post-styloid space, CS extension), pattern C (post-styloid space, pre-styloid space extension), and pattern D (all spaces). The Kaplan-Meier analysis and multivariate Cox regression models were used. RESULTS: PPSI was diagnosed in 63.4% of cases, with patterns A, B, C, and D in 14.3%, 3.8%, 25.3%, and 18.6% of cases, respectively. No prognostic heterogeneity was observed between pattern B and pattern C (p > 0.05). Thus, the degree of PPSI was based on the number of subspaces involved: grade 0 (none), grade 1 (one), grade 2 (two), and grade 3 (three), which could independently predict overall survival (OS) (p < 0.001). T3 patients with grade 0/1 PPSI (slight-T3) had a better prognosis than those with grade 2/3 PPSI (severe-T3) in terms of OS, locoregional-free survival (LRFS), and progression-free survival (PFS) (all p < 0.001), whose hazard ratios were higher and lower than those with T1 and T2, respectively. Combining the T2 and slight-T3 groups as the proposed T2 provided significant differences in OS, LRFS, and PFS between T2 and T3 (all p < 0.05). CONCLUSIONS: The risk of death increased with the number of parapharyngeal subspaces involved. The degree of PPSI is recommended to optimize T3 heterogeneity. KEY POINTS: • Parapharyngeal space involvement was proposed to differentiate patient risk groups based on the number of involved subspaces: grade 0 (none), grade 1 (one), grade 2 (two), or grade 3 (three). • The degree of parapharyngeal space involvement was an independent negative prognosticator for OS. • The degree of parapharyngeal space involvement may influence T-staging in patients with nasopharyngeal carcinoma.

A deep learning-based radiomic nomogram for prognosis and treatment decision in advanced nasopharyngeal carcinoma: A multicentre study.

BACKGROUND: Induction chemotherapy (ICT) plus concurrent chemoradiotherapy (CCRT) and CCRT alone were the optional treatment regimens in locoregionally advanced nasopharyngeal carcinoma (NPC) patients. Currently, the choice of them remains equivocal in clinical practice. We aimed to develop a deep learning-based model for treatment decision in NPC. METHODS: A total of 1872 patients with stage T3N1M0 NPC were enrolled from four Chinese centres and received either ICT+CCRT or CCRT. A nomogram was constructed for predicting the prognosis of patients with different treatment regimens using multi-task deep learning radiomics and pre-treatment MR images, based on which an optimal treatment regimen was recommended. Model performance was assessed by the concordance index (C-index) and the Kaplan-Meier estimator. FINDINGS: The nomogram showed excellent prognostic ability for disease-free survival in both the CCRT (C-index range: 0.888-0.921) and ICT+CCRT (C-index range: 0.784-0.830) groups. According to the prognostic difference between treatments using the nomogram, patients were divided into the ICT-preferred and CCRT-preferred groups. In the ICT-preferred group, patients receiving ICT+CCRT exhibited prolonged survival over those receiving CCRT in the internal and external test cohorts (hazard ratio [HR]: 0.17, p<0.001 and 0.24, p=0.02); while the trend was opposite in the CCRT-preferred group (HR: 6.24, p<0.001 and 12.08, p<0.001). Similar results for treatment decision using the nomogram were obtained in different subgroups stratified by clinical factors and MR acquisition parameters. INTERPRETATION: Our nomogram could predict the prognosis of T3N1M0 NPC patients with different treatment regimens and accordingly recommend an optimal treatment regimen, which may serve as a potential tool for promoting personalized treatment of NPC. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, Beijing Natural Science Foundation, Strategic Priority Research Program of CAS, Project of High-Level Talents Team Introduction in Zhuhai City, Beijing Natural Science Foundation, Beijing Nova Program, Youth Innovation Promotion Association CAS.

Development of a dual-labeled, hydrolysis probe-based, real-time quantitative PCR assay for detection of both genotypes of duck circovirus-1 (DuCV-1) and DuCV-2.

In this study, we developed a real-time quantitative polymerase chain reaction (qPCR) assay based on a dual-labeled hydrolysis probe to simultaneously detect both duck circovirus (DuCV) 1 and DuCV-2. The reproducibility, sensitivity and specificity of the primer set and probe were evaluated using other duck pathogens. The detection limit was 20 copies per µL. The intra-assay coefficients of variation (CVs) were ≤ 0.73% and the inter-assay CVs were ≤ 1.89%. No cross-reaction occurred with other duck pathogens. In addition, the qPCR assay was successfully applied to the simultaneous detection of DuCV-1 and DuCV-2 in clinical field samples. Therefore, this assay will be useful for laboratory diagnosis and epidemiological field studies of DuCV.

Aldehyde Dehydrogenase 2 Mediates Alcohol-Induced Colorectal Cancer Immune Escape through Stabilizing PD-L1 Expression.

Despite the great success of immunotherapy in a small subset of cancer patients, most colorectal cancer (CRC) patients do not respond to programmed cell death receptor 1 (PD-1) blockade immunotherapy. There is an urgent medical need to elucidate how cancer cells evade immune response and to develop novel means to boost the efficacy of immune checkpoint inhibitors. In this study, alcohol induces ligand programmed cell death receptor 1 (PD-L1) expression of CRC cells in vitro and in vivo. Alcohol exposure is shown to induce aldehyde dehydrogenase 2 (ALDH2) expression that is a crucial enzyme involved in alcohol metabolism, and low level of lymphocytes infiltration in the murine CRC model and patients. Intriguingly, ALDH2 and PD-L1 protein expression are positively correlated in tumor tissues from the CRC patients. Mechanistically, ALDH2 stabilizes PD-L1 protein expression by physically interacting with the intracellular segment of PD-L1 and inhibiting its proteasome-dependent degradation mediated by an E3 ubiquitin ligase Speckle Type POZ Protein (SPOP). Importantly, inhibition of ALDH2 reduces PD-L1 protein in CRC cells and promotes tumor-infiltrating T cells (TILs) infiltration, presumably leading to the significant potentiation of anti-PD-1 antibody efficacy in a mouse CT26 CRC model. The findings highlight a crucial role played by ALDH2 to facilitate alcohol-mediated tumor escape from immunity surveillance and promote tumor progression.

Comprehensive Identification and Alternative Splicing of Microexons in Drosophila.

Interrupted exons in the pre-mRNA transcripts are ligated together through RNA splicing, which plays a critical role in the regulation of gene expression. Exons with a length ≤ 30 nt are defined as microexons that are unique in identification. However, microexons, especially those shorter than 8 nt, have not been well studied in many organisms due to difficulties in mapping short segments from sequencing reads. Here, we analyzed mRNA-seq data from a variety of Drosophila samples with a newly developed bioinformatic tool, ce-TopHat. In addition to the Flybase annotated, 465 new microexons were identified. Differentially alternatively spliced (AS) microexons were investigated between the Drosophila tissues (head, body, and gonad) and genders. Most of the AS microexons were found in the head and two AS microexons were identified in the sex-determination pathway gene fruitless.

Excessive vitamin B6 during treatment is related to poor prognosis of patients with nasopharyngeal carcinoma: A U-shaped distribution suggests low dose supplement.

BACKGROUND & AIM: Several studies explored the association of vitamin B6 intake with the risk of cancers. However, it is unclear whether different doses of vitamin B6 have distinct effects on the prognosis of nasopharyngeal carcinoma (NPC) patients. This study investigated the relationship between different doses of B6 intake and the prognosis of NPC patients. METHODS: This retrospective cohort analysis included 792 newly diagnosed NPC patients with a median follow-up of 62.05 months. Restricted cubic spline and maximally selected rank statistics were performed to determine the cut-off value of vitamin B6 during treatment (VB6DT). Kaplan-Meier method and log-rank tests were performed to analyze survival outcomes. A multivariable Cox proportional hazard model was performed to determine the independent prognostic factors. RESULTS: NPC patients were divided into three groups according to the cut-off value of VB6DT: non-users (0 mg/d), VB6DT > 8.6 mg/d, and VB6DT ≤ 8.6 mg/d. Patients with VB6DT > 8.6 mg/d had significantly lower 5-year overall survival (OS) (83.5% vs. 90.8%, p = 0.006), distant metastasis-free survival (DMFS) (83.5% vs. 91.0%, p = 0.004), and progression-free survival (PFS) (73.7% vs. 81.7%, p = 0.011) and slightly but not significantly lower 5-year local recurrence-free survival (LRFS) (87.7% vs. 90.7%, p = 0.214) than the non-users. Patients with VB6DT ≤ 8.6 mg/d had slightly but not significantly better 5-year OS (93.3% vs. 90.8%, p = 0.283) than the non-users, while all other primary endpoints were similar (p > 0.50). Multivariable analyses confirmed that VB6DT > 8.6 mg/d was an independent negative prognostic factor of OS (p = 0.010), DMFS (p = 0.017), and PFS (p = 0.030) but not of LRFS (p = 0.428). CONCLUSIONS: Excessive VB6DT higher than the cut-off value is an independent negative prognostic factor for NPC patients. Additionally, low dose intake improved OS only slightly but not significantly.

Grading Soft Tissue Involvement in Nasopharyngeal Carcinoma Using Network and Survival Analyses: A Two-Center Retrospective Study.

BACKGROUND: Soft tissue involvement (STI) indicates poor prognosis in nasopharyngeal carcinoma (NPC). However, only a few studies have systematically assessed this extension using network analysis. PURPOSE: To investigate the prognostic value of STI and to propose an improved STI grading system for NPC therapy. STUDY TYPE: Retrospective study. POPULATION: A total of 1225 consecutive patients with pathologically confirmed NPC treated with intensive-modulated radiotherapy from January 2010 to March 2014 were enrolled from two centers. FIELD STRENGTH/SEQUENCE: T1- and T2-weighted imaging and enhanced T1-weighted imaging with fast spin echo sequence at 1.5 or 3.0 T. ASSESSMENT: The levator veli palatini and tensor veli palatini involvement were graded "mild," prevertebral muscle involvement, "moderate," medial pterygoid, lateral pterygoid, and the infratemporal fossa involvement, "severe" STI. The above STI sites were evaluated separately by three radiologists using MRI images and graded using network analysis. Overall survival (OS) and progression-free survival (PFS) were assessed. STATISTICAL TESTS: Kaplan-Meier method, Cox's proportional hazards model, and concordance index (C-index) were used. RESULTS: Five-year OS and PFS rates between mild and moderate groups (90.5% vs. 81.7%, P < 0.05 and 82.9% vs. 72.5%, P < 0.05, respectively) and between moderate and severe groups (81.7% vs. 70.4%, P < 0.05 and 72.5% vs. 61.2%, P < 0.05, respectively) revealed significant differences. The C-index of the nomogram with STI grading was higher compared with current T-classification (OS 0.641 vs. 0.604, P < 0.05 and PFS 0.605 vs. 0.581, P < 0.05, respectively). Significant OS differences were observed between patients with severe STI who underwent induction chemotherapy (IC) and those who did not (84.5% vs. 70.7%, P < 0.05). DATA CONCLUSION: STI grading was an independent prognostic factor for OS and PFS in NPC patients and it may be help to improve the accuracy in predicting survival outcomes. Patients with severe STI might benefit from IC to improve OS. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.