Complete Response to Locoregional Therapy Plus Immunotherapy for Hepatocellular Carcinoma.

Importance: Previous studies showed that 42% to 50% of patients with locally advanced hepatocellular carcinoma (HCC) achieved complete remission (CR) after combined locoregional therapy (LRT) plus immunotherapy (IO). However, data on predictors of CR and long-term clinical outcomes without surgery and after discontinuation of IO are lacking. Objective: To assess the long-term clinical outcomes among patients with unresectable HCC who achieved CR after LRT-IO and were placed on a watch-and-wait protocol. Design, Setting, and Participants: This cohort study included patients with unresectable HCC who achieved CR after LRT-IO in 2 prospective studies between January 2018 and December 2022. The time of data cutoff was June 2023. Radiologic CR was defined per modified Response Evaluation Criteria in Solid Tumors. All patients underwent close surveillance after CR without surgical interventions, and IO was discontinued. Exposure: All patients had received stereotactic body radiotherapy followed by anti-programmed cell death protein 1 or anti-programmed death ligand 1 therapy. Forty-nine patients had received a dose of transarterial chemoembolization before stereotactic body radiotherapy. Main Outcomes and Measures: The primary outcome was the 3-year overall survival (OS) rate. Secondary outcomes included the 3-year time-to-progression rate, 3-year local control rate, and relapse pattern. Factors associated with CR were analyzed using multivariate analyses. Results: A total of 63 patients were enrolled (58 male [92.1%]; median age, 69 years [range, 18-90 years]); 38 patients (60.3%) had macrovascular invasion, and the median tumor diameter was 10 cm (range, 3.8-31.1 cm). The median follow-up time was 34.7 months (95% CI, 6.5-64.6 months). Twenty-nine patients (46.0%) achieved CR. The patients achieving CR had a significantly better 3-year OS rate than patients not achieving CR (75.5% [95% CI, 58.2%-98.3%] vs 28.1% [95% CI, 7.4%-29.4%]; P < .001). Among the 29 patients with CR, the 3-year time-to-progression rate was 58.7% (95% CI, 38.7%-79.1%) and the 3-year local control rate was 90.5% (95% CI, 78.2%-100%). Ten patients (34.5%) developed recurrence; among them, 6 (60.0%) with solitary intrahepatic disease relapse underwent curative surgical treatment. The absence of tumor vascular invasion (odds ratio, 0.30; 95% CI, 0.10-0.89) and the sum of the largest lesion diameters of 8 cm or less (odds ratio, 0.26; 95% CI, 0.07-0.98) were associated with CR. Conclusions and Relevance: This cohort study of LRT-IO with long-term follow-up data found a durable response in patients with locally advanced unresectable HCC. Long-term survival was attainable in patients with radiologic CR. Further randomized clinical trials are warranted.

Single-Slice Hounsfield Unit (HU) Value of the Chinese Proximal Humerus on Routine Chest CT: A Study on Opportunistically Screening for Low Bone Density / Valor de Unidad Hounsfield (HU) de Corte Único del Húmero Proximal Chino en una Tomografía Computarizada de Tórax de Rutina: Un Estudio sobre la Detección Oportunista de Baja Densidad Ósea

SUMMARY: A Study on Relationship between Single-Slice Hounsfield Unit(HU) value of the Chinese proximal humerus and Bone Mineral Density(BMD) Using Routine Chest CT and Dual-energy X-ray Absorptiometry(DEXA) was performed. Data were collected from 240 individuals who underwent DEXA and routine chest CT scans (including full images of the proximal humerus) on the same day at 967 Hospitals between January 2019 and December 2021. The method of measuring single-slice HU values of the proximal humerus on routine chest CT scans exhibited high reliability and repeatability (intraclass correlation coefficient > 0.961, P < 0.001). A strong positive correlation was observed between single-slice HU values of the proximal humerus and DEXA results, with the 20-mm HU value demonstrating the highest correlation. Across different BMI groups, the Area Under Curve (AUC) for the 20-mm HU value was consistently the largest (AUC=0.701- 0.813, P< 0.05). Therefore, the 20-mm HU value can be considered a reliable reference for the opportunistic screening of low BMD, with reference values of -4HU for underweight individuals, -13HU for normal weight individuals, -7HU for overweight individuals, and -16HU for obese individuals. Values below these thresholds indicate a risk of low BMD. This study enriches the Chinese BMD data and offers a swift and effective approach for opportunistically screening low BMD.

Se realizó un estudio sobre la relación entre el valor de la Unidad Hounsfield (HU) de corte único del húmero proximal chino y la densidad mineral ósea (DMO) mediante TC de tórax de rutina y absorciometría de rayos X de energía dual (DEXA). Se recopilaron datos de 240 personas que se sometieron a DEXA y tomografías computarizadas de rutina de tórax (incluidas imágenes completas del húmero proximal) el mismo día en 967 hospitales entre enero de 2019 y diciembre de 2021. El método para medir los valores de HU de un solo corte del húmero proximal en las tomografías computarizadas de tórax mostraron alta confiabilidad y repetibilidad (coeficiente de correlación intraclase > 0,961, P < 0,001). Se observó una fuerte correlación positiva entre los valores de HU de un solo corte del húmero proximal y los resultados de DEXA, demostrando el valor de HU de 20 mm la correlación más alta. En diferentes grupos de IMC, el área bajo la curva (AUC) para el valor HU de 20 mm fue consistentemente el más grande (AUC = 0,701-0,813, P <0,05). Por lo tanto, el valor de HU de 20 mm puede considerarse una referencia fiable para el cribado oportunista de DMO baja, con valores de referencia de -4 HU para personas con bajo peso, -13 HU para personas con peso normal, -7 HU para personas con sobrepeso y -16 HU para personas obesas. Los valores por debajo de estos umbrales indican un riesgo de DMO baja. Este estudio es un aporte para los datos chinos sobre la DMO y ofrece un enfoque rápido y eficaz para detectar de forma oportunista la DMO baja.

Dual-tracer PET/CT in the management of hepatocellular carcinoma.

Background & Aims: Combined 18F-fluorodeoxyglucose (FDG) and 11C-acetate (dual-tracer) positron-emission tomography/computed tomography (PET/CT) is being increasingly performed for the management of hepatocellular carcinoma (HCC), although its role is not well defined. Therefore, we evaluated its effectiveness in (i) staging, (ii) characterization of indeterminate lesions on conventional imaging, and (iii) detection of HCC in patients with unexplained elevations in serum alpha-fetoprotein (AFP) levels. Methods: We retrospectively assessed 525 consecutive patients from three tertiary centers between 2014 and 2020. For staging, we recorded new lesion detection rates, changes in the Barcelona Clinic Liver Cancer (BCLC) classification, and treatment allocation due to dual-tracer PET/CT. To characterize indeterminate lesions and unexplained elevation of serum AFP levels, the sensitivity and specificity of dual-tracer PET/CT in diagnosing HCC were evaluated. A multidisciplinary external review and a cost-benefit analysis of patients for metastatic screening were also performed. Results: Dual-tracer PET/CT identified new lesions in 14.3% of 273 staging patients, resulting in BCLC upstaging in 11.7% and treatment modifications in 7.7%. It upstaged 8.1% of 260 patients undergoing metastatic screening, with estimated savings of US$495 per patient. It had a sensitivity and specificity of 80.7% (95% CI 71.2-88.6%) and 94.8% (95% CI 90.4-98.6%), respectively, for diagnosing HCC in 201 indeterminate lesions. It detected HCC in 45.1% of 51 patients with unexplained elevations in serum AFP concentrations. External review revealed substantial agreement between local and external image interpretation and patient assessment (n = 273, κ = 0.822; 95% CI 0.803-0.864). Conclusions: Dual-tracer PET/CT provides added value beyond conventional imaging in patients with HCC by improving staging, confirming HCC diagnosis with high accuracy in patients with indeterminate lesions, and detecting HCC in patients with unexplained elevation of serum AFP. Impact and implications: Compared to CT or MRI, dual-tracer positron-emission tomography/computed tomography (PET/CT) led to upstaging in 12% of patients with hepatocellular carcinoma (HCC) undergoing staging, resulting in treatment modification in 8% of cases and a cost saving of US$495 per patient. It also accurately detected HCC in high-risk cases where CT or MRI were equivocal or normal. Dual-tracer PET/CT provides added value beyond conventional imaging in patients with HCC by improving staging, confirming HCC diagnosis with high accuracy in patients with indeterminate lesions, and detecting HCC in patients with unexplained elevation of serum AFP.

Dectin-1 induces TRPV1 sensitization and contributes to visceral hypersensitivity of irritable bowel syndrome in male mice.

BACKGROUND: Visceral hypersensitivity is considered the core pathophysiological mechanism that causes abdominal pain in patients with irritable bowel syndrome (IBS). Fungal dysbiosis has been proved to contribute to visceral hypersensitivity in IBS patients. However, the underlying mechanisms for Dectin-1, a major fungal recognition receptor, in visceral hypersensitivity are poorly understood. This study aimed to explore the role of Dectin-1 in visceral hypersensitivity and elucidate the impact of Dectin-1 activity on the function of transient receptor potential vanilloid type 1 (TRPV1). METHODS: Visceral hypersensitivity model was established by the intracolonic administration of 0.1 mL TNBS (130 µg/mL in 30% ethanol) in the male mice. Fluconazole and nystatin were used as fungicides. Laminarin, a Dectin-1 antagonist and gene knockout (Clec7a-/-) mice were used to interrupt the function of Dectin-1. Colorectal distension-electromyogram recording was performed to assess visceral sensitivity. Immunostaining experiment was performed to determine the localization of Dectin-1 in dorsal root ganglion (DRG) neurons. Calcium imaging study was performed to assay TRPV1-mediated calcium influx in acutely dissociated DRG neurons. RESULTS: Pretreatment with fungicides, administration of laminarin or genetic deletion of Clec7a alleviated TNBS-induced visceral hypersensitivity in male mice. The expression of Dectin-1 was upregulated in the DRG and colon of TNBS-treated mice. Colocalization of Dectin-1 and TRPV1 was observed in DRG neurons. Importantly, pretreatment with curdlan, a Dectin-1 agonist, increased TRPV1-mediated calcium influx. CONCLUSIONS: Dectin-1 contributes to visceral hypersensitivity in IBS or in inflammatory bowel disease in remission and activation of Dectin-1 induces TRPV1 sensitization. SIGNIFICANCE STATEMENT: This work provides direct evidence for the functional regulation of TRPV1 channel by Dectin-1 activity, proposing a new mechanism underlying TRPV1 sensitization. Control of intestinal fungi might be beneficial for the treatment of refractory abdominal pain in patients with IBS or IBD in remission.

Door-to-antibiotic time and mortality in patients with sepsis: Systematic review and meta-analysis.

OBJECTIVES: To evaluate whether the timing of initial antibiotic administration in patients with sepsis in hospital affects mortality. METHODS: This systematic review and meta-analysis included studies from inception up to 19 May 2022. Interventional and observational studies including adult human patients with suspected or confirmed sepsis and reported time of antibiotic administration with mortality were included. Data were extracted by two independent reviewers. Summary estimates were calculated by using random-effects model. The primary outcome was mortality. RESULTS: We included 42 studies comprising 190,896 patients with sepsis. Pooled data showed that the OR for patient mortality who received antibiotics ≤1 hr was 0.83 (95 %CI: 0.67 to 1.04) when compared with patients who received antibiotics >1hr. Significant reductions in the risk of death in patients with earlier antibiotic administration were observed in patients ≤3 hrs versus >3 hrs (OR: 0.80, 95 %CI: 0.68 to 0.94) and ≤6 hrs vs 6 hrs (OR: 0.57, 95 %CI: 0.39 to 0.82). CONCLUSIONS: Our findings show an improvement in mortality in sepsis patients with early administration of antibiotics at <3 and <6 hrs. Thus, these results suggest that antibiotics should be administered within 3 hrs of sepsis recognition or ED arrival regardless of the presence or absence of shock.

Sorted-Cell Sequencing on HCC Specimens Reveals EPS8L3 as a Key Player in CD24/CD13/EpCAM-Triple Positive, Stemness-Related HCC Cells.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a heterogeneous cancer with varying levels of liver tumor initiating or cancer stem cells in the tumors. We aimed to investigate the expression of different liver cancer stem cell (LCSC) markers in human HCCs and identify their regulatory mechanisms in stemness-related cells. METHODS: We used an unbiased, single-marker sorting approach by flow cytometry, fluorescence-activated cell sorting, and transcriptomic analyses on HCC patients' resected specimens. Knockdown approach was used, and relevant functional assays were conducted on the identified targets of interest. RESULTS: Flow cytometry on a total of 60 HCC resected specimens showed significant heterogeneity in the expression of LCSC markers, with CD24, CD13, and EpCAM mainly contributing to this heterogeneity. Concomitant expression of CD24, CD13, and EpCAM was detected in 32 HCC samples, and this was associated with advanced tumor stages. Transcriptomic sequencing on the HCC cells sorted for these individual markers identified epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3) as a common gene associated with the 3 markers and was functionally validated in HCC cells. Knocking down EPS8L3 suppressed the expression of all 3 markers. To search for the upstream regulation of EPS8L3, we found SP1 bound to EPS8L3 promoter to drive EPS8L3 expression. Furthermore, using Akt inhibitor MK2206, we showed that Akt signaling-driven SP1 drove the expression of the 3 LCSC markers. CONCLUSIONS: Our findings suggest that Akt signaling-driven SP1 promotes EPS8L3 expression, which is critical in maintaining the downstream expression of CD24, CD13, and EpCAM. The findings provide insight into potential LCSC-targeting therapeutic strategies.

Survival Outcome Analysis of Stereotactic Body Radiotherapy and Immunotherapy (SBRT-IO) versus SBRT-Alone in Unresectable Hepatocellular Carcinoma.

Introduction: While combination of stereotactic body radiotherapy (SBRT) and immunotherapy are promising, their efficacy and safety have not been compared with SBRT-alone in patients with unresectable hepatocellular carcinoma (HCC). Methods: This retrospective study included 100 patients with nonmetastatic, unresectable HCC in two hospitals. Eligible patients had tumor nodules ≤3 and Child-Pugh liver function score of A5 to B7. Seventy patients received SBRT-alone, and 30 patients underwent combined SBRT and immunotherapy (SBRT-IO). Overall survival (OS), time to progression (TTP), overall response rate (ORR), and toxicity were analyzed. We adjusted for the potential confounding factors using propensity score matching. Results: The median tumor size was 7.3 cm (range, 2.6-18 cm). Twenty-five (25%) of patients had vascular invasion. Before propensity score matching, the 1-year and 3-year OS rate was 89.9% and 59.8% in the SBRT-IO group and 75.7% and 42.3% in SBRT-alone group (p = 0.039). After propensity score matching (1:2), 25 and 50 patients were selected from the SBRT-IO and SBRT-alone group. The 1-year and 3-year OS was 92.0% and 63.9% in the SBRT-IO group versus 74.0% and 43.3% in the SBRT-alone group (p = 0.034). The 1-year and 3-year TTP was better in SBRT-IO group (1-year: 68.9% vs. 58.9% and 3-year: 61.3% vs. 32.5%, p = 0.057). The ORR of 88% (complete response [CR]: 56%, partial response [PR]: 22%) in SBRT-IO arm was significantly better than 50% (CR: 20%, PR: 30%) in the SBRT-alone arm (p = 0.006). Three patients (12%) developed ≥grade 3 immune-related treatment adverse events (n = 2 hepatitis, n = 1 dermatitis) leading to permanent treatment discontinuation. Conclusion: Adding immunotherapy to SBRT resulted in better survival with manageable toxicities. Prospective randomized trial is warranted.

Patient and public involvement workshop to shape artificial intelligence-supported connected asthma self-management research.

Digital interventions with artificial intelligence (AI) can potentially support people with asthma to reduce the risk of exacerbation. Engaging patients throughout the development process is essential to ensure usability of the intervention for the end-users. Using our Connected for Asthma (C4A) intervention as an exemplar, we explore how patient involvement can shape a digital intervention. Seven Patient and Public Involvement (PPI) colleagues from the Asthma UK Centre for Applied Research participated in four advisory workshops to discuss how they would prefer to use/interact with AI to support living with their asthma, the benefit and caveats to use the AI that incorporated asthma monitoring and indoor/outdoor environmental data. Discussion focussed on the three most wanted use cases identified in our previous studies. PPI colleagues wanted AI to support data collection, remind them about self-management tasks, teach them about asthma environmental triggers, identify risk, and empower them to confidently look after their asthma whilst emphasising that AI does not replace clinicians. The discussion informed the key components in the next C4A interventions, including the approach to interacting with AI, the technology features and the research topics. Attendees highlighted the importance of considering health inequities, the presentation of data, and concerns about data accuracy, data privacy, security and ownership. We have demonstrated how patient roles can shift from that of 'user' (the traditional 'tester' of a digital intervention), to a co-design partner who shapes the next iteration of the intervention. Technology innovators should seek practical and feasible strategies to involve PPI colleagues throughout the development cycle of a digital intervention; supporting researchers to explore the barriers, concerns, enablers and advantages of implementing digital healthcare.

Correlation of pathological examination with indocyanine green (ICG) intensity gradients: a prospective study in patients with liver tumor.

BACKGROUND: Intraoperative indocyanine green (ICG) fluorescence imaging has been shown to be a new and innovative way to illustrate the optimal resection margin in hepatectomy for hepatocellular carcinoma. This study investigated its accuracy in resection margin determination by looking into the correlation of ICG intensity gradients with pathological examination results of resected specimens. METHODS: This was a prospective, single-center, non-randomized controlled study. Patients who had liver tumors indicating liver resection were recruited. The hypothesis was that the use of intraoperative near-infrared/ICG fluorescence imaging would be a promising guiding tool for removing hepatocellular carcinoma with a better resection margin. Patients were given ICG (0.25 mg/kg) 1 day before operation. Resected specimens were inspected under a fluorescent imaging system. Biopsies were taken from tumors and normal tissue. Color signals obtained from ICG fluorescence imaging were compared with biopsies for analysis. RESULTS: Twenty-two patients were recruited for study. The median size of their tumors was 2.25 cm. One patient had resection margin involvement. Under ICG fluorescence, the tumors typically lighted up as yellow color, wrapped by a zone of green color. Tumors of 17 patients (77.3%) displayed yellow color and were confirmed malignancy, while tumors of 12 patients (54.5%) displayed green color and were confirmed malignancy. Receiver operating characteristic curve was used to measure the sensitivity and specificity of the green color to look for a clear resection margin. The area under the curve was 85.3% (p = 0.019, 95% confidence interval 0.696-1.000), with a sensitivity of 0.706 and specificity of 1.000. CONCLUSION: The use of ICG fluorescence can be helpful in determining resection margins. Resection of tumor should include complete resection of the green zone shown in the fluorescence image.

Lamprey VDAC2: Suppressing hydrogen peroxide-induced 293T cell apoptosis by downregulating BAK expression.

The voltage-dependent anion channel 2 (VDAC2) is the abundant protein in the outer mitochondrial membrane. Opening VDAC2 pores leads to the induction of mitochondrial energy and material transport, facilitating interaction with various mitochondrial proteins implicated in essential processes such as cell apoptosis and proliferation. To investigate the VDAC2 in lower vertebrates, we identified Lr-VDAC2, a homologue of VDAC2 found in lamprey (Lethenteron reissneri), sharing a sequence identity of greater than 50 % with its counterparts. Phylogenetic analysis revealed that the position of Lr-VDAC2 aligns with the lamprey phylogeny, indicating its evolutionary relationship within the species. The Lr-VDAC2 protein was primarily located in the mitochondria of lamprey cells. The expression of the Lr-VDAC2 protein was elevated in high energy-demanding tissues, such as the gills, muscles, and myocardial tissue in normal lampreys. Lr-VDAC2 suppressed H2O2 (hydrogen peroxide)-induced 293 T cell apoptosis by reducing the expression levels of Caspase 3, Caspase 9, and Cyt C (cytochrome c). Further research into the mechanism indicated that the Lr-VDAC2 protein inhibited the pro-apoptotic activity of BAK (Bcl-2 antagonist/killer) protein by downregulating its expression at the protein translational level, thus exerting an anti-apoptotic function similar to the role of VDAC2 in humans.

ERS International Congress 2023: highlights from the Respiratory Clinical Care and Physiology Assembly.

It is a challenge to keep abreast of all the clinical and scientific advances in the field of respiratory medicine. This article contains an overview of laboratory-based science, clinical trials and qualitative research that were presented during the 2023 European Respiratory Society International Congress within the sessions from the five groups of Assembly 1 (Respiratory Clinical Care and Physiology). Selected presentations are summarised from a wide range of topics: clinical problems, rehabilitation and chronic care, general practice and primary care, electronic/mobile health (e-health/m-health), clinical respiratory physiology, exercise and functional imaging.

Association Between HLA-DRB1 Alleles and Graves' Disease in Asian Populations: A Meta-Analysis.

Graves' disease (GD) is an autoimmune disease that primarily affects the thyroid gland. It is the most common cause of hyperthyroidism. Genetic studies have shown that human leukocyte antigen (HLA) plays an important role in the development of GD. In this article, we performed a meta-analysis determined to evaluate the relationship between HLA-DRB1 alleles and GD. This meta-analysis included 9 studies (3582 cases in the case group and 23070 cases in the control group) and 27 alleles was performed. The combined results showed that, compared with the control group, GD patients have a significant increase in the frequency of DRB1*1403 (OR=2.50, 95% CI=1.78-3.51, pc<0.0001) and have a significant decrease in frequencies of DRB1* 0101 (OR=0.45, 95% CI=0.34-0.59, pc<0.0001) and DRB1*0701 (OR=0.44, 95% CI=0.35-0.55, pc<0.0001). The meta-analysis indicated that, in Asian populations, DRB1*1403 is a risk allele for GD, and DRB1*0101 and DRB1*0701 are protective against the occurrence of GD. We surprisingly discovered that the susceptibility alleles for GD in Asian populations are completely different from Caucasians and the protective alleles for GD in Asians are quite similar to those of Caucasians. The results of our study may provide new opportunities for gene-targeted therapy for GD in Asian populations.

Identification and characterization of circadian clock genes in the head transcriptome of Conopomorpha sinensis Bradley.

Conopomorpha sinensis Bradley is the most detrimental pest to litchi and longan in China. Adult eclosion, locomotion, mating and oviposition of C. sinensis usually occur at night, regulated by a circadian rhythm. Nevertheless, our understanding of the linkages between adult circadian rhythms and clock genes remains inadequate. To address this gap, transcriptomic analysis was conducted on female and male heads (including antennae) of C. sinensis using the Illumina HiSeq 6000 platform to identify major circadian clock-related genes. The annotated sequences were analyzed by BLASTx, and candidate clock genes were classified based on conservation, predicted domain architectures, and phylogenetic analysis. The analysis revealed a higher conservation of these genes among the compared moths. Further, the expression profile analysis showed a significant spatiotemporal and circadian rhythmic accumulation of some clock genes during development. The candidate clock genes were predominantly expressed in the head, highlighting their crucial function in circadian rhythm regulation. Moreover, CsinPer, CsinTim1, and CsinCry1 displayed similar dynamic expressions with a peak expression level in the 4th age adults, suggesting their involvement in regulation of courtship and mating behaviors. The CsinPer and CsinTim1 mRNA oscillated strongly with a similar phase, containing a peak expression just before the female mating peak. This work will greatly contribute to understanding the circadian clock system of C. sinensis and provide valuable information for further studies of the molecular mechanisms involved in rhythmicity in fruit-boring pests.

C-terminal binding protein 2 is a novel tumor suppressor targeting the MYC-IRF4 axis in multiple myeloma.

ABSTRACT: Multiple myeloma (MM) cells are addicted to MYC and its direct transactivation targets IRF4 for proliferation and survival. MYC and IRF4 are still considered "undruggable," as most small-molecule inhibitors suffer from low potency, suboptimal pharmacokinetic properties, and undesirable off-target effects. Indirect inhibition of MYC/IRF4 emerges as a therapeutic vulnerability in MM. Here, we uncovered an unappreciated tumor-suppressive role of C-terminal binding protein 2 (CTBP2) in MM via strong inhibition of the MYC-IRF4 axis. In contrast to epithelial cancers, CTBP2 is frequently downregulated in MM, in association with shortened survival, hyperproliferative features, and adverse clinical outcomes. Restoration of CTBP2 exhibited potent antitumor effects against MM in vitro and in vivo, with marked repression of the MYC-IRF4 network genes. Mechanistically, CTBP2 impeded the transcription of MYC and IRF4 by histone H3 lysine 27 deacetylation (H3K27ac) and indirectly via activation of the MYC repressor IFIT3. In addition, activation of the interferon gene signature by CTBP2 suggested its concomitant immunomodulatory role in MM. Epigenetic studies have revealed the contribution of polycomb-mediated silencing and DNA methylation to CTBP2 inactivation in MM. Notably, inhibitors of Enhance of zeste homolog 2, histone deacetylase, and DNA methyltransferase, currently under evaluation in clinical trials, were effective in restoring CTBP2 expression in MM. Our findings indicated that the loss of CTBP2 plays an essential role in myelomagenesis and deciphers an additional mechanistic link to MYC-IRF4 dysregulation in MM. We envision that the identification of novel critical regulators will facilitate the development of selective and effective approaches for treating this MYC/IRF4-addicted malignancy.

Evolutionary analysis of SLC10 family members and insights into function and expression regulation of lamprey NTCP.

The Na ( +)-taurocholate cotransporting polypeptide (NTCP) is a member of the solute carrier family 10 (SLC10), which consists of 7 members (SLC10a1-SLC10a7). NTCP is a transporter localized to the basolateral membrane of hepatocytes and is primarily responsible for the absorption of bile acids. Although mammalian NTCP has been extensively studied, little is known about the lamprey NTCP (L-NTCP). Here we show that L-NTCP follows the biological evolutionary history of vertebrates, with conserved domain, motif, and similar tertiary structure to higher vertebrates. L-NTCP is localized to the cell surface of lamprey primary hepatocytes by immunofluorescence analysis. HepG2 cells overexpressing L-NTCP also showed the distribution of L-NTCP on the cell surface. The expression profile of L-NTCP showed that the expression of NTCP is highest in lamprey liver tissue. L-NTCP also has the ability to transport bile acids, consistent with its higher vertebrate orthologs. Finally, using a farnesoid X receptor (FXR) antagonist, RT-qPCR and flow cytometry results showed that L-NTCP is negatively regulated by the nuclear receptor FXR. This study is important for understanding the adaptive mechanisms of bile acid metabolism after lamprey biliary atresia based on understanding the origin, evolution, expression profile, biological function, and expression regulation of L-NTCP.

Evidence for chronic headaches induced by pathological changes of myodural bridge complex.

Clinical studies have shown that there may be a certain relationship between pathological changes of the myodural bridge complex (MDBC) and chronic headaches of unknown cause. But there is still a lack of experimental evidence to explain the possible mechanism. This study aims to further confirm this relationship between MDBC and chronic headaches and explore its potential occurrence mechanism in rats. Bleomycin (BLM) or phosphate-buffered saline (PBS) was injected into the myodural bridge fibers of rats to establish the hyperplastic model of MDBC. After 4 weeks, the occurrence of headaches in rats was evaluated through behavioral scores. The immunohistochemistry staining method was applied to observe the expression levels of headache-related neurotransmitters in the brain. Masson trichrome staining results showed that the number of collagen fibers of MDBC was increased in the BLM group compared to those of the other two groups. It revealed hyperplastic changes of MDBC. The behavioral scores of the BLM group were significantly higher than those of the PBS group and the blank control group. Meanwhile, expression levels of CGRP and 5-HT in the headache-related nuclei of the brain were increased in the BLM group. The current study further confirms the view that there is a relationship between pathological changes of MDBC and chronic headaches of unknown cause. This study may provide anatomical and physiological explanations for the pathogenesis of some chronic headaches of unknown cause.

Stage-by-stage analysis of the effect of blood transfusion on survival after curative hepatectomy for hepatocellular carcinoma-a retrospective study.

OBJECTIVE: This study is to examine the impact of perioperative (intraoperative/postoperative) blood transfusion on the outcomes of curative hepatectomy for hepatocellular carcinoma. Hepatectomy is a well-established curative treatment for hepatocellular carcinoma, and blood transfusion cannot always be avoided in treating the disease. METHODS: A retrospective study of patients having curative hepatectomy for hepatocellular carcinoma from January 2010 to December 2019 at a single center was conducted. The patients were stratified by their disease stage. Patients with and without perioperative blood transfusion were matched by propensity-score matching and compared for each disease stage. Univariate and multivariate analyses were performed to identify prognostic factors for overall survival for each stage. RESULTS: A total of 846 patients were studied. Among them, 125 received perioperative blood transfusion and 720 did not. Patients with blood transfusion had worse disease-free and overall survival. After stratification and matching, the ratios of transfusion to non-transfusion were 33:165 (stage 1), 28:140 (stage 2), and 45:90 (stage 3). Perioperative blood transfusion was associated with a higher incidence of postoperative complications in all three disease stages (p = 0.004/0.006/0.017), and hence longer hospitalization (p < 0.001 in all stages), but had no significant impact on hospital mortality (p = 0.119/0.118/0.723), 90-day mortality (p = 0.259/0.118/0.723), disease-free survival (p = 0.128/0.826/0.511), or overall survival (p = 0.869/0.122/0.122) in any disease stage. Prognostic factors for overall survival included tumor size, tumor number, alpha-fetoprotein level, and postoperative complication of grade ≥ 3A. CONCLUSION: Perioperative blood transfusion was associated with a higher incidence of complications but had no significant impact on survival after curative hepatectomy for hepatocellular carcinoma.

Dynamic Changes in Long-Standing Multiple Sclerosis Revealed by Longitudinal Structural Network Analysis Using Diffusion Tensor Imaging.

BACKGROUND AND PURPOSE: DTI can be used to derive conventional diffusion measurements, which can measure WM abnormalities in multiple sclerosis. DTI can also be used to construct structural brain networks and derive network measurements. However, few studies have compared their sensitivity in detecting brain alterations, especially in longitudinal studies. Therefore, in this study, we aimed to determine which type of measurement is more sensitive in tracking the dynamic changes over time in MS. MATERIALS AND METHODS: Eighteen patients with MS were recruited at baseline and followed up at 6 and 12 months. All patients underwent MR imaging and clinical evaluation at 3 time points. Diffusion and network measurements were derived, and their brain changes were evaluated. RESULTS: None of the conventional DTI measurements displayed statistically significant changes during the follow-up period; however, the nodal degree, nodal efficiency, and nodal path length of the left middle frontal gyrus and bilateral inferior frontal gyrus, opercular part showed significant longitudinal changes between baseline and at 12 months, respectively. CONCLUSIONS: The nodal degree, nodal efficiency, and nodal path length of the left middle frontal gyrus and bilateral inferior frontal gyrus, opercular part may be used to monitor brain changes over time in MS.

Eucalyptol, limonene and pinene enteric capsules attenuate airway inflammation and obstruction in lipopolysaccharide-induced chronic bronchitis rat model via TLR4 signaling inhibition.

BACKGROUND: Chronic bronchitis (CB), a type of chronic obstructive pulmonary disease (COPD), poses a significant global health burden owing to its high morbidity and mortality rates. Eucalyptol, limonene and pinene enteric capsules (ELPs) are clinically used as expectorants to treat various respiratory diseases, including CB, but their acting mechanisms remain unclear. In this study, we investigated the anti-CB effects of ELP in a rat model of lipopolysaccharide (LPS)-induced CB. The molecular mechanisms underlying its inhibitory effects on airway inflammation were further explored in LPS-stimulated Beas-2B cells. METHODS: ELP was characterized using gas chromatography. The production of inflammatory mediators in bronchoalveolar lavage fluid (BALF) was determined using an enzyme-linked immunosorbent assay. The expression of MUC5AC, MUC5B, and p-p65 in the lung tissue was measured using immunohistochemical staining. The gene expression of inflammatory mediators was determined using qRT-PCR. The expression levels of the target proteins were detected by western blotting. Nuclear localization of p65 was determined using an immunofluorescence assay. RESULTS: Compared to the CB model rats, ELP-treated rats showed reduced airway resistance, inflammation, and goblet cell hyperplasia. In BALF, ELP decreased the levels of inflammatory mediators, including TNF-α, IL-6, MIP-1α, and CCL5. ELP also suppressed LPS-induced elevation of MUC5AC, MUC5B, and p-p65 in the lung tissue. The metabolic pathway changes caused by LPS challenge were improved by ELP treatment. In LPS-exposed Beas-2B cells, ELP treatment inhibited the expression of TNFA, IL6, CCL5, MCP1, and MIP2A and decreased the phospho-levels of toll-like receptor 4 (TLR4) signaling-related proteins, including p-p38, p-JNK, p-ERK, p-TBK1, p-IKKα/ß, p-IκB, p-p65, and p-c-Jun. ELP also hindered the nuclear translocation of p65, c-Jun, and IRF3. CONCLUSIONS: This study showed that ELP has a potential therapeutic effect in LPS-induced CB rat model, possibly by suppressing TLR4 signaling. These results justify the clinical use of ELP for the treatment of pulmonary inflammatory diseases.

Personalized Use of Disease-Modifying Therapies in Multiple Sclerosis.

Multiple sclerosis is an important neurological disease affecting millions of young patients globally. It is encouraging that more than ten disease-modifying drugs became available for use in the past two decades. These disease-modifying therapies (DMTs) have different levels of efficacy, routes of administration, adverse effect profiles and concerns for pregnancy. Much knowledge and caution are needed for their appropriate use in MS patients who are heterogeneous in clinical features and severity, lesion load on magnetic resonance imaging and response to DMT. We aim for an updated review of the concept of personalization in the use of DMT for relapsing MS patients. Shared decision making with consideration for the preference and expectation of patients who understand the potential efficacy/benefits and risks of DMT is advocated.