Chronic hepatitis B baseline viral load and on-treatment liver cancer risk: A multinational cohort study of HBeAg-positive patients.

BACKGROUND AND AIMS: A single-nation study reported that pretreatment HBV viral load is associated with on-treatment risk of HCC in patients who are HBeAg-positive without cirrhosis and with chronic hepatitis B initiating antiviral treatment. We aimed to validate the association between baseline HBV viral load and on-treatment HCC risk in a larger, multinational cohort. APPROACH AND RESULTS: Using a multinational cohort from Korea, Hong Kong, and Taiwan involving 7545 adult patients with HBeAg-positive, without cirrhosis and with chronic hepatitis B who started entecavir or tenofovir treatment with baseline HBV viral load ≥5.00 log 10 IU/mL, HCC risk was estimated by baseline viral load. HBV viral load was analyzed as a categorical variable. During continuous antiviral treatment (median, 4.28 y), HCC developed in 200 patients (incidence rate, 0.61 per 100 person-years). Baseline HBV DNA level was independently associated with on-treatment HCC risk in a nonlinear pattern. HCC risk was lowest with the highest baseline viral load (≥8.00 log 10 IU/mL; incidence rate, 0.10 per 100 person-years), but increased sharply as baseline viral load decreased. The adjusted HCC risk was 8.05 times higher (95% CI, 3.34-19.35) with baseline viral load ≥6.00 and <7.00 log 10 IU/mL (incidence rate, 1.38 per 100 person-years) compared with high (≥8.00 log 10 IU/mL) baseline viral load ( p <0.001). CONCLUSIONS: In a multinational cohort of adult patients with HBeAg-positive without cirrhosis and with chronic hepatitis B, baseline HBV viral load was significantly associated with HCC risk despite antiviral treatment. Patients with the highest viral load who initiated treatment had the lowest long-term risk of HCC development.

Bacteroides vulgatus SNUG 40005 Restores Akkermansia Depletion by Metabolite Modulation.

BACKGROUND & AIMS: Weight loss and exercise intervention have been reported to increase the interaction between Bacteroides spp and Akkermansiamuciniphila (Am), although the underlying mechanisms and consequences of the interaction remain unknown. METHODS: Using a healthy Korean twin cohort (n = 582), we analyzed taxonomic associations with host body mass index. B vulgatus strains were isolated from mice and human subjects to investigate the strain-specific effect of B vulgatus SNUG 40005 (Bvul) on obesity. The mechanisms underlying Am enrichment by Bvul administration were investigated by multiple experiments: (1) in vitro cross-feeding experiments, (2) construction of Bvul mutants with the N-acetylglucosaminidase gene knocked out, and (3) in vivo validation cohorts with different metabolites. Finally, metabolite profiling in mouse and human fecal samples was performed. RESULTS: An interaction between Bvul and Am was observed in lean subjects but was disrupted in obese subjects. The administration of Bvul to mice fed a high-fat diet decreased body weight, insulin resistance, and gut permeability. In particular, Bvul restored the abundance of Am, which decreased significantly after a long-term high-fat diet. A cross-feeding analysis of Am with cecal contents or Bvul revealed that Am enrichment was attributed to metabolites produced during mucus degradation by Bvul. The metabolome profile of mouse fecal samples identified N-acetylglucosamine as contributing to Am enrichment, which was confirmed by in vitro and in vivo experiments. Metabolite network analysis of the twin cohort found that lysine serves as a bridge between N-acetylglucosamine, Bvul, and Am. CONCLUSIONS: Strain-specific microbe-microbe interactions modulate the mucosal environment via metabolites produced during mucin degradation in the gut.

Multiregional analysis of combined hepatocellular-cholangiocarcinoma reveals histologic diversity and molecular clonality.

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare type of liver tumour that exhibits both hepatocytic and biliary differentiation within the same tumour. The histology and genomic alterations of recurrent/metastatic cHCC-CC are poorly understood. We selected six patients with cHCC-CC whose recurrent or metastatic tumours were histologically confirmed. Four patients with classic cHCC-CCs and two with intermediate cell carcinomas (ICs) were included. The clinicopathological features were evaluated, and next-generation sequencing was performed in 17 multiregional and longitudinal tumour samples. The histology of recurrent/metastatic lesions of classic cHCC-CCs was variable: hepatocellular carcinoma (HCC) was observed in one (25.0%) patient, cHCC-CC in one (25.0%) patient, and cholangiocarcinoma (CC) in two (50.0%) patients. Among 13 samples from four classic cHCC-CC patients, the most frequent pathological variants were TP53 (46.2%), TERT promoter (38.5%), ARID1A mutations (23.1%), and MET amplification (30.8%). In the sequencing analysis of each HCC and CC component, three (75.0%) of the four classic cHCC-CCs shared pathogenic variants. A large proportion of mutations, both pathogenic and those of undetermined significance, were shared by each HCC and CC component. Regarding ICs, the ATM mutation was detected in one patient. In conclusion, the histology of recurrent/metastatic cHCC-CCs was heterogeneous. Genomic profiling of classic cHCC-CCs revealed similar genomic alterations to those of HCC. Considerable overlapping genomic alterations in each HCC and CC component were observed, suggesting a monoclonal origin. Genetic alterations in ICs were different from those in either HCC or CC, suggesting the distinct nature of this tumour.

Hepatocellular carcinoma risk in patients with chronic hepatitis B receiving tenofovir- vs. entecavir-based regimens: Individual patient data meta-analysis.

BACKGROUND & AIMS: The comparative risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving tenofovir disoproxil fumarate (TDF) vs. entecavir (ETV) remains controversial. In this individual patient data (IPD) meta-analysis, we aimed to compare HCC risk between the two drugs and identify subgroups who may benefit more from one treatment than the other. METHODS: Published meta-analyses, electronic databases and congress proceedings were searched to identify eligible studies through January 2021. We compared HCC risk between the two drugs using a multivariable Cox proportional hazards model with anonymised IPD from treatment-naïve patients with CHB receiving TDF or ETV for ≥1 year. Treatment effect consistency was explored in propensity score matching (PSM), weighting (PSW) and subgroup analyses for age, sex, hepatitis B e-antigen (HBeAg) positivity, cirrhosis and diabetes status. RESULTS: We included 11 studies from Korea, Taiwan and Hong Kong involving 42,939 patients receiving TDF (n = 6,979) or ETV (n = 35,960) monotherapy. Patients receiving TDF had significantly lower HCC risk (adjusted hazard ratio [HR] 0.77; 95% CI 0.61-0.98; p = 0.03). Lower HCC risk with TDF was consistently observed in PSM (HR 0.73; 95% CI 0.59-0.88; p <0.01) and PSW (HR 0.83; 95% CI 0.67-1.03; p = 0.10) analyses and in all subgroups, with statistical significance in the ≥50 years of age (HR 0.76; 95% CI 0.58-1.00; p <0.05), male (HR 0.74; 95% CI 0.58-0.96; p = 0.02), HBeAg-positive (HR 0.69; 95% CI 0.49-0.97; p = 0.03) and non-diabetic (HR 0.79; 95% CI 0.63-1.00; p <0.05) subgroups. CONCLUSION: TDF was associated with significantly lower HCC risk than ETV in patients with CHB, particularly those with HBeAg positivity. Longer follow-up may be needed to better define incidence differences between the treatments in various subgroups. IMPACT AND IMPLICATIONS: Previous aggregate data meta-analyses have reported inconsistent conclusions on the relative effectiveness of tenofovir disoproxil fumarate and entecavir in reducing hepatocellular carcinoma risk in patients with chronic hepatitis B (CHB). This individual patient data meta-analysis on 11 studies involving 42,939 patients from Korea, Taiwan and Hong Kong suggested that tenofovir disoproxil fumarate-treated patients have a significantly lower hepatocellular carcinoma risk than entecavir-treated patients, which was observed in all subgroups of clinical interest and by different analytical methodologies. These findings should be taken into account by healthcare providers when determining the optimal course of treatment for patients with CHB and may be considered in ensuring that treatment guidelines for CHB remain pertinent.

View-independent gait events detection using CNN-transformer hybrid network.

Accurate gait detection is crucial in utilizing the ample health information embedded in it. Vision-based approaches for gait detection have emerged as an alternative to the exacting sensor-based approaches, but their application has been rather limited due to complicated feature engineering processes and heavy reliance on lateral views. Thus, this study aimed to find a simple vision-based approach that is view-independent and accurate. A total of 22 participants performed six different actions representing standard and peculiar gaits, and the videos acquired from these actions were used as the input of the deep learning networks. Four networks, including a 2D convolutional neural network and an attention-based deep learning network, were trained with standard gaits, and their detection performance for both standard and peculiar gaits was assessed using measures including F1-scores. While all networks achieved remarkable detection performance, the CNN-Transformer network achieved the best performance for both standard and peculiar gaits. Little deviation by the speed of actions or view angles was found. The study is expected to contribute to the wider application of vision-based approaches in gait detection and gait-based health monitoring both at home and in clinical settings.

MicroRNA and Messenger RNA Expression Profiles in Canine Mammary Gland Tumor.

Canine mammary gland tumor (CMT) is the most frequently diagnosed neoplasm in intact female dogs. As prognosis depends on the malignancy of tumors and metastasis levels, early and accurate diagnosis are crucial for prolongation of life expectancy. The genetic similarity of dogs with humans in addition to environmental and physiological similarities make them ideal models for the study of cancer. In this study, we analyzed differentially expressed microRNAs followed by RNA-Seq to investigate the alterations in mRNA levels based on the malignancy (benign, malignant) and the biopsy locations (tumors, surrounding normal tissues). We identified multiple breast cancer-related genes regardless of malignancy. We found cfa-miR-503 to be the only miRNA that showed altered expression in response to malignancy in CMTs. Although further validation is needed, cfa-miR-503 could be used as a potential diagnostic biomarker as well as a potential RNA-based anti-tumor drug in malignant CMTs.

Longitudinal Study of Bone Height Change between Two Approaches for Sinus Floor Elevation.

Background and Objectives: The purpose of this study is to assess the long-term maintenance of each approach of sinus elevation, the crestal approach and lateral approach, by comparing the radiographic results of each technique. Materials and Methods: In total, 103 patients who had undergone an implant procedure with either the crestal approach or lateral approach method applied to their maxillary molar edentulous area were included. Using orthopantomographs, the radiographic changes were consistently evaluated over 3 years after the procedure (immediately after procedure and 1 year, 2 years and 3 years after implant placement) Results: The radiographic evaluation after 3 years of implantation with sinus elevation showed a significant amount of bone formation (8.07 mm for crestal approach and 12.00 mm for lateral approach method). The largest amount of grafted height loss occurred during the 1 year, but the resorption was minimal (0.98 mm for crestal approach and 0.95 mm for lateral approach method) over the entire 3 years. Conclusions: Although the lateral approach showed more bone growth, the amount of bone resorption was similar to that of the crestal approach. Both methods showed the highest amount of bone resorption in the first year, and the amount of change thereafter was insignificant. It is judged that both methods can be used according to the situation to help implant placement.

Comparison of biochemical response during antiviral treatment in patients with chronic hepatitis B infection.

BACKGROUND & AIMS: This multicenter cohort study aimed to compare the real-world biochemical response rates during tenofovir alafenamide (TAF), tenofovir disoproxil fumarate (TDF), and entecavir (ETV) treatment in chronic hepatitis B virus (HBV) infection patients. METHODS: Overall, 1282 treatment-naïve patients with CHB who commenced TAF (n = 270), TDF (n = 617), or ETV (n = 395) were analysed for biochemical response rates during the antiviral treatment using a time-dependent Cox proportional hazard model after the inverse probability of treatment weighting (IPTW). RESULTS: Patients treated with ETV were older (55.1 ± 11.5 years) than TAF or TDF (P < .0001). ETV was more frequently prescribed to patients with diabetes mellitus (DM, P = .003), hypertension (P < .0001), chronic kidney disease (P < .0001), and negative e-antigen (P < .0001). Cumulative biochemical response rate was independently lower in patients with radiologic fatty liver (HR, 0.75; 95% CI, 0.61-0.94) and obese patients without DM (HR, 0.85; 95% CI, 0.68-0.98) according to multivariable Cox analyses based on time-dependent variables after IPTW for age, sex, liver cirrhosis, baseline e-antigen, ALT, and HBV DNA levels. ETV treated patients (HR, 1.38; 95% CI, 1.13-1.68) showed higher biochemical response rates compared with TAF- or TDF-treated patients after adjusting for similar parameters. CONCLUSIONS: In real-world practice, ETV was preferable for older, hepatitis B e-antigen negative patients with underlying comorbidities. Biochemical responses in patients treated with ETV, TAF, and TDF were significantly affected by metabolic factors such as fatty liver, obesity, and DM. However, the mechanism behind the higher biochemical response rate in patients treated with ETV should be investigated further.

Interspecies differences in clinical characteristics and risk factors for third-generation cephalosporin resistance between Escherichia coli and Klebsiella pneumoniae bloodstream infection in patients with liver cirrhosis.

This retrospective study aimed to clarify the interspecies differences in the clinical characteristics and risk factors of bloodstream infection (BSI) due to third-generation cephalosporin-resistant (3GC-R) Escherichia coli (EC) and Klebsiella pneumoniae (KP) in patients with liver cirrhosis (LC). KP BSI had more comorbidities and higher treatment failure rate than EC BSI. Non-alcoholic LC was a risk factor for treatment failure in EC, whereas it was not associated with KP. Risk factors for BSI due to 3GC-R strain were nosocomial infection in EC, and ß-lactam/fluoroquinolone treatment ≤ 30 days in KP. These results could help predict outcomes of BSI and improve clinical practice.

Incidence and Pattern of Aminotransferase Elevation During Anti-Hypertensive Therapy With Angiotensin-II Receptor Blockers.

BACKGROUND: Angiotensin type II receptor blockers (ARBs) are the most widely used anti-hypertensive drugs. This study aimed to elucidate the likelihood and pattern of ARB-induced liver injury in a hospital-based cohort. METHODS: Data of patients receiving fimasartan (n = 5,543), candesartan (n = 6,406), valsartan (n = 6,040), and losartan (n = 9,126) were retrieved from the clinical data warehouse of two tertiary hospitals. Patients with alanine aminotransferase (ALT) levels > 5 times the upper normal limit were assessed according to the Roussel Uclaf Causality Assessment Method (RUCAM). RESULTS: A total of 27,115 patients were enrolled, including 14,630 (54.0%) men, with a mean age of 64.6 years (standard deviation, 13.6). During 31,717 person-years of ARB therapy, serum ALT levels > 120 IU/L were found in 558 (2.1%) person-years, and levels > 200 IU/L were found in 155 (0.6%) person-years. The incidence of ALT elevation > 120 IU/L per 106 cumulative defined daily doses was 6.6, 3.6, 3.9, and 4.0 in the fimasartan, candesartan, valsartan, and losartan groups, respectively (P = 0.002). An ALT level > 200 IU/L with RUCAM score ≥ 6 was found in 20 patients, suggesting probable drug-induced liver injury for 11 (0.2%) patients receiving fimasartan, five (0.1%) receiving candesartan, four (0.1%) receiving valsartan, and none receiving losartan (P < 0.001). CONCLUSION: Approximately 2% of patients receiving ARB therapy had significant ALT elevation (4.24/106 cumulative defined daily doses [cDDDs]), which was associated with probable ARB-related liver injury in 0.07% of patients (0.15/106 cDDDs). Elevation of ALT was more commonly associated with fimasartan than the other ARBs. Clinicians should be aware of the possibility of ARB-related ALT elevation in patients with unexplained chronic abnormal ALT.

A Rapid Prototyping Method for Sub-MHz Single-Element Piezoelectric Transducers by Using 3D-Printed Components.

We present a rapid prototyping method for sub-megahertz single-element piezoelectric transducers by using 3D-printed components. In most of the early research phases of applying new sonication ideas, the prototyping quickness is prioritized over the final packaging quality, since the quickness of preliminary demonstration is crucial for promptly determining specific aims and feasible research approaches. We aim to develop a rapid prototyping method for functional ultrasonic transducers to overcome the current long lead time (>a few weeks). Here, we used 3D-printed external housing parts considering a single matching layer and either air backing or epoxy-composite backing (acoustic impedance > 5 MRayl). By molding a single matching layer on the top surface of a piezoceramic in a 3D-printed housing, an entire packaging time was significantly reduced (<26 h) compared to the conventional methods with grinding, stacking, and bonding. We demonstrated this prototyping method for 590-kHz single-element, rectangular-aperture transducers for moderate pressure amplitudes (mechanical index > 1) at focus with temporal pulse controllability (maximum amplitude by <5-cycle burst). We adopted an air-backing design (Type A) for efficient pressure outputs, and bandwidth improvement was tested by a tungsten-composite-backing (Type B) design. The acoustic characterization results showed that the type A prototype provided 3.3 kPa/Vpp far-field transmitting sensitivity with 25.3% fractional bandwidth whereas the type B transducer showed 2.1 kPa/Vpp transmitting sensitivity with 43.3% fractional bandwidth. As this method provided discernable quickness and cost efficiency, this detailed rapid prototyping guideline can be useful for early-phase sonication projects, such as multi-element therapeutic ultrasound array and micro/nanomedicine testing benchtop device prototyping.

Gait Events Prediction Using Hybrid CNN-RNN-Based Deep Learning Models through a Single Waist-Worn Wearable Sensor.

Elderly gait is a source of rich information about their physical and mental health condition. As an alternative to the multiple sensors on the lower body parts, a single sensor on the pelvis has a positional advantage and an abundance of information acquirable. This study aimed to improve the accuracy of gait event detection in the elderly using a single sensor on the waist and deep learning models. Data were gathered from elderly subjects equipped with three IMU sensors while they walked. The input taken only from the waist sensor was used to train 16 deep-learning models including a CNN, RNN, and CNN-RNN hybrid with or without the Bidirectional and Attention mechanism. The groundtruth was extracted from foot IMU sensors. A fairly high accuracy of 99.73% and 93.89% was achieved by the CNN-BiGRU-Att model at the tolerance window of ±6 TS (±6 ms) and ±1 TS (±1 ms), respectively. Advancing from the previous studies exploring gait event detection, the model demonstrated a great improvement in terms of its prediction error having an MAE of 6.239 ms and 5.24 ms for HS and TO events, respectively, at the tolerance window of ±1 TS. The results demonstrated that the use of CNN-RNN hybrid models with Attention and Bidirectional mechanisms is promising for accurate gait event detection using a single waist sensor. The study can contribute to reducing the burden of gait detection and increase its applicability in future wearable devices that can be used for remote health monitoring (RHM) or diagnosis based thereon.

Aspergillosis of the Maxillary Sinus Associated With Dental Implant.

Aspergillosis is a fungal disease caused by the fungus Aspergillus; this disease frequently involves the lungs and occasionally the maxillary sinus. Aspergillosis in the maxillary sinus usually has the characteristics of a noninvasive form. It has been suggested that spores of aspergillus can be inhaled into the maxillary sinus via the osteomeatal complex or via an oroantral fistula after dental procedures, such as an extraction. However, maxillary aspergillosis related to implant installation has rarely been reported. This report regards unusual cases of maxillary aspergillosis associated with dental implant therapies in healthy patients. The cases were successfully treated with the surgical removal of the infected or necrotic tissues.

Effectiveness of liraglutide 3 mg for the treatment of obesity in a real-world setting without intensive lifestyle intervention.

OBJECTIVE: We investigated the efficacy and safety of liraglutide 3 mg daily in combination with diet and exercise 2, 4, and 6 months after initiation in real-world settings in Korea. METHODS: People first using liraglutide starting in 2018 were recruited from ten sites in Korea. Body weight and body mass index (BMI) were measured after 2, 4, and 6 months and compared with baseline values. RESULTS: The full cohort comprised 769 participants: 672 in the 2-month group, 427 in the 4-month group, and 219 in the 6-month group. The baseline mean ± standard deviation of BMI and body weight were 32.2 ± 5.1 kg/m2, and 87.5 ± 18.8 kg, respectively. Body weight and BMI decreased after initiation of liraglutide treatment: -2.94 kg and -1.08 kg/m2 at 2 months; -4.23 kg and -1.55 kg/m2 at 4 months, and -5.14 kg and -1.89 kg/m2 at 6 months (all P < 0.001). In the 6-month cohort, 52.5% and 18.3% of subjects lost ≥5% and ≥10% of body weight, respectively. After 6 months, systolic and diastolic blood pressure decreased significantly by 3.90 and 1.93 mmHg, respectively. In those with diabetes mellitus, HbA1c and fasting glucose levels decreased significantly by 1.14% and 27.8 mg/dl, respectively. Among all participants, 27.6% experienced adverse effects, including nausea (20.8%), vomiting (5.2%), diarrhoea (2.5%), and skin rash (3.6%). Documented reasons for discontinuation of treatment were lack of effect (4.4%), adverse events (4.3%), and high cost (3.1%). CONCLUSIONS: In real-world settings in Korea, daily treatment with liraglutide 3 mg was associated with clinically meaningful weight loss without serious adverse events.

Automatic prediction of left cardiac chamber enlargement from chest radiographs using convolutional neural network.

OBJECTIVE: To develop deep learning-based cardiac chamber enlargement-detection algorithms for left atrial (DLCE-LAE) and ventricular enlargement (DLCE-LVE), on chest radiographs METHODS: For training and internal validation of DLCE-LAE and -LVE, 5,045 chest radiographs (CRs; 2,463 normal and 2,393 LAE) and 1,012 CRs (456 normal and 456 LVE) matched with the same-day echocardiography were collected, respectively. External validation was performed using 107 temporally independent CRs. Reader performance test was conducted using the external validation dataset by five cardiothoracic radiologists without and with the results of DLCE. Classification performance of DLCE was evaluated and compared with those of the readers and conventional radiographic features, including cardiothoracic ratio, carinal angle, and double contour. In addition, DLCE-LAE was tested on 5,277 CRs from a healthcare screening program cohort. RESULTS: DLCE-LAE showed areas under the receiver operating characteristics curve (AUROCs) of 0.858 on external validation. On reader performance test, DLCE-LAE showed better results than pooled radiologists (AUROC 0.858 vs. 0.651; p < .001) and significantly increased their performance when used as a second reader (AUROC 0.651 vs. 0.722; p < .001). DLCE-LAE also showed a significantly higher AUROC than conventional radiographic findings (AUROC 0.858 vs. 0.535-0.706; all ps < .01). In the healthcare screening cohort, DLCE-LAE successfully detected 71.0% (142/200) CRs with moderate-to-severe LAE (93.5% [29/31] of severe cases), while yielding 11.8% (492/4,184) false-positive rate. DLCE-LVE showed AUROCs of 0.966 and 0.594 on internal and external validation, respectively. CONCLUSION: DLCE-LAE outperformed and improved cardiothoracic radiologists' performance in detecting LAE and showed promise in screening individuals with moderate-to-severe LAE in a healthcare screening cohort. KEY POINTS: • Our deep learning algorithm outperformed cardiothoracic radiologists in detecting left atrial enlargement on chest radiographs. • Cardiothoracic radiologists improved their performance in detecting left atrial enlargement when aided by the algorithm. • On a healthcare-screening cohort, our algorithm detected 71.0% (142/200) radiographs with moderate-to-severe left atrial enlargement while yielding 11.8% (492/4,184) false-positive rate.

Computed Tomography-Measured Liver Volume Predicts the Risk of Hepatocellular Carcinoma Development in Chronic Hepatitis C Patients.

AIM: In this retrospective cohort study, we evaluated the significance of liver volume in the prediction of hepatocellular carcinoma (HCC) in 277 chronic hepatitis C (CHC) patients who received dynamic computed tomography (CT) during surveillance. METHODS: Liver volumes were measured on portal venous phase of CT images by using ImageJ software. Liver volume index, a ratio of the standard liver volume expected by weight and height to the measured liver volume, was calculated to adjust for normal variations. The cohort was randomly divided to derivation (n = 100) and validation sets (n = 177) for the generation of a liver volume-based Cox prediction model and validation of a liver volume-based nomogram, respectively. RESULTS: The liver volume index was independent of weight or height, and it predicted further development of HCC (hazard ratio [HR] 16.30, 95% CI 6.70-39.62; p < 0.001). Liver cirrhosis, gamma-glutamyl transferase, and liver volume index were independent predictors of HCC, and nomogram-based prediction score from these three parameters identified high-risk patients at the cutoff of 110 in both derivation (p < 0.001) and validation cohort (p < 0.001). CONCLUSION: Liver volume-based prediction model stratifies the risk of developing HCC in CHC patients whose initial dynamic CT study gave negative results.

Differential Angiogenic Potential of 3-Dimension Spheroid of HNSCC Cells in Mouse Xenograft.

The experimental animal model is still essential in the development of new anticancer drugs. We characterized mouse tumors derived from two-dimensional (2D) monolayer cells or three-dimensional (3D) spheroids to establish an in vivo model with highly standardized conditions. Primary cancer-associated fibroblasts (CAFs) were cultured from head and neck squamous cell carcinoma (HNSCC) tumor tissues and co-injected with monolayer cancer cells or spheroids into the oral mucosa of mice. Mice tumor blood vessels were stained, followed by tissue clearing and 3D Lightsheet fluorescent imaging. We compared the effect of exosomes secreted from 2D or 3D culture conditions on the angiogenesis-related genes in HNSCC cells. Our results showed that both the cells and spheroids co-injected with primary CAFs formed tumors. Interestingly, vasculature was abundantly distributed inside the spheroid-derived but not the monolayer-derived mice tumors. In addition, cisplatin injection more significantly decreased spheroid-derived but not monolayer-derived tumor size in mice. Additionally, exosomes isolated from co-culture media of FaDu spheroid and CAF upregulated angiogenesis-related genes in HNSCC cells as compared to exosomes from FaDu cell and CAF co-culture media under in vitro conditions. The mouse tumor xenograft model derived from 3D spheroids of HNSCC cells with primary CAFs is expected to produce reliable chemotherapy drug screening results given the robust angiogenesis and lack of necrosis inside tumor tissues.

Inhibitory Activities of Dimeric Ellagitannins Isolated from Cornus alba on Benign Prostatic Hypertrophy.

Benign prostatic hypertrophy (BPH) is an intractable chronic inflammatory disease. We studied the efficacy of two ellagitannins, namely camptothin B (1) and cornusiin A (2) that were isolated from Cornus alba (CA) for the treatment of BPH, which is a common health issue in older men. The ellagitannins (1 and 2) were evaluated on its inhibitory activities of the enzyme 5α-reductase and tumor necrosis factor (TNF)-α, its interleukin (IL)-1ß, IL-6, and IL-8 production, and its anti-proliferation and apoptosis induction in prostate cells that show hypertrophy (RWPE-1 cell). In inhibition of 5α-reductase, the ellagitannins (1 and 2) showed potential effects, compared to the positive control, finasteride. In the case of IL-1ß, IL-6, IL-8, and TNF-α, 1 and 2 showed good inhibitory effects as compared to the control group treated with LPS. The ellagitannins (1 and 2) were also shown to inhibit proliferation of, and induce apoptosis in, the RWPE-1 cell. These results suggest that the ellagitannins (1 and 2) may be good candidates for the treatment of BPH.

A case of acute liver failure due to hepatitis E virus, liver transplantation, and development of de novo autoimmune hepatitis.

Acute hepatitis E virus (HEV) infection could lead to acute liver failure (ALF), which requires liver transplantation (LT). HEV infection could progress to chronic infection in an immunosuppressed host. De novo autoimmune hepatitis (AIH) is a rare occurrence of AIH during post-LT immunosuppressive therapy in patients who underwent LT due to not AIH but some other etiology. Here, we report the first case of ALF due to HEV infection, the recurrence of HEV after LT that responded to ribavirin therapy, and then the development of de novo AIH showing a complete response to glucocorticoid therapy but multiple relapses after steroid withdrawal. This peculiar case suggests that HEV could have a pathogenic role in the development of the de novo AIH; additionally, this case report could help clinicians make therapeutic decisions in the post-LT condition.

Comparison of the on-treatment risks for hepatocellular carcinoma between entecavir and tenofovir: A propensity score matching analysis.

BACKGROUND AND AIM: Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) may reduce the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB). However, it is not clear whether there is difference in the on-treatment HCC risks between ETV and TDF. METHODS: In this retrospective cohort study, we compared the on-treatment HCC incidence of ETV and TDF in 1340 consecutive nucleos(t)ide analog-naïve CHB patients by propensity score (PS) matching analysis. PS was calculated by using age, sex, drinking history, diabetes, liver cirrhosis, hepatitis B e antigen positivity, hepatitis B virus DNA, hepatitis B s antigen titer, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alpha-fetoprotein, albumin, bilirubin, prothrombin time, platelet count, and calendar year of treatment initiation as covariates. The HCC risk was assessed by Cox regression with death and liver transplantation as competing risks in the 1:1 PS-matched cohorts (n = 596). RESULTS: TDF had higher cumulative virologic response (P = 0.027) whereas ETV showed higher AST and ALT normalization rates (P = 0.005 and < 0.001, respectively) in PS-matched cohorts. HCC risk was similar between ETV and TDF, either by PS-matching analysis (hazard ratio [HR] for TDF over ETV = 2.06, 95% confidence interval [CI] = 0.98-4.33, P = 0.058) or inverse probability of treatment weighting analysis (HR = 1.30, 95% CI = 0.81-2.10; P = 0.276). CONCLUSIONS: ETV and TDF treatment was associated with similar risk for HCC development in CHB patients.