Background and Aims
Early recurrence of hepatocellular carcinoma (HCC) after surgical resection compromises patient survival. Timely detection of HCC recurrence and its clonality is required to ...implement salvage therapies appropriately. This study examined the feasibility of virus‐host chimera DNA (vh‐DNA), generated from junctions of hepatitis B virus (HBV) integration in the HCC chromosome, as a circulating biomarker for this clinical setting.
Approach and Results
HBV integration in 50 patients with HBV‐related HCC was determined by the Hybridization capture‐based next‐generation sequencing (NGS) platform. For individual HCC, the vh‐DNA was quantified by specific droplet digital PCR (ddPCR) assay in plasma samples collected before and 2 months after surgery. HBV integrations were identified in 44 out of 50 patients with HBV‐related HCC. Tumor‐specific ddPCR was developed to measure the corresponding vh‐DNA copy number in baseline plasma from each patient immediately before surgery. vh‐DNA was detected in 43 patients (97.7%), and the levels correlated with the tumor sizes (detection limit at 1.5 cm). Among the plasma collected at 2 months after surgery, 10 cases (23.3%) still contained the same signature vh‐DNA detected at baseline, indicating the presence of residual tumor cells. Nine of them (90%) experienced HCC recurrence within 1 year, supporting vh‐DNA as an independent risk factor in predicting early recurrence. Analysis of circulating vh‐DNA at recurrence further helped identify the clonal origin. A total of 81.8% of recurrences came from original HCC clones sharing the same plasma vh‐DNA, whereas 18.2% were from de novo HCC.
Conclusions
vh‐DNA was shown to be a circulating biomarker for detecting the tumor load in majority of patients with HBV‐related HCC and aided in monitoring residual tumor and recurrence clonality after tumor resection.
Immune checkpoint inhibitors (ICIs) with nivolumab and pembrolizumab are promising agents for advanced hepatocellular carcinoma (HCC) but lack of effective biomarkers. We aimed to investigate the ...potential predictors of response and factors associated with overall survival (OS) for ICI treatment in unresectable HCC patients. Ninety-five patients who received nivolumab or pembrolizumab for unresectable HCC were enrolled for analyses. Radiologic evaluation was based on RECIST v1.1. Factors associated with outcomes were analyzed. Of 90 patients with evaluable images, the objective response rate (ORR) was 24.4%. Patients at Child-Pugh A or received combination treatment had higher ORR. Early alpha-fetoprotein (AFP) >10% reduction (within 4 weeks) was the only independent predictor of best objective response (odds ratio: 7.259,
= 0.001). For patients with baseline AFP ≥10 ng/mL, significantly higher ORR (63.6% vs. 10.2%,
< 0.001) and disease control rate (81.8% vs. 14.3%,
< 0.001) were observed in those with early AFP reduction than those without. In addition, early AFP reduction and albumin-bilirubin (ALBI) grade or Child-Pugh class were independent factors associated with OS in different models. In conclusion, a 10-10 rule of early AFP response can predict objective response and survival to ICI treatment in unresectable HCC. ALBI grade and Child-Pugh class determines survival by ICI treatment.
Since April 2022, waves of SARS-CoV-2 Omicron variant cases have surfaced in Taiwan and spread throughout the island. Using high-throughput sequencing of the SARS-CoV-2 genome, we analyzed 2,405 ...PCR-positive swab samples from 2,339 persons and identified the Omicron BA.2.3.7 variant as a major lineage within recent community outbreaks in Taiwan.
Summary
A major challenge of modern agricultural biotechnology is the optimization of plant architecture for enhanced productivity, stress tolerance and water use efficiency (WUE). To optimize plant ...height and tillering that directly link to grain yield in cereals and are known to be tightly regulated by gibberellins (GAs), we attenuated the endogenous levels of GAs in rice via its degradation. GA 2‐oxidase (GA2ox) is a key enzyme that inactivates endogenous GAs and their precursors. We identified three conserved domains in a unique class of C20 GA2ox, GA2ox6, which is known to regulate the architecture and function of rice plants. We mutated nine specific amino acids in these conserved domains and observed a gradient of effects on plant height. Ectopic expression of some of these GA2ox6 mutants moderately lowered GA levels and reprogrammed transcriptional networks, leading to reduced plant height, more productive tillers, expanded root system, higher WUE and photosynthesis rate, and elevated abiotic and biotic stress tolerance in transgenic rice. Combinations of these beneficial traits conferred not only drought and disease tolerance but also increased grain yield by 10–30% in field trials. Our studies hold the promise of manipulating GA levels to substantially improve plant architecture, stress tolerance and grain yield in rice and possibly in other major crops.
BackgroundImmune checkpoint inhibitors (ICIs) are promising agents for unresectable hepatocellular carcinoma (uHCC), but lack effective biomarker to predict outcomes. The gut microbiome can modulate ...tumor response to immunotherapy, but its effect on HCC remains unclear.MethodsFrom May 2018 to February 2020, patients receiving ICI treatment for uHCC were prospectively enrolled; their fecal samples were collected before treatment. The fecal microbiota and metabolites were analyzed from 20 patients with radiology-proven objective responses (OR) and 21 randomly selected patients with progressive disease (PD). After March 2020, 33 consecutive Child-Pugh-A patients were recruited as a validation cohort. Additionally, feces from 17 healthy volunteers were collected for comparison of background microbes.ResultsA significant dissimilarity was observed in fecal bacteria between patients with OR and patients with PD before immunotherapy. Prevotella 9 was enriched in patients with PD, whereas Lachnoclostridium, Lachnospiraceae, and Veillonella were predominant in patients with OR. Ursodeoxycholic acid and ursocholic acid were significantly enriched in the feces of patients with OR and strongly correlated with the abundance of Lachnoclostridium. The coexistence of Lachnoclostridium enrichment and Prevotella 9 depletion significantly predicted better overall survival (OS). In the validation cohort, better progression-free survival (PFS) and OS were noted in patients who had a preferable microbial signature in comparison with counter-group (PFS: 8.8 months vs 1.8 months; OS: not reached vs 6.5 months, both p<0.001).ConclusionsFecal microbiota and bile acids were associated with outcomes of immunotherapy for uHCC. These findings highlight the potential role of gut microbiota and metabolites as biomarkers to predict outcomes of ICI-treated HCC.
The treatment of chronic hepatitis C (CHC) has evolved from interferon (IFN)-based therapy to direct acting antivirals (DAAs). The effect of antiviral treatment on outcome of hepatocellular carcinoma ...(HCC) patients with CHC has not been well analyzed in Taiwan.
From April 2015 to May 2018, 199 HCC patients with CHC undergoing DAAs treatment, including 127 having prospectively longitudinal observation, were enrolled. Among them, 107 BCLC 0/A patients achieving curative treatment of HCC were further compared with a historical cohort of 42 HCC patients experienced pegylated interferon (Peg-IFN) plus ribavirin for CHC after curative treatment.
The sustained virological response (SVR) rates were 95.0% in BCLC stage 0/A (114/120), 97.1% in BCLC B (68/70), and 77.8% in BCLC C (7/9). The median recurrence-free survivals (RFS) between the DAA and IFN arms were of no difference by counting either from antiviral treatment (29.3 mo vs 39.2 mo, p = 0.764) or from curative treatment (65.8 mo vs 44.0 mo, p = 0.130), respectively. Achievement of SVR was the key independent factor associated with RFS and overall survival. The pattern of recurrence was also similar between the DAA and IFN arms. For intermediate stage HCC patients, the median time to tumor progression was 9.2 months from the initiation of DAA therapy, and 90% of patients maintained in BCLC B till 12 months after the DAA treatment.
The SVR is high within BCLC B HCV-HCC patients by DAAs treatment. The risk of HCC recurrence and progression is not increased by DAAs.
We report the unprecedented dual properties of excited-state structural planarization and thermally activated delayed fluorescence (TADF) of 10-dimesitylboryl phenoxazine, i.e., PXZBM. Bearing a ...nonplanar phenoxazine moiety, PXZBM shows the lowest lying absorption onset at ∼390 nm in nonpolar solvents such as cyclohexane but reveals an anomalously large Stokes-shifted (∼14 500 cm–1) emission maximized at 595 nm. In sharp contrast, when a phenylene spacer is added between phenoxazine and dimesitylboryl moieties of PXZBM, the 10-(4-dimesitylborylphenyl)phenoxazine PXZPBM in cyclohexane reveals a much blue-shifted emission at 470 nm despite its red-shifted absorption maximized at 420 nm (cf. PXZBM). The emission of PXZBM further reveals solvent polarity dependence, being red-shifted from 595 nm in cyclohexane to 645 nm in CH2Cl2. For rationalization, the steric hindrance between phenoxazine and the dimesitylboryl unit in PXZBM caused a puckered arrangement of phenoxazine at the ground state. Upon electronic excitation, as supported by the femtosecond early relaxation dynamics, spectral–temporal evolution and energetics calculated along the reaction potential energy surfaces, the diminution of N → B electron transfer reduces π-conjugation and elongates the N–B bond length, inducing the fast phenoxazine planarization with a time constant of 890 ± 100 fs. The associated charge-transfer reaction from phenoxazine (donor) to dimesitylboryl unit (acceptor) results in a further red-shifted emission in polar solvents. In stark contrast, PXZPBM shows a planar phenoxazine and undergoes excited-state charge transfer only. Despite the distinct difference in excited-state relaxation dynamics, both PXZBM and PXZPBM exhibit efficient TADF capable of producing highly efficient orange and green organic light emitting diodes with peak efficiencies of 10.9% (30.3 cd A–1 and 18.7 lm W–1) and 22.6% (67.7 cd A–1 and 50.0 lm W–1).
Cancer stem cell (CSC) theory has drawn much attention, with evidence supporting the contribution of stem cells to tumor initiation, relapse, and therapy resistance.
To screen drugs that target CSCs ...to improve the current treatment outcome and overcome drug resistance in patients with lung cancer.
We used publicly available embryonic stem cell and CSC-associated gene signatures to query the Connectivity Map for potential drugs that can, at least in part, reverse the gene expression profile of CSCs. High scores were noted for several phenothiazine-like antipsychotic drugs, including trifluoperazine. We then treated lung CSCs with different EGFR mutation status with trifluoperazine to examine its anti-CSC properties. Lung CSCs resistant to epidermal growth factor receptor-tyrosine kinase inhibitor or cisplatin were treated with trifluoperazine plus gefitinib or trifluoperazine plus cisplatin. Animal models were used for in vivo validation of the anti-CSC effect and synergistic effect of trifluoperazine with gefitinib.
We demonstrated that trifluoperazine inhibited CSC tumor spheroid formation and down-regulated the expression of CSC markers (CD44/CD133). Trifluoperazine inhibited Wnt/β-catenin signaling in gefitinib-resistant lung cancer spheroids. The combination of trifluoperazine with either gefitinib or cisplatin overcame drug resistance in lung CSCs. Trifluoperazine inhibited the tumor growth and enhanced the inhibitory activity of gefitinib in lung cancer metastatic and orthotopic CSC animal models.
Using in silico drug screening by Connectivity Map followed by empirical validations, we repurposed an existing phenothiazine-like antipsychotic drug, trifluoperazine, as a potential anti-CSC agent that could overcome epidermal growth factor receptor-tyrosine kinase inhibitor and chemotherapy resistance.
Summary Background Whether concomitant therapy is superior to bismuth quadruple therapy or 14-day triple therapy for the first-line treatment of Helicobacter pylori infection remains poorly ...understood. We aimed to compare the efficacy and safety of 10-day concomitant therapy, 10-day bismuth quadruple therapy, and 14-day triple therapy in the first-line treatment of H pylori. Methods In this multicentre, open-label, randomised trial, we recruited adult patients (aged >20 years) with H pylori infection from nine medical centres in Taiwan. Patients who had at least two positive tests from the rapid urease test, histology, culture, or serology or who had a single positive13 C-urea breath test for gastric cancer screening were eligible for enrolment. Patients were randomly assigned (1:1:1) to either concomitant therapy (lansoprazole 30 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, all given twice daily) for 10 days; bismuth quadruple therapy (bismuth tripotassium dicitrate 300 mg four times a day, lansoprazole 30 mg twice daily, tetracycline 500 mg four times a day, and metronidazole 500 mg three times a day) for 10 days; or triple therapy (lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg, all given twice daily) for 14 days. A computer-generated permuted block randomisation sequence with a block size of 6 was used for randomisation, and the sequence was concealed in an opaque envelope until the intervention was assigned. Investigators were masked to treatment allocation. The primary outcome was the eradication frequency of H pylori with first-line therapy assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT01906879. Findings Between July 17, 2013, and April 20, 2016, 5454 patients were screened for eligibility. Of these, 1620 patients were randomly assigned in this study. The eradication frequencies were 90·4% (488/540 95% CI 87·6–92·6) for 10-day bismuth quadruple therapy, 85·9% (464/540 82·7–88·6) for 10-day concomitant therapy, and 83·7% (452/540 80·4–86·6) for 14-day triple therapy in the intention-to-treat analysis. 10-day bismuth quadruple therapy was superior to 14-day triple therapy (difference 6·7% 95% CI 2·7–10·7, p=0·001), but not 10-day concomitant therapy. 10-day concomitant therapy was not superior to 14-day triple therapy. The frequency of adverse events was 67% (358/533) in patients treated with 10-day bismuth quadruple therapy, 58% (309/535) in patients treated with 10-day concomitant therapy, and 47% (252/535) in patients treated with 14-day triple therapy. Interpretation Bismuth quadruple therapy is preferable to 14-day triple therapy in the first-line treatment in the face of rising prevalence of clarithromycin resistance. Concomitant therapy given for 10 days might not be optimum and a longer treatment length should be considered. Funding National Taiwan University Hospital and Ministry of Science and Technology of Taiwan.
Data regarding the real-world effectiveness and safety of sofosbuvir/velpatasvir (SOF/VEL) with or without low-dose ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection and ...severe renal impairment (RI) are limited. We evaluated the performance of SOF/VEL with or without low-dose RBV in HCV-infected patients with chronic kidney disease stage 4 or 5.
191 patients with compensated (n=181) and decompensated (n=10) liver diseases receiving SOF/VEL (400/100 mg/day) alone and SOF/VEL with low-dose RBV (200 mg/day) for 12 weeks were retrospectively recruited at 15 academic centres in Taiwan. The effectiveness was determined by sustained virological response at off-treatment week 12 (SVR
) in evaluable (EP) and per-protocol populations (PP). The safety profiles were assessed.
The SVR
rates by EP and PP analyses were 94.8% (95% CI 90.6% to 97.1%) and 100% (95% CI 97.9% to 100%). In patients with compensated liver disease, the SVR
rates were 95.0% and 100% by EP and PP analyses. In patients with decompensated liver disease, the SVR
rates were 90.0% and 100% by EP and PP analyses. Ten patients who failed to achieve SVR
were attributed to non-virological failures. Among the 20 serious adverse events (AEs), none were judged related to SOF/VEL or RBV. The AEs occurring in ≥10% included fatigue (14.7%), headache (14.1%), nausea (12.6%), insomnia (12.0%) and pruritus (10.5%). None had ≥grade 3 total bilirubin or alanine aminotransferase elevations.
SOF/VEL with or without low-dose RBV is effective and well-tolerated in HCV-infected patients with severe RI.
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