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Currently, coronavirus disease 2019 (COVID-19) is still spreading in a global scale, exerting a massive health and socioeconomic crisis. Deep insights into the molecular functions of the viral proteins and the pathogenesis of this infectious disease are urgently needed. In this review, we comprehensively describe the proteome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and summarize their protein interaction map with host cells. In the protein interaction network between the virus and the host, a total of 787 host prey proteins that appeared in at least two studies or were verified by co-immunoprecipitation experiments. Together with 29 viral proteins, a network of 1762 proximal interactions were observed. We also review the proteomics results of COVID-19 patients and proved that SARS-CoV-2 hijacked the host’s translation system, post-translation modification system, and energy supply system via viral proteins, resulting in various immune disorders, multiple cardiomyopathies, and cholesterol metabolism diseases.

Supplementary Figure S1: IgG negative control demonstrated no added effect on the chemotherapy induced apoptosis; Supplementary Figure S2: Secretory GEP levels in Hep3B and Huh7 culture supernatants; Supplementary Figure S3: Combined GEP antibody and high dose cisplatin eradicated the established intrahepatic xenografts.

Immunoevasion is an emerging hallmark of cancer. Impairment of natural killer (NK) cytotoxicity is a mechanism to evade host immunosurveillance. Granulin–epithelin precursor (GEP) is a hepatic oncofetal protein regulating growth, invasion, and chemoresistance in hepatocellular carcinoma (HCC). We examined the role of GEP in conferring HCC cells the ability to evade NK cytotoxicity. In HCC cell lines, GEP overexpression reduced, whereas GEP suppression enhanced sensitivity to NK cytotoxicity. GEP downregulated surface expression of MHC class I chain–related molecule A (MICA), ligand for NK stimulatory receptor NK group 2 member D (NKG2D), and upregulated human leukocyte antigen-E (HLA-E), ligand for NK inhibitory receptor CD94/NKG2A. Functionally, GEP augmented production of soluble MICA, which suppressed NK activation. Matrix metalloproteinase (MMP)2 and MMP9 activity was involved partly in the GEP-regulated MICA shedding from HCC cells. In primary HCCs (n = 80), elevated GEP (P < 0.001), MICA (P < 0.001), and HLA-E (P = 0.089) expression was observed when compared with those in nontumor (n = 80) and normal livers (n = 10). Serum GEP (P = 0.010) and MICA (P < 0.001) levels were higher in patients with HCC (n = 80) than in healthy individuals (n = 30). High serum GEP and/or MICA levels were associated with poor recurrence-free survival (log-rank test, P = 0.042). Importantly, GEP blockade by mAbs sensitized HCC cells to NK cytotoxicity through MICA. In summary, GEP rendered HCC cells resistant to NK cytotoxicity by modulating MICA expression, which could be reversed by GEP blockade using antibody. Serum GEP and MICA levels are prognostic factors and can be used to stratify patients for targeted therapy. Cancer Immunol Res; 2(12); 1209–19. ©2014 AACR.

Supplementary Table 1. Clinico-pathological features of HCC in relation to sGEP and sMICA levels. Supplementary Table 2. Cox regression analyses for recurrence-free survival on sGEP/sMICA levels and tumor stage. Supplementary Figure 1. Cytotoxicity of NK cells isolated by positive and negative selection. Supplementary Figure 2. Correlation between NKG2D expression on NK cells with (A) sGEP and (B) sMICA in sera of HCC patients. Supplementary Figure 3. Association of serum GEP or MICA levels with recurrence-free survival in HCC patients.

It is unclear whether improvement in patient-reported outcomes (PROs) relative to baseline symptom burden in Crohn's disease (CD) is associated with subsequent endoscopic remission.To evaluate the relationship between dominant PRO resolution post-induction and achievement of clinical and endoscopic remission.This post-hoc analysis of clinical trial data from 251 participants evaluated the relationship between the resolution of the dominant PRO (most severely elevated baseline PRO) or clinical response (CDAI ≥100 reduction) after induction therapy with biologics (post-induction) and 1-year clinical remission (CDAI150) and/or endoscopic remission (SES-CD3). Multivariate logistic regression models evaluated the relationship between post-induction-dominant PRO resolution and 1-year outcomes adjusted for confounders.Participants with dominant PRO resolution post-induction had higher odds of combined endoscopic and clinical remission compared to those without resolution (aOR: 1.94 [95% CI: 1.01-3.74], P = 0.047). Combining dominant PRO resolution with post-induction endoscopic response (SES-CD ≥50% reduction) was associated with higher odds of 1-year endoscopic and clinical remission (aOR: 6.89 [95% CI: 1.65-28.72], P = 0.008). Clinical and PRO2 response (≥30% decrease in stool frequency and/or ≥30% decrease in abdominal pain score and both not worse than baseline) at post-induction did not predict these outcomes. No significant differences were observed with 1-year endoscopic remission for post-induction-dominant PRO resolution, clinical or PRO2 response.Post-induction resolution of dominant PRO, but not clinical or PRO2 response, was strongly associated with 1-year endoscopic and clinical remission. Resolution of dominant baseline PRO after induction therapy may be informative for 1-year outcomes. Further validation is required.

OBJECTIVE: The aim of this study was to define robust benchmark values for the surgical treatment of perihilar cholangiocarcinomas (PHC) to enable unbiased comparisons. BACKGROUND: Despite ongoing efforts, postoperative mortality and morbidity remains high after complex liver surgery for PHC. Benchmark data of best achievable results in surgical PHC treatment are however still lacking. METHODS: This study analyzed consecutive patients undergoing major liver surgery for PHC in 24 high-volume centers in 3 continents over the recent 5-year period (2014-2018) with a minimum follow-up of 1 year in each patient. Benchmark patients were those operated at high-volume centers (≥50 cases during the study period) without the need for vascular reconstruction due to tumor invasion, or the presence of significant co-morbidities such as severe obesity (body mass index ≥35), diabetes, or cardiovascular diseases. Benchmark cutoff values were derived from the 75th or 25th percentile of the median values of all benchmark centers. RESULTS: Seven hundred eight (39%) of a total of 1829 consecutive patients qualified as benchmark cases. Benchmark cut-offs included: R0 resection ≥57%, postoperative liver failure (International Study Group of Liver Surgery): ≤35%; in-hospital and 3-month mortality rates ≤8% and ≤13%, respectively; 3-month grade 3 complications and the CCI: ≤70% and ≤30.5, respectively; bile leak-rate: ≤47% and 5-year overall survival of ≥39.7%. Centers operating mostly on complex cases disclosed better outcome including lower post-operative liver failure rates (4% vs 13%; P = 0.002). Centers from Asia disclosed better outcomes. CONCLUSION: Surgery for PHC remains associated with high morbidity and mortality with now the availability of benchmark values covering 21 outcome parameters, which may serve as key references for comparison in any future analyses of individuals, group of patients or centers.

Salvage liver transplantation (SLT) is the ideal treatment for patients with recurrent hepatocellular carcinoma (HCC) and liver cirrhosis. The optimal timing for offering SLT was controversial. This study aimed at investigating the impact of time to recurrence and other prognostic factors on survival outcome after SLT. Between May 2000 and April 2019, patients who had undergone hepatectomy or ablation for HCC and later received SLT in Queen Mary Hospital were included. Clinico-pathological data during primary treatment and SLT were retrospectively reviewed. Kaplan–Meier analysis and log-rank test were used to determine overall and disease-free survival after SLT. Prognostic factors affecting overall and disease-free survival were determined by multivariate analysis using Cox regression analysis. P-value of less than 0.05 was considered statistically significant. Fifty-three patients were identified within the specified period including 22 patients in early recurrence group (ER group, time to recurrence within 1 year) and 31 patients in late recurrence group (LR group, time to recurrence more than 1 year). The 1-, 5-, and 10-year overall survival after primary treatment was 100%, 76.6%, and 61.1% in the ER group and 100%, 90%, and 76.4% in the LR group (p = 0.59). There were no statistical differences in overall survival (p = 0.84) and disease-free survival (p = 0.85) after SLT between ER and LR group. Pre-transplant alpha-fetoprotein > = 400 ng/mL (p = 0.007) and macrovascular invasion in explant (p = 0.002) were independent risk factors for shorter overall survival after primary treatment. Time to recurrence after primary treatment of HCC did not affect survival outcome after SLT. With careful patient selection, SLT could be offered to patient with early or late tumor recurrence.

BACKGROUND AND AIMS There are no prospective data on stereotactic body radiation therapy (SBRT) as a bridge to liver transplantation for HCC. This study aimed to evaluate the efficacy and safety of SBRT as bridging therapy, with comparison with transarterial chemoembolization (TACE) and high-intensity focused ultrasound (HIFU). APPROACH AND RESULTS Patients were prospectively enrolled for SBRT under a standardized protocol from July 2015 and compared with a retrospective cohort of patients who underwent TACE or HIFU from 2010. The primary endpoint was tumor control rate at 1 year after bridging therapy. Secondary endpoints included cumulative incidence of dropout, toxicity, and posttransplant survival. During the study period, 150 patients were evaluated (SBRT, n = 40; TACE, n = 59; HIFU, n = 51). The tumor control rate at 1 year was significantly higher after SBRT compared with TACE and HIFU (92.3%, 43.5%, and 33.3%, respectively; P = 0.02). With competing risk analysis, the cumulative incidence of dropout at 1 and 3 years after listing was lower after SBRT (15.1% and 23.3%) compared with TACE (28.9% and 45.8%; P = 0.034) and HIFU (33.3% and 45.1%; P = 0.032). Time-to-progression at 1 and 3 years was also superior after SBRT (10.8%, 18.5% in SBRT, 45%, 54.9% in TACE, and 47.6%, 62.8% in HIFU; P

There remains limited data supporting the efficacy of dietary therapy in adults with Crohn's disease (CD). This was a pilot study of the McMaster Elimination diet for CD (MED-CD), which excludes several potentially detrimental ingredients commonly found in the Western diet.Prospective study in adults with mild-moderately active CD [Harvey-Bradshaw Index (HBI) scores 5-16] and endoscopic disease activity ofgt;7 (or ≥4 for isolated ileal disease) as measured by the Simple Endoscopic Score for Crohn's disease (SES-CD). Patients were treated for 2 weeks using oral enteral nutrition (EN). Those with symptomatic improvement (HBI score reduction ≥2) were transitioned to the MED-CD for 12 weeks. Outcomes of interest included satisfactory adherence (≥20 on the modified medical adherence report scale-5 questionnaire), clinical remission (CR) (HBI ≤4), clinical response (HBI reduction ≥3), endoscopic response (SES-CD reduction ≥50%), and endoscopic remission (ER) (SES-CDlt;3).A total of 17 patients were treated with 2 weeks of EN. Of these, 13 were deemed responders and treated with 12 weeks of MED-CD. Satisfactory adherence was reported among 11/13 (84.6%) at week 6 and 8/12 (67%) at week 14. Of the 13 patients who responded to EN by week 2, 5 (38.5%) had attained CR at week 2 and maintained CR until week 14 using MED-CD. Endoscopic response was observed in 6 (46.2%) participants and ER was seen in 2 (15.4%).Two weeks of oral EN followed by 12 weeks of the MED-CD was acceptable by most adult patients who enroled in this study.

Several medications have been suspected to contribute to the etiology of inflammatory bowel disease (IBD). This study assessed the association between medication use and risk of developing IBD using the Prospective Urban Rural Epidemiology (PURE) cohort.This was a prospective cohort study of 133,137 individuals between the ages of 20-80 from 24 countries. Country-specific validated questionnaires documented baseline and follow-up medication use. Participants were followed prospectively at least every 3 years. The main outcome was development of IBD, including Crohn's disease (CD) and ulcerative colitis (UC). Short-term (baseline but not follow-up use) and long-term use (baseline and subsequent follow-up use) were evaluated. Results are presented as adjusted odds ratios (aOR) with 95% confidence intervals (CI).During a median follow-up of 11.0 years [interquartile range (IQR) 9.2-12.2], there were 571 incident IBD cases (143 CD and 428 UC). Incident IBD was significantly associated with baseline antibiotic [aOR: 2.81 (95% CI: 1.67-4.73), p=0.0001] and hormonal medication use [aOR: 4.43 (95% CI: 1.78-11.01), p=0.001]. Among females, previous or current oral contraceptive use was also associated with IBD development [aOR: 2.17 (95% CI: 1.70-2.77), p0.001]. NSAID users were also observed to have increased odds of IBD [aOR: 1.80 (95% CI: 1.23-2.64), p=0.002], which was driven by long-term use [aOR: 5.58 (95% CI: 2.26-13.80), p0.001]. All significant results were consistent in direction for CD and UC with low heterogeneity.Antibiotics, hormonal medications, oral contraceptives, and long-term NSAID use were associated with increased odds of incident IBD after adjustment for covariates.

European journal of nuclear medicine and molecular imaging 48(5), 1371-1389 (2021). doi:10.1007/s00259-020-05094-1, Published by Springer-Verl., Heidelberg [u.a.]

Fission protein 1 (FIS1) and dynamin-related protein 1 (DRP1) were initially described as being evolutionarily conserved for mitochondrial fission, yet in humans the role of FIS1 in this process is unclear and disputed by many. In budding yeast where Fis1p helps to recruit the DRP1 ortholog from the cytoplasm to mitochondria for fission, an N-terminal "arm" of Fis1p is required for function. The yeast Fis1p arm interacts intramolecularly with a conserved tetratricopeptide repeat core and governs in vitro interactions with yeast DRP1. In human FIS1, NMR and X-ray structures show different arm conformations, but its importance for human DRP1 recruitment is unknown. Here, we use molecular dynamics simulations and comparisons to experimental NMR chemical shifts to show the human FIS1 arm can adopt an intramolecular conformation akin to that observed with yeast Fis1p. This finding is further supported through intrinsic tryptophan fluorescence and NMR experiments on human FIS1 with and without the arm. Using NMR, we observed the human FIS1 arm is also sensitive to environmental changes. We reveal the importance of these findings in cellular studies where removal of the FIS1 arm reduces DRP1 recruitment and mitochondrial fission similar to the yeast system. Moreover, we determined that expression of mitophagy adapter TBC1D15 can partially rescue arm-less FIS1 in a manner reminiscent of expression of the adapter Mdv1p in yeast. These findings point to conserved features of FIS1 important for its activity in mitochondrial morphology. More generally, other tetratricopeptide repeat-containing proteins are flanked by disordered arms/tails, suggesting possible common regulatory mechanisms.

It is uncertain whether patients with ulcerative colitis (UC) and delayed symptomatic response to therapy have as robust and durable a response as earlier responders to therapy. We compared clinical outcomes of early and delayed responders to vedolizumab and adalimumab for patients with moderate-severe UC.This was a post hoc analysis of the VARSITY study. Patients with early partial Mayo score (PMS) remission (PMS ≤1 at week 4/6 of therapy) were compared with those with delayed PMS remission (PMS ≤1 at week 14 and not week 4/6). Differences in proportions of patients achieving week 52 clinical remission (CR) (PMS = 0), endoscopic improvement (EI) (Mayo endoscopic subscore ≤1), and histoendoscopic mucosal improvement (HEMI) (Mayo endoscopic subscore ≤1 and Geboes score highest grade3.2) were assessed. Confounders were adjusted for using multivariate logistic regression.A total of 147 vedolizumab-treated and 110 adalimumab-treated patients attained early or late PMS remission. Those who attained early PMS remission with vedolizumab were more likely to attain week 52 CR than participants with delayed PMS remission with vedolizumab (69.1% [67/97] vs 50.0% [25/50], aOR 2.43 [95% CI 1.11-5.33], P = 0.027). Week 52 HEMI was more likely among early vedolizumab PMS remitters (63.9% [62/97] vs 40.0% [20/50], aOR 2.60 [95% CI 1.20-5.62], P = 0.015). Week 52 EI was similar between early and delayed PMS remitters to vedolizumab. No differences were observed in week 52 CR, EI, or HEMI between early and delayed PMS remitters to adalimumab.Patients with UC who achieve early PMS remission with vedolizumab have greater odds of week 52 remission compared with delayed responders.

High placebo response rates in clinical trials of ulcerative colitis (UC) have been reported previously. However, data from patient-level analyses are lacking. We assessed factors associated with clinical and endoscopic placebo response among placebo-treated patients in clinical trials of UC.We performed a post hoc analysis of pooled clinical trial data from GEMINI-1, ACT-1, ACT-2, PURSUIT, ULTRA-2, OCTAVE-1, and OCTAVE-2. Predictors were assessed in placebo-treated patients for their association with end of induction (week 6 of 8) clinical response (reduction in total Mayo score of ≥3 and ≥30% from baseline with ≥1 point decrease in rectal bleeding subscore [RBS] or absolute RBS ≤1); clinical remission (total Mayo score ≤2 and no subscore1); endoscopic healing (Mayo endoscopic subscore ≤1); partial Mayo score of 0; patient-reported outcome 2-item remission (RBS of 0 and stool frequency ≤1), resolution of rectal bleeding, and stool frequency normalization. Predictors on univariate analyses with P.05 were included in multivariate logistic regression models.Placebo-treated patients with normal serum C-reactive protein and albumin levels were more likely to attain clinical response (71 of 437 [16.3%] vs 49 of 660 [7.4%]; adjusted odds ratio, 2.76; 95% confidence interval, 1.19-5.41; P = .018). Compared with patients with a Mayo endoscopic score of 2, patients with a Mayo endoscopic score of 3 were less likely to attain clinical response (105 of 556 [18.8%] vs 179 of 675 [25.9%]; adjusted odds ratio, 0.33; 95% confidence interval, 0.16-0.68; P = .003). Similar findings were observed for clinical remission and resolution of rectal bleeding.Biomarkers such as normal serum C-reactive protein and albumin and baseline endoscopic severity were found to affect placebo response rates in clinical trials of UC. These findings have implications for clinical trial design in UC.

Intrinsic DNA properties such as bending play a crucial role in diverse biological systems. A recent advantage in the high-throughput method called loop-seq makes it possible to determine bendability of hundred thousand 50-bp DNA duplexes in one experiment. However, it’s still infeasible to assess whole sequence bendability in large genomes such as human, which needs thousands of loop-seq experiments. Here we introduce ‘BendNet’ – a neural network to accurately predict the intrinsic DNA bending at base-resolution by only given DNA sequences. BendNet can increase the resolution of experimental results, and can predict DNA bendability for any new given sequences in high accuracy. We applied BendNet to the human genome and observed high-stiffness regions located at both transcriptional start sites and transcriptional end sites. Such stiffness patterns are different for coding and non-coding genes, which matches distinct nucleosome occupancy patterns. As expected, most transcription factors (TFs) bind in DNA of low bendability. In contrast, we observed an unusually high bendability within binding elements of specific TFs such as EBF1 and regulators of genome folding such as CTCF. These factors either co-bind or compete with nucleosomes to carry out their functions. More interestingly, CTCF binding regions exhibit the highest bendability than other DNA elements, implying their potential role in trapping and holding the CTCF in the exact locations to make sure CTCF as stable anchor in loop extrusion process. Our work provides a tool to assess DNA bendability for large-scale DNA sequences and expands our understanding on DNA mechanics in chromatin regulation and genome folding.

Current psychosocial interventions in schizophrenia are evidenced to improve patients' illness-related knowledge, mental status and relapse rate, but substantive benefits to patients, such as their functioning and insight into the illness, remain uncertain. This multi-centre randomised clinical trial aimed to examine the effects of mindfulness-based psycho-education group intervention for adult patients with early-stage schizophrenia over an 18-month follow-up. The controlled trial was conducted with a repeated-measure, three-arm design at two psychiatric outpatient clinics in Jilin (China) and Hong Kong. A stratified random sample of 180 outpatients with schizophrenia spectrum disorders (60/group) was randomly assigned to a mindfulness-based psycho-education group programme, psycho-education group and treatment-as-usual group. The primary outcomes on patients' psychosocial functioning and other patient outcomes, such as psychotic symptoms, in the three groups were compared over the 18-month follow-up (baseline and 1-week, 9-month and 18-month post-intervention). One hundred and sixty (89%) patients completed at least two post-tests. Their mean age and duration of illness were 25–28 years (SD = 6.1–7.8) and 2.1–2.5 years (SD = 1.3–2.0; range 4–54 months), respectively. Compared with the two other groups, the mindfulness-based group exhibited a significantly greater improvement with moderate to large effect sizes (Cohen's d = 0.49–0.98) in functioning (p = 0.005), duration of psychiatric re-hospitalisations (p = 0.007), psychotic symptoms (p = 0.008) and illness insight (p = 0.001) over the 18-month follow-up. Supplementary MRI findings indicated that the mindfulness-based intervention resulted in significant changes in gray matter volume and density in brain regions concerning attention and emotional regulation. Mindfulness-oriented psycho-education group intervention can be an effective intervention for adults with early-stage schizophrenia and exert long-term effects on patients' functioning and mental conditions.

Background An accurate prediction model of early recurrence of hepatocellular carcinoma (HCC) after hepatectomy is important to ascertain the postoperative adjuvant treatment and surveillance. Methods This is a retrospective cohort study including 1125 patients with HCC underwent curative hepatic resection. They were randomly divided into training (n = 562) and validation (n = 563) sets. Early intrahepatic recurrence within 18 months from surgery is the primary outcome. In the training set, a prediction scoring model (Recurrent Liver Cancer Score RLCS) was developed, which was legitimised in the validation set. Results RLCS was developed based on four clinicopathologic risk factors (serum alpha fetoprotein, tumor size, multiple tumors or satellite nodules, and microvascular invasion). Low-risk and high-risk groups had statistically significant differences in early recurrence rates (18% vs. 43.8%). The 5-year recurrence-free survival rates of low risk and high risk groups were 52.9% and 27.8%, respectively. This model showed good calibration and discriminatory ability in the validation set (c-index of 0.647). Conclusion RLCS is a user-friendly prediction scoring model which can accurately predict the occurrence of early intrahepatic recurrence of HCC. It establishes the basis of postoperative adjuvant treatment and surveillance in future studies.

Background & Aims The impact of hepatitis B core antibody (anti-HBc) positive liver grafts on survival and the risk of de novo hepatitis B virus (HBV) infection after liver transplantation (LT) remain controversial. Therefore, we aimed to analyze this risk and the associated outcomes in a large cohort of patients. Methods This was a retrospective study that included all adults who underwent LT at Queen Mary Hospital, Hong Kong, between 2000 and 2015. Data were retrieved from a prospectively collected database. Antiviral monotherapy prophylaxis was given for patients receiving grafts from anti-HBc positive donors. Results A total of 964 LTs were performed during the study period, with 416 (43.2%) anti-HBc positive and 548 (56.8%) anti-HBc negative donors. The median follow-up time was 7.8 years. Perioperative outcomes (hospital mortality, complications, primary nonfunction and delayed graft function) were similar between the 2 groups. The 1-, 5- and 10-year graft survival rates were comparable in anti-HBc positive (93.3%, 85.3% and 76.8%) and anti-HBc negative groups (92.5%, 82.9% and 78.4%, p = 0.944). The 1-, 5- and 10-year patient survival rates in anti-HBc positive group were 94.2%, 87% and 79% and were similar to the anti-HBc negative group (93.5%, 84% and 79.7%, p = 0.712). One-hundred and eight HBsAg negative recipients received anti-HBc positive grafts, of whom 64 received lamivudine and 44 entecavir monotherapy prophylaxis. The risk of de novo HBV was 3/108 (2.8%) and all occurred in the lamivudine era. There were 659 HBsAg-positive patients and 308 (46.7%) received anti-HBc positive grafts. The risk of HBV recurrence was similar between the 2 groups. Donor anti-HBc status did not impact on long-term patient and graft survival, or the risk of hepatocellular carcinoma recurrence after LT. Conclusions De novo HBV was exceedingly rare especially with entecavir prophylaxis. Anti-HBc positive grafts did not impact on perioperative and long-term outcomes after transplant. Lay summary The risk of de novo hepatitis B infection after liver transplantation was rare when using hepatitis B core positive liver grafts with entecavir monotherapy prophylaxis. Hepatitis B core antibody status did not impact on perioperative and long-term outcomes after liver transplantation. This provides support for the clinical use of hepatitis B core positive liver grafts when required.

IMPORTANCE: Living-donor liver transplant (LDLT) offers advantages over deceased-donor liver transplant (DDLT) of improved intention-to-treat outcomes and management of the shortage of deceased-donor allografts. However, conflicting data still exist on the outcomes of LDLT in patients with hepatocellular carcinoma (HCC). OBJECTIVE: To investigate the potential survival benefit of an LDLT in patients with HCC from the time of waiting list inscription. DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study with an intention-to-treat design analyzed the data of patients aged 18 years or older who had an HCC diagnosis and were on a waiting list for a first transplant. Patients from 12 collaborative centers in Europe, Asia, and the US who were on a transplant waiting list between January 1, 2000, and December 31, 2017, composed the international cohort. The Toronto cohort comprised patients from 1 transplant center in Toronto, Ontario, Canada who were on a waiting list between January 1, 2000, and December 31, 2015. The international cohort centers performed either an LDLT or a DDLT, whereas the Toronto cohort center was selected for its capability to perform both LDLT and DDLT. The benefit of LDLT was tested in the 2 cohorts before and after undergoing an inverse probability of treatment weighting (IPTW) analysis. Data were analyzed from February 1 to May 31, 2020. MAIN OUTCOMES AND MEASURES: Intention-to-treat death was defined as a patient death that occurred for any reason and was calculated from the time of waiting list inscription for liver transplant to the last follow-up date (December 31, 2019). Four multivariable Cox proportional hazards regression models for intention-to-treat death were created. RESULTS: A total of 3052 patients were analyzed in the international cohort, of whom 2447 were men (80.2%) and the median (IQR) age at first referral was 58 (53-63) years. The Toronto cohort comprised 906 patients, of whom 743 were men (82.0%) and the median (IQR) age at first referral was 59 (53-63) years. In all the settings, LDLT was an independent protective factor, reducing the risk of overall death by 49% in the pre-IPTW analysis for the international cohort (HR, 0.51; 95% CI, 0.36-0.71; P

Supplemental material, sj-pdf-1-jct-10.1177_2380084421999365 for Social, Psychological, and Behavioral Predictors of Salivary Bacteria, Yeast in Caries-Free Children by D.T. Kopycka- Kedzierawski, K. Scott-Anne, P.G. Ragusa, M. Cvetanovska, K. Flint, C. Feng, G.E. Watson, C.L. Wong, R.J. Billings, R.J. Quivey and T.G. O’Connor in JDR Clinical & Translational Research

Y-box-binding protein 1 (YB-1) is a multifunctional RNA binding protein involved in virtually every step of RNA metabolism. However, the functions and mechanisms of YB-1 in one of the most aggressive cancers, glioblastoma, are not well understood. In this study, we found that YB-1 protein was markedly overexpressed in glioblastoma and acted as a critical activator of both mTORC1 and mTORC2 signaling. Mechanistically, YB-1 bound the 5'UTR of CCT4 mRNA to promote the translation of CCT4, a component of the CCT chaperone complex, that in turn activated the mTOR signaling pathway by promoting mLST8 folding. In addition, YB-1 autoregulated its own translation by binding to its 5'UTR, leading to sustained activation of mTOR signaling. In patients with glioblastoma, high protein expression of YB-1 correlated with increased expression of CCT4 and mLST8 and activated mTOR signaling. Importantly, the administration of RNA decoys specifically targeting YB-1 in a mouse xenograft model resulted in slower tumor growth and better survival. Taken together, these findings uncover a disrupted proteostasis pathway involving a YB-1/CCT4/mLST8/mTOR axis in promoting glioblastoma growth, suggesting that YB-1 is a potential therapeutic target for the treatment of glioblastoma.

OBJECTIVE The aim of this study was to determine the outcomes of living donor liver transplantation (LDLT) according to various graft-to-recipient weight ratio (GRWR). BACKGROUND The standard GRWR in LDLT is >0.8%. Our center accepted predicted GRWR ≥0.6% in selected patients. METHODS Data from patients who underwent LDLT from 2001 to 2017 were included. Patients were stratified according to actual GRWR (Group 1:GRWR ≤0.6%; Group 2: 0.6% 0.8%). RESULTS There were 545 LDLT (group 1 = 39; group 2 = 159; group 3 = 347) performed. Pretransplant predicted GRWR showed good correlation to actual GRWR (R2 = 0.834) and these figures differed within a ± 10%margin (P = 0.034) using an equivalence test. There were more left lobe grafts in group 1 (33.3%) than group 2 (10.7%) and 3 (2.9%). Median donor age was 10% was rare.There was no difference in postoperative complication, vascular and biliary complication rate between groups. Over one-fifth (20.5%) of group 1 patients required portal flow modulation (PFM) and was higher than group 2 (3.1%) and group 3 (4%) (P = 0.001). Twenty-six patients developed small-for-size syndrome (SFSS): 5 of 39 (12.8%) in group 1 and 21 of 159 (13.2%) in group 2 and none in group 3 (P < 0.001). There were 2 hospital mortalities; otherwise, the remaining patients [24/26 (92.3%)] survive with a functional liver graft. The 5-year graft survival rates were 85.4% versus 87.8% versus 84.7% for group 1, 2, and 3, respectively (P = 0.718). GRWR did not predict worse survivals in multivariable analysis. CONCLUSIONS Graft size in LDLT can be lowered to 0.6% after careful recipient selection, with low incidence of SFSS and excellent outcomes. Accurate graft weight prediction, donor-recipient matching, meticulous surgical techniques, appropriate use of PFM, and vigilant perioperative care is important to the success of such approach.

Singapore was one of the first countries to be affected by COVID-19, with the index patient diagnosed on 23 January 2020. For two weeks in February, we had the highest number of COVID-19 cases behind China. In this article, we summarize the key national and institutional policies that were implemented in response to COVID-19. We also describe in detail, with relevant data, how our vascular surgery practice has changed due to these policies and COVID-19. We show that with a segregated team model, the vascular surgery unit can still function whilst reducing risk of cross-contamination. We explain the various strategies adopted to reduce outpatient and inpatient volume. We provide a detailed breakdown of the type of vascular surgical cases that were performed during the COVID-19 pandemic and compared it to preceding months. We discuss our operating room and personal protective equipment protocols when managing a COVID-19 patient and share how we continue surgical training amidst the pandemic. We also discuss the challenges we might face in the future as COVID-19 regresses.

Background and Aims Previous recommendations suggested living donor liver transplantation (LDLT) should not be considered for patients with Model for End‐Stage Liver Disease (MELD) > 25 and hepatorenal syndrome (HRS). Approach and Results Patients who were listed with MELD > 25 from 2008 to 2017 were analyzed with intention‐to‐treat (ITT) basis retrospectively. Patients who had a potential live donor were analyzed as ITT‐LDLT, whereas those who had none belonged to ITT‐deceased donor liver transplantation (DDLT) group. ITT‐overall survival (OS) was analyzed from the time of listing. Three hundred twenty‐five patients were listed (ITT‐LDLT n = 212, ITT‐DDLT n = 113). The risk of delist/death was lower in the ITT‐LDLT group (43.4% vs. 19.8%, P 25 and patients with both MELD > 25 and HRS (56% vs. 33.8%, P 25 (88% vs. 85.4%, P = 0.279) and patients with both MELD > 25 and HRS (77% vs. 76.4%, P = 0.701) after LDLT and DDLT, respectively. The LDLT group has a higher rate of renal recovery by 1 month (77.4% vs. 59.1%, P = 0.003) and 3 months (86.1% vs, 74.5%, P = 0.029), whereas the long‐term estimated glomerular filtration rate (eGFR) was similar between the 2 groups. ITT‐LDLT reduced the hazard of mortality (hazard ratio = 0.387‐0.552) across all MELD strata. Conclusions The ITT‐LDLT reduced waitlist mortality and allowed an earlier access to transplant. LDLT in patients with high MELD/HRS was feasible, and they had similar perioperative outcomes and better renal recovery, whereas the long‐term survival and eGFR were comparable with DDLT. LDLT should be considered for patients with high MELD/HRS, and the application of LDLT should not be restricted with a MELD cutoff.

Summary: Background: Whether primary liver transplantation (PLT) or upfront curative treatment with salvage liver transplantation (SLT) is a better treatment option for early hepatocellular carcinoma (HCC) is controversial. This study aims to compare the long-term survival starting from the time of primary treatment between the two approaches for early HCC using propensity score matching (PSM) analysis. Methods: From 1995 to 2014, 175 patients with early HCC undergoing either PLT (n = 149) or SLT (n = 26) were retrospectively reviewed in a prospectively collected database. Patients' demographic data, tumor characteristics, short-term and long-term outcome were compared between two groups after PSM. Results: After matching, the baseline characteristics were comparable between mPLT group (n = 45) and mSLT group (n = 25). The tumor recurrence rate after transplant was significantly higher in mSLT group than mPLT group (28% vs. 15.6%). Calculating from the time of primary treatment, the 1, 3, and 5-year overall survival rates were comparable between mPLT group (97.8%, 91.1% and 86.3%) and mSLT group (100%, 95% and 85%). However, the 1, 3, and 5-year recurrence-free survival rates were significantly better in mPLT group than mSLT group (95.6% vs. 90%, 86.6% vs. 80% and 84.3% vs. 70%). SLT approach and high pre-treatment serum alpha-fetoprotein level (>200 ηg/mL) were poor prognostic factors for recurrence-free survival after transplant. Conclusions: PLT may be a better treatment option for early HCC, whereas SLT approach for HCC should be cautiously considered under the circumstance of organ shortage. Keywords: Primary transplantation, Salvage transplantation, Hepatocellular carcinoma, Propensity score matching

Immunotherapy with checkpoint inhibitor programmed cell death 1 (PD-1)/programmed death ligand-1 (PD-L1) antibodies demonstrates improvements in treatment of advanced non–small cell lung cancer. Treatment stratification depends on immunohistochemical PD-L1 measurement of biopsy material, an invasive method that does not account for spatiotemporal heterogeneity. Using a single-domain antibody, NM-01, against PD-L1, radiolabeled site-specifically with 99mTc for SPECT imaging, we aimed to assess the safety, radiation dosimetry, and imaging characteristics of this radiopharmaceutical and correlate tumor uptake with PD-L1 immunohistochemistry results.Methods: Sixteen patients (mean age, 61.7 y; 11 men) with non–small cell lung cancer were recruited. Primary tumor PD-L1 expression was measured by immunohistochemistry. NM-01 was radiolabeled with [99mTc(OH2)3(CO)3]+ complex binding to its C-terminal hexahistidine tag. Administered activity was 3.8–10.4 MBq/kg, corresponding to 100 μg or 400 μg of NM-01. Whole-body planar and thoracic SPECT/CT scans were obtained at 1 and 2 h after injection in all patients, and 5 patients underwent additional imaging at 10 min, 3 h, and 24 h for radiation dosimetry calculations. All patients were monitored for adverse events.Results: No drug-related adverse events occurred in this study. The mean effective dose was 8.84 × 10−3 ± 9.33 × 10−4 mSv/MBq (3.59 ± 0.74 mSv per patient). Tracer uptake was observed in the kidneys, spleen, liver, and bone marrow. SPECT primary tumor–to–blood-pool ratios (T:BP) varied from 1.24 to 2.3 (mean, 1.79) at 1 h and 1.24 to 3.53 (mean, 2.22) at 2 h (P = 0.005). Two-hour primary T:BP ratios correlated with PD-L1 immunohistochemistry results (r = 0.68, P = 0.014). Two-hour T:BP was lower in tumors with ≤1% PD-L1 expression (1.89 vs. 2.49, P = 0.048). Nodal and bone metastases showed tracer uptake. Heterogeneity (>20%) between primary tumor and nodal T:BP was present in 4 of 13 patients.Conclusion: This first-in-human study demonstrates that 99mTc-labeled anti–PD-L1-single-domain antibody SPECT/CT imaging is safe and associated with acceptable dosimetry. Tumor uptake is readily visible against background tissues, particularly at 2 h when the T:BP ratio correlates with PD-L1 immunohistochemistry results.

Stereotactic body radiotherapy (SBRT) is a novel noninvasive treatment for unresectable hepatocellular carcinoma (HCC). Whether its efficacy is comparable to radiofrequency ablation (RFA), a recommended therapy for unresectable HCC, is unknown. The present study aims to compare the clinical outcome between SBRT and RFA for patients with unresectable HCC. The clinical data of 60 patients with unresectable HCC from January 2018 to January 2021 were retrospectively reviewed. There were 22 cases treated by SBRT and 38 cases by RFA. The short-term and long-term clinical outcomes were compared. There was no significant difference in the baseline demographic characteristics between two groups. The complete remission rate at 3 months was comparable between SBRT group (81.8%) and RFA group (89.4%). Local tumor control rate was also similar between two groups (90.9% vs. 94.7%). There was no severe complication (grade IIIa or above) in both groups. The 1-year and 2-year overall survival rates were 88.2% and 85.7% in SBRT group and 100% and 75% in RFA group, respectively. There was no statistical significant difference between groups (P = .576). SBRT can achieve similar short and long-term clinical outcome as RFA for unresectable HCC. Future prospective clinical study is needed to justify its role in patients with HCC.

Steel reinforcement (also referred to as rebar) design plays an important role in reinforced concrete (RC) structures in terms of strength requirements, cost and buildability. Currently, rebar design is performed at the individual member level with few considerations of the interference between different intersecting members, leading to potential clashes and buildability issues. Design for Manufacture and Assembly (DfMA) is a cutting-edge technology concept that improves the design for higher buildability by incorporating knowledge from downstream manufacture and assembly activities into the early design phase. This paper presents an innovative DfMA-oriented approach for rebar design optimization with Building Information Modeling (BIM) and a hybrid metaheuristic algorithm. Firstly, activities related to the manufacture and assembly of rebar are identified to apply DfMA principles, followed by the proposed BIM-based optimization framework. Secondly, multi-objective cost design formulation including both the material cost and the installation cost is proposed, incorporating the design code requirements and DfMA considerations. Following this, key modules for implementation are presented including the rebar layout searching, the hybrid genetic algorithm incorporated with Hooke and Jeeves’s method for optimization and rebar clash avoidance. The illustrative example shows that the proposed approach can generate a series of practical rebar layouts, and a trade-off between the material cost and installation cost is found, which means excessive emphasis on minimizing one of them will lead to the rise of the other.