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Background & Aims: Pelvic exenteration (PE) surgery is now a widely accepted procedure that is increasingly being performed worldwide but has significant morbidity. Although nutrition status, body mass index (BMI) and postoperative nutrition support practices are modifiable risk factors, few studies have examined the relationship of these with clinical outcomes following PE. The aim of this study was therefore to investigate the impact of these factors on postoperative complications and length of hospital stay (LOHS) following PE., Methods: This was a retrospective cohort study of all patients having total PE surgery at a tertiary teaching hospital from 2012 to 2021 (n = 69). Multivariable analyses were undertaken to confirm univariate associations and adjust for confounding variables. Binary logistic regression was undertaken to explore predictors of infectious and Grade III or above Clavien-Dindo complications, and negative binomial regression to identify predictors of LOHS., Results: Patients who were malnourished according to the Subjective Global Assessment were 5.66 (OR 5.66, 95% CI 1.07-29.74, p = 0.041) times more likely to develop an infectious complication. Increasing BMI was independently associated with development of Grade III or above Clavien-Dindo complications (p = 0.040). For each additional day until full diet commencement, there was a 19% (OR: 1.19, 95% CI 1.05-1.34, p = 0.005) increased incidence of significant complications and a 5.6% (IRR: 1.056, 95% CI: 1.02-1.09, p = 0.002) longer LOHS on multivariable analysis. There was a high rate of prolonged postoperative ileus (78%). The implementation of a nutrition support pathway with routine postoperative parenteral nutrition (PN) resulted in patients achieving adequate nutrition 7 days faster (p < 0.001) with minimal line-related complications (1.4% line-related thrombus). Routine PN did not impact ileus rates (p = 0.33) or time to diet commencement (p = 0.6)., Conclusions: Preoperative malnutrition and higher BMI were associated with complications following PE. Delay to full diet commencement was associated with increased complications and longer LOHS. Routine postoperative PN appears safe and resulted in patients achieving adequate nutrition faster., Competing Interests: Declaration of competing interest Emma Osland has received compensation to attend a Baxter advisory board meeting. The other authors have no potential conflict of interest to declare., (Copyright © 2024 European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Introduction: T4 nasopharyngeal carcinoma (NPC) with close proximity to critical organs at risk (OARs) is usually underdosed during radiotherapy in order to respect radiation constraints. N3 disease has high risk of distant metastasis. Induction chemotherapy (IC) provides advantages of sparing of OARs during subsequent chemoradiotherapy (CCRT) and early eradication of micrometastasis. However, factors predicting successes of IC in this patient group are not well-studied., Methods: 104 T4 or N3 NPC patients were retrospectively reviewed during 2007-2018. They were planned for IC followed by CCRT using intensity-modulated radiotherapy., Results: In the whole group, five-year failure-free survival (FFS), locoregional failure-free survival (LRFS), distant failure-free survival (DFFS) and overall survival (OS) were 40.9%, 45.7%, 46.9% and 53.6% respectively. Isolated marginal failure rate was 5% (4/80) among patients with primary tumours located close to critical OARs. Pre-IC gross tumour volume primary (GTVp) total volume > 110 cm 3 correlated with worse five-year LRFS (OR 6.37, P = 0.008), DFFS (OR 8.89, P = 0.003) and OS (OR 50.12, P < 0.001). In the T4 subgroup, IC improved D100% GTVp from 61.39 Gy to 64.71 Gy (P < 0.001) and V100% GTVp from 98.78% to 99.28% (P < 0.001)., Conclusion: Our study demonstrated improved dosimetric parameters and low isolated marginal failure rate. It supported the use of IC and CCRT for tumours located close to critical OARs. Further research is warranted to compare predictive roles of pre- and post-IC tumour volumes. For high-risk patients being defined by pre-IC volume or other prognostic models, treatment escalation should be considered., (© 2022 Royal Australian and New Zealand College of Radiologists.)

Transcriptional reactivation of telomerase catalytic subunit (TERT) is a frequent hallmark of cancer, occurring in 90% of human malignancies. However, specific mechanisms driving TERT reactivation remain obscure for many tumor types and in particular gastric cancer (GC), a leading cause of global cancer mortality. Here, through comprehensive genomic and epigenomic analysis of primary GCs and GC cell lines, we identified the transcription factor early B cell factor 1 (EBF1) as a TERT transcriptional repressor and inactivation of EBF1 function as a major cause of TERT upregulation. Abolishment of EBF1 function occurs through 3 distinct (epi)genomic mechanisms. First, EBF1 is epigenetically silenced via DNA methyltransferase, polycomb-repressive complex 2 (PRC2), and histone deacetylase activity in GCs. Second, recurrent, somatic, and heterozygous EBF1 DNA-binding domain mutations result in the production of dominant-negative EBF1 isoforms. Third, more rarely, genomic deletions and rearrangements proximal to the TERT promoter remobilize or abolish EBF1-binding sites, derepressing TERT and leading to high TERT expression. EBF1 is also functionally required for various malignant phenotypes in vitro and in vivo, highlighting its importance for GC development. These results indicate that multimodal genomic and epigenomic alterations underpin TERT reactivation in GC, converging on transcriptional repressors such as EBF1.

Objective: Genomic structural variations (SVs) causing rewiring of cis -regulatory elements remain largely unexplored in gastric cancer (GC). To identify SVs affecting enhancer elements in GC ( enhancer-based SVs ), we integrated epigenomic enhancer profiles revealed by paired-end H3K27ac ChIP-sequencing from primary GCs with tumour whole-genome sequencing (WGS) data (PeNChIP-seq/WGS)., Design: We applied PeNChIP-seq to 11 primary GCs and matched normal tissues combined with WGS profiles of >200 GCs. Epigenome profiles were analysed alongside matched RNA-seq data to identify tumour-associated enhancer-based SVs with altered cancer transcription. Functional validation of candidate enhancer-based SVs was performed using CRISPR/Cas9 genome editing, chromosome conformation capture assays (4C-seq, Capture-C) and Hi-C analysis of primary GCs., Results: PeNChIP-seq/WGS revealed ~150 enhancer-based SVs in GC. The majority (63%) of SVs linked to target gene deregulation were associated with increased tumour expression. Enhancer-based SVs targeting CCNE1 , a key driver of therapy resistance, occurred in 8% of patients frequently juxtaposing diverse distal enhancers to CCNE1 proximal regions. CCNE1 -rearranged GCs were associated with high CCNE1 expression, disrupted CCNE1 topologically associating domain (TAD) boundaries, and novel TAD interactions in CCNE1 -rearranged primary tumours. We also observed IGF2 enhancer-based SVs, previously noted in colorectal cancer, highlighting a common non-coding genetic driver alteration in gastric and colorectal malignancies., Conclusion: Integrated paired-end NanoChIP-seq and WGS of gastric tumours reveals tumour-associated regulatory SV in regions associated with both simple and complex genomic rearrangements. Genomic rearrangements may thus exploit enhancer-hijacking as a common mechanism to drive oncogene expression in GC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background:: The midsole is an essential assembly of footwear for retaining the shape of the shoe, delivering support to the foot, and serving as a cushioning and stability device for walking. To improve leg muscle balance and muscle co-contraction, we propose a new midsole design for high heels with different hardness levels at the forefoot region., Methods:: Five healthy women participated in the study, with a mean ± SD age of 21.80 ± 4.09 years, and duration of high-heeled shoe wear of 5.20 ± 4.09 years. Two midsole conditions, control and multiple-hardness midsole (MHM), with heel heights of 2 (flat), 5, and 8 cm were used. The main outcome measures were to examine the acute effects of MHM by electromyography on muscle activity balance and co-contraction at varying heel heights during shuttle walk., Results:: Use of the MHM significantly reduced the muscle activity ratio between the medial and lateral gastrocnemius muscles ( P = .043) during push-off to heel strike with a heel height of 5 cm (-22.74%) and heel strike to midstance with a heel height of 8 cm (-22.26%). The increased co-contraction indices of the tibialis anterior-peroneus longus muscles (14.35% with an 8-cm heel height) and tibialis anterior-soleus muscles (15.18% with a 5-cm heel height) are significant ( P = .043), with a large effect size ( d = 0.8)., Conclusions:: These results deliver important implications in advancing the engineering of MHM design without changing the in-shoe volume to enhance leg muscle balance and co-contraction during walking.

Human pluripotent stem cells (hPSCs) can be a renewable source for generating cardiomyocyte (CM) for treating myocardial infraction. In our previous publication, we described an integrated microcarrier-based wave reactor process for the expansion and differentiation of hPSCs to CMs on a rocker based platform. However, this platform is limited in terms of linear scalability and CMs purity. The present study describes ways to overcome these limitations by the use of a stirred scalable platform and incorporation of an additional lactate based purification step which increases CM purity. Efficient CM differentiation in stirred spinners was achieved by (1) Addition of ascorbic acid (AS) during the differentiation phase which resulted in an increase of 38.42% in CM yield (0.84 ± 0.03 × 10 6 vs 1.17 ± 0.07 × 10 6  CM/mL for cultures without AS and with AS respectively) and (2) Change of agitation regime to a shorter static intervals one (from 66 min off/6 min on (66/6) to 8 min off/1 min on (8/1)) during the first 3 days of differentiation which resulted in 22% increase in CM yield (1.50 ± 0.10 × 10 6 vs 1.23 ± 0.07 × 10 6  CM/mL). The combination of AS addition and change in agitation regime resulted in a production yield of 1.50 ± 0.10 × 10 6  CM/mL which is comparable to that achieved in the rocker platform as described before (1.61 ± 0.36 × 10 6  CM/mL). Increase in CM purity was achieved by changing of culture medium to RPMI1640 (without glucose) + 5 mM lactate +0.6 mM AS at day 10 of differentiation which resulted in 44.5% increase in CM purity at day 15. The increase in purity of CMs was due to the death of the non-CM cells (~76% of cell death). It is important to note that in the absence of glucose, lactate was consumed at a rate of 0.01 mmol/10 6  cells/h. Addition of glucose, even in small amounts, during the purification step prevents the process of CM purification, due to the growth of the non-CM cell population. In summary, hPSC (hESC-HES3 and hiPSC-IMR90) can be efficiently differentiated to CMs in a scalable spinner process which integrates 7 days of expansion (3.01 ± 0.51 × 10 6 to 3.50 ± 0.65 × 10 6  cells/mL) followed by 10 days of WNT modulated CM differentiation and 5 days of lactate based purification. CM yield of 1.38 ± 0.22 × 10 6 to 1.29 ± 0.42 × 10 6  CM/mL with 72.5 ± 8.35% to 83.12 ± 8.73% cardiac troponin-T positive cells were obtained from these cultures., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel-Lindau ( VHL ) tumor suppressor. Roles for noncoding cis -regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profiles, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specific aspects of malignancy. Superenhancer profiling identified ZNF395 as a ccRCC-specific and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivo VHL loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α-HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter-enhancer interactions. Subtype-specific driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression. Significance: Comprehensive epigenomic profiling of ccRCC establishes a compendium of somatically altered cis -regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL , a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specific promoter-enhancer complexes. Cancer Discov; 7(11); 1284-305. ©2017 AACR. See related commentary by Ricketts and Linehan, p. 1221 This article is highlighted in the In This Issue feature, p. 1201 ., (©2017 American Association for Cancer Research.)

Nasopharyngeal carcinoma (NPC) is endemic in southern China, and its incidence in Hong Kong is relatively high. Radiotherapy is the mainstay treatment for NPC due to its relatively high radiosensitivity and deep-seated anatomical position, which is not readily accessible by surgery. Although the technique of radiotherapy in NPC has been advancing and offers promising treatment outcome, complications around the irradiation areas are inevitable and the quality of life of the post-radiotherapy patients is often compromised. Trismus, which is defined as the restricted mouth opening or jaw movement due to the disorder of temporo-mandibular joint (TMJ), is one of the possible late complications for radiotherapy of NPC and is found in 5-17% of the post-radiotherapy (post-RT) patients. Trismus at early stage may only affect the speech, but in severe cases nutritional intake and oral hygiene condition may deteriorate seriously. This article reviewed the possible causes of radiation-induced TMJ damage, the various assessments including imaging modalities and possible treatments. The conclusion is that the availability of simple, yet effective examinations for trismus is essential for delaying the progression and restoring TMJ functions. Although there is no absolutely effective treatment for trismus, many supportive, restorative and palliative management are possible under different clinical situations.

The kidney is a major target for drug-induced toxicity, and the renal proximal tubule is frequently affected. Nephrotoxicity is typically detected only late during drug development, and the nephrotoxic potential of newly approved drugs is often underestimated. A central problem is the lack of preclinical models with high predictivity. Validated in vitro models for the prediction of nephrotoxicity are not available. Major problems are related to the identification of appropriate cell models and end points. As drug-induced kidney injury is associated with inflammatory reactions, we explored the expression of inflammatory markers as end point for renal in vitro models. In parallel, we developed a new cell model. Here, we combined these approaches and developed an in vitro model with embryonic stem-cell-derived human renal proximal tubular-like cells that uses the expression of interleukin (IL)-6 and IL-8 as end points. The predictivity of the model was evaluated with 41 well-characterized compounds. The results revealed that the model predicts proximal tubular toxicity in humans with high accuracy. In contrast, the predictivity was low when well-established standard in vitro assays were used. Together, the results show that high predictivity can be obtained with in vitro models employing pluripotent stem cell-derived human renal proximal tubular-like cells.