PBX4 functions as a potential novel oncopromoter in colorectal cancer: a comprehensive analysis of the PBX gene family.

Pre-B-cell leukaemia (PBX) is a transcription factor family (PBX1, PBX2, PBX3 and PBX4) that regulates important cellular functions and has been identified to be involved in human cancers. This study aimed to explore the expression of PBX genes and their clinical significance in colorectal cancer (CRC). We analysed the differential expression of PBX genes in CRC vs. normal tissue, using the Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov/) and ONCOMINE platform (https://www.oncomine.org/). The UALCAN (http://ualcan.path.uab.edu/) interactive OMICS web-server was used to evaluate the epigenetic regulation of PBX genes via their promoter methylation status. We found that only PBX4 was upregulated whereas PBX1 and PBX3 were downregulated (644 tumour vs. 51 normal samples) (P<0.001). The methylation status of PBX4 promoter appeared to be decreased (P=1.4e-07) whereas the methylation status of PBX1 and PBX3 promoters was increased (P=3.8e-04 and P=3.2e-07, respectively) in cancer vs. normal samples. To determine the prognostic value of PBXs, we conducted a Kaplan-Meier survival analysis and multivariable COX regression. We observed that high PBX4 expression was associated with increased risk for a worse overall survival (OS) in the TCGA CRC patient cohort (n=639), (HR 1.46, 95% CI 1.14-1.88, P=0.003) adjusted for age, gender, tumour location and metastases. We conducted in vitro gene expression modulation experiments to investigate the impact of PBX4 overexpression in CRC cell (HCT116) growth. Additionally, we evaluated the RNA expression of epithelial-mesenchymal transition (EMT) and angiogenesis markers. In vitro studies showed that PBX4 overexpression increased CRC cell proliferation (P<0.001) and upregulated the expression of EMT markers VIM, CDH1, CDH2, ZEB1, SNAI1 (P<0.05) and angiomarker VEGFA (P<0.0001). Lastly, through the Cistrome data browser (http://dbtoolkit.cistrome.org/) we investigated putative transcriptional regulators and we performed gene set enrichment analysis in Enrichr server (https://maayanlab.cloud/Enrichr/) to identify related biological processes. Nineteen factors were identified to be putative regulators of PBX4 and gene set enrichment analysis showed that biological processes related to cell cycle and cell proliferation were enriched (GO:0051726: CDK8, JUN, JUND, and IRF1, P=0.001). In conclusion, our study identified PBX4 as a potential novel oncopromoter in CRC and its overexpression was found to be associated with increased risk for worse survival rate.

Neurohormonal Changes in the Gut-Brain Axis and Underlying Neuroendocrine Mechanisms following Bariatric Surgery.

Obesity is a complex, multifactorial disease that is a major public health issue worldwide. Currently approved anti-obesity medications and lifestyle interventions lack the efficacy and durability needed to combat obesity, especially in individuals with more severe forms or coexisting metabolic disorders, such as poorly controlled type 2 diabetes. Bariatric surgery is considered an effective therapeutic modality with sustained weight loss and metabolic benefits. Numerous genetic and environmental factors have been associated with the pathogenesis of obesity, while cumulative evidence has highlighted the gut-brain axis as a complex bidirectional communication axis that plays a crucial role in energy homeostasis. This has led to increased research on the roles of neuroendocrine signaling pathways and various gastrointestinal peptides as key mediators of the beneficial effects following weight-loss surgery. The accumulate evidence suggests that the development of gut-peptide-based agents can mimic the effects of bariatric surgery and thus is a highly promising treatment strategy that could be explored in future research. This article aims to elucidate the potential underlying neuroendocrine mechanisms of the gut-brain axis and comprehensively review the observed changes of gut hormones associated with bariatric surgery. Moreover, the emerging role of post-bariatric gut microbiota modulation is briefly discussed.

Diagnostic Modalities of Non-Alcoholic Fatty Liver Disease: From Biochemical Biomarkers to Multi-Omics Non-Invasive Approaches.

Non-Alcoholic Fatty Liver Disease (NAFLD) is currently the most common cause of chronic liver disease worldwide, and its prevalence is increasing globally. NAFLD is a multifaceted disorder, and its spectrum includes steatosis to steatohepatitis, which may evolve to advanced fibrosis and cirrhosis. In addition, the presence of NAFLD is independently associated with a higher cardiometabolic risk and increased mortality rates. Considering that the vast majority of individuals with NAFLD are mainly asymptomatic, early diagnosis of non-alcoholic steatohepatitis (NASH) and accurate staging of fibrosis risk is crucial for better stratification, monitoring and targeted management of patients at risk. To date, liver biopsy remains the gold standard procedure for the diagnosis of NASH and staging of NAFLD. However, due to its invasive nature, research on non-invasive tests is rapidly increasing with significant advances having been achieved during the last decades in the diagnostic field. New promising non-invasive biomarkers and techniques have been developed, evaluated and assessed, including biochemical markers, imaging modalities and the most recent multi-omics approaches. Our article provides a comprehensive review of the currently available and emerging non-invasive diagnostic tools used in assessing NAFLD, also highlighting the importance of accurate and validated diagnostic tools.

HOXB9 Overexpression Promotes Colorectal Cancer Progression and Is Associated with Worse Survival in Liver Resection Patients for Colorectal Liver Metastases.

As is known, HOXB9 is an important factor affecting disease progression and overall survival (OS) in cancer. However, its role in colorectal cancer (CRC) remains unclear. We aimed to explore the role of HOXB9 in CRC progression and its association with OS in colorectal liver metastases (CRLM). We analysed differential HOXB9 expression in CRC using the Tissue Cancer Genome Atlas database (TCGA). We modulated HOXB9 expression in vitro to assess its impact on cell proliferation and epithelial-mesenchymal transition (EMT). Lastly, we explored the association of HOXB9 protein expression with OS, using an institutional patient cohort (n = 110) who underwent liver resection for CRLM. Furthermore, HOXB9 was upregulated in TCGA-CRC (n = 644) vs. normal tissue (n = 51) and its expression levels were elevated in KRAS mutations (p < 0.0001). In vitro, HOXB9 overexpression increased cell proliferation (p < 0.001) and upregulated the mRNA expression of EMT markers (VIM, CDH2, ZEB1, ZEB2, SNAI1 and SNAI2) while downregulated CDH1, (p < 0.05 for all comparisons). Conversely, HOXB9 silencing disrupted cell growth (p < 0.0001). High HOXB9 expression (HR = 3.82, 95% CI: 1.59-9.2, p = 0.003) was independently associated with worse OS in CRLM-HOXB9-expressing patients after liver resection. In conclusion, HOXB9 may be associated with worse OS in CRLM and may promote CRC progression, whereas HOXB9 silencing may inhibit CRC growth.

A Systematic Review on HOX Genes as Potential Biomarkers in Colorectal Cancer: An Emerging Role of HOXB9.

Emerging evidence shows that Homeobox (HOX) genes are important in carcinogenesis, and their dysregulation has been linked with metastatic potential and poor prognosis. This review (PROSPERO-CRD42020190953) aims to systematically investigate the role of HOX genes as biomarkers in CRC and the impact of their modulation on tumour growth and progression. The MEDLINE, EMBASE, Web of Science and Cochrane databases were searched for eligible studies exploring two research questions: (a) the clinicopathological and prognostic significance of HOX dysregulation in patients with CRC and (b) the functional role of HOX genes in CRC progression. Twenty-five studies enrolling 3003 CRC patients, showed that aberrant expression of HOX proteins was significantly related to tumour depth, nodal invasion, distant metastases, advanced stage and poor prognosis. A post-hoc meta-analysis on HOXB9 showed that its overexpression was significantly associated with the presence of distant metastases (pooled OR 4.14, 95% CI 1.64-10.43, I2 = 0%, p = 0.003). Twenty-two preclinical studies showed that HOX proteins are crucially related to tumour growth and metastatic potential by affecting cell proliferation and altering the expression of epithelial-mesenchymal transition modulators. In conclusion, HOX proteins may play vital roles in CRC progression and are associated with overall survival. HOXB9 may be a critical transcription factor in CRC.

Parecoxib's effects on anastomotic and abdominal wound healing: a randomized Controlled trial.

BACKGROUND: Current evidence regarding the effects of selective cyclooxygenase inhibitors on gastrointestinal anastomoses is controversial. An experimental randomized control study was conducted in our institution to histopathologically evaluate the consequences of parecoxib, on intestinal and abdominal wound healing. METHODS: Twenty-four adult Wistar rats underwent laparotomy, ascending colon transection, and hand-sewn anastomosis. They were randomized to receive either parecoxib (0.5 mg/kg twice daily) or 0.9% normal saline by intraperitoneal injection postoperatively. Animals were euthanatized either on the third or the seventh postoperative day. Semiquantitative methods were used to evaluate both intestinal and abdominal wounds for inflammatory cell composition, angiogenesis, fibroblasts, granular tissue, collagen deposition, epithelization, and presence of necrosis, exudate, and abscess formation. Results are presented as (parecoxib: median [IQR] versus control: median [IQR], P-value). RESULTS: No macroscopic anastomotic leakage or wound dehiscence was observed. Intestinal anastomoses in the parecoxib group, showed significantly decreased epithelization (2 [1] versus 3 [1], [P = 0.004]) and collagen deposition (2 [0] versus 3 [1], [P = 0.041]). No difference was observed in angiogenesis (3 [1] versus 2.5 [1], [P = 0.158]). Abdominal wall specimens appeared to demonstrate decreased epithelization (2 [2] versus 4 [0.5], [P = 0.0004]) in the treatment group. No difference between the two groups was identified regarding collagen deposition (2.5 [1] versus 2 [0.5], [P = 0.280]) and angiogenesis (2.5 [1] versus 2 [1], [P = 0.633]). Necrosis was significantly more present in the parecoxib group in both specimen types, (3.5 [1] versus 2.5 [1], [P = 0.017]) and (3 [1] versus 1 [0.5], [P < 0.0001]). CONCLUSIONS: The present study shows that despite the absence of clinical adverse effects, parecoxib can impair anastomotic and abdominal wound healing on a histopathological level.

Mortality after endovascular treatment of infrarenal abdominal aortic aneurysms - the newer the better?

Although endovascular repair of infrarenal abdominal aortic aneurysms (EVAR) presents a delicate alternative treatment for abdominal aortic aneurysms (AAA) with lower perioperative mortality, its long-term efficacy remains a matter of concern. The purpose of this study was to evaluate the currently reported mortality evidence after EVAR and to examine the possible effect of aneurysm status and the study period on mortality rates. The PubMed and Cochrane bibliographical databases were thoroughly searched for studies reporting on more than 1 000 patients with non-ruptured or ruptured infrarenal AAA, treated with EVAR from August 1991 to September 2016. A total of 10 910 titles/abstracts were retrieved and 121 studies were deemed relevant. Twenty-six studies met the inclusion criteria and reported on 354 500 patients with a mean age of 74.6 years. Almost all of the studies referred to elective EVAR and the mean aneurysm size was 5.58 cm. The most common early complication for elective EVAR was perioperative bleeding (1.9 %), whereas hospital-acquired pneumonia was a major concern in urgent EVAR (28.5 %). Conversion rate to open surgery was 1.2 %. The 30-day all-cause mortality rate was 4.84 % (1.7 % for non- ruptured aneurysms, 33.8 % for ruptured aneurysms).The overall all-cause late mortality in a mean follow-up period of 23.8 months was 19.1 %. The aneurysm-related late mortality rate was 3.4 %. With respect to the time period of patient enrollment, studies reporting on patients recruited before 2006 were found to face more secondary complications and higher late mortality rates than patients enrolled after 2005.The endovascular treatment of large and anatomically suitable infrarenal AAA in selected patients remains a safe alternative to open repair. Our findings demonstrate that newer studies show better long-term outcomes than the older ones, proposing a possible improvement of EVAR techniques and perioperative care and providing encouraging evidence for a wider application of EVAR.

Tension enterothorax and hepatothorax due to a diaphragmatic hernia: successful emergency repair of a life-threatening condition.

A 70-year-old female patient presented with acute severe respiratory distress at a district general hospital. Medical history included type 2 diabetes, recurrent pulmonary embolisms and pre-existing diaphragmatic hernia containing part of the liver. Despite initial treatment with steroid inhalers, her clinical picture rapidly deteriorated requiring emergency intubation and positive pressure ventilation. Imaging investigations revealed tension enterothorax and hepatothorax with tracheal deviation. The patient was transferred and underwent an emergency laparotomy at the Regional Oesophagogastric Unit. A large diaphragmatic hernia (central tendon defect) which contained the duodenum, porta hepatis, right lobe of liver, gallbladder and right colon was reduced and successfully repaired. Her postoperative course was uneventful with no signs of recurrence at 2 months follow-up.This case describes an extremely rare and life-threatening condition of tension enterothorax and hepatothorax, which should be considered in the differential diagnosis of acute respiratory distress with tracheal deviation.

Personality differences among junior postgraduate trainees in the United Kingdom.

IMPORTANCE: An early understanding of the personality profiles of junior trainees may be valuable for supporting the professional and educational development of tomorrow's doctors. OBJECTIVE: This study aims to describe the personality profile of junior trainees and to explore whether the personality profiles differed according to the level of training, specialty choice, or gender. DESIGN: The Mental Muscle Diagram Indicator was distributed electronically. SETTING: South West London, Health Education England South London. PARTICIPANTS: A total of 157 junior trainees completed the personality questionnaire. Specifically, there were core surgical (n = 40), core medical (n = 24), and foundation trainees (n = 93). RESULTS: The preferential profile across all groups was Extroversion (E), Sensing (S), Feeling (F), and Perception (P). More foundation doctors favored an extrovert and sensing personality when compared with core trainees (72% vs 60.4% and 77.4% vs 57.5%, respectively). More core surgical trainees appeared to prefer Extroversion when compared with their medical counterparts (66.7% vs 54.2%). More core medical trainees favored an intuitive behavior when compared with their surgical colleagues (50% vs 35%). Significantly, more female trainees (83.3%) displayed an extrovert personality than male trainees (66.7%) did. CONCLUSIONS: According to the Mental Muscle Diagram Indicator analysis, this work shows that the more junior the trainees are in their career, the more they tend to enjoy human interaction and to favor acting before thinking. The most junior trainees tend to be slightly more interested in dealing with facts rather than ideas and favor a flexible approach of life. The reducing ratio of Extroversion and Sensing in the core trainees when compared with foundation doctors may suggest that clinical experience has an effect on personality. As trainees begin to progress, they may tend to reflect more on their practice and to start thinking about more long term. These results suggest that a greater understanding of their personality preferences and how they might change with experience may help trainees to develop a greater personal and professional insight.

Improving the accuracy of operation coding in surgical discharge summaries.

Procedural coding in surgical discharge summaries is extremely important; as well as communicating to healthcare staff which procedures have been performed, it also provides information that is used by the hospital's coding department. The OPCS code (Office of Population, Censuses and Surveys Classification of Surgical Operations and Procedures) is used to generate the tariff that allows the hospital to be reimbursed for the procedure. We felt that the OPCS coding on discharge summaries was often incorrect within our breast and endocrine surgery department. A baseline measurement over two months demonstrated that 32% of operations had been incorrectly coded, resulting in an incorrect tariff being applied and an estimated loss to the Trust of £17,000. We developed a simple but specific OPCS coding table in collaboration with the clinical coding team and breast surgeons that summarised all operations performed within our department. This table was disseminated across the team, specifically to the junior doctors who most frequently complete the discharge summaries. Re-audit showed 100% of operations were accurately coded, demonstrating the effectiveness of the coding table. We suggest that specifically designed coding tables be introduced across each surgical department to ensure accurate OPCS codes are used to produce better quality surgical discharge summaries and to ensure correct reimbursement to the Trust.

An overview of laparoscopic techniques in abdominal aortic aneurysm repair.

BACKGROUND: Since 1993, various laparoscopic techniques have been developed to make laparoscopic treatment of abdominal aortic aneurysms (AAAs) a possible therapeutic alternative. We aim to review all published clinical studies on laparoscopic surgery of AAAs and juxtarenal abdominal aortic aneurysms (JAAAs). METHODS: A thorough search of English-language literature published between January 1966 and December 2012 was performed. Studies that reported the results of laparoscopic surgical procedures as the intended repair strategy in patients with AAAs and JAAAs were selected using specific inclusion criteria. Only case series containing more than five patients were included. Outcome measures of eligible studies were extracted, tabulated, and then analyzed cumulatively, using a purely descriptive approach. RESULTS: Fourteen studies were included in the analysis encompassing 933 patients with AAAs (mean age, 68.5 years; age range, 46-88) averaging 55.8 mm in diameter and 96 patients with JAAAs (mean age, 71 years; age range, 50-81) averaging 57 mm in diameter. The mean follow-up was 15.3 months for the AAA cases and 32.8 months for the JAAA cases. Hand-assisted laparoscopy, in particular, had a low 30-day mortality rate, short cross-clamping and operative times, few perioperative and postoperative complications, high graft patency rates, and short length of both hospital and intensive care unit stay. CONCLUSIONS: Laparoscopic surgical procedures are a safe, feasible, and worthwhile alternative for patients with AAAs and JAAAs. Hand-assisted laparoscopy, in particular, was associated with low morbidity and mortality and short hospital and intensive care unit stay. However, the final decision regarding the best laparoscopic treatment should be left to the surgeon because of the limits of the data.