Mechanical strain influence on functional signaling of neurons in vitro

Neuronal cells are embedded in the soft brain tissue and are protected by the thick meninges, as well as the rigid skull bones. Despite being highly sensitive and vastly protected, neurons are prone to internal and external mechanical forces. Many internal tensile loading scenarios affect neurons during development, growth and blood flow. Moreover, neurons are exposed to be strained externally by regular body movements or to be severely injured as a result of serious falls, accidents or tumor formation. In specific cases neuronal tissue could be dissected where intercellular connections get an entire cut and may cause cell death for some neurons in a network, such as the case of brain surgery to remove a tumor or to implant a neurostimulator device. However, limited experimental data is available for the mechanobiology of brain cells and it remained quite unattended. Beside the chemical and molecular cues, some studies reported the importance of the mechanical input in nervous tissue homeostasis. Latest studies, show the key role of the physical microenvironment, such as topographical cues and stiffness alterations. Moreover, reports on physiological cyclic mechanical strain show the potential to accelerate axonal growth. While strain induced responses on the molecular and structural levels has been identified, much less is known about the consequences of these changes to neuronal functionality. As neurons are the basic functional units in transmitting information in the nervous system, the functional behavior of neurons under mechanical strain is the focus of this dissertation. In the context of this thesis, primary cortical neurons were functionally characterized upon exposure to physiological and traumatic uniaxial stretch conditions within different developing stages. Also, spontaneous signaling events were characterized upon single cellular compartment loss induced by laser ablation. The dynamic changes in cells was determined by recording spatial and temporal changes in Ca2+ concentrations ([Ca2+]) of single-cells and on synchronized network level using the Cal-590 AM Ca2+ indicator. The focus here is on both the immediate cell response and to their long-term adaptation to mechanical strain. This work shows that neurons are robust and can functionally tolerate cyclic stretching of up to 30% strain by keeping active communication between cells no matter if strain is applied at different periods during neuronal network formation. Simulating traumatic brain injuries using rapid stretch pulses identified a threshold for functional impairment of about 60% with a high ability to adapt and restore cellular connectivity with time. In spite of the broad range of assessed strains, cells keep maintained without further effects on cell viability, inflammatory responses or synapse formation. Co-cultures with astrocytes revealed more stable and better communicating networks while functional responses to strain remained unaffected. Laser-induced death of single cellular compartment resulted in an increased intracellular calcium concentration [Ca2+]i in neurons surrounding the ablated point. The [Ca2+]i-increase was distance-dependent as closely connected neurons to the ablated cell were highly affected by Ca2+ inflow compared with other cells. Furthermore, the increased [Ca2+]i caused a temporarily interruption in neuronal spiking activity that recovered gradually with time. In spite of the distance-dependent alterations, the overall network functionality was unaffected and the level of connectivity was maintained in the long-term analysis. Taken together, this research work illustrates the internal dynamic responses of neurons to multiple loading conditions and to single-cell death. These data will be advantageous in developing more effective neuronal tolerance criteria to injury. Understanding and pushing the limits of nerve stretch holds tremendous potential for tissue engineering efforts to prevent nervous system injury and facilitate nerve repair

Reservoir formation in shallow granular flows through a contraction

We consider flow of dry granular matter down an inclined chute with a localized contraction. Measurements and analysis show that changes in particle volume fraction are important, especially across granular bores. For fixed upstream conditions and depending on the nozzle width of the contraction, we observe either small oblique jumps, a reservoir with a steady jump, or a reservoir with an upstream traveling bore. Shallow layer theory extended to include porosity changes qualitatively predicts these regimes. Implications for volcanic debris \ud ows are discussed

The role of artificial intelligence in prospective real-time histological prediction of colorectal lesions during colonoscopy: a systematic review and meta-analysis

Artificial intelligence (AI) presents a novel platform for improving disease diagnosis. However, the clinical utility of AI remains limited to discovery studies, with poor translation to clinical practice. Current data suggests that 26% of diminutive pre-malignant lesions and 3.5% of colorectal cancers are missed during colonoscopies. The primary aim of this study was to explore the role of artificial intelligence in real-time histological prediction of colorectal lesions during colonoscopy. A systematic search using MeSH headings relating to “AI”, “machine learning”, “computer-aided”, “colonoscopy”, and “colon/rectum/colorectal” identified 2290 studies. Thirteen studies reporting real-time analysis were included. A total of 2958 patients with 5908 colorectal lesions were included. A meta-analysis of six studies reporting sensitivities (95% CI) demonstrated that endoscopist diagnosis was superior to a computer-assisted detection platform, although no statistical significance was reached (p = 0.43). AI applications have shown encouraging results in differentiating neoplastic and non-neoplastic lesions using narrow-band imaging, white light imaging, and blue light imaging. Other modalities include autofluorescence imaging and elastic scattering microscopy. The current literature demonstrates that despite the promise of new endoscopic AI models, they remain inferior to expert endoscopist diagnosis. There is a need to focus developments on real-time histological predictions prior to clinical translation to demonstrate improved diagnostic capabilities and time efficiency

Prognostic and predictive utility of GPD1L in human hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. GPD1L, a member of the glycerol-3-phosphate dehydrogenase family, has emerged as a potential tumour suppressor gene, with high expression associated with a favourable prognosis in various cancers. Despite an intriguing inverse relationship observed with HCC, the precise role and underlying function of GPD1L in HCC remain poorly understood. Here, we aimed to investigate the prognostic significance, molecular characteristics, and predictive potential of GPD1L overexpression in HCC. Analysis of independent datasets revealed a significant correlation between high GPD1L expression and poor survival in HCC patients. Spatial and single cell transcriptome datasets confirmed elevated GDP1L expression in tumour tissue compared to adjacent normal tissue. GPD1L exhibited increased expression and promoter demethylation with advancing tumour stage, confirming positive selection during tumorigeneses. GPD1L overexpression was associated with metabolic dysregulation and enrichment of gene sets related to cell cycle control, epithelial-mesenchymal transition, and E2F targets. Moreover, we demonstrated an inverse correlation between GPD1L expression and therapeutic response for three therapeutic agents (PF-562271, Linsitinib, and BMS-754807), highlighting its potential as a predictive biomarker for HCC treatment outcomes. These data provide insights into the prognostic significance, molecular characteristics, and predictive potential of GPD1L in HCC

Evaluation of the oesophagogastric cancer associated microbiome: a systematic review and quality assessment

Objective. Oesophagogastric cancer is the fifth most common cancer worldwide, with poor survival outcomes. The role of bacteria in the pathogenesis of oesophagogastric cancer remains poorly understood. Design. A systematic search identified studies assessing the oesophagogastric cancer microbiome. The primary outcome was to identify bacterial enrichment specific to oesophagogastric cancer. Secondary outcomes included appraisal of the methodology, diagnostic performance of cancer bacteria and the relationship between oral and tissue microbiome. Results. A total of 9295 articles were identified, and 87 studies were selected for analysis. Five genera were enriched in gastric cancer: Lactobacillus, Streptococcus, Prevotella, Fusobacterium and Veillonella. No clear trends were observed in oesophageal adenocarcinoma. Streptococcus, Prevotella and Fusobacterium were abundant in oesophageal squamous cell carcinoma. Functional analysis supports the role of immune cells, localised inflammation and cancer-specific pathways mediating carcinogenesis. STORMS reporting assessment identified experimental deficiencies, considering batch effects and sources of contamination prevalent in low-biomass samples. Conclusions. Functional analysis of cancer pathways can infer tumorigenesis within the cancer–microbe–immune axis. There is evidence that study design, experimental protocols and analytical techniques could be improved to achieve more accurate and representative results. Whole-genome sequencing is recommended to identify key metabolic and functional capabilities of candidate bacteria biomarkers

Teaching to transform surgical culture: an educational programme and thematic analysis in a general surgery department

Introduction General surgery departments are busy, meaning educational opportunities may be sporadic. Clinical priorities can sometimes supersede teaching and trainees may feel alienated at the periphery of the working community. In this study, we demonstrate how a reflective, multidisciplinary general surgery teaching programme was established and use this to assess the impact of structured teaching on surgical doctors of all grades in the department. Methods Twelve semi-structured telephone interviews were conducted with participants of varying grades. Transcripts were analysed using a grounded theory thematic analysis, revealing four themes: the value of teaching; learning as a community; barriers to successful training; and culture of surgery. Discussion Teaching helped juniors construct healthy narratives around general surgery and encouraged a process of professional identity formation. Pairing junior and senior colleagues allowed both to develop their skills, and reflective learning revealed new learning opportunities. Transparency across the ‘community of practice’ was achieved and the programme helped juniors overcome negative stereotypes of intimidation embedded in the hidden surgical curriculum. Conclusion Reflective, multidisciplinary learning can challenge the hidden curriculum and encourage team cohesion. A commitment to critical reflective teaching will be vital in cultivating surgeons of the future

Risk factors for unexpected admission following arthroscopic and open treatment of shoulder instability: a national database study of 11,230 cases

Background Shoulder instability procedures have low morbidity; however, complications can arise that result in readmission to an inpatient healthcare facility. The purpose of this study is to identify the demographics and risk factors associated with unplanned 30-day readmission and reoperation following arthroscopic and open treatment for shoulder instability. Methods The American College of Surgeons National Surgical Quality Improvement Program database was queried to find patients who underwent shoulder instability surgery from 2015 to 2019. Independent sample Student t-tests, chi-square, and (where appropriate) Fisher’s exact tests were used in univariate analyses to identify demographic, lifestyle, and perioperative variables related to 30-day readmission and reoperation following repair for shoulder instability. Multivariate logistic regression modeling was subsequently performed. Results Of the 11,230 cases included in our sample, only 0.54% were readmitted, and 0.23% underwent reoperation within the 30-day postoperative period. Multivariate logistic regression modeling confirmed that the following patient variables were associated with statistically significantly increased odds of readmission and reoperation: open repair, congestive heart failure (CHF), and hospital length of stay. Conclusions Unplanned 30-day readmission and reoperation after shoulder instability surgery is infrequent. Patients with American Society of Anesthesiologists class II, CHF, longer than average hospital length of stay, or an open procedure have higher odds of readmission than patients without those factors. Patients who have CHF, longer than average hospital length of stay, and open surgery have higher odds of reoperation than others. Arthroscopic procedures should be used to manage shoulder instability, if possible. Level of evidence III

Liver transplantation for non-resectable liver metastases from colorectal cancer: a systematic review and meta-analysis

Backgrounds Colorectal liver metastases were historically considered a contraindication to liver transplantation, but dismal outcomes for those with metastatic colorectal cancer and advancements in liver transplantation (LT) have led to a renewed interest in the topic. We aim to compare the current evidence for liver transplantation for non-resectable colorectal liver metastases (NRCLM) with the current standard treatment of palliative chemotherapy. Methods A systematic review and meta-analysis of proportions was conducted following screening of MEDLINE, EMBASE, SCOPUS and CENTRAL for studies reporting liver transplantation for colorectal liver metastases. Post-operative outcomes measured included one-, three- and five-year survival, overall survival, disease-free survival and complication rate. Results Three non-randomised studies met the inclusion criteria, reporting a total of 48 patients receiving LT for NRCLM. Survival at one-, three- and five-years was 83.3–100%, 58.3–80% and 50–80%, respectively, with no significant difference detected (p = 0.22, p = 0.48, p = 0.26). Disease-free survival was 35–56% with the most common site of recurrence being lung. Thirteen out of fourteen deaths were due to disease recurrence. Conclusion Although current evidence suggests a survival benefit conferred by LT in NRCLM compared to palliative chemotherapy, the ethical implications of organ availability and allocation demand rigorous justification. Concomitant improvements in the management of patients following liver resection and of palliative chemotherapy regimens is paramount