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BackgroundColorectal carcinoma (CRC) has emerged as one of the most widespread cancers and was the third leading cause of cancer-related mortality in 2020. The role of the podosomal protein Tks4 in tumor formation and progression is well established, including its involvement in gastric carcinoma and hepatocellular carcinoma; however, exploration of Tks4 and its associated EMT-regulating interactome in the context of colon cancer remains largely unexplored.MethodsWe conducted a comprehensive bioinformatic analysis to investigate the mRNA and protein expression levels of Tks4 and its associated partner molecules (CD2AP, GRB2, WASL, SRC, CTTN, and CAPZA1) across different tumor types. We quantified the expression levels of Tks4 and its partner molecules using qPCR, utilizing a TissueScan colon cancer array. We then validated the usefulness of Tks4 and its associated molecules as biomarkers via careful statistical analyses, including Pearson’s correlation analysis, principal component analysis (PCA), multiple logistic regression, confusion matrix analysis, and ROC analysis.ResultsOur findings indicate that the co-expression patterns of the seven examined biomarker candidates better differentiate between tumor and normal samples compared with the expression levels of the individual genes. Moreover, variable importance analysis of these seven genes revealed four core genes that yield consistent results similar to the seven genes. Thus, these four core genes from the Tks4 interactome hold promise as potential combined biomarkers for colon adenocarcinoma diagnosis and prognosis.ConclusionOur proposed biomarker set from the Tks4 interactome shows promising sensitivity and specificity, aiding in colon cancer prevention and diagnosis.

Landmark trials (Z0011 and AMAROS) have demonstrated that axillary lymph node dissection (ALND) can be safely omitted in patients with breast cancer and 1–2 positive sentinel nodes. Extrapolating from these and other cardinal studies such as NSABP B-04, guidelines state that patients with 1–2 needle biopsy-proven positive lymph nodes undergoing upfront surgery can have sentinel lymph node biopsy (SLNB) alone. The purpose of this study is to systematically review the literature to identify studies examining the direct application of SLNB in such patients. EMBASE and Ovid MEDLINE were searched from inception to 3 May 2022. Studies including patients with nodal involvement confirmed on pre-operative biopsy and undergoing SLNB were identified. Studies with neoadjuvant chemotherapy were excluded. Search resulted in 2518 records, of which 68 full-text studies were reviewed, ultimately yielding only 2 studies meeting inclusion criteria. Both studies used targeted axillary surgery (TAS) with pre-operative localization of the biopsy-proven positive node in addition to standard SLNB techniques. In a non-randomized single-center prospective study, Lee et al. report no regional recurrences in patients undergoing TAS or ALND, and no difference in distant recurrence or mortality at 5 years. In the prospective multicenter TAXIS trial by Webber et al., the median number of positive nodes retrieved with TAS in patients undergoing upfront surgery was 2 (1, 4 IQR). Within the subset of patients who underwent subsequent ALND, 61 (70.9%) had additional positive nodes, with 26 (30.2%) patients having ≥4 additional positive nodes. Our review demonstrates that there is limited direct evidence for SLNB alone in clinically node-positive patients undergoing upfront surgery. Available data suggest a high proportion of patients with residual disease in this setting. While the totality of the data, mostly indirect evidence, suggests SLNB alone may be safe, we call on clinicians and researchers to prospectively collect data on this patient population to better inform decision-making.

Abstract Background With over 26% of Canadian adults living with obesity, undergraduate medical education (UGME) should prepare medical students to manage this chronic disease. It is currently unknown how the management of patients living with obesity is taught within UGME curricula in Canada. This study (1) examined the knowledge and self-reported competence of final-year medical students in managing patients living with obesity, and (2) explored how this topic is taught within UGME curricula in Canada. Methods We distributed two online surveys: one to final-year medical students, and another to UGME deans at 9 English-speaking medical schools in Canada. The medical student survey assessed students’ knowledge and self-reported competence in managing patients living with obesity. The dean’s survey assessed how management of patients living with obesity is taught within the UGME curriculum. Results One hundred thirty-three (6.9%) and 180 (9.3%) out of 1936 eligible students completed the knowledge and self-reported competence parts of the survey, respectively. Mean knowledge score was 10.5 (2.1) out of 18. Students had greatest knowledge about etiology of obesity and goals of treatment, and poorest knowledge about physiology and maintenance of weight loss. Mean self-reported competence score was 2.5 (0.86) out of 4. Students felt most competent assessing diet for unhealthy behaviors and calculating body mass index. Five (56%) out of 9 deans completed the survey. A mean of 14.6 (5.0) curricular hours were spent on teaching management of patients living with obesity. Nutrition and bariatric surgery were most frequently covered topics, with education delivered most often via large-group sessions and clinical activities. Conclusions Canadian medical students lack adequate knowledge and feel inadequately prepared to manage patients living with obesity. Changes to UGME curricula may help address this gap in education.

Abstract Molecular descriptor (2D) and three dimensional (3D) shape based similarity methods are widely used in ligand based virtual drug design. In the present study pairwise structure comparisons among a set of 4858 DTP compounds tested in the NCI60 tumor cell line anticancer drug screen were computed using chemical hashed fingerprints and 3D molecule shapes to calculate 2D and 3D similarities, respectively. Additionally, pairwise biological activity similarities were calculated by correlating the 60 element vectors of pGI50 values corresponding to the cytotoxicity of the compounds across the NCI60 panel. Subsequently, we compared the power of 2D and 3D structural similarity metrics to predict the toxicity pattern of compounds. We found that while the positive predictive value and sensitivity of 3D and molecular descriptor based approaches to predict biological activity are similar, a subset of molecule pairs yielded contradictory results. By simultaneously requiring similarity of biological activities and 3D shapes, and dissimilarity of molecular descriptor based comparisons, we identify pairs of scaffold hopping candidates displaying characteristic core structural changes such as heteroatom/heterocycle change and ring closure. Attempts to discover scaffold hopping candidates of mitoxantrone recovered known Topoisomerase II (Top2) inhibitors, and also predicted new, previously unknown chemotypes possessing in vitro Top2 inhibitory activity.

Gastrocolic fistulas are observed in association with several conditions. Traditionally, peptic ulcer disease was commonly implicated in the formation of gastrocolic fistulas; however, this is now a rare etiology. Here, we present a case of gastrocolic fistula secondary to peptic ulcer disease alone, in addition to reviewing the literature and providing options for diagnosis and treatment.

We have assembled a network of cell-fate determining transcription factors that play a key role in the specification of the ventral neuronal subtypes of the spinal cord on the basis of published transcriptional interactions. Asynchronous Boolean modelling of the network was used to compare simulation results with reported experimental observations. Such comparison highlighted the need to include additional regulatory connections in order to obtain the fixed point attractors of the model associated with the five known progenitor cell types located in the ventral spinal cord. The revised gene regulatory network reproduced previously observed cell state switches between progenitor cells observed in knock-out animal models or in experiments where the transcription factors were overexpressed. Furthermore the network predicted the inhibition of Irx3 by Nkx2.2 and this prediction was tested experimentally. Our results provide evidence for the existence of an as yet undescribed inhibitory connection which could potentially have significance beyond the ventral spinal cord. The work presented in this paper demonstrates the strength of Boolean modelling for identifying gene regulatory networks.

BackgroundEffective management and care of diabetes is crucial to reducing associated risks such as heart disease and kidney failure. With increasing access and use of the Internet, online chronic disease management is being explored as a means of providing patients with support and the necessary tools to monitor and manage their disease. ObjectiveThe objective of our study was to evaluate the experience of patients and providers using an online diabetes management portal for patients. MethodsParticipants were recruited from a large sample population of 887 for a follow-up questionnaire to be completed after 6 months of using the patient portal. Participants were presented with the option to participate in an additional interview and, if the participant agreed, a time and date was scheduled for the interview. A 5-item, open-ended questionnaire was used to capture providers' opinions of the patient portal. Providers included general practitioners (GPs), nurses, nurse practitioners (NPs), dieticians, diabetes educators (DECs), and other clinical staff. ResultsA total of 854 patients were consented for the questionnaire. Seventeen (8 male, 9 female) patients agreed to participate in a telephone interview. Sixty-four health care providers completed the five open-ended questions; however, an average of 48.2 responses were recorded per question. Four major themes were identified and will be discussed in this paper. These themes have been classified as: facilitators of disease management, barriers to portal use, patient-provider communication and relationship, and recommendations for portal improvements. ConclusionsThis qualitative study shows that online chronic disease management portals increase patient access to information and engagement in their health care, but improvements in the portal itself may improve usability and reduce attrition. Furthermore, this study identifies a grey area that exists in the roles that GPs and AHPs should play in the facilitation of online disease management.

Abstract Background The progress through the eukaryotic cell division cycle is driven by an underlying molecular regulatory network. Cell cycle progression can be considered as a series of irreversible transitions from one steady state to another in the correct order. Although this view has been put forward some time ago, it has not been quantitatively proven yet. Bifurcation analysis of a model for the budding yeast cell cycle has identified only two different steady states (one for G1 and one for mitosis) using cell mass as a bifurcation parameter. By analyzing the same model, using different methods of dynamical systems theory, we provide evidence for transitions among several different steady states during the budding yeast cell cycle. Results By calculating the eigenvalues of the Jacobian of kinetic differential equations we have determined the stability of the cell cycle trajectories of the Chen model. Based on the sign of the real part of the eigenvalues, the cell cycle can be divided into excitation and relaxation periods. During an excitation period, the cell cycle control system leaves a formerly stable steady state and, accordingly, excitation periods can be associated with irreversible cell cycle transitions like START, entry into mitosis and exit from mitosis. During relaxation periods, the control system asymptotically approaches the new steady state. We also show that the dynamical dimension of the Chen's model fluctuates by increasing during excitation periods followed by decrease during relaxation periods. In each relaxation period the dynamical dimension of the model drops to one, indicating a period where kinetic processes are in steady state and all concentration changes are driven by the increase of cytoplasmic growth. Conclusion We apply two numerical methods, which have not been used to analyze biological control systems. These methods are more sensitive than the bifurcation analysis used before because they identify those transitions between steady states that are not controlled by a bifurcation parameter (e.g. cell mass). Therefore by applying these tools for a cell cycle control model, we provide a deeper understanding of the dynamical transitions in the underlying molecular network.

Morbid obesity is considered a relative contraindication for liver transplantation (LTX) because of increased risk of complications. The aim of this study was to investigate the role of bariatric surgery before, during, and after LTX. A systematic review of MEDLINE, EMBASE, CENTRAL, and PubMed databases was performed for studies investigating bariatric surgery in patients before, during, or after LTX. Random-effects meta-analysis of proportions was used to calculate pooled effect estimates. One hundred eighty-seven patients underwent bariatric surgery before LTX (8 studies). After surgery, 82% (95% confidence interval, 62%–97%) of patients were successfully listed for LTX and 70% (95% confidence interval, 40%–93%) successfully received LTX. The 30-day mortality rate was 0%. The graft survival rate after 1 year was 70% (95% confidence interval, 30%–99%). Thirty-day minor and major complications rate was 4% and 1%, respectively. Thirty-two patients underwent bariatric surgery during LTX (2 studies). The 30-day mortality rate after surgery was 0% and 1-year graft survival was 100%. Sixty-four patients underwent bariatric surgery after LTX (9 studies). The 30-day mortality was 0%, but 5 deaths occurred beyond 30 days (7.8%). Bariatric surgery may be safe and feasible as a bridge to LTX for patients who would otherwise be ineligible and post-LTX patients for weight loss. [ABSTRACT FROM AUTHOR]

In 2013, 18% of Canadian adults had obesity (body mass index [BMI] >30 kg/m2), compared with 25.7% of Canada's Indigenous population. Bariatric surgery is an effective treatment for obesity, but has not been studied in Canadian Indigenous populations. To determine the effects of bariatric surgery in the Indigenous Ontario population. Multicenter data from the publicly funded Ontario bariatric program and registry. Prospectively collected data using all surgical patients between March 2010 and 2018 was included in initial analysis and included the following postoperative outcomes: diabetes, hypertension, and gastroesophageal reflux disease. Demographic characteristics, baseline characteristics, and univariate outcomes were assessed using Pearson Χ2 or t tests. Multivariable regression for BMI change was used with complete case analysis and multiple imputation. Of 16,629 individuals initially identified, 338 self-identified as Indigenous, 13,502 as Non-Indigenous, and 2789 omitted ethnicity and were excluded. Baseline demographic characteristics were not statistically different; rates of hypertension (P =.03) and diabetes (P <.001) were higher in the Indigenous population. Univariable analysis showed similar 1-year BMI change (Indigenous: 15.8 ± 6.0 kg/m2; Non-Indigenous: 16.1 ± 5.6 kg/m2, P =.362). After adjustment, BMI change was not different between groups at 6 months (effect size =.07, 95% confidence interval −.45 to.58, P =.803) and 1 year (effect size = −.24, 95% confidence interval −.93 to.45, P =.489). Rates of co-morbidities were similar at 1 year between the 2 populations, despite differences at baseline. Six-month and 1-year follow-up rates were higher in the Non-Indigenous population (P <.001, P =.005, respectively). Weight loss and resolution of obesity-related co-morbidities are similar in Indigenous and Non-Indigenous patients. Access to surgery, patient selection, and long-term results merit further investigation. • Similar baseline comorbidities; higher rate of hypertension, diabetes in Indigenous • Indigenous patients undergo similar preoperative care to Non-Indigenous • Indigenous patients have higher rates of comorbidity resolution post-operatively [ABSTRACT FROM AUTHOR]

Background Preoperative breast magnetic resonance imaging (mri) is commonly requested by surgeons in the initial workup of women with breast cancer; however, its use is controversial. We performed a survey of breast cancer surgeons across Canada to investigate current knowledge about, attitudes to, and self-reported use of preoperative breast mri in a publicly funded health care system in light of the limited evidence to support it. Methods All identified general surgeons in Canada were mailed a survey instrument designed to probe current practice and knowledge of published trials. Results Of 403 responding surgeons, 233 (58%) indicated that they performed breast cancer surgery. Of those 233, 218 (94%) had access to breast mri and completed the entire survey. Overall, 54.6% of responding surgeons felt that breast mri was useful in surgical planning, and more than half (58.3%) indicated that their frequency of use was likely to increase over the next 5 years. Surgeons found preoperative mri most useful in detecting mammographically occult disease (71.5% of respondents) and in planning for breast-conserving surgery (57.3%). The main limitations reported were timely access to mri (51%) and false positives (36.7%). Responses suggest a knowledge gap in awareness of published trials in breast mri. Conclusions Our study found that, in early-stage breast cancer, self-reported use of mri by breast cancer surgeons in Canada varied widely. Reported indications did not align with published data, and significant gaps in self-reported knowledge of the data were evident. Our results would support the development and dissemination of guidelines to optimize use of mri. [ABSTRACT FROM AUTHOR]

Background Recently the impact of completion axillary lymph node dissection (cALND) after positive sentinel lymph node biopsy on significant outcomes has been questioned, leading to variation in surgical practice. To address this variation, a multidisciplinary working group created a regional guideline for cALND. We explored the views and experiences of surgeons, medical oncologists (MOs), radiation oncologists (ROs) in a qualitative study that examined guideline implementation in practice. Methods The Pathman framework (awareness, agreement, adoption and adherence) informed the interview guide design and analysis. Semi-structured interviews were conducted with MOs, ROs and surgeons and transcribed. Transcripts were coded independently by 2 members of the study team and analyzed. Disagreements were resolved through consensus. Results Twenty-eight physicians (5 MO; 6RO; 17S) of 41 (68% of those approached) were interviewed. Ten of 11 (91%) hospital sites (54% community; 46% academic) and all 4 cancer clinics within the region were represented. Twenty-seven physicians (96%) were aware of the guideline, with all physicians reporting agreement and general adherence to the guideline. Most physicians indicated nodal factors, age and patient preference were key components of cALND decision-making. Physicians from all disciplines perceived that the guideline helped reduce variation in practice across the region. There were concerns that the guideline could be applied rigidly and not permit individual decision-making. Conclusions Physicians identified breast cancer as an increasingly complex and multidisciplinary issue. Facilitators to guideline implementation included perceived flexibility and buy-in from all disciplines, while individual patient factors and controversial supporting evidence may hinder its implementation. [ABSTRACT FROM AUTHOR]

Abstract: Background: We surveyed Canadian General Surgeons to examine decision-making in early stage breast cancer. Methods: A modified Dillman Method was used for this mail survey of 1443 surgeons. Practice patterns and factors that influence management choices for: preoperative assessment, definition of margin status, surgical techniques and recommendations for re-excision were assessed. Results: The response rate was 51% with 41% treating breast cancer. Most (80%) were community surgeons, with equal distribution of low/medium/high volume and years of practice categories. Approximately 25% of surgeons “sometimes or frequently” performed diagnostic excisional biopsies while 90% report “frequently” or “always” performing preoperative core biopsies. There was marked variation in defining negative and close margins, in the use of intra-operative margin assessment techniques and recommendations for re-excision. Conclusions: Responses revealed significant variation in attitudes and practices. These findings likely reflect an absence of consensus in the literature and potential gaps between best evidence and practice. [Copyright &y& Elsevier]