Emerging clinical role of proprotein convertase subtilisin/kexin type 9 inhibition-Part two: Current and emerging concepts in the clinical use of PCSK9 inhibition.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as a novel class of drugs with cardioprotective effects through their lipid-lowering effects. OBJECTIVE: This review aims to discuss existing and novel strategies of PCSK9 inhibition, providing an overview of established randomized controlled trials and ongoing outcome trials that assess the efficacy and long-term safety of PCSK9 inhibitors. It also explores the evolving role of PCSK9 beyond lipid metabolism and outlines the pleiotropic actions of PCSK9 inhibition in various disorders and future directions including novel strategies to target PCSK9. CONCLUSION: PCSK9 inhibition shows promise not only in lipid metabolism but also in other disease processes, including atherosclerotic plaque remodeling, acute coronary syndrome, stroke, inflammation, and immune response.

Emerging clinical role of proprotein convertase subtilisin/kexin type 9 inhibition-Part one: Pleiotropic pro-atherosclerotic effects of PCSK9.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily recognized for its role in lipid metabolism, but recent evidence suggests that it may have broader implications due to its diverse tissue expression. OBJECTIVE: This review aims to explore the multifaceted functions of PCSK9, highlighting its pro-atherosclerotic effects, including its impact on circulating lipoprotein variables, non-low-density lipoprotein receptors, and various cell types involved in atherosclerotic plaque development. CONCLUSIONS: PCSK9 exhibits diverse roles beyond lipid metabolism, potentially contributing to atherosclerosis through multiple pathways. Understanding these mechanisms could offer new insights into therapeutic strategies targeting PCSK9 for cardiovascular disease management.

A Review on Emerging Techniques for Diagnosis of Colorectal Cancer.

Common detection methods in practice for diagnosing colorectal cancer (CRC) are painful and invasive leading to less participation of individuals for CRC diagnosis. Whereas, improved or enhanced imaging systems and other minimally invasive techniques with shorter detection times deliver greater detail and less discomfort in individuals. Thus, this review is a summary of the diagnostic tests, ranging from the simple potential use in developing a flexible CRC treatment to the patient's potential benefits in receiving less invasive procedures and the advanced treatments that might provide a better assessment for the diagnosis of CRC and reduce the mortality related to CRC.

Novel compounds that synergize with aminoglycoside G418 or eRF3 degraders for translational readthrough of nonsense mutant TP53 and PTEN.

The TP53 and PTEN tumour suppressor genes are inactivated by nonsense mutations in a significant fraction of human tumours. TP53 nonsense mutatant tumours account for approximately one million new cancer cases per year worldwide. We have screened chemical libraries with the aim of identifying compounds that induce translational readthrough and expression of full-length p53 protein in cells with nonsense mutation in this gene. Here we describe two novel compounds with readthrough activity, either alone or in combination with other known readthrough-promoting substances. Both compounds induced levels of full-length p53 in cells carrying R213X nonsense mutant TP53. Compound C47 showed synergy with the aminoglycoside antibiotic and known readthrough inducer G418, whereas compound C61 synergized with eukaryotic release factor 3 (eRF3) degraders CC-885 and CC-90009. C47 alone showed potent induction of full-length PTEN protein in cells with different PTEN nonsense mutations. These results may facilitate further development of novel targeted cancer therapy by pharmacological induction of translational readthrough.

Negative DNA supercoiling makes protein-mediated looping deterministic and ergodic within the bacterial doubling time.

Protein-mediated DNA looping is fundamental to gene regulation and such loops occur stochastically in purified systems. Additional proteins increase the probability of looping, but these probabilities maintain a broad distribution. For example, the probability of lac repressor-mediated looping in individual molecules ranged 0-100%, and individual molecules exhibited representative behavior only in observations lasting an hour or more. Titrating with HU protein progressively compacted the DNA without narrowing the 0-100% distribution. Increased negative supercoiling produced an ensemble of molecules in which all individual molecules more closely resembled the average. Furthermore, in only 12 min of observation, well within the doubling time of the bacterium, most molecules exhibited the looping probability of the ensemble. DNA supercoiling, an inherent feature of all genomes, appears to impose time-constrained, emergent behavior on otherwise random molecular activity.

Recreating the microscopic direct access Draf 2a frontal sinusotomy in the endoscopic era and comparison to an angled instrument approach.

PURPOSE: Microscopic Draf 2a frontal sinusotomy relied on direct access. However, the modern-day endoscopic approach is hindered by the anterior-posterior dimensions of the frontal recess. The nasofrontal beak, angled endoscopes, and variable frontal recess anatomy make the surgery challenging. Carolyn's window frontal sinusotomy removes the limitation of anterior-posterior dimensions and is an endoscopic version of the microscopic Draf 2a. This study aims to compare the perioperative outcomes and morbidity from endoscopic direct access Draf 2a compared to angled access Draf 2a. METHODS: Consecutive adult patients (> 18 years) seen at a tertiary referral clinic who underwent Draf 2a frontal sinus surgery using either endoscopic direct access (Carolyn's window) or endoscopic angled instrumentation were included. Patients who underwent Carolyn's window were compared to those with angled Draf 2a frontal sinusotomy. RESULTS: One hundred patients (age 51.96 ± 15.85 years, 48.0% female, follow-up 60.75 ± 17.34 months) were included. 44% of patients used Carolyn's window approach. 100% [95% CI 98.2-100%] of patients achieved successful frontal sinus patency. Both groups were comparable for early morbidities (bleeding, pain, crusting, and adhesions) and late morbidities (retained frontal recess partitions). There were no other morbidities in the early and late postoperative periods. CONCLUSION: The endoscopic direct access Draf 2a, or Carolyn's window, removes the anteroposterior diameter limitation. The frontal sinus patency and early and late surgical morbidities of direct access Draf 2a were comparable with the angled Draf 2a frontal sinusotomy. Surgical modifications, often with drills and bone removal, can be successfully made to enhance access in endoscopic sinus surgery without concern for additional morbidity.

Intrapleural transplantation of allogeneic pancreatic islets achieves glycemic control in a diabetic non-human primate.

Clinical islet transplantation has relied almost exclusively on intraportal administration of pancreatic islets, as it has been the only consistent approach to achieve robust graft function in human recipients. However, this approach suffers from significant loss of islet mass from a potent immediate blood-mediated inflammatory response (IBMIR) and a hypoxic environment. To avoid these negative aspects of the portal site, we explored an alternative approach in which allogeneic islets were transplanted into the intrapleural space of a non-human primate (NHP), treated with an immunosuppression regimen previously reported to secure routine survival and tolerance to allogeneic islets in NHP. Robust glycemic control and graft survival were achieved for the planned study period of >90 days. Our observations suggest the intrapleural space provides an attractive locale for islet transplantation due to its higher oxygen tension, ability to accommodate large transplant tissue volumes, and a lack of IBMIR-mediated islet damage. Our preliminary results reveal the promise of the intrapleural space as an alternative site for clinical islet transplantation in the treatment of type 1 diabetes.

Differential expression and transcription factor binding associated with genotype at a pharmacogenetic variant in OPRD1.

BACKGROUND: The functional mechanism is unknown for many genetic variants associated with substance use disorder phenotypes. Rs678849, an intronic variant in the delta-opioid receptor gene (OPRD1), has been found to predict regional brain volume, addiction risk, and the efficacy of buprenorphine/naloxone in treating opioid use disorder. The variant has also been implicated as an expression quantitative trait locus (eQTL) for several genes. OBJECTIVES: The objective of this study was to identify functional differences between the two alleles of rs678849 in vitro. We hypothesized that the two alleles of rs678849 would have different effects on transcriptional activity due to differential interactions with transcription factors. METHODS: 15bp regions containing the C or T alleles of rs678849 were cloned into luciferase constructs and transfected into BE(2)C neuroblastoma cells to test the effect on transcription. Electrophoretic mobility shift assays (EMSA) using nuclear lysates from BE(2)C cell or human postmortem medial prefrontal cortex were used to identify proteins that differentially bound the two alleles. RESULTS: At 24 hours post-transfection, the C allele construct had significantly lower luciferase expression than the T allele construct and empty vector control (ANOVA p < .001). Proteomic analysis and supershift assays identified XRCC6 as a transcription factor specifically binding the C allele, whereas hnRNP D0 was found to specifically bind the T allele. CONCLUSION: These functional differences between the C and T alleles may help explain the psychiatric and neurological phenotype differences predicted by rs678849 genotype and the potential role of the variant as an eQTL.

Metaviz: interactive statistical and visual analysis of metagenomic data.

Large studies profiling microbial communities and their association with healthy or disease phenotypes are now commonplace. Processed data from many of these studies are publicly available but significant effort is required for users to effectively organize, explore and integrate it, limiting the utility of these rich data resources. Effective integrative and interactive visual and statistical tools to analyze many metagenomic samples can greatly increase the value of these data for researchers. We present Metaviz, a tool for interactive exploratory data analysis of annotated microbiome taxonomic community profiles derived from marker gene or whole metagenome shotgun sequencing. Metaviz is uniquely designed to address the challenge of browsing the hierarchical structure of metagenomic data features while rendering visualizations of data values that are dynamically updated in response to user navigation. We use Metaviz to provide the UMD Metagenome Browser web service, allowing users to browse and explore data for more than 7000 microbiomes from published studies. Users can also deploy Metaviz as a web service, or use it to analyze data through the metavizr package to interoperate with state-of-the-art analysis tools available through Bioconductor. Metaviz is free and open source with the code, documentation and tutorials publicly accessible.

Pilot Validation of a 3-Dimensional Printed Pituitary Adenoma, Vascular Injury, and Cerebrospinal Fluid Leak Surgical Simulator.

BACKGROUND AND OBJECTIVES: Endoscopic skull base surgery is a subspecialty field which would benefit significantly from high-fidelity surgical simulators. Giving trainees the opportunity to flatten their learning curve by practicing a variety of procedures on surgical simulators will inevitably improve patient outcomes. METHODS: Four neurosurgeons, 8 otolarynologists, and 6 expert course faculty agreed to participate. All participants were asked to perform a transsphenoidal exposure and resection of a pituitary adenoma, repair a cerebrospinal fluid (CSF) leak, control a carotid injury, and repair a skull base defect. The content, face, and construct validity of the 3-dimensional printed model was examined. RESULTS: The heart rate of the participants significantly increased from baseline when starting the carotid injury simulation (mean 90 vs 121, P = .029) and significantly decreased once the injury was controlled (mean 121 vs 110, P = .033, respectively). The participants reported a significant improvement in anxiety in facing a major vascular injury, as well as an increase in their confidence in management of major vascular injury, resecting a pituitary adenoma and repair of a CSF leak using a 5-point Likert scale (mean 4.42 vs 3.58 P = .05, 2 vs 3.25 P < .001, 2.36 vs 4.27 P < .001 and 2.45 vs 4.0 P = .001, respectively). The mean Objective Structured Assessment of Technical Skills score for experienced stations was 4.4, significantly higher than the Objective Structured Assessment of Technical Skills score for inexperienced stations (mean 3.65, P = .016). CONCLUSION: We have demonstrated for the first time a validated 3-dimensional printed surgical simulator for endoscopic pituitary surgery that allows surgeons to practice a transsphenoidal approach, surgical resection of a pituitary adenoma, repair of a CSF leak in the diaphragma sellae, control of a carotid injury, and repair of skull base defect.

A Unique Delusion with Depression in Early Stage of Neurocognitive Disorder Due to Vascular Disease: Considerations for Clinicians.

As global aging becomes more prominent, neurocognitive disorders (NCD) incidence has increased. Patients with NCD usually have an impairment in one or more cognitive domains, such as attention, planning, inhibition, learning, memory, language, visual perception, and spatial or social skills. Studies indicate that 50-80% of these adults will develop neuropsychiatric symptoms (NPS), such as apathy, depression, anxiety, disinhibition, delusions, hallucinations, and aberrant motor behavior. The progression of NCD and subsequent NPS requires tremendous care from trained medical professionals and family members. The behavioral symptoms are often more distressing than cognitive changes, causing caregiver distress/depression, more emergency room visits and hospitalizations, and even earlier institutionalization. This signifies the need for early identification of individuals at higher risk of NPS, understanding the trajectory of their NCD, and exploring treatment modalities. In this case report and review, we present an 82-year-old male admitted to our facility for new-onset symptoms of depression, anxiety, and persecutory delusions. He has no significant past psychiatric history, and his medical history is significant for extensive ischemic vascular disease requiring multiple surgeries and two episodes of cerebrovascular accident (CVA). On further evaluation, the patient was diagnosed with major NCD, vascular subtype. We discuss differential diagnoses and development of NPS from NCD in order to explain the significance of more thorough evaluation by clinicians for early detection and understanding of NCD prognosis.

SLO2.1/NALCN Functional Complex Activity in Mouse Myometrial Smooth Muscle Cells During Pregnancy.

At the end of pregnancy, the uterus transitions from a quiescent to a highly contractile state. This is partly due to depolarization of the resting membrane potential in uterine (myometrial) smooth muscle cells (MSMCs). Experiments with human MSMCs showed that the membrane potential is regulated by a functional complex between the sodium (Na+)-activated potassium (K+) channel SLO2.1 and the Na+ Leak Channel Non-Selective (NALCN). In human MSMCs, Na+ entering through NALCN activates SLO2.1, leading to K+ efflux, membrane hyperpolarization (cells become more negative inside), and reduced contractility. Decreased SLO2.1/NALCN activity results in reduced K+ efflux, leading to membrane depolarization, Ca2+ influx via voltage-dependent calcium channels, and increased MSMC contractility. However, all of these experiments were performed with MSMCs isolated from women at term, so the role of the SLO2.1/NALCN complex early in pregnancy was speculative. To address this question here, we examined the role of the SLO2.1/NALCN complex in regulating mouse MSMC membrane potential across pregnancy. We report that Slo2.1 and Nalcn expression change along pregnancy, being more highly expressed in MSMCs from non-pregnant and early pregnant mice than in those from late-pregnant mice. Functional studies revealed that SLO2.1 channels mediate a significant portion of the K+ current in mouse MSMCs, particularly in cells from non-pregnant and early pregnant mice. Activation of SLO2.1 by Na+ influx through NALCN led to membrane hyperpolarization in MSMCs from early pregnancy but not in MSMCs from later pregnancy. Moreover, we found that the NALCN/SLO2.1 complex regulates intracellular Ca2+ responses more in MSMCs from non-pregnant and early pregnancy mice than in MSMCs from late pregnancy. Together, these findings reveal that the SLO2.1/NALCN functional complex is conserved between mouse and humans and functions throughout pregnancy. This work could open avenues for targeted pharmacological interventions in pregnancy-related complications.

Understanding the molecular mechanism responsible for developing therapeutic radiation-induced radioresistance of rectal cancer and improving the clinical outcomes of radiotherapy - A review.

Rectal cancer accounts for the second highest cancer-related mortality, which is predominant in Western civilizations. The treatment for rectal cancers includes surgery, radiotherapy, chemotherapy, and immunotherapy. Radiotherapy, specifically external beam radiation therapy, is the most common way to treat rectal cancer because radiation not only limits cancer progression but also significantly reduces the risk of local recurrence. However, therapeutic radiation-induced radioresistance to rectal cancer cells and toxicity to normal tissues are major drawbacks. Therefore, understanding the mechanistic basis of developing radioresistance during and after radiation therapy would provide crucial insight to improve clinical outcomes of radiation therapy for rectal cancer patients. Studies by various groups have shown that radiotherapy-mediated changes in the tumor microenvironment play a crucial role in developing radioresistance. Therapeutic radiation-induced hypoxia and functional alterations in the stromal cells, specifically tumor-associated macrophage (TAM) and cancer-associated fibroblasts (CAF), play a crucial role in developing radioresistance. In addition, signaling pathways, such as - the PI3K/AKT pathway, Wnt/ß-catenin signaling, and the hippo pathway, modulate the radiation responsiveness of cancer cells. Different radiosensitizers, such as small molecules, microRNA, nanomaterials, and natural and chemical sensitizers, are being used to increase the effectiveness of radiotherapy. This review highlights the mechanism responsible for developing radioresistance of rectal cancer following radiotherapy and potential strategies to enhance the effectiveness of radiotherapy for better management of rectal cancer.

Nondisordered Cannabis Use Among US Adolescents.

Importance: Cannabis use is increasingly viewed by adolescents as not harmful. Youths with cannabis use disorder (CUD) are recognized by clinicians as being at risk for adverse outcomes, yet little is known about the associations between subclinical cannabis use (ie, nondisordered cannabis use [NDCU]) and adverse psychosocial events. Objective: To describe the prevalence and demographics of NDCU and to compare associations of cannabis use with adverse psychosocial events among adolescents with no cannabis use, NDCU, and CUD. Design, Setting, and Participants: This cross-sectional study used a nationally representative sample derived from the 2015 to 2019 National Survey on Drug Use and Health. Participants were adolescents aged 12 to 17 years, separated into 3 distinct groups: nonuse (no recent cannabis use), NDCU (recent cannabis use below diagnostic threshold), and CUD. Analysis was conducted from January to May 2022. Exposures: CUD, NDCU, or cannabis nonuse. NDCU was defined as endorsing recent cannabis use but not meeting the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) CUD criteria. CUD was defined using DSM-5 criteria. Main Outcomes and Measures: The main outcomes were prevalence of adolescents meeting criteria for NDCU and associations between adverse psychosocial events and NDCU, adjusted for sociodemographic characteristics. Results: The 68 263 respondents (mean [SD] age, 14.5 [1.7] years; 34 773 [50.9%] males) included in the analysis represented an estimated yearly mean of 25 million US adolescents during 2015 to 2019. Among respondents, 1675 adolescents (2.5%) had CUD, 6971 adolescents (10.2%) had NDCU, and 59 617 adolescents (87.3%) reported nonuse. Compared with nonusers, individuals with NDCU had approximately 2 to 4 times greater odds of all adverse psychosocial events examined, including major depression (adjusted odds ratio [aOR], 1.86; 95% CI, 1.67-2.08), suicidal ideation (aOR, 2.08; 95% CI, 1.88-2.29), slower thoughts (aOR, 1.76; 95% CI, 1.58-1.96), difficulty concentrating (aOR, 1.81; 95% CI, 1.65-2.00), truancy (aOR, 1.90; 95% CI, 1.67-2.16), low grade point average (aOR, 1.80; 95% CI, 1.62-2.00), arrest (aOR, 4.15; 95% CI, 3.17-5.43), fighting (aOR, 2.04; 95% CI, 1.80-2.31), and aggression (aOR, 2.16; 95% CI, 1.79-2.62). Prevalence of adverse psychosocial events was greatest for adolescents with CUD (range, 12.6% to 41.9%), followed by NDCU (range, 5.2% to 30.4%), then nonuse (range, 0.8% to 17.3%). Conclusions and Relevance: In this cross-sectional study of US adolescents, past-year NDCU was approximately 4 times as prevalent as past-year CUD. A stepwise gradient association was observed for odds of adverse psychosocial events between adolescent NDCU and CUD. In the context of US normalization of cannabis use, prospective research into NDCU is necessary.

Recent Advancements, Limitations, and Future Perspectives of the use of Personalized Medicine in Treatment of Colon Cancer.

Due to the heterogeneity of colon cancer, surgery, chemotherapy, and radiation are ineffective in all cases. The genomic profile and biomarkers associated with the process are considered in personalized medicine, along with the patient's personal history. It is based on the response of the targeted therapies to specific genetic variations. The patient's genetic transcriptomic and epigenetic features are evaluated, and the best therapeutic approach and diagnostic testing are identified through personalized medicine. This review aims to summarize all the necessary, updated information on colon cancer related to personalized medicine. Personalized medicine is gaining prominence as generalized treatments are finding it challenging to contain colon cancer cases which currently rank fourth among global cancer incidence while being the fifth largest in total death cases worldwide. In personalized therapy, patients are grouped into specific categories, and the best therapeutic approach is chosen based on evaluating their molecular features. Various personalized strategies are currently being explored in the treatment of colon cancer involving immunotherapy, phytochemicals, and other biomarker-specific targeted therapies. However, significant challenges must be overcome to integrate personalized medicine into healthcare systems completely. We look at the various signaling pathways and genetic and epigenetic alterations associated with colon cancer to understand and identify biomarkers useful in targeted therapy. The current personalized therapies available in colon cancer treatment and the strategies being explored to improve the existing methods are discussed. This review highlights the advantages and limitations of personalized medicine in colon cancer therapy. The current scenario of personalized medicine in developed countries and the challenges faced in middle- and low-income countries are also summarized. Finally, we discuss the future perspectives of personalized medicine in colon cancer and how it could be integrated into the healthcare systems.

Endoscopic Endonasal Biopsy for Diagnosis of Undifferentiated Lesions of the Cavernous Sinus.

BACKGROUND: Radiologically undifferentiated lesions of the cavernous sinus can pose a diagnostic challenge. Although radiotherapy is the mainstay for treatment of cavernous sinus lesions, histologic diagnosis allows access to a wide variety of alternative treatment modalities. The region is considered a high-risk area for open transcranial surgical access, and the endoscopic endonasal approach presents an alternative technique for biopsy. METHODS: A retrospective case series was performed of all patients undergoing endoscopic endonasal biopsy of isolated cavernous sinus lesions at 2 tertiary institutions. The primary outcomes were the percentage of patients in whom a histologic diagnosis was achieved and the proportion of patients in whom therapy differed from radiotherapy alone. Secondary outcomes included preoperative and postoperative 22-item Sino-Nasal Outcome Test symptom scores, as well as perioperative adverse outcomes. RESULTS: Eleven patients underwent endoscopic endonasal biopsy, with a diagnosis achieved in 10 patients. The most common diagnosis was perineural spread of squamous cell carcinoma, followed by perineuroma and single cases of metastatic melanoma, metastatic adenoid cystic carcinoma, mycobacterium lepri infection, neurofibroma, and lymphoma. Six patients had treatments other than radiotherapy, including immunotherapy, antibiotics, corticosteroids, chemotherapy, and observation alone. There was no significant difference in prebiopsy and postbiopsy 22-item Sino-Nasal Outcome Test scores. There was 1 case of epistaxis requiring return to theater for cautery of the sphenopalatine artery and there were no mortalities. CONCLUSIONS: In a limited case series, endoscopic endonasal biopsy was safe and effective in obtaining diagnosis for cavernous sinus lesions and had a significant impact on therapeutic decision making.

A concise review on miRNAs as regulators of colon cancer stem cells and associated signalling pathways.

Despite recent therapy advances and a better understanding of colon cancer biology, it remains one of the major causes of death. The cancer stem cells, associated with the progression, metastasis, and recurrence of colon cancer, play a major role in promoting the development of tumour and are found to be chemo resistant. The stroma of the tumour, which makes up the bulk of the tumour mass, is composed of the tumour microenvironment. With the advent of theranostic and the development of personalised medicine, miRNAs are becoming increasingly important in the context of colon malignancies. A holistic understanding of the regulatory roles of miRNAs in cancer cells and cancer stem cells will allow us to design effective strategies to regulate miRNAs, which could lead to improved clinical translation and creating a potent colon cancer treatment strategy. In this review paper, we briefly discuss the history of miRNA as well as the mechanisms of miRNA and cancer stem cells that contribute to the tumour growth, apoptosis, and advancement of colon cancer. The usefulness of miRNA in colorectal cancer theranostic is further concisely reviewed. We conclude by holding a stance in addressing the prospects and possibilities for miRNA by the disclosure of recent theranostic approaches aimed at eradicating cancer stem cells and enhancing overall cancer treatment outcomes.

An Updated Review on Molecular Biomarkers in Diagnosis and Therapy of Colorectal Cancer.

Colorectal cancer is one of the most common cancer types worldwide. Since colorectal cancer takes time to develop, its incidence and mortality can be treated effectively if it is detected in its early stages. As a result, non-invasive or invasive biomarkers play an essential role in the early diagnosis of colorectal cancer. Many experimental studies have been carried out to assess genetic, epigenetic, or protein markers in feces, serum, and tissue. It may be possible to find biomarkers that will help with the diagnosis of colorectal cancer by identifying the genes, RNAs, and/or proteins indicative of cancer growth. Recent advancements in the molecular subtypes of colorectal cancer, DNA methylation, microRNAs, long noncoding RNAs, exosomes, and their involvement in colorectal cancer have led to the discovery of numerous new colorectal cancer biomarkers. In small-scale investigations, most biomarkers appear promising. However, large-scale clinical trials are required to validate their effectiveness before routine clinical implementation. Hence, this review focuses on small-scale investigations and results of big data analysis that may provide an overview of the biomarkers for the diagnosis, therapy, and prognosis of colorectal cancer.

Bioengineered omental transplant site promotes pancreatic islet allografts survival in non-human primates.

The transplanting islets to the liver approach suffers from an immediate posttransplant loss of islets of more than 50%, progressive graft dysfunction over time, and precludes recovery of grafts should there be serious complications such as the development of teratomas with grafts that are stem cell-derived islets (SC-islets). The omentum features an attractive extrahepatic alternative site for clinical islet transplantation. We explore an approach in which allogeneic islets are transplanted onto the omentum, which is bioengineered with a plasma-thrombin biodegradable matrix in three diabetic non-human primates (NHPs). Within 1 week posttransplant, each transplanted NHP achieves normoglycemia and insulin independence and remains stable until termination of the experiment. Success was achieved in each case with islets recovered from a single NHP donor. Histology demonstrates robust revascularization and reinnervation of the graft. This preclinical study can inform the development of strategies for ß cell replacement including the use of SC-islets or other types of novel cells in clinical settings.

Association of MicroRNA-652 Expression with Radiation Response of Colorectal Cancer: A Study from Rectal Cancer Patients in a Swedish Trial of Preoperative Radiotherapy.

BACKGROUND: Radiotherapy is a standard adjuvant therapy in patients with progressive rectal cancer, but many patients are resistant to radiotherapy, leading to poor prognosis. Our study identified microRNA-652 (miR-652) value on radiotherapy response and outcome in rectal cancer patients. METHODS: miR-652 expression was determined by qPCR in primary rectal cancer from 48 patients with and 53 patients without radiotherapy. The association of miR-652 with biological factors and the prognosis was examined. The biological function of miR-652 was identified through TCGA and GEPIA database searches. Two human colon cancer cell lines (HCT116 p53+/+ and p53-/-) were used for in vitro study. The molecular interactions of miR-652 and tumor suppressor genes were studied through a computational approach. RESULTS: In RT patients, miR-652 expression was significantly decreased in cancers when compared to non-radiotherapy cases (P = 0.002). High miR-652 expression in non-RT patients was with increased apoptosis marker (P = 0.036), ATM (P = 0.010), and DNp73 expression (P = 0.009). High miR-652 expression was related to worse disease-free survival of non-radiotherapy patients, independent of gender, age, tumor stage, and differentiation (P = 0.028; HR = 7.398, 95% CI 0.217-3.786). The biological functional analysis further identified the prognostic value and potential relationship of miR-652 with apoptosis in rectal cancer. miR-652 expression in cancers was negatively related to WRAP53 expression (P = 0.022). After miR-652 inhibition, the estimation of reactive oxygen species, caspase activity, and apoptosis in HCT116 p53+/+ cells was significantly increased compared with HCT116 p53-/- cells after radiation. The results of the molecular docking analysis show that the miR652-CTNNBL1 and miR652-TP53 were highly stable. CONCLUSION: Our findings suggest the potential value of miR-652 expression as a marker for the prediction of radiation response and clinical outcome in rectal cancer patients.