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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., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

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., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

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., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

The optic nerve sheath is a rare site for schwannoma, to our knowledge 19 optic nerve sheath schwannoma (ONSS) cases have been reported. Difficulty can arise in diagnosis as imaging findings can be relatively non-specific. We describe a case of ONSS that mimicked orbital cavernous venous malformation pre-operatively. A 43-year-old woman presented with right subacute visual loss, reduced vision to 6/48 and signs of optic neuropathy. Endocapsular excision of the mass, which was adherent to the optic nerve, was accomplished from an endoscopic endonasal approach utilizing a 5-hand technique of retrocaruncular dissection. Histology showed spindle-shaped tumour cells with S100 positivity, consistent with ONSS. At 6 months post-operatively vision had improved to 6/6. We show that an endoscopic endonasal approach, augmented by transcaruncular retraction, can be utilized to excise ONSS with an excellent outcome. We review published cases of ONSS, including demographic and clinical features, differential diagnosis based on radiological features, and described outcomes, which are generally poor., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Microglia, the resident immune cells of the central nervous system, are intimately involved in the brain's most basic processes, from pruning neural synapses during development to preventing excessive neuronal activity throughout life. Studies have reported both helpful and harmful roles for microglia at the blood-brain barrier (BBB) in the context of disease. However, less is known about microglia-endothelial cell interactions in the healthy brain. To investigate the role of microglia at a healthy BBB, we used the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia and analyzed the BBB ultrastructure, permeability, and transcriptome. Interestingly, we found that, despite their direct contact with endothelial cells, microglia are not necessary for the maintenance of BBB structure, function, or gene expression in the healthy brain. However, we found that PLX5622 treatment alters brain endothelial cholesterol metabolism. This effect was independent from microglial depletion, suggesting that PLX5622 has off-target effects on brain vasculature., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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/β-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.

Purpose of Review: We reviewed a wide body of emerging research highlighting the possibility for premenstrual exacerbations of mood symptoms in polycystic ovary syndrome (PCOS)., Recent Findings: Neuroendocrine dysregulation, sensitivity to ovarian hormone fluctuations as well as higher levels and types of adverse childhood experiences and demographic factors are emerging factors explaining high rates of psychiatric disorders in PCOS. Ovulatory dysfunction, common in PCOS, significantly interferes with one's identity and quality of life. Results on pharmacologic and non-pharmacologic treatments for mood symptoms are mixed, though improvements in the physical sequalae of PCOS could also improve mood symptoms. However, significant improvements on the methodological quality are needed, particularly the evaluation of mood symptoms across the menstrual cycle. Evidence is preliminary on whether there are premenstrual exacerbations of psychiatric symptoms in PCOS. Prospective, longitudinal studies with larger sample sizes are needed to comprehensively understand the psychiatric profile in PCOS., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We report the case of a man in his 50s who developed acute respiratory distress syndrome and right heart failure, necessitating intubation and initiation of inhaled nitric oxide (iNO) to decrease right ventricular afterload and improve the right heart function. The course was complicated by acute anaemia, with a diagnostic workup revealing methaemoglobinaemia and evidence of oxidative haemolysis indicated by blister and bite cells on peripheral blood film. The patient received conservative management, including successive red blood cell transfusion and gradual iNO weaning due to suspected glucose-6-phosphate dehydrogenase (G6PD) deficiency. Discontinuation of iNO led to the resolution of both oxidative haemolysis and methaemoglobinaemia. Subsequent enzymatic assay, conducted 4 months later, confirmed G6PD deficiency. This case highlights a rare instance of concurrent methaemoglobinaemia and oxidative haemolytic anaemia following iNO in a patient with underlying G6PD deficiency., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

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, Ca 2+ 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 Ca 2+ 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., Competing Interests: Conflict of Interests: Authors declare no conflict of interests.

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., (Copyright © 1964–2024 by MedWorks Media Inc, Los Angeles, CA All rights reserved. Printed in the United States.)

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.

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 novel 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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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.

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 β cell replacement including the use of SC-islets or other types of novel cells in clinical settings., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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.

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.

(1) Background: CD163, a specific macrophage receptor, affects the progression of malignant tumors. Unfortunately, the regulation and expression of CD163 are poorly understood. In this study, we determined the expressions of CD163 in TMA samples from CRC patients and combined them with patient data from several Swedish hospitals. (2) Methods: The expressions of CD163 in tissue samples from CRC patients were examined. After combining 472 CRC patients’ gene expression and 438 CRC patients’ clinical data with the TCGA database, 964 cases from the GEO database, and experimental expression data from 1247 Swedish CRC patients, we selected four genes (PCNA, LOX, BCL2, and CD163) and analyzed the tumor-infiltrating immune cells (TICs) and CRC prognosis. (3) Results: Based on histopathological TMA analysis, CD163 was strongly expressed in the stroma of both normal and cancer tissues, and the expressions in normal and cancer cells varied from negative to strong. The results from public databases show decreased expression of CD163 in cancer tissue compared to normal mucosa (|log FC| > 1 and FDR < 0.01), and it is a negative prognostic factor for CRC patients (p-value < 0.05). Through tumor microenvironment (TME) analysis, we found a potential influence of CD163 on immune cell infiltration. Furthermore, the enrichment analysis indicated the possible interaction with other proteins and biological pathways. (4) Conclusions: CD163 is expressed differently in CRC tissue and is a negative prognostic factor. Its expression is associated with the TME and tumor purity of CRC. Considering all results, CD163 has the potential to be a predictive biomarker in the investigation of CRC.

Background: Acute myeloid leukemia (AML) is associated with poor prognosis, particularly in elderly patients with comorbidities. Combining azacitidine (AZA) with BCL-2 inhibitor venetoclax (VEN) demonstrated significant improvement in outcomes for newly-diagnosed AML patients compared to AZA alone. However, this regimen is myelosuppressive, and the incidence of invasive fungal infections (IFIs) and impact of antifungal prophylaxis are not well defined., Methods: This retrospective cohort study evaluated newly-diagnosed AML patients treated with VEN/AZA at the University of Colorado Hospital from January 2014 to August 2020. Patients with history of prior IFI were excluded. Primary outcome was IFI incidence during VEN/AZA therapy. χ 2 and Fisher exact tests assessed the impact of patient demographics, AML-specific risk factors, and receipt of antifungal prophylaxis on IFI incidence., Results: 144 VEN/AZA-treated AML patients were included in the study. 25 (17%) patients developed IFI: 8% (n = 2) "proven," 24% (n = 6) "probable," and 68% (n = 17) "possible" per European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium criteria. There was no statistically significant association between IFI incidence with age, sex, or European LeukemiaNet classification. 10 patients received antifungal prophylaxis; none developed IFI. IFI incidence rate per 1000 patient-days was greatest 0-9 days after starting VEN/AZA, at 8.39., Conclusions: Incidence of "proven" and "probable" IFI in our VEN/AZA-treated AML cohort was 5.6%, in-line with incidence rates reported by recent similar studies. Furthermore, IFI incidence decreased as days from starting VEN/AZA therapy increased., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The synthetic lethal association between BRCA deficiency and poly (ADP-ribose) polymerase (PARP) inhibition supports PARP inhibitor (PARPi) clinical efficacy in BRCA-mutated tumors. PARPis also demonstrate activity in non-BRCA mutated tumors presumably through induction of PARP1-DNA trapping. Despite pronounced clinical response, therapeutic resistance to PARPis inevitably develops. An abundance of knowledge has been built around resistance mechanisms in BRCA-mutated tumors, however, parallel understanding in non-BRCA mutated settings remains insufficient. In this study, we find a strong correlation between the epithelial-mesenchymal transition (EMT) signature and resistance to a clinical PARPi, Talazoparib, in non-BRCA mutated tumor cells. Genetic profiling demonstrates that SNAI2, a master EMT transcription factor, is transcriptionally induced by Talazoparib treatment or PARP1 depletion and this induction is partially responsible for the emerging resistance. Mechanistically, we find that the PARP1 protein directly binds to SNAI2 gene promoter and suppresses its transcription. Talazoparib treatment or PARP1 depletion lifts PARP1-mediated suppression and increases chromatin accessibility around SNAI2 promoters, thus driving SNAI2 transcription and drug resistance. We also find that depletion of the chromatin remodeler CHD1L suppresses SNAI2 expression and reverts acquired resistance to Talazoparib. The PARP1/CHD1L/SNAI2 transcription axis might be therapeutically targeted to re-sensitize Talazoparib in non-BRCA mutated tumors., (© 2022. The Author(s).)

Islet transplantation to treat insulin-dependent diabetes is greatly limited by the need for maintenance immunosuppression. We report a strategy through which cotransplantation of allogeneic islets and streptavidin (SA)-FasL-presenting microgels to the omentum under transient rapamycin monotherapy resulted in robust glycemic control, sustained C-peptide levels, and graft survival in diabetic nonhuman primates for >6 months. Surgical extraction of the graft resulted in prompt hyperglycemia. In contrast, animals receiving microgels without SA-FasL under the same rapamycin regimen rejected islet grafts acutely. Graft survival was associated with increased number of FoxP3 + cells in the graft site with no significant changes in T cell systemic frequencies or responses to donor and third-party antigens, indicating localized tolerance. Recipients of SA-FasL microgels exhibited normal liver and kidney metabolic function, demonstrating safety. This localized immunomodulatory strategy succeeded with unmodified islets and does not require long-term immunosuppression, showing translational potential in β cell replacement for treating type 1 diabetes.

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., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

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.

Differential expressions and functions of various micoRNAs (miRNAs) have been intensively studied in both colon and rectal cancers. However, the importance of miRNAs on radiotherapy (RT) response and clinical outcome in rectal cancer patients remains unclear. In this study, we used real-time polymerase chain reaction to examine the expressions of miR-302a, miR-105, and miR-888 in normal mucosa and cancer tissue from rectal cancer patients with and without preoperative RT. The biological function of miR-302a, miR-105, and miR-888 expression was further analyzed and identified through the public databases: TCGA (The Cancer Genome Atlas) and GEPIA (Gene Expression Profiling Interactive Analysis). The results showed that the expression of miR-105 in rectal cancer was higher than that in normal mucosa in RT ( P = 0.042) and non-RT patients ( P = 0.003) and was associated with mucinous histological type ( P = 0.004), COX-2 ( P = 0.042), and p73 expression ( P = 0.030). The expression of miR-302a was shown more frequently in cancers with necrosis ( P = 0.033) and with WRAP53 expression ( P = 0.015), whereas miR-888 expression occurred more frequently in tumors with protein the expression of survivin ( P = 0.015), AEG-1 (astrocyte elevated gene-1) ( P = 0.003), and SATB1 (special AT-rich sequence binding protein 1) ( P = 0.036). Moreover, TargetScan also predicted AEG-1 and SATB1 as putative targets for miR-888. The miRNA-gene network analysis showed that ABI2 was associated with all the three miRNAs, with lower expression and good diagnostic value in rectal cancers. The TCGA database demonstrated the association of miR-105 expression with high carcinoembryonic antigen level ( P = 0.048). RT reduced the expressions of miR-302a, miR-105, and miR-888. Prognostic analysis showed that miR-888 expression was independently associated with worse survival of patients without RT [overall survival, P = 0.001; disease-free survival, P = 0.009]. Analysis of biological function revealed that the protein serine/threonine kinase activity and PI3K-AKT signaling pathway were the most significantly enriched functions and pathways, respectively. Our findings suggest that miR-105 is involved in rectal cancer pathogenesis and miR-888 is associated with prognosis. MiR-302a, miR-105, and miR-888 have potential influence on the pathogenesis, RT, and prognosis of rectal cancer., (Copyright © 2020 Meng, Pathak, Zhang, Adell, Jarlsfelt, Holmlund, Wang, Zhang, Zhang, Zhou and Sun.)

Previous studies have shown that forced expression of core cardiogenic transcription factors can directly reprogram fibroblasts to induced cardiomyocyte-like cells (iCMs). This cardiac reprogramming approach suggests a potential strategy for cardiomyocyte regeneration. However, a major challenge of this approach remains the low conversion rate. Here, we showed that ensuring expression of four cardiogenic transcription factors (i.e. Gata4 (G), Hand2 (H), Mef2c (M), and Tbx5 (T)) in individual fibroblasts is an initial bottleneck for cardiac reprogramming. Following co-transduction of three or four retroviral vectors encoding individual cardiogenic transcription factors, only a minor subpopulation of cells indeed expressed all three (GMT) or four (GHMT) factors. By selectively analyzing subpopulations of cells expressing various combinations of reprogramming factors, we found that co-expression of GMT in individual fibroblasts is sufficient to induce sarcomeric proteins. However, only a small fraction of those cells expressing GMT were able to develop organized sarcomeric structures and contractility. In contrast, ensuring expression of GHMT markedly enhanced the development of contractile cardiac structures and functions in fibroblasts, although its incremental effect on sarcomeric protein induction was relatively small. Our findings provide new insights into the mechanistic basis of inefficient cardiac reprogramming and can help to devise efficient reprogramming strategies.

Interactive and integrative data visualization tools and libraries are integral to exploration and analysis of genomic data. Web based genome browsers allow integrative data exploration of a large number of data sets for a specific region in the genome. Currently available web-based genome browsers are developed for specific use cases and datasets, therefore integration and extensibility of the visualizations and the underlying libraries from these tools is a challenging task. Genomic data visualization and software libraries that enable bioinformatic researchers and developers to implement customized genomic data viewers and data analyses for their application are much needed. Using recent advances in core web platform APIs and technologies including Web Components, we developed the Epiviz Component Library, a reusable and extensible data visualization library and application framework for genomic data. Epiviz Components can be integrated with most JavaScript libraries and frameworks designed for HTML. To demonstrate the ease of integration with other frameworks, we developed an R/Bioconductor epivizrChart package, that provides interactive, shareable and reproducible visualizations of genomic data objects in R, Shiny and also create standalone HTML documents. The component library is modular by design, reusable and natively extensible and therefore simplifies the process of managing and developing bioinformatic applications., Competing Interests: No competing interests were disclosed.

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.

Circumferential defects following salvage pharyngolaryngectomy present significant challenges in reconstructive surgery. The gastro-omental free flap has been shown to reduce the incidence of major fistula and catastrophic complications. The current technique for harvest of the flap requires laparotomy, which is potentially associated with significant post-operative complications. Laparoscopic harvest of the gastro-omental free flap can negate some of the risks associated with open surgery. We describe here the operative technique for laparoscopic gastro-omental free flap harvest for use in reconstruction following total pharyngolaryngectomy. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1696-1698, 2017., (© 2017 Wiley Periodicals, Inc.)

Background: Episodic or recurrent sinonasal symptoms are often suspected as "sinus" in origin. With normal sinus radiology between events, the diagnosis of recurrent acute rhinosinusitis (RecARS) is made. However, other conditions can produce episodic symptoms. In this study we analyze acutely performed computed tomography (CT) in a population with suspected or self-diagnosed "sinus" disease., Methods: Patients referred to a tertiary clinic for suspected RecARS were assessed. Sinus changes were defined by CT (initial assessment) and during the acute event, by a semiurgent CT performed during the symptomatic episode. Mucosal thickening, ostiomeatal compromise, and severe septal deformity were recorded. Symptom profile was assessed during both time-points with the 22-item Sino-Nasal Outcome Test (SNOT-22)., Results: Forty-eight patients (49.5 ± 14.7 years of age, 70.8% female) were assessed. At presentation, 75% were resolute in a diagnosis of "sinus." Baseline Lund-Mackay scores were <6 (median 0 [interquartile range 1]). Ostiomeatal compromise was 6.8% left and 4.5% right at baseline. Of the patients who returned for acute CT (n = 27), SNOT-22 and subdomains were similar to baseline. Septal deviation was similar (13.6% vs 15.3%). Acutely, ostiomeatal compromise was 0% left and 7.4% right (n = 2). Of these 2 patients with ostiomeatal compromise, 1 was diagnosed with RecARS (4%) and the other with triptan-responsive migraine, with incidental sinus changes. Final diagnosis was rhinitis (47%), headache/migraine (37%), and facial pain otherwise undefined (12.5%)., Conclusion: Patients with a history of "recurrent acute sinusitis" and normal CT scans between episodes rarely have abnormal CT findings during acute exacerbations of symptoms. Antibiotics and surgical intervention are often inappropriate in this population., (© 2017 ARS-AAOA, LLC.)

Recent studies have demonstrated the frequency selectivity of air-conducted (AC) and bone-conducted (BC) stimuli in eliciting ocular vestibular evoked myogenic potentials (oVEMPs). In this study, frequency tuning of the oVEMP was assessed in patients with superior canal dehiscence (SCD) and compared with responses previously reported for healthy subjects. Six (five unilateral) SCD patients were stimulated using AC sound (50-1,200 Hz) and BC transmastoid vibration (50-1,000 Hz). Stimuli were delivered at two standardized intensities: one the same as previously used for healthy controls and the other at 10 dB above vestibular threshold (a similar relative intensity to that used in controls). For AC stimulation, SCD patients had larger oVEMP amplitudes across all frequencies tested for both stimulus intensities. Normalized tuning curves demonstrated greater high-frequency responses with the stronger stimulus. For BC stimulation, larger oVEMP amplitudes were produced at frequencies at and above 100 Hz using standard intensity stimuli. For the matched intensity above vestibular threshold, enhancement of the oVEMP response was present in SCD patients for 500-800 Hz only. We conclude that SCD causes greater facilitation for AC than BC stimuli. The high-frequency response is likely to originate from the superior (anterior) canal and is consistent with models of inner ear changes occurring in SCD.

Ocular vestibular evoked myogenic potentials (oVEMPs) are a recently described clinical measure of the vestibulo-ocular reflex. Studies demonstrating differences in frequency tuning between air-conducted and bone-conducted (BC) oVEMPs suggest a separate vestibular (otolith) origin for each stimulus modality. In this study, 10 healthy subjects were stimulated with BC stimuli using a hand-held minishaker. Frequencies were tested in the range of 50-1,000 Hz using both a constant-force and constant-acceleration method. Subjects were stimulated at the mastoid process and the forehead. For constant-force stimulation at both sites, maximum acceleration occurred around 100 Hz, in differing axes. Both forms of stimulation had low-frequency peaks of oVEMP amplitudes (constant force: mastoid, 80-150 Hz; forehead, 50-125 Hz; constant acceleration: mastoid, 100-200 Hz; forehead, 80-150 Hz), for both sites of application, despite differences in the magnitude and direction of evoked head acceleration. For mastoid stimulation, ocular responses changed from out of phase to in phase for 400 Hz and above. Our results demonstrate that BC stimuli show tuning around 100 Hz, independent of stimulus site, that is not due to skull properties. The findings are consistent with an effect on a receptor with a resonance around 100 Hz, most likely the utricle.

The ocular vestibular evoked myogenic potential (oVEMP) is a relatively new method used to assess otolith-ocular pathways in humans. When elicited using air-conducted (AC) sound stimulation, the oVEMP is thought to reflect mostly saccular activation. However, it has been recently suggested that utricular afferents may also contribute to the AC evoked oVEMP. While previous frequency tuning studies of the AC evoked oVEMP report predominately high frequency sensitivity (>400 Hz), few have included the lower frequencies (<200 Hz) at which it has been proposed the utricle is most sensitive. In this study, ten normal subjects were stimulated with AC sound delivered unilaterally using headphones over frequencies from 50 to 1,200 Hz at a near constant A-weighted intensity of 120 dB peak sound pressure level. For AC stimulation, the oVEMP demonstrated maximum amplitudes around 600 Hz, with a second, smaller peak occurring around 100 Hz. The AC evoked oVEMP tuning has two peaks, a dominant one consistent with excitation of the saccule and a smaller one consistent with excitation of the utricle.