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The Journal of Biological Chemistry May 2024The metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), inhibits pro-oncogenic signaling in pancreatic cancer (PC). This investigation dissected a novel...
The metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), inhibits pro-oncogenic signaling in pancreatic cancer (PC). This investigation dissected a novel mechanism induced by NDRG1 on WNT/β-catenin signaling in multiple PC cell-types. NDRG1 overexpression decreased β-catenin and down-regulated glycogen synthase kinase-3β (GSK-3β) protein levels and its activation. However, β-catenin phosphorylation at Ser33, Ser37, and Thr41 that are classically induced by GSK-3β were significantly increased after NDRG1 overexpression, suggesting a GSK-3β-independent mechanism. Intriguingly, NDRG1 overexpression up-regulated protein kinase Cα (PKCα), with PKCα silencing preventing β-catenin phosphorylation at Ser33, Ser37, and Thr41, and decreasing β-catenin expression. Further, NDRG1 and PKCα were demonstrated to associate, with PKCα stabilization occurring after NDRG1 overexpression. In fact, PKCα half-life increased from 1.5 ± 0.8 h (3) in control cells to 11.0 ± 2.5 h (3) after NDRG1 overexpression. Thus, NDRG1 overexpression leads to the association of NDRG1 with PKCα and PKCα stabilization, resulting in β-catenin phosphorylation at Ser33, Ser37, and Thr41. In fact, the association between PKCα, NDRG1, and β-catenin was identified, with the formation of a potential metabolon that promotes the latter β-catenin phosphorylation. This anti-oncogenic activity of NDRG1 was multi-modal, with the above mechanism accompanied by the down-regulation of the nucleo-cytoplasmic shuttling protein, p21-activated kinase 4 (PAK4), that is involved in β-catenin nuclear translocation, inhibition of AKT phosphorylation (Ser473), and decreased β-catenin phosphorylation at Ser552 that suppresses its transcriptional activity. These mechanisms of NDRG1 activity are important to dissect to understand the marked anti-cancer efficacy of NDRG1-inducing thiosemicarbazones that up-regulate PKCα and inhibit WNT signaling.
PubMed: 38815861
DOI: 10.1016/j.jbc.2024.107417 -
Cardiorenal Medicine May 2024Congestion, marked by elevated cardiac filling pressures and their repercussions, is a contributing factor to morbidity and mortality in heart failure and critical... (Review)
Review
Congestion, marked by elevated cardiac filling pressures and their repercussions, is a contributing factor to morbidity and mortality in heart failure and critical illness. Relying on traditional methods for bedside evaluation often leads to inadequate decongestion and increased hospital readmissions. Point-of-care ultrasound (POCUS), particularly multi-organ POCUS, including the Venous Excess Ultrasound (VExUS), offers a promising approach in this scenario. VExUS enables the quantification of systemic venous congestion, aiding in fluid overload states by assessing inferior vena cava and venous Doppler waveforms. This comprehensive review delves into the latest developments in comprehending and evaluating congestion, shedding light on technical intricacies to enhance the effective application of VExUS. Recent studies emphasize the importance of evaluating signs of hemodynamic congestion before administering intravenous fluids, highlighting the concept of 'fluid tolerance'. Moreover, VExUS-guided decongestion significantly improves decongestion rates in acute decompensated heart failure patients with acute kidney injury. Newer studies also highlight the prognostic implications of VExUS in the general ICU cohorts not confining to cardiac surgery patients. However, performing VExUS without understanding technical pitfalls may lead to clinical errors. Technical considerations in performing VExUS include nuances related to inferior vena cava and internal jugular vein ultrasound and familiarity with Doppler principles, optimal settings, and artifacts. Additionally, local structural alterations such as those seen in liver and kidney disease impact Doppler waveforms, emphasizing the need for careful interpretation. Overall, VExUS presents a valuable tool for assessing congestion and guiding management, provided clinicians are familiar with its technical complexities and interpret findings judiciously.
PubMed: 38815571
DOI: 10.1159/000539469 -
CA: a Cancer Journal For Clinicians May 2024Tumor-agnostic therapies represent a paradigm shift in oncology by altering the traditional means of characterizing tumors based on their origin or location. Instead,... (Review)
Review
Tumor-agnostic therapies represent a paradigm shift in oncology by altering the traditional means of characterizing tumors based on their origin or location. Instead, they zero in on specific genetic anomalies responsible for fueling malignant growth. The watershed moment for tumor-agnostic therapies arrived in 2017, with the US Food and Drug Administration's historic approval of pembrolizumab, an immune checkpoint inhibitor. This milestone marked the marriage of genomics and immunology fields, as an immunotherapeutic agent gained approval based on genomic biomarkers, specifically, microsatellite instability-high or mismatch repair deficiency (dMMR). Subsequently, the approval of NTRK inhibitors, designed to combat NTRK gene fusions prevalent in various tumor types, including pediatric cancers and adult solid tumors, further underscored the potential of tumor-agnostic therapies. The US Food and Drug Administration approvals of targeted therapies (BRAF V600E, RET fusion), immunotherapies (tumor mutational burden ≥10 mutations per megabase, dMMR) and an antibody-drug conjugate (Her2-positive-immunohistochemistry 3+ expression) with pan-cancer efficacy have continued, offering newfound hope to patients grappling with advanced solid tumors that harbor particular biomarkers. In this comprehensive review, the authors delve into the expansive landscape of tissue-agnostic targets and drugs, shedding light on the rationale underpinning this approach, the hurdles it faces, presently approved therapies, voices from the patient advocacy perspective, and the tantalizing prospects on the horizon. This is a welcome advance in oncology that transcends the boundaries of histology and location to provide personalized options.
PubMed: 38814103
DOI: 10.3322/caac.21844 -
Acta Dermato-venereologica May 2024Martorell hypertensive ischaemic leg ulcer (Martorell HYTILU) is a rare but significant cause of distal leg ulcers. Although hypertension and diabetes are known factors... (Comparative Study)
Comparative Study
Martorell hypertensive ischaemic leg ulcer (Martorell HYTILU) is a rare but significant cause of distal leg ulcers. Although hypertension and diabetes are known factors in its development, the precise pathogenesis of Martorell HYTILU remains elusive. To reach a better understanding of Martorell HYTILU, transcriptomic analysis was conducted through RNA sequencing and immunohistochemical comparison of Martorell HYTILU (n = 17) with chronic venous ulcers (n = 4) and healthy skin (n = 4). Gene expression analysis showed a marked activation of immune-related pathways in both Martorell HYTILU and chronic venous ulcers compared with healthy skin. Notably, neutrophil activity was substantially higher in Martorell HYTILU. While pathway analysis revealed a mild downregulation of several immune pathways in Martorell HYTILU compared with chronic venous ulcers, keratinization, cornification, and epidermis development were significantly upregulated in Martorell HYTILU. Additionally, STAC2, a gene encoding for a protein promoting the expression of the calcium channel Cav1.1, was significantly upregulated in Martorell HYTILU and was detected perivascularly in situ (Martorell HYTILU n = 24; chronic venous ulcers n = 9, healthy skin n = 11). The high expression of STAC2 in Martorell HYTILU suggests that increased calcium influx plays an important role in the pathogenesis of the disease. Consequently, calcium channel antagonists could be a promising treatment avenue for Martorell HYTILU.
Topics: Humans; Male; Female; Varicose Ulcer; Aged; Chronic Disease; Hypertension; Middle Aged; Skin; Ischemia; Gene Expression Profiling; Transcriptome; Case-Control Studies; Leg Ulcer; Aged, 80 and over
PubMed: 38813744
DOI: 10.2340/actadv.v104.40090 -
Expert Review of Vaccines 2024Rotavirus is a leading cause of severe diarrheal disease and death in children under five years of age worldwide. Vaccination is one of the most important public health... (Review)
Review
INTRODUCTION
Rotavirus is a leading cause of severe diarrheal disease and death in children under five years of age worldwide. Vaccination is one of the most important public health interventions to reduce this significant burden.
AREAS COVERED
This literature review examined vaccination coverage, hospitalization rate, mortality, genotypic distribution, immunogenicity, cost-effectiveness, and risk versus benefit of rotavirus vaccination in children in South America. Nine out of twelve countries in South America currently include a rotavirus vaccine in their national immunization program with coverage rates in 2022 above 90%.
EXPERT OPINION
Introduction of the rotavirus vaccination has led to a marked reduction in hospitalizations and deaths from diarrheal diseases in children under 5 years, particularly infants under 1 year, in several South American countries. In Brazil, hospitalizations decreased by 59% and deaths by 21% (30-38% in infants). In Peru, hospitalizations in infants fell by 46% and deaths by 37% (56% in infants). Overall, data suggest that rotavirus vaccination has reduced rotavirus deaths by 15-50% in various South American countries. There is some evidence that immunity wanes after the age of 1-year old. Ongoing surveillance of vaccine coverage and changes in morbidity and mortality is important to maximize protection against this disease.
Topics: Humans; Rotavirus Vaccines; Rotavirus Infections; Diarrhea; Infant; Hospitalization; South America; Child, Preschool; Immunization Programs; Vaccination; Cost-Benefit Analysis; Rotavirus; Vaccination Coverage; Cost of Illness
PubMed: 38813689
DOI: 10.1080/14760584.2024.2360212 -
Ultrasound International Open 2024Arthroscopy is one of the most common interventions in orthopedics. Hence it is important to train users early in order to ensure the safest possible identification...
Arthroscopy is one of the most common interventions in orthopedics. Hence it is important to train users early in order to ensure the safest possible identification of access portals (AP). This prospective study aimed to compare a palpatory (PalpMethod) with a sonographic (SonoMethod) method for AP location in the shoulder and knee joints. The study included trainee doctors (n=68) attending workshops (lasting approx. 90 minutes). In these workshops a teaching video initially demonstrated the PalpMethod and SonoMethod of AP identification. An experienced operator first marked the access portals on the test subject with a UV pen (determined ideal point [DIP]). Adhesive film was then affixed to the puncture regions. Subsequently participants marked on shoulders and knees first the point determined by palpation, then the point determined by sonography. Analysis involved DIP visualization with a UV lamp and employed a coordinate system around the central DIP. In addition, participants completed an evaluation before and after the workshop. The analysis included 324 measurements (n=163 shoulders and n= 161 knees). The majority of participants had not previously attended any courses on manual examination (87.9%) or musculoskeletal ultrasound (93.9%). Overall, the markings participants made on the shoulder using the SonoMethod were significantly closer to the DIP than those made by the PalpMethod (Palp 18.8mm ± 14.5mm vs. Sono 11.2mm ± 7.2mm; p<0.001). On the knee, however, the markings made by the PalpMethod were significantly closer to the DIP overall (Palp 8.0mm ± 3.2mm vs. Sono 12.8mm ± 5.2mm; p<0.001). Conclusion The results show that the SonoMethod produces more accurate markings on the shoulder, while the PalpMethod is superior for the knee.
PubMed: 38812890
DOI: 10.1055/a-2271-0098 -
SAGE Open Medical Case Reports 2024Acute ischemic colitis is a pathology as frequent as it is serious and requires urgent management. It's often occurring in a context of particular thromboembolic or...
Acute ischemic colitis is a pathology as frequent as it is serious and requires urgent management. It's often occurring in a context of particular thromboembolic or hypovolemic risk, but certain clinical situations are not commonly known to provide mesenteric ischemia. Herein, we report the case of a 47-year-old man who presented with a severe acute colitis occurring in the course of acute exacerbation of a chronic obstructive pulmonary diseases with maintained stability of hemodynamic state. The diagnosis of acute ischemic colitis complicating an exacerbation of chronic obstructive pulmonary diseases was made. A clinical and biological improvement quickly marked the patient's condition after the management of the respiratory problem.
PubMed: 38812834
DOI: 10.1177/2050313X241256862 -
Frontiers in Microbiology 2024Cancer remains a significant global health challenge, claiming nearly 10 million lives in 2020 according to the World Health Organization. In the quest for novel... (Review)
Review
Cancer remains a significant global health challenge, claiming nearly 10 million lives in 2020 according to the World Health Organization. In the quest for novel treatments, fungi, especially species, have emerged as a valuable source of bioactive compounds with promising anticancer properties. This study conducts a comprehensive bibliometric analysis to map the research landscape of in oncology, examining publications from 1982 to the present. We observed a marked increase in research activity starting in 2000, with a notable peak from 2005 onwards. The analysis identifies key contributors, including Mohamed GG, who has authored 15 papers with 322 citations, and El-Sayed Asa, with 14 papers and 264 citations. Leading countries in this research field include India, Egypt, and China, with King Saud University and Cairo University as the leading institutions. Prominent research themes identified are "endophyte," "green synthesis," "antimicrobial," "anti-cancer," and "biological activities," indicating a shift towards environmentally sustainable drug development. Our findings highlight the considerable potential of for developing new anticancer therapies and underscore the necessity for further research to harness these natural compounds for clinical use.
PubMed: 38812679
DOI: 10.3389/fmicb.2024.1379602 -
Frontiers in Immunology 2024Adipose tissue mesenchymal stem/stromal cells (ASC) can be used as advanced therapy medicinal product in regenerative and cancer medicine. We previously demonstrated...
INTRODUCTION
Adipose tissue mesenchymal stem/stromal cells (ASC) can be used as advanced therapy medicinal product in regenerative and cancer medicine. We previously demonstrated Supernatant Rich in Growth Factors (SRGF) can replace fetal bovine serum (FBS) to expand ASC by a clinical grade compliant protocol. The therapeutic potential of ASC is based also on their homing capacity toward inflammatory/cancer sites: oriented cell migration is a fundamental process in this scenario. We investigated the impact of SRGF on ASC migration properties.
METHODS
The motility/migration potential of ASC expanded in 5% SRGF was analyzed, in comparison to 10% FBS, by standard wound healing, bidimensional chemotaxis and transwell assays, and by millifluidic transwell tests. Mechanisms involved in the migration process were investigated by transient protein overexpression.
RESULTS
In comparison to standard 10% FBS, supplementation of the cell culture medium with 5% SRGF, strongly increased migration properties of ASC along the chemotactic gradient and toward cancer cell derived soluble factors, both in static and millifluidic conditions. We showed that, independently from applied migratory stimulus, SRGF expanded ASC were characterized by far lower expression of α-smooth muscle actin (αSMA), a protein involved in the cell migration machinery. Overexpression of αSMA induced a significant and marked decrease in migration capacity of SRGF expanded ASC.
DISCUSSION
In conclusion, 5% SRGF addition in the cell culture medium increases the migration potential of ASC, reasonably through appropriate downregulation of αSMA. Thus, SRGF could potentially improve the therapeutic impact of ASC, both as modulators of the immune microenviroment or as targeted drug delivery vehicles in oncology.
Topics: Humans; Cell Movement; Intercellular Signaling Peptides and Proteins; Adipose Tissue; Mesenchymal Stem Cells; Blood Platelets; Cells, Cultured; Culture Media; Actins; Female
PubMed: 38812519
DOI: 10.3389/fimmu.2024.1404228 -
Journal of Translational Medicine May 2024The aging process of the kidneys is accompanied with several structural diseases. Abnormal fiber formation disrupts the balance of kidney structure and function, causing...
The aging process of the kidneys is accompanied with several structural diseases. Abnormal fiber formation disrupts the balance of kidney structure and function, causing to end-stage renal disease and subsequent renal failure. Despite this, the precise mechanism underlying renal damage in aging remains elusive. In this study, ABI3BP gene knockout mice were used to investigate the role of ABI3BP in renal aging induced by irradiation. The results revealed a significant increase in ABI3BP expression in HK2 cells and kidney tissue of aging mice, with ABI3BP gene knockout demonstrating a mitigating effect on radiation-induced cell aging. Furthermore, the study observed a marked decrease in Klotho levels and an increase in ferroptosis in renal tissue and HK2 cells following irradiation. Notably, ABI3BP gene knockout not only elevated Klotho expression but also reduced ferroptosis levels. A significant negative correlation between ABI3BP and Klotho was established. Further experiments demonstrated that Klotho knockdown alleviated the aging inhibition caused by ABI3BP downregulation. This study identifies the upregulation of ABI3BP in aged renal tubular epithelial cells, indicating a role in promoting ferroptosis and inducing renal aging by inhibiting Klotho expression.
Topics: Klotho Proteins; Animals; Ferroptosis; Aging; Kidney; Mice, Knockout; Humans; Cell Line; Glucuronidase; Mice, Inbred C57BL; Mice; Carrier Proteins; Male
PubMed: 38812032
DOI: 10.1186/s12967-024-05300-w