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Analytical Chemistry Dec 2019Cancer drug resistance mechanisms such as tumor heterogeneity and adaptable feedback loops are prevalent issues facing cancer therapy development. Drug resistance can be...
Cancer drug resistance mechanisms such as tumor heterogeneity and adaptable feedback loops are prevalent issues facing cancer therapy development. Drug resistance can be unique to a cancer type and, most importantly, to each individual cancer patient. Consequently, testing different dosages and therapeutics directly on each individual patient sample (i.e., tumor and cancer cells) has compelling advantages compared to large scale in vitro drug testing and is a step toward personalized drug selection and effective treatment development. Recently, microfluidic-based chemo-sensitivity assays on patient biopsies have been proposed. Despite their novelty, these platforms usually rely on optical labels, optical equipment, or complex microfabricated channel geometries and structures. In this work, we proposed a novel lab on a chip platform capable of real-time and continuous screening of drug efficacy on (cancer) cell subpopulations without the need of labels or bulky readout optical equipment. In this platform, several label-free and rapid techniques have been implemented for the precise capturing of cells of interest in parallel with the real-time measurement and characterization of the effectiveness of candidate therapeutic agents. To demonstrate the utility of the platform, the effect of an apoptotic inducer, topoisomerase I inhibitor, 7-ethyl-10-hydrocamptothecin (SN38) on human colorectal carcinoma cancer cells (HCT 116) was used as a study model. Additionally, electrical results were optically verified to examine the continuous measurements of the biological mechanisms, specifically, apoptosis and necrosis, during therapeutic agent characterizations. The proposed device is a versatile platform which can also be easily redesigned for the automated and arrayed analysis of cell-drug interaction down to the single cell level. Our platform is another step toward enabling the personalized screening of drug efficacy on individual patients' samples that potentially leads to a better understanding of drug resistance and the optimization of patients' treatments.
Topics: Apoptosis; DNA Topoisomerases, Type I; Drug Monitoring; Drug Resistance, Neoplasm; Electric Impedance; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Irinotecan; Lab-On-A-Chip Devices; Models, Biological; Neoplasms; Precision Medicine; Topoisomerase I Inhibitors
PubMed: 31710202
DOI: 10.1021/acs.analchem.9b03291 -
Analytical Cellular Pathology... 2019Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver. Hepatectomy and liver transplantation (LT) are regarded as the radical treatment, but... (Review)
Review
Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver. Hepatectomy and liver transplantation (LT) are regarded as the radical treatment, but great majority of patients are already in advanced stage on the first diagnosis and lose the surgery opportunity. Multifarious image-guided interventional therapies, termed as locoregional ablations, are recommended by various HCC guidelines for the clinical practice. Transarterial chemoembolization (TACE) is firstly recommended for intermediate-stage (Barcelona Clinic Liver Cancer (BCLC) B class) HCC but has lower necrosis rates. Radiofrequency ablation (RFA) is effective in treating HCCs smaller than 3 cm in size. Microwave ablation (MWA) can ablate larger tumor within a shorter time. Combination of TACE with RFA or MWA is effective and promising in treating larger HCC lesions but needs more clinical data to confirm its long-term outcome. The combination of TACE and RFA or MWA against hepatocellular carcinoma needs more clinical data for a better strategy. The characters and advantages of TACE, RFA, MWA, and TACE combined with RFA or MWA are reviewed to provide physician a better background on decision.
Topics: Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Humans; Liver Neoplasms; Microwaves; Radiofrequency Ablation
PubMed: 31534899
DOI: 10.1155/2019/8619096 -
Analytical Cellular Pathology... 2022Acute kidney injury (AKI) is an important public health concern and characterized as tubular death involved in apoptosis and necrosis. Autophagy is rapidly induced in...
Acute kidney injury (AKI) is an important public health concern and characterized as tubular death involved in apoptosis and necrosis. Autophagy is rapidly induced in tubules and associates with renal tubular cells homeostasis to have a complex link with tubular death in AKI. Numb is a multifunctional protein and exerts protective role in tubular death in AKI induced by Cisplatin. However, the effect of Numb on tubular autophagy remains to be investigated. In the present study, the protein expression of LC3 and Beclin-1 related to autophagy was analyzed in Cisplatin-induced AKI mice with knocking down Numb. In model of tubular injury induced by Cisplatin , downregulation of Numb in NRK-52E cells also inhibited the activation of autophagy accompanied with the decreased protein level of p53. Overexpression of Numb in NRK-52E cells activated autophagy with increased LC3 and Beclin-1 expression accompanied with increased protein level of p53. Moreover, autophagy activation following Numb overexpression was suppressed by p53 inhibitor pifithrin-. These data indicate that Numb promotes p53-mediated activation of tubular autophagy in AKI induced by Cisplatin and therefore may provide important targets for the treatment of AKI.
Topics: Acute Kidney Injury; Animals; Autophagy; Beclin-1; Cisplatin; Membrane Proteins; Mice; Tumor Suppressor Protein p53
PubMed: 35795076
DOI: 10.1155/2022/8213683 -
Journal of Pharmaceutical and... Sep 2023Recent studies presented the crucial role of montelukast (MON, a leukotriene receptor antagonist) against gouty arthritis and its protective effect on drug-induced liver...
A feasible HPTLC method for concurrent quantitation of allopurinol-montelukast co-therapy in plasma and evaluation of their hepatic and renal effects in rats: Analytical, biochemical, and histopathological study.
Recent studies presented the crucial role of montelukast (MON, a leukotriene receptor antagonist) against gouty arthritis and its protective effect on drug-induced liver and kidney injury. Allopurinol (ALO, a selective xanthine oxidase inhibitor) is also used for treatment of hyperuricemia, however, it induces hepatotoxicity and acute kidney injury. Therefore, this study introduces the first analytical/biochemical/histopathological assay for MON-ALO co-therapy and aims to: inspect the hepatic and renal impacts of ALO, MON and their combination in rats via biochemical and histopathological examinations, propose and validate a facile HPTLC method for concurrent estimation of ALO-MON binary mixture in human plasma, and employ this method to attain the targeted drugs in real rat plasma. First, the cited drugs in human plasma were simultaneously separated utilizing silica gel G 60 F-TLC plates. The separated bands were scanned at 268 nm demonstrating appropriate linearities (50.0-2000.0 ng band for each drug) and correlations (0.9986 and 0.9992 for ALO and MON, correspondingly). The calculated detection and quantitation limits, as well as recoveries confirmed the method's reliability. This procedure was validated, and the stability studies were achieved according to Bioanalytical Method Validation Guideline. This work was extended to investigate the possible hepatic and renal effects of ALO, MON and their co-therapy in rats. Using rat's gastric tube, the following was administered to four groups of male Wistar rats: Group Ia and Ib as control (received either saline or DMSO), Groups II, III, and IV were given MON, ALO, and MON+ALO, respectively. Good correlation between the measured biochemical parameters and the observed histopathological changes was encountered. Considerable drop in aspartate transaminase and alanine transaminase levels, in addition to lower liver damage changes were observed in the combination group compared to MON or ALO-treated groups. Regarding renal changes, ALO-MON co-therapy caused elevation in the serum creatinine and blood urea nitrogen levels when compared to controls and MON- or ALO-treated groups. Severe proteinaceous casts accumulation in kidney tubular lumen, severe congestion, and severe tubular necrosis were also noticed in the combination group. Lastly, this study suggests ALO-MON co-treatment not only as a preventive therapy against gouty arthritis but also as a new line to minimize ALO-induced hepatic injury. However, co-administration of ALO and MON should be further studied to assess the benefits and risks in various tissues, adjust the MON dosing, and monitor its nephrotoxic effect.
Topics: Humans; Rats; Male; Animals; Rats, Wistar; Allopurinol; Arthritis, Gouty; Reproducibility of Results; Kidney; Liver
PubMed: 37186992
DOI: 10.1016/j.jpba.2023.115439 -
The American Journal of Gastroenterology Sep 2023Anal ulcerations are frequently observed in Crohn's disease (CD). However, their natural history remains poorly known, especially in pediatric-onset CD.
INTRODUCTION
Anal ulcerations are frequently observed in Crohn's disease (CD). However, their natural history remains poorly known, especially in pediatric-onset CD.
METHODS
All patients with a diagnosis of CD before the age of 17 years between 1988 and 2011 within the population-based registry EPIMAD were followed retrospectively until 2013. At diagnosis and during follow-up, the clinical and therapeutic features of perianal disease were recorded. An adjusted time-dependent Cox model was used to evaluate the risk of evolution of anal ulcerations toward suppurative lesions.
RESULTS
Among the 1,005 included patients (females, 450 [44.8%]; median age at diagnosis 14.4 years [interquartile range 12.0-16.1]), 257 (25.6%) had an anal ulceration at diagnosis. Cumulative incidence of anal ulceration at 5 and 10 years from diagnosis was 38.4% (95% confidence interval [CI] 35.2-41.4) and 44.0% (95% CI 40.5-47.2), respectively. In multivariable analysis, the presence of extraintestinal manifestations (hazard ratio [HR] 1.46, 95% CI 1.19-1.80, P = 0.0003) and upper digestive location (HR 1.51, 95% CI 1.23-1.86, P < 0.0001) at diagnosis were associated with the occurrence of anal ulceration. Conversely, ileal location (L1) was associated with a lower risk of anal ulceration (L2 vs L1 HR 1.51, 95% CI 1.11-2.06, P = 0.0087; L3 vs L1 HR 1.42, 95% CI 1.08-1.85, P = 0.0116). The risk of fistulizing perianal CD (pCD) was doubled in patients with a history of anal ulceration (HR 2.00, 95% CI 1.45-2.74, P < 0.0001). Among the 352 patients with at least 1 episode of anal ulceration without history of fistulizing pCD, 82 (23.3%) developed fistulizing pCD after a median follow-up of 5.7 years (interquartile range 2.8-10.6). In these patients with anal ulceration, the diagnostic period (pre vs biologic era), exposure to immunosuppressants, and/or anti-tumor necrosis factor did not influence the risk of secondary anoperineal suppuration.
DISCUSSION
Anal ulceration is frequent in pediatric-onset CD, with nearly half of patients presenting with at least 1 episode after 10 years of evolution. Fistulizing pCD is twice as frequent in patients with present or past anal ulceration.
Topics: Female; Child; Humans; Adolescent; Crohn Disease; Follow-Up Studies; Retrospective Studies; Fissure in Ano; Rectal Fistula
PubMed: 37104674
DOI: 10.14309/ajg.0000000000002301 -
Artificial Organs Jun 2022Fecal incontinence caused by sphincter dysfunction is a difficult medical problem that has not been fully resolved. The artificial anal sphincter provides a new...
BACKGROUND
Fecal incontinence caused by sphincter dysfunction is a difficult medical problem that has not been fully resolved. The artificial anal sphincter provides a new therapeutic strategy for fecal incontinence. In order to solve the biomechanical compatibility problem between the artificial anal sphincter and intestinal tissue in clinical application, a design of constant force artificial anal sphincter was assessed in this paper.
METHODS
The constant force properties and safety of this novel device were evaluated by an experiment conducted in pig intestines with various thicknesses. The constant force characteristic of the device was evaluated by the intestinal pressure of the pig intestine. The safety of the device was evaluated by the surface contact stress of the pig intestine clamped by an artificial anal sphincter.
RESULTS
The average measured value of the intestinal pressure of the pig intestines with three thicknesses is about 55.3 mm Hg, the maximum pressure difference is 1 mm Hg, and the fluctuation error of constant clamping load is about 1.8%. The constant clamping load fluctuation error of the four measuring points of the pig intestines with three thicknesses is less than 2%. Even if the thickness of the pig intestines is changed, the measured contact stress value is lower than 10 kPa, which may avoid bit damage for the intestinal tissue.
CONCLUSIONS
This study demonstrates that the novel artificial sphincter has constant force properties and safety, which prevent ischemic necrosis of soft tissues caused by excessive pressure. Therefore, this study raises the possibility of the long-term efficacy of artificial anal sphincter.
Topics: Anal Canal; Animals; Artificial Organs; Fecal Incontinence; Prosthesis Design; Shape Memory Alloys; Swine
PubMed: 35060136
DOI: 10.1111/aor.14177 -
BioImpacts : BI 2023The mixed flavonoid supplement (MFS) [Trimethoxy Flavones (TMF) + epigallocatechin-3-gallate (EGCG)] can be used to suppress inflammatory ulcers as an ethical medicine...
The mixed flavonoid supplement (MFS) [Trimethoxy Flavones (TMF) + epigallocatechin-3-gallate (EGCG)] can be used to suppress inflammatory ulcers as an ethical medicine in Ayurveda. The inflammation of the rectum and anal regions is mostly attributed to nuclear factor kappa beta (NF-κB) signaling. NF-κB stimulates the expression of matrix metalloproteinase (MMP9), inflammatory cytokines tumor necrosis factor (TNF-α), and interleukin-1β (IL-1β). Although much research targeted the NF-κB and MMP9 signaling pathways, a subsequent investigation of target mediators in the inflammatory ulcer healing and NF-κB pathway has not been done. The docking studies of compounds TMF and EGCG were performed by applying PyRx and available software to understand ligand binding properties with the target proteins. The synergistic ulcer healing and anti-arthritic effects of MFS were elucidated using dextran sulfate sodium (DSS)-induced colon ulcer in Swiss albino rats. The colon mucosal injury was analyzed by colon ulcer index (CUI) and anorectic tissue microscopy. The IL-1β, tumor necrosis factor (TNF-α), and the pERK, MMP9, and NF-κB expressions in the colon tissue were determined by ELISA and Western blotting. RT-PCR determined the mRNA expression for inflammatory marker enzymes. The docking studies revealed that EGCG and TMF had a good binding affinity with MMP9 (i.e., -6.8 and -6.0 Kcal/mol) and NF-kB (-9.4 and 8.3 kcal/mol). The high dose MFS better suppressed ulcerative colitis (UC) and associated arthritis with marked low-density pERK, MMP9, and NF-κB proteins. The CUI score and inflammatory mediator levels were suppressed with endogenous antioxidant levels in MFS treated rats. The MFS effectively unraveled anorectic tissue inflammation and associated arthritis by suppressing NF-κB-mediated MMP9 and cytokines.
PubMed: 36817000
DOI: 10.34172/bi.2022.23523 -
Molecular Medicine Reports Dec 2023Abnormal activation of microglia and the production of proinflammatory cytokines can lead to chronic neuroinflammation, which is an important pathological characteristic...
Abnormal activation of microglia and the production of proinflammatory cytokines can lead to chronic neuroinflammation, which is an important pathological characteristic of Parkinson's disease (PD). Neferine is a chemical compound extracted from lotus seed which has previously been reported to exert protective effects on the development of several types of cancer, myocardial injury and hypoxic‑ischemic encephalopathy. However, its effect on microglial functions in neuroinflammation remains to be clarified. The present study used network pharmacology and screening in a lipopolysaccharide (LPS) model to demonstrate that neferine suppresses the production of inducible nitric oxide synthase, interleukin‑6 and tumor necrosis factor α in LPS‑treated BV‑2 cells. The working concentration of neferine did not exert cytotoxic effects on BV‑2 cells. Mechanistically, neferine attenuated inflammation by inhibiting the phosphorylation and nuclear translocation of the NF‑κB p65 subunit. In vivo, neferine protected mice from the inflammatory response in the substantia nigra and inhibited the development of nervous disorders in the 1‑methyl‑4‑phenyl‑1,2,3,6‑tetrahydropyridine‑induced PD model. The present study demonstrated that neferine inhibited LPS‑mediated activation of microglia by inhibiting NF‑κB signaling. These findings may provide a new reference for the prevention and future treatment of PD.
Topics: Mice; Animals; Parkinson Disease; Microglia; NF-kappa B; Neuroinflammatory Diseases; Lipopolysaccharides; Cell Line; Anti-Inflammatory Agents; Inflammation; Nitric Oxide
PubMed: 37921051
DOI: 10.3892/mmr.2023.13122 -
PloS One 2024The pathogenesis of anal sacculitis has not been extensively investigated, although atopic dogs seem to be predisposed to the disease. The aim of this study was... (Comparative Study)
Comparative Study
The pathogenesis of anal sacculitis has not been extensively investigated, although atopic dogs seem to be predisposed to the disease. The aim of this study was therefore to characterize and compare the bacterial microbiota and pro-inflammatory cytokines in the anal sacs of dogs from three groups (healthy dogs, untreated atopic dogs and atopic dogs receiving antipruritic treatment or allergen-specific immunotherapy) in order to determine whether changes could be at the origin of anal sacculitis in atopic dogs. Bacterial populations of anal sac secretions from fifteen healthy dogs, fourteen untreated and six treated atopic dogs were characterized by sequencing the V4 region of the 16S rRNA gene using Illumina technology. Proinflammatory cytokines were analyzed with the Luminex multiplex test. Community membership and structure were significantly different between the anal sacs of healthy and untreated atopic dogs (P = 0.002 and P = 0.003, respectively) and between those of untreated and treated atopic dogs (P = 0.012 and P = 0.017, respectively). However, the community structure was similar in healthy and treated atopic dogs (P = 0.332). Among the proinflammatory cytokines assessed, there was no significant difference between groups, except for interleukin 8 which was higher in the anal sacs of untreated atopic dogs compared to treated atopic dogs (P = 0.02), and tumor necrosis factor-alpha which was lower in the anal sacs of healthy dogs compared to treated atopic dogs (P = 0.04). These results reveal a dysbiosis in the anal sacs of atopic dogs, which may partially explain the predisposition of atopic dogs to develop bacterial anal sacculitis. Treatments received by atopic dogs (oclacitinib, desloratadine and allergen-specific immunotherapy) shift the microbiota of the anal sacs towards that of healthy dogs. Further studies are required to identify significant cytokines contributing to anal sacculitis in atopic dogs.
Topics: Animals; Dogs; Cytokines; Dog Diseases; Anal Sacs; Male; Microbiota; Female; RNA, Ribosomal, 16S; Dermatitis, Atopic; Case-Control Studies; Bacteria
PubMed: 38814946
DOI: 10.1371/journal.pone.0298361 -
Journal of Gastrointestinal Cancer Mar 2022While the treatment for early stage rectal cancer is surgery, when a diagnosis is made at a locally advanced stage, it is recommended to start treatment with neoadjuvant...
BACKGROUND/AIM
While the treatment for early stage rectal cancer is surgery, when a diagnosis is made at a locally advanced stage, it is recommended to start treatment with neoadjuvant chemoradiotherapy. Therefore, it is important to determine which patients will respond best to neoadjuvant treatment. The aim of this study was to investigate which hematological, histopathological, and radiological parameters can predict the response to chemoradiotherapy.
METHODS AND MATERIAL
A retrospective examination was made of 43 patients who underwent surgery following neoadjuvant chemoradiotherapy because of locally advanced stage rectal cancer. Demographic data were collected from the patient files, and the radiological, histopathological, and laboratory findings before neoadjuvant chemoradiotherapy were compared with the findings after treatment.
RESULTS
In the postoperative evaluation, a pathological complete response was determined in 25.50% of the patients. Lymphovascular invasion, perineural invasion, and absence of necrosisis were seen to be statistically related to major response (p < 0.05), and in patients where the tumor was closer than 6 cm to the anal verge, the response was better CONCLUSION: When the findings were examined, histopathological lymphovascular invasion, perineural invasion, the presence of necrosis, and the anal verge distance were evaluated as parameters predicting the response to neoadjuvant chemoradiotherapy in rectal cancer.
Topics: Chemoradiotherapy; Demography; Humans; Neoadjuvant Therapy; Rectal Neoplasms; Retrospective Studies; Treatment Outcome
PubMed: 34472012
DOI: 10.1007/s12029-021-00697-9