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Pharmacological Research Feb 2023Age-related gastrointestinal decline contributes to whole-organism frailty and mortality. Genistein is known to have beneficial effects on age-related diseases, but its...
Age-related gastrointestinal decline contributes to whole-organism frailty and mortality. Genistein is known to have beneficial effects on age-related diseases, but its precise role in homeostasis of the aging gut remains to be elucidated. Here, wild-type aging mice and Zmpste24 progeroid mice were used to investigate the role of genistein in lifespan and homeostasis of the aging gut in mammals. A series of longitudinal, clinically relevant measurements were performed to evaluate the effect of genistein on healthspan. It was found that dietary genistein promoted a healthier and longer life and was associated with a decrease in the levels of systemic inflammatory cytokines in aging mice. Furthermore, dietary genistein ameliorated gut dysfunctions, such as intestinal inflammation, leaky gut, and impaired epithelial regeneration. A distinct genistein-mediated alteration in gut microbiota was observed by increasing Lachnospira abundance and short-chain fatty acid (SCFA) production. Further fecal microbiota transplantation and dirty cage sharing experiments indicated that the gut microbiota from genistein-fed mice rejuvenated the aging gut and extended the lifespan of progeroid mice. It was demonstrated that genistein-associated SCFAs alleviated tumor necrosis factor alpha-induced intestinal organoid damage. Moreover, genistein-associated propionate promoted regulatory T cell-derived interleukin 10 production, which alleviated macrophage-derived inflammation. This study provided the first data, to the authors' knowledge, indicating that dietary genistein modulates homeostasis in the aging gut and extends the healthspan and lifespan of aging mammals. Moreover, the existence of a link between genistein and the gut microbiota provides a rationale for dietary interventions against age-associated frailty.
Topics: Mice; Animals; Longevity; Genistein; Frailty; Fatty Acids, Volatile; Aging; Inflammation; Gastrointestinal Microbiome; Homeostasis; Mice, Inbred C57BL; Mammals
PubMed: 36693599
DOI: 10.1016/j.phrs.2023.106676 -
Cancer Medicine Feb 2023Dirty necrosis (DN) in renal cell carcinoma (RCC) is morphologically characterized by abundant neutrophil infiltration and has significant potential as an unfavorable...
AIM
Dirty necrosis (DN) in renal cell carcinoma (RCC) is morphologically characterized by abundant neutrophil infiltration and has significant potential as an unfavorable prognostic indicator. This study aimed to analyze the pathological and biological features of DN.
MATERIALS AND METHODS
A total of 81 RCC tumors, including 33 cases of DN and 48 cases of tumor necrosis without DN features (ghost necrosis [GN]), were enrolled in this study. We compared the number of neutrophils; the activation of cell death pathways, including ferroptosis, NETosis, and apoptosis; the rate of epithelial-mesenchymal transition (EMT); and proliferation status using immunohistochemistry. We further assessed the effect of the necrosis type on systemic inflammation.
RESULTS
DN tumors had a significantly higher number of neutrophils in both areas around the necrotic foci and far from the necrotic foci. Ferroptosis status did not differ between DN and GN; however, DN tumors had significantly larger areas exhibiting cell detritus with neutrophil extracellular traps (NETs) detected by citrullinated histone H3 (citH3) than GN tumors. DN tumors also had more apoptotic cells within areas around the necrotic foci. There was no significant difference between the EMT and proliferation status between DN and GN groups. Systemic inflammation markers including C-reactive protein (CRP), CRP-to-albumin ratio (CRP/Alb), platelet-to-lymphocyte ratio (PLR), and hemoglobin were significantly higher in patients with DN. In addition, some of these inflammation markers (CRP/Alb and PLR) significantly decreased after surgery.
CONCLUSIONS
DN in RCC is characterized by NETs production and systemic inflammation.
Topics: Humans; Carcinoma, Renal Cell; Inflammation; Neutrophils; C-Reactive Protein; Kidney Neoplasms; Necrosis
PubMed: 36127822
DOI: 10.1002/cam4.5249 -
Cancer Science May 2023Dirty necrosis (DN) is a form of tumor necrosis (TN) with prominent neutrophil infiltration and cell detritus in the necrotic foci. This study aimed to characterize the...
Dirty necrosis (DN) is a form of tumor necrosis (TN) with prominent neutrophil infiltration and cell detritus in the necrotic foci. This study aimed to characterize the clinicopathological features of DN in metastatic lung cancers of the colon and rectum (MLCRs). A total of 227 patients who underwent pulmonary metastasectomy and complete resection for MLCR were included in this study. TN was evaluated using digitally scanned resection specimens. These slides were immunostained for biomarkers of NETosis (citrullinated histone H3 [citH3] and myeloperoxidase [MPO]), and the area positive for citH3 and MPO was further quantified. TN was observed in 216 cases (95.2%), and 54 (25.0%) of these cases had DN. The presence of TN was not associated with a worse prognosis; however, patients with DN had a significantly shorter overall survival than those without DN (p < 0.01). Furthermore, the presence of DN was a poor prognostic factor in both the univariate and multivariate analyses. Immunohistochemical analysis revealed that the percentage of citH3-positive and MPO-positive areas in the DN-positive cases was significantly higher than that in the DN-negative cases (p < 0.01 and p < 0.01, respectively). In surgically resected MLCR, DN is the characteristic TN subtype associated with poor prognosis and neutrophil extracellular traps (NETs).
Topics: Humans; Prognosis; Rectum; Histones; Lung Neoplasms; Colon; Necrosis; Neutrophils
PubMed: 36369892
DOI: 10.1111/cas.15647 -
Journal of Ultrasound Mar 2023Necrotizing fasciitis is one of the most common soft tissue infections, with a high risk of major amputation and a mortality ranging from 6 to 33% which has not changed...
Necrotizing fasciitis is one of the most common soft tissue infections, with a high risk of major amputation and a mortality ranging from 6 to 33% which has not changed in the past 20 years. Early surgical resection of necrotic tissue plays a key role in determining the prognosis. Nawijn et al. identified an optimal 6 hours window from presentation to surgery. Symptoms of necrotizing fasciitis mimic those of common skin infections, such as erysipelas and cellulitis, making rapid surgical management difficult. In this context, the aid of point-of-care-ultrasound is a valuable tool for early diagnosis, detecting the presence of subcutaneous thickening, gas and perifascial liquid. Other characteristic ultrasound findings include the "cobblestone" appearance of the subcutaneous soft tissues and reverberation artifacts due to hyperechoic outbreaks, defined as "snow globes" due to the presence of heterogeneous swirling material, and "dirty shadowing" due to the foggy shadow created by the gas.
Topics: Humans; Fasciitis, Necrotizing; Prognosis; Necrosis; Point-of-Care Testing; Soft Tissue Infections
PubMed: 36609958
DOI: 10.1007/s40477-022-00717-9 -
Medical Journal, Armed Forces India Sep 2022Colorectal cancer (CRC) is one of the commonest cancers worldwide, with incidence rates in India being around 4%. It is a heterogeneous disease with multiple established...
BACKGROUND
Colorectal cancer (CRC) is one of the commonest cancers worldwide, with incidence rates in India being around 4%. It is a heterogeneous disease with multiple established prognostic factors. Ten to fifteen percent originate from microsatellite instability (MSI) pathway, characterized by defect in mismatch repair (MMR) gene. Identification of MMR defective protein is relevant for diagnosis, prognosis, and prediction. Certain clinical and histological features are known to be associated with defective MMR genes. The objectives of this study are to find the prevalence of MSI in CRC to identify features associated with MSI and assess the value of histopathology in predicting MSI.
METHODS
We evaluated various clinical and histological parameters for identifying prognostically favorable colon cancers in a tertiary hospital. One hundred fifty colon cancers were evaluated, and MSI status was correlated with clinicopathologic variables.
RESULTS
The prevalence of MSI in CRC was found to be 11.3%. The factors associated with MSI were tumor differentiation, stage, tumor site, tumor size, tumor-infiltrating lymphocytes, Crohn's-like lymphoid reaction, and dirty necrosis. We have defined a "P" score for prediction of MSI using the clinicohistological parameters, which could be used to select patients who are to be tested for MSI.
CONCLUSION
Assessment of clinical and histopathological features will help in patient stratification and selection of patients for MSI testing. The evaluation is economical, reproducible, and easy to apply.
PubMed: 36147411
DOI: 10.1016/j.mjafi.2021.03.024 -
Radiation Oncology (London, England) Oct 2022To introduce and compare multiple biological effectiveness guided (BG) proton plan optimization strategies minimizing variable relative biological effectiveness (RBE)...
BACKGROUND
To introduce and compare multiple biological effectiveness guided (BG) proton plan optimization strategies minimizing variable relative biological effectiveness (RBE) induced dose burden in organs at risk (OAR) while maintaining plan quality with a constant RBE.
METHODS
Dose-optimized (DOSEopt) proton pencil beam scanning reference treatment plans were generated for ten cranial patients with prescription doses ≥ 54 Gy(RBE) and ≥ 1 OAR close to the clinical target volume (CTV). For each patient, four additional BG plans were created. BG objectives minimized either proton track-ends, dose-averaged linear energy transfer (LET), energy depositions from high-LET protons or variable RBE-weighted dose (D) in adjacent serially structured OARs. Plan quality (RBE = 1.1) was assessed by CTV dose coverage and robustness (2 mm setup, 3.5% density), dose homogeneity and conformity in the planning target volumes and adherence to OAR tolerance doses. LET, D (Wedenberg model, α/β = 10 Gy, α/β = 2 Gy) and resulting normal tissue complication probabilities (NTCPs) for blindness and brainstem necrosis were derived. Differences between DOSEopt and BG optimized plans were assessed and statistically tested (Wilcoxon signed rank, α = 0.05).
RESULTS
All plans were clinically acceptable. DOSEopt and BG optimized plans were comparable in target volume coverage, homogeneity and conformity. For recalculated D in all patients, all BG plans significantly reduced near-maximum D to critical OARs with differences up to 8.2 Gy(RBE) (p < 0.05). Direct D optimization primarily reduced absorbed dose in OARs (average ΔD = 2.0 Gy; average ΔLET = 0.1 keV/µm), while the other strategies reduced LET (average ΔD < 0.3 Gy; average ΔLET = 0.5 keV/µm). LET-optimizing strategies were more robust against range and setup uncertaintes for high-dose CTVs than D optimization. All BG strategies reduced NTCP for brainstem necrosis and blindness on average by 47% with average and maximum reductions of 5.4 and 18.4 percentage points, respectively.
CONCLUSIONS
All BG strategies reduced variable RBE-induced NTCPs to OARs. Reducing LET in high-dose voxels may be favourable due to its adherence to current dose reporting and maintenance of clinical plan quality and the availability of reported LET and dose levels from clinical toxicity reports after cranial proton therapy. These optimization strategies beyond dose may be a first step towards safely translating variable RBE optimization in the clinics.
Topics: Humans; Proton Therapy; Protons; Radiotherapy Planning, Computer-Assisted; Necrosis; Blindness
PubMed: 36273132
DOI: 10.1186/s13014-022-02143-x -
Journal of Biomedical Optics Jun 2014Dirty necrosis within glandular lumina is often considered as a characteristic of colorectal carcinomas (CRCs) that is a diagnostically useful feature of CRCs with DNA...
Dirty necrosis within glandular lumina is often considered as a characteristic of colorectal carcinomas (CRCs) that is a diagnostically useful feature of CRCs with DNA microsatellite instability (MSI). Multiphoton microscopy (MPM), which is based on the second-harmonic generation and two-photon excited fluorescence signals, was used to identify dirty necrosis. Our results demonstrated that MPM has the ability to exhibit the microstructure of dirty necrosis and the signal intensity as well as an emission spectrum that can help to differentiate dirty necrosis from cancer cells. These findings indicate that MPM may be helpful in distinguishing MSI colorectal carcinoma via the identification of dirty necrosis.
Topics: Collagen; Colonic Neoplasms; Elasticity; Humans; Intestinal Mucosa; Lasers; Microscopy, Fluorescence, Multiphoton; Necrosis; Rectal Neoplasms; Rectum; Reproducibility of Results
PubMed: 24967914
DOI: 10.1117/1.JBO.19.6.066008 -
Cureus Apr 2024Background Microsatellite instability (MSI) is a genetic condition caused by errors in DNA repair genes that cause colorectal cancer (CRC). The literature contradicts...
Background Microsatellite instability (MSI) is a genetic condition caused by errors in DNA repair genes that cause colorectal cancer (CRC). The literature contradicts the frequency of MSI in sporadic CRCs and its effect on prognosis. This study investigated the distribution of clinicopathologic features and the relationship between MSI and survival outcomes. Methodology This is a retrospective study of 101 consecutive cases of CRC and immunohistochemical studies. All cases were retrospectively reviewed and reevaluated by histological grade, lymphovascular invasion, perineural invasion, tumor borders, dirty necrosis, tumor-infiltrating lymphocytes (TILs), Crohn's-like lymphoid reaction, mucinous and medullary differentiation, and tumoral budding from pathological slides. An immunohistochemical study was performed in appropriate blocks for using MLH-1, MSH-2, MSH-6, and PMS-2. We collected the clinical stage, pathological tumor stage, lymph node metastasis, age, sex, tumor diameter, distant metastasis, localization, and survival information from patients' clinical data. Results There was no statistically significant difference between the two groups regarding age, gender, tumor diameter, histological grade, tumor border, dirty necrosis, TILs, N and M stage, perineural and lymphovascular invasion, mucinous differentiation, medullary differentiation, and tumor budding characteristics of the patients. The MSI-H group was more frequently located in the right colon and transverse colon (p < 0.001), and the T stage was higher among them than in the MSI-L group (p = 0.014). Upon multivariate regression analysis, MSI status had no significant effect on survival time. Age and stage N and M were independent prognostic factors for colon cancer prognosis. Conclusions Our study presented the distribution of clinicopathological features and their relationship with MSI for 101 regional CRC patients. MSI status was detected by immunohistochemistry. Identifying MSI in CRCs may help personalize therapy planning. As the distribution of the features may vary from population to population, further investigations are needed on this topic.
PubMed: 38590982
DOI: 10.7759/cureus.57814 -
The Korean Journal of Gastroenterology... Oct 2022An ectopic pancreas rarely transforms into a malignancy, and the symptoms vary from patient to patient. The most commonly observed site of an ectopic pancreas is the...
An ectopic pancreas rarely transforms into a malignancy, and the symptoms vary from patient to patient. The most commonly observed site of an ectopic pancreas is the antrum of the stomach. A 59-year-old male patient with severe abdominal pain underwent CT. A 9.6 cm-sized well-defined exophytic huge mass with heterogenic density was located between the stomach distal antrum and duodenum. A malignant submucosal tumor was suspected because of the exophytic dirty huge mass. Initially, surgery was considered to confirm the histological evaluation. After 2 months, the abdominal pain disappeared, and the follow-up MRI scan showed a decrease in size, which contained a necrotic component inside. It was confirmed that the parenchymal tissue was the pancreas. The pathology through EUS-guided fine needle aspiration (EUS-FNA) was normal pancreatic acinar cells, smooth muscle fragments, squamous cyst, and some neutrophils (abscess). Walled-off necrosis occurs as a complication of acute pancreatitis with parenchymal tissues and surrounding tissues, but complications of ectopic pancreatitis occurred in this case. Abdominal pain due to ectopic pancreas leading to the formation of a giant abscess has been reported as a very rare case. Diagnosis through biopsy is most important when a malignant submucosal tumor is suspected. In addition, it is important to determine the clinical features, examination findings, such as EUS, CT, and MRI, and the changes according to the follow-up period. This paper reports a case of ectopic pancreas, resulting in necrotic tissue and walled-off necrosis, abdominal pain, and spontaneous improvement.
Topics: Male; Humans; Middle Aged; Stomach Neoplasms; Abscess; Acute Disease; Pancreatitis; Pancreas; Abdominal Pain; Necrosis; Pancreatic Neoplasms
PubMed: 36281553
DOI: 10.4166/kjg.2022.078 -
PloS One 2021Emerging data suggest a negative role of cyclooxygenase-2 (COX-2) in colorectal carcinomas (CRC). Investigating this in developing communities such as ours helps to...
BACKGROUND
Emerging data suggest a negative role of cyclooxygenase-2 (COX-2) in colorectal carcinomas (CRC). Investigating this in developing communities such as ours helps to contribute to existing understanding of these lesions.
METHODS AND FINDINGS
Formalin-fixed paraffin-embedded CRC colectomy tissues and their corresponding non-tumour margins of resected tissues were sectioned and stained with COX-2 antibody. Adenomatous polyp tissues from non-cancer bearing individuals were similarly processed for comparison. COX-2 expression was scored for percentage (< 5% = 0; 6%-25% = 1; 26%-50% = 2; 51%-75% = 3; 76%-100% = 4) and intensity (no staining = 0; yellow = 2; yellowish-brown = 3, brown = 4). Total immunoscore (percentage + intensity score) ≥ 2 was regarded as positive COX-2 expression. Outcome was statistically evaluated with clinicopathological data to determine COX-2 expression-associated and predictor variables. Ninety-five CRC cases and 27 matched non-tumour tissues as well as 31 adenomatous polyps met the inclusion criteria. Individuals with CRC had a mean age of 56.1 ± 12.6 years while those with adenomatous polyps had a median age of 65 years (range 43-88). COX-2 was differentially overexpressed in CRCs (69/95; 72.6%) and in adenomatous polyps (17/31; 54.8%) than in non-tumour tissues 5/27 (18.5%); p < 0.001). The difference in COX-2 expression between CRC and polyps was non-significant (p > 0.065). Tumour grade, advanced pT-stage, tumour-infiltrating lymphocytes, and dirty necrosis were also significantly associated with COX-2 expression (p < 0.035; 0.043, 0.035 and 0.004, respectively). Only dirty necrosis and Crohns-like lymphocytic aggregates predicted COX-2 expression (p < 0.05).
CONCLUSION
This study showed a progressive increase in COX-2 expression from normal to adenomatous polyp and CRC tissues, this being associated with poorer prognostic indicators. Although COX-2 appears early in CRC, it may play a secondary role in promoting tumour growth and invasiveness.
Topics: Adenomatous Polyps; Adult; Aged; Aged, 80 and over; Black People; Case-Control Studies; Colorectal Neoplasms; Cyclooxygenase 2; Female; Humans; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Necrosis; Neoplasm Staging; Nigeria; Odds Ratio; Retrospective Studies
PubMed: 34314467
DOI: 10.1371/journal.pone.0255235