Histological Response Research Articles

Fecal calprotectin measurement as a biomarker of severe disease phenotype in celiac disease and non-celiac enteropathies

BackgroundFecal calprotectin (FC) is a non-invasive biomarker of gut inflammation, but its role in celiac disease (CD) and non-celiac enteropathies (NCEs) is undefined. AimsTo retrospectively evaluate FC in patients with CD and NCEs as a tool for assessing disease activity and predicting long-term outcomes. MethodsPatients with uncomplicated and complicated CD, and NCEs with data on FC, evaluated at our center between June-2008 and December-2023, were enrolled. The relationship between elevated FC (>50 mg/kg) and disease activity was statistically analysed and Cox regression adjusted for age and sex was used to compare development of complications and mortality in patients with elevated and normal FC. Results177 patients (109F, mean age at diagnosis 39±20 years, 132 CD, 17 complicated CD, 28 NCEs) were enrolled. 55 patients had elevated FC, which was associated with lack of clinical and histological response to therapy (both p < 0.001). During a median follow-up of 103 months (IQR 54–176), 22 patients developed complications (15.4 %) and 21 died (11.9 %). Elevated FC was significantly more common in complicated CD (70.6 %) and NCEs (67.9 %) than in uncomplicated CD (18.2 %), p < 0.001. Elevated FC was independently predictive of developing complications (HR 4.8,95 %CI 1.4–17.7, p = 0.01) and mortality (HR 4.8,95 %CI 1.6–14.3, p < 0.01). ConclusionFC is a promising non-invasive biomarker for assessing disease severity and long-term outcomes in CD and NCEs.

18 F-FDG PET Metabolic Parameters for the Prediction of Histological Response to Induction Chemotherapy in Osteosarcoma and Ewing Sarcoma : A Systematic Review and Network Meta-analysis.

This study aimed to evaluate the ability of 18 F-FDG PET/CT metabolic parameters to predict the histological response to neoadjuvant chemotherapy in patients with osteosarcoma and Ewing sarcoma. This systematic review and network meta-analysis adhered to the PRISMA-NMA and Cochrane guidelines. Electronic databases were searched from January 2008 to January 2024; this search was supplemented by snowballing methods. The risk of bias was evaluated with QUADAS-2, and evidence certainty was assessed using the GRADE approach. The prognostic value of 18 F-FDG PET/CT parameters, including pretreatment and posttreatment SUVs (SUV1, SUV2 and the SUV2/SUV1 ratio), metabolic tumor volume (MTV1, MTV2, ΔMTV), and total lesion glycolysis (TLG1, TLG2, ΔTLG), was examined. The meta-analysis of 18 studies (714 patients) identified the ΔTLG, ΔMTV, and SUV ratio as superior predictors of histological response. The changes in metabolic activity, as indicated by these parameters, provided a robust indication of treatment effectiveness. Baseline parameters showed limited predictive value compared with posttreatment assessments. The study's robustness was confirmed through meta-regression, which revealed that the predictive value of the SUV2 and SUV ratio was consistent across various cutoff thresholds. 18 F-FDG PET/CT metabolic parameters, particularly those measuring changes posttherapy, are effective in predicting the histological response in patients with osteosarcoma and Ewing sarcoma. These findings underscore the potential of 18 F-FDG PET/CT in guiding early treatment decisions, thereby enhancing personalized therapeutic approaches.

Low CD86 expression is a predictive biomarker for clinical response to the therapeutic human papillomavirus vaccine IGMKK16E7: results of a post hoc analysis.

Although therapeutic human papillomavirus vaccines could offer a noninvasive treatment for patients with cervical intraepithelial neoplasia, none has been clinically implemented. Oral administration of the therapeutic human papillomavirus vaccine IGMKK16E7 results in the histological regression of human papillomavirus 16-positive cervical intraepithelial neoplasia 2/3 to normal (complete response). We investigated biomarkers that could predict complete response after oral administration of IGMKK16E7. Forty-two patients administered high-dose oral IGMKK16E7 in a phase I/II trial were included. Cervix-exfoliated cells were collected before vaccine administration. Gene expression of CD4, CD8, FOXP3, programmed cell death 1 protein, CTLA4, CD103, CD28, CD80, CD86, and programmed cell death 1 ligand 1 in the cells was measured by quantitative reverse transcriptase-polymerase chain reaction. Receiver operating characteristic curve analysis and Mann-Whitney tests were used to explore potential biomarkers. Pearson correlation coefficient analysis was used to correlate gene expression profiles with clinical outcome. The only predictive biomarker of vaccine response for which receiver operating characteristic curve analysis showed significant diagnostic performance with histological complete response was CD86 (area under the curve = 0.71, 95% confidence interval = 0.53 to 0.88, P = .020). Patients with complete response had significantly lower CD86 expression (CD86-low) than patients with no complete response (P = .035). The complete response rates for CD86-low and CD86-highpatients were 50% and 19%, respectively, and CD86-low patients had a significantly higher complete response rate (P = .047). Compared with all patients, the CD86-low group had a 1.5-fold increase in the complete response rate. Gene expression of CD86 and CTLA4 showed the strongest positive correlation with clinical outcomes in the incomplete response group (P < .001). Low expression of CD86 in exfoliated cervical cells can be used as a pretreatment biomarker to predict histological complete response after IGMKK16E7 administration.

Features of preeclampsia in patients with chronic kidney disease

Aims: to study the characteristics of preeclampsia (PE) in women with chronic kidney disease (CKD) compared to PE in the general population.Method: a prospective observational study analyzed the course of PE in 24 women with a previously established diagnosis of CKD (Group 1) and 39 women in the general population (Group 2) without a complicating somatic history. In patients with CKD with a known pregestational creatinine level, the physiological response of the kidneys to pregnancy was assessed, defined as a decrease in serum creatinine by more than 10% in the first trimester. The angiogenic ratio (sFlt-1/PLGF) was studied in 13 patients with CKD.Results: the two groups did not differ in age or parity. In the first group, 16 patients had CKD stage 1-2, 5 had CKD 3A, and one patient each had CKD 3B, 4 and 5 (the later receiving hemodialysis). Nineteen (79%) of women with CKD had hypertension, proteinuria (PU), renal impairment or a combination of these factors before conception. Only 3 out of 16 patients had a physiological renal response. Early PE developed in 58.3% of patients with CKD compared to 35.3% in second group (p = 0.082). The duration of PE inversely correlated with the stage of CKD (r = -0.630; p = 0.001). As pregnancy progressed in patients with CKD, PU increased, reaching nephrotic level in 54% of women by the time of PE. HELLP syndrome or isolated hematological signs of TMA were noted in 8 patients in the general population group, and in 1 in the CKD group. The average sFlt-1/PLGF value in patients with early stages of CKD (n = 9) was 81.0±24.0, with late stages (n = 4) it was 14±8.Conclusion: the study identified the features of PE in CKD: early onset, increased PU reaching nephrotic level in half of the cases by the time PE is diagnosed, and the absence of a histological renal response to pregnancy in the 1st trimester. The lack of changes in the angiogenic coefficient in women with PE and late-stage CKD requires further study in a larger group of patients.

DENTIN-PULP COMPLEX IN DEEP CARIES

Deep caries progress highlights the gradual shift from reactionary to reparative tertiary dentine as main feature illustrated by transition between the secondary and tertiary dentin. Three sorts of odontoblasts are described to exhibit their dentinogenic potential in genesis of reparative dentine, the still active primary odontoblasts, the formerly quiescent odontoblasts recently reactivated by molecular signals sent from carious lesion, and the secondary odontoblasts resulting from pulp stem cells. This complex cellular secretor involvement in dentinogenesis presume a range of resulting matrices that explain the miscellaneous mineralized final structures encountered in natural evolution of deep caries and especially as therapeutic outcome in pulp capping. Depending on intensity of cariogenic stimuli the effect may be either reactionary dentin relying on a mild action or reparative dentin, mirroring a strong microbial action. The histological response of dentin-pulp complex comprises any exclusive reactionary or reparative tertiary dentin feature as both conditions usually may cohabitate as mishmash in the same pulp.

Health-related quality of life (HRQL) assessments in a 52-week, double-blind, randomized, placebo-controlled phase III study of resmetirom (MGL-3196) in patients with metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis.

Resmetirom, liver-directed thyroid-hormone receptor-β agonist, received approval for metabolic dysfunction-associated steatohepatitis (MASH) treatment. We assessed health-related quality of life (HRQL) in patients with MASH treated with resmetirom. Patients with MASH/NASH without cirrhosis and with confirmed/suspected fibrosis were enrolled in a 54-month double-blind randomized placebo-controlled phase III clinical trial with serial biopsy assessments at baseline and week 52 (MAESTRO-NASH, NCT03900429). HRQL was assessed using Chronic Liver Disease Questionnaire-NASH (CLDQ-NAFLD) and Liver Disease Quality of Life (LDQOL). Baseline HRQL score changes by treatment group (resmetirom 80mg, resmetirom 100mg, or placebo) and histological response (improvement of fibrosis without worsening of NAS or resolution of MASH/NASH without worsening of fibrosis) were compared after 52 weeks. Included were 966 intention-to-treat patients: 323 received resmetirom 100mg, 322 resmetirom 80mg, and 321 placebo. By weeks 24 and 52, patients receiving 80 or 100mg resmetirom experienced HRQL improvement in CLDQ-NAFLD Worry domain (mean +0.21 to +0.24, p < 0.05). At week 52, subjects who met histologic endpoints after treatment with resmetirom (100mg and 80mg pooled) experienced HRQL improvement in CLDQ-NAFLD Worry +0.46 (41% met minimal clinically important difference [MCID]), LDQOL domains: Role Emotional +3.0 (28% met MCID), Health Distress +8.1 (38% MCID), Stigma +3.5 (39% MCID), and total LDQOL +2.2 (35% MCID) (all p < 0.05). Similar improvements were noted in histologic responders from 100mg or 80mg resmetirom groups when separated-no improvements in placebo or nonresponders. Baseline F3 histologic responders had similar/more pronounced HRQL improvements. Patients with MASH/NASH with fibrosis improvement or the resolution of MASH with resmetirom experienced clinically meaningful and statistically significant HRQL improvements.

Histological, hormonal and metabolic response triggered by N-1-naphthylphthalamic acid-induced stem swelling in Solidago canadensis L.

Histological, hormonal and metabolic response triggered by N-1-naphthylphthalamic acid-induced stem swelling in Solidago canadensis L.

Decreases in cT1 and liver fat content reflect treatment-induced histological improvements in MASH

MRI biomarkers of liver disease are robust and reproducible alternatives to liver biopsy. Emerging data suggest that absolute reduction in iron corrected T1 (cT1) of ≥ 80 ms and relative reduction in liver fat content of 30% reflect histological improvement. We aimed to validate the associations of changes to these noninvasive biomarkers with histological improvement, specifically the resolution of steatohepatitis. A retrospective analysis of participants from three interventional clinical trials who underwent multiparametric MRI to measure liver cT1 and liver fat content (LFC) (LiverMultiScan) alongside biopsies at baseline and end of study. Responders were defined as those achieving resolution of steatohepatitis with no worsening in fibrosis. Differences in the magnitude of change in cT1 and LFC between responders and non-responders was assessed. Individual patient data from 150 participants were included. There was a significant decrease in liver cT1 (-119 ms vs. -49 ms) and liver fat content (-65% vs. -29%) in responders compared to non-responders (P < .001) respectively. The diagnostic accuracy to identify responders was 0.72 (AUC) for both. The Youden's index for cT1 to separate responders from non-responders was -82 ms and for liver fat was a 58% relative reduction. Those achieving a ≥ 80 ms reduction in cT1 were 5-times more likely to achieve histological response (sens 0.68; spec 0.70). Those achieving a 30% relative reduction in liver fat were ∼4 times more likely to achieve a histological response (sens 0.77; spec 0.53). These results, from three combined drug trials, demonstrate that changes in multiparametric MRI markers of liver health (cT1 and PDFF) can predict histological response for steatohepatitis following therapeutic intervention. There is great interest in identifying suitable biomarkers that can be used to replace liver biopsy, or to identify those patients who would benefit from one, in both the clinical management of MASH and in drug development. We investigated the utility of two MRI-derived non-invasive tests, iron corrected T1 mapping (cT1) and liver fat content from proton density fat fraction (PDFF), to predict histological improvement in patients who had undergone experimental treatment for MASH. Using data from 150 people who participated in one of three clinical trials, we observed that a reduction in cT1 by over 80 ms and a relative reduction in PDFF of over 58% were the optimal thresholds for change that predicted resolution of steatohepatitis. PDFF as a marker of liver fat, and cT1 as a specific measure of liver disease activity, are both effective at identifying those who are likely responding to drug interventions and experiencing improvements in overall liver health. NCT02443116, NCT03976401, NCT03551522.

Unraveling the immune response of the spleen in sepsis using green-synthesized silver nanoparticles from pomegranate peel extracts.

Sepsis is a serious disease characterized by an inappropriate host response to infection, resulting in widespread inflammation and systemic organ failure. The aim of this research is to investigate the possibility of pomegranate peel-derived silver nanoparticles (PGNP) as a potential alternative therapy for sepsis. Characterization using transmission electron microscopy revealed 10-30 nm spherical nanoparticles. In a rat model of sepsis, PGNP treatment improved spleen health, histology, and immune response as compared with septic rats. In rats treated with PGNP during sepsis, significant alterations in oxidative stress markers (p < .01) were observed. These included elevated levels of glutathione (0.63 ± 0.08 mmol/mg protein), reduced concentrations of nitric oxide (8.7 ± 0.8 μ mol/mg protein) and malondialdehyde (2.2 ± 0.3 nmol/mg protein), as well as increased activity of superoxide dismutase (159 ± 33 U/mg protein). Following PGNP administration, gene expression analysis revealed a decrease in spleen IL-1β, IL-6, and TNF-α, highlighting its anti-inflammatory potential. Furthermore, PGNP effectively controlled apoptosis-related genes (Bax, Bcl-2, and Casp3), indicating its role in cellular survival pathways. This study sheds light on the immunological regulation of the spleen during sepsis using PGNP, demonstrating its potential as a new effective treatment approach. The study emphasizes the necessity of continuing to investigate and develop alternative medicines, particularly in light of antibiotic resistance and the global impact of sepsis. RESEARCH HIGHLIGHTS: The study explored the potential medicinal benefits of pomegranate peel-derived silver nanoparticles (PGNP) in the treatment of sepsis. PGNP suppressed pro-inflammatory cytokines and enhanced the immune response. The study recommends PGNP as a viable substitute treatment.

Ouroboros: cross-linking protein expression perturbations and cancer histology imaging with generative-predictive modeling.

Imagine if we could simultaneously predict spatial protein expression in tissues from their routine Hematoxylin and Eosin (H&E) stained images, and create tissue images given protein expression profiles thus enabling virtual simulations of how protein expression alterations impact histology in complex diseases like cancer. Such an approach could lead to more informed diagnostic and therapeutic decisions for precision medicine at lower costs and shorter turnaround times, more detailed insights into underlying disease pathology as well as improvement in predictive and generative performance. In this study, we investigate the intricate correlation between protein expressions obtained from Hyperion mass cytometry and histopathological microstructures in conventional H&E stained glioblastoma (GBM) samples, unveiling morphological patterns and cellular-level spatial alterations associated with protein expression changes. To model these complex relationships, we propose a novel generative-predictive framework called Ouroboros for producing H&E images from protein expressions and simultaneously predicting protein expressions from H&E images. Our comprehensive sample-independent validation over 9920 tissue spots from 4 GBM samples encompassing visual image analysis, quantitative analysis, subspace alignment and perturbation experiments shows that the proposed generative-predictive approach offers significant improvements in predicting protein expression from images in comparison to baseline methods as well as accurate generation of virtual GBM sample images. This proof of concept study can contribute to advancing our understanding of histological responses to protein expression perturbations and lays the foundations for further developments in this area. Implementation and associated data for the proposed approach are available at the URL: https://github.com/Srijay/Ouroboros.

Synergistic impact of Chlorella vulgaris, zinc oxide- and/or selenium nanoparticles dietary supplementation on broiler’s growth performance, antioxidant and blood biochemistry

The current study explored the influence of dietary supplementation of Chlorella vulgaris dried powder (CV) with zinc-oxide-nanoparticles (ZnO-NPs), and/or selenium-nanoparticles (Se-NPs) on broilers’ growth, antioxidant capacity, immune status, histological responses, and gene expression of some related genes. Several 200 one-day-old Cobb-500 male chicks were distributed into 5 groups with four replicates each. In the 1st group, birds were fed the basal diet (BD). In the 2nd, 3rd, 4th, and 5th groups, birds received the BD supplemented with CV only, CV + ZnO-NPs, CV + Se-NPs, and CV + ZnO-NPs + Se-NPs, respectively. The CV dried powder, ZnO-NPs, and Se-NPs were added to the BD at a rate of 1 g, 40 mg, and 0.3 mg/kg diet, respectively. After 6 weeks of feeding, increases in final body weights (P < 0.05), body weight gain (P < 0.05), and feed intake (P < 0.05) were linked with improvements in FCR (P < 0.05) and intestinal morphometric indices (P < 0.05), and marked up-regulations of MYOS (P < 0.05), GHR (P < 0.05), and IGF (P < 0.05) genes were established. Additionally, distinct increases in antioxidant enzyme activities of SOD (P < 0.05), and GPX (P < 0.05) with increases in the mRNA copies of their genes were measured. Moreover, slight improvement in immunity indices, WBCs count (P > 0.05), and phagocytic and lysozyme activities (P > 0.05) were found. However, distinct increases in phagocytic index (P < 0.05) and up-regulations of IL-1β and TNF, and down-regulation of IL-10 mRNA levels were reported (P < 0.05). These findings were prominent in the case of the separate supplementation of CV with ZnO-NPs or Se-NPs confirming the synergistic mechanisms of CV with ZnO-NPs or Se-NPs. Thus, the synergetic supplementation of CV with ZnO-NPs, or Se-NPs in the broiler’s diet could augment their growth and antioxidant response.

Clinical Significance of Body Weight Loss During Chemotherapy for Advanced Gastric Cancer Undergoing Conversion Surgery.

The purpose of the present study was to assess the clinical impact of body weight loss (BWL) during chemotherapy in patients with initially unresectable advanced gastric cancer who underwent conversion surgery. This retrospective study included 61 patients with stage IV gastric cancer who underwent conversion surgery after chemotherapy, and body weight changes during chemotherapy were examined. Based on receiver operating characteristic (ROC) curve analysis of body weight change for disease recurrence, the cutoff value of BWL was determined. Based on the BWL cutoff value, patients were classified into two groups. Body weight change ranged from 28.2% to -21.8%. The cut-off value of BWL was set at 6% based on the ROC analysis. Of the 61 patients, 45 (74%) and 16 (26%) had <6% and ≥6% BWL, respectively. Patients with ≥6% BWL had peritoneal dissemination, pathological lymph node metastasis, residual tumor status of R1-2, and disease recurrence compared with those with <6% BWL (all p<0.05). The median survival times after conversion surgery were 21 and 63 months in the ≥6% and <6% BWL groups, respectively (p<0.01). Univariate analysis identified BWL as an independent prognostic factor (p=0.01), although histological response alone was significantly associated with survival in the multivariate analysis (p=0.02). Patients with severe BWL during chemotherapy may be excluded from the indication of conversion surgery.

Histological and immunohistochemical soft-tissue response to cylindrical and concave abutments: Multicenter randomized clinical trial.

This study aimed to analyze the influence of concave and cylindrical abutments on peri-implant soft tissue. Dimensions, collagen fiber orientation, and immunohistochemical data were assessed. A multicenter, split-mouth, double-blind randomized clinical trial was conducted. Two groups were analyzed: cylindrical abutments and concave abutments. After a 12-week healing period, peri-implant soft tissue samples were collected, processed, and evaluated for dimensions, collagen fiber orientation, and immunohistochemical data. Inflammatory infiltration and vascularization were assessed, and the abutment surfaces were analyzed using scanning electron microscopy. The statistical analysis was performed using the SPSS version 20.0 statistical package. A total of 74 samples in 37 patients were evaluated. Histological evaluation of peri-implant soft tissue dimensions revealed significant differences between concave and cylindrical abutments. Concave abutments exhibited greater total height (concave: 3.57±0.28 - cylindrical: 2.95±0.27) and barrier epithelium extension (concave: 2.46±0.17 - cylindrical: 1.89±0.21) (p<0.05), while the supracrestal connective tissue extension (concave: 1.11±0.17 - cylindrical: 1.03±0.16) was slightly greater (p>0.05). Collagen fiber orientation favored concave abutments (23.76±5.86), with significantly more transverse/perpendicular fibers than for cylindrical abutments (15.68±4.57). The immunohistochemical analysis evidenced greater inflammatory and vascular intensity in the lower portion for both abutments, though concave abutments showed lower overall intensity (concave: 1.05±0.78 - cylindrical: 1.97±0.68) (p<0.05). The abutment surface analysis demonstrated a higher percentage of tissue remnants on concave abutments (42.47±1.32; 45.12±3.03) (p<0.05). Within the limitations of this study, concave abutments presented significantly greater peri-implant tissue height, linked to an extended barrier epithelium, versus cylindrical abutments in thick tissue phenotype. This enhanced soft tissue sealing, favoring a greater percentage of transversely oriented collagen fibers. The concave design reduced chronic inflammatory exudation with T and B cells, thus minimizing the risk of chronic inflammation. This study looked at how 2 different shapes of dental implant abutments (the parts that connect the implant to the crown), specifically concave and cylindrical, affect the soft tissue around the implants. We wanted to see how these shapes influenced the tissue's size, structure, and health. We conducted a clinical trial with 37 patients, comparing the 2 types of abutments in the same mouth over 12weeks. Our findings showed that the concave abutments led to a taller and more extensive layer of protective tissue around the implant compared to the cylindrical ones. This protective tissue had more favorable collagen fiber orientation, which is important for the strength and health of the tissue. Additionally, the concave abutments resulted in less inflammation and better tissue integration. In conclusion, concave abutments may provide better support and health for the soft tissue around dental implants, reducing the risk of chronic inflammation and potentially leading to better long-term outcomes for patients with dental implants.

Transcriptome, histology, and enzyme activities analysis of liver in Phoxinus lagowskii to the low temperature stress and recovery

Assessing the response and resilience of fish to low temperatures over different time scales can provide valuable insights into their mechanisms of adaptation to cold conditions. Farmed Amur minnows (Phoxinus lagowskii) frequently encounter low temperatures, especially during winter. However, the specific responses of P. lagowskii to low-temperature stress remain largely unexplored. In this study, we examined serum glucose and cortisol levels, histological changes, enzymes associated with phosphate and carbohydrate metabolism, triglyceride levels, and liver transcriptomics under various conditions: control (CK), short-term cold exposure (6 days, SC), prolonged cold exposure (14 days, PC), and recovery (RY) from cold exposure at 2 °C. Liver vacuolation was observed during short-term cold exposure. Additionally, we analyzed the enzymatic activity related to carbohydrate and lipid metabolism in serum and liver. Liver transcriptomic data revealed that the PPAR signaling pathway and autophagy-related genes were enriched during short-term cold exposure. Carbohydrate metabolism-related pathways, including the AMPK and MAPK signaling pathways, were significantly enriched after prolonged cold exposure. Metabolic pathways such as fat digestion and absorption, glycine, serine, and threonine metabolism, and arginine and proline metabolism were significantly enriched in the recovery group. Rapid warming after prolonged cold stress allowed P. lagowskii to recover quickly. These findings suggest that P. lagowskii has a strong adaptive capacity for energy metabolism during prolonged cold exposure and the ability to recover rapidly from cold stress. A comprehensive examination of the histological, physiological, biochemical, and molecular responses of P. lagowskii to low temperatures is crucial for developing effective strategies for cultivating this species in challenging environments.

Impact of Photobiomodulation and Melatonin on Periodontal Healing of Periodontitis in Immunosuppressed Rats.

Introduction: Periodontitis is an inflammatory disease due to bacterial origin; it has a chronic course and progresses by immunosuppressive therapy. However, adjuvant therapies such as photobiomodulation (PBM) and melatonin can reduce the severity of the inflammation and inhibit the progression of periodontitis. Therefore, the present study evaluated the effects of PBM (PBM) and melatonin, as adjuvant therapies, on periodontal healing in immunosuppressed rats with periodontitis. Methods: Random allocation was performed on 36 albino Wistar rats, divided into the following groups: control, periodontitis, immunosuppressant only, immunosuppressant+PBM, immunosuppressant+melatonin, and immunosuppressant+melatonin+PBM. Periodontitis caused by ligature in all groups, except for the control group. Subcutaneous administration of dexamethasone was performed in the immunosuppressant groups for immunosuppression. All the groups except the control group received scaling and root planning (SRP). Each group was subdivided into three equal subgroups according to the evaluation period: (A), one week, (B) two weeks (C), 4 weeks. Histological examination was done with haematoxylin & eosin and Masson's Trichrome for inflammation and periodontal healing. Statistical Analysis of the data was done by using the chi-square test. The significance level was set at P≤0.05. Results: Regarding the inflammatory response and periodontal healing, histological examination revealed statistically significant difference in all treated groups in comparison with the control untreated immunosuppressed group (P<0.001). The combined application of melatonin and PBM resulted in a best histological response presented by lower inflammatory response and better periodontal healing, when compared with all other treated groups (P<0.001). Conclusion: After considering the circumstances of this research, the combination of melatonin and PBM by a 650 nm diode laser with output power of 100 mw for one minute for three sessions appeared to be a beneficial adjunct in periodontal healing in immunosuppressed rats with periodontitis.

Antimicrobial treatment for human intestinal spirochaetosis: a systematic review

IntroductionThe antimicrobial treatment options for patients with intestinal spirochaetosis (caused by Brachyspira pilosicoli and Brachyspira aalborgi) are not well defined. We aimed to systematically review the literature to explore antimicrobial...

18 Unraveling the Impact of Tumor Microenvironment on Immunotherapy Response/Resistance in Human Sarcomatoid Clear Cell Renal Cell Carcinoma: Insights from a Novel Mouse Model

Abstract Background Renal cell carcinoma (RCC) with histological sarcomatoid de-differentiation (sRCC) has a historically poor prognosis across all RCC subtypes. Recently, immunotherapy with anti-PD1 + anti-CTLA4 combo has significantly improved disease-specific survival, and complete response are seen in upwards of 20% of patients. However, half of sRCC patients still have no response to this immunotherapy, and the mechanism of response remains unclear. Methods Our preliminary bulk RNA sequencing data reveal a distinct tumor microenvironment (TME) in human sRCC tumors, characterized by heightened immune cell infiltration, particularly enriched for regulatory T cells (Tregs). Subsequently, we delineated the spatial gene expression topography within sRCC and clear cell renal cell carcinoma (ccRCC) regions, culminating in the development of the sRCC signature. Concurrently, we established an innovative immunocompetent murine model of sRCC. Leveraging CRISPR technology, we replicated the human sRCC genotype by knocking out Vhl, Bap1, and Cdkn2a/2b genes in a mouse telomerase reverse transcriptase (mTERT) overexpressing renal proximal tubule epithelial cell line. This effort yielded a successfully engineered mouse implantable sRCC cell line bearing VhlMutBap1DelCdkn2aDelCdkn2bDel (HJRCC68N). Results The syngeneic mouse sRCC model we developed faithfully replicates human sRCC histology and tumor microenvironment and recapitulates the sRCC signature identified in human sRCC regions. Importantly, like in humans, mouse sRCC tumors exhibit a heterogeneous response to anti-PD1 + anti-CTLA4 combination, and anti-CTLA4 monotherapy, reflecting the clinical variability observed in human patients. Furthermore, transcriptomic analysis from our mouse model reveals the involvement of type 1 immunity in responder, providing insights into overcoming immunotherapy resistance. Conclusions In conclusion, our study unveiled distinct changes in the TME at the transcriptomic and spatial gene expression levels in human sRCC. Leveraging our novel murine model, which faithfully replicates human sRCC histology, TME characteristics, and mixed response to immunotherapy, we elucidated the involvement of type 1 immunity in treatment response. These insights offer valuable pathways for overcoming immunotherapy resistance and pave the way for the development of tailored treatment strategies aimed at improving outcomes for sRCC patients.

Proton pump inhibitor effect on esophageal protein signature of eosinophilic esophagitis, prediction, and evaluation of treatment response.

Recently, we have identified a dysregulated protein signature in the esophageal epithelium of eosinophilic esophagitis (EoE) patients including proteins associated with inflammation and epithelial barrier function; however, the effect of proton pump inhibitor (PPI) treatment on this signature is unknown. Herein, we used a proteomic approach to investigate: (1) whether PPI treatment alters the esophageal epithelium protein profile observed in EoE patients and (2) whether the protein signature at baseline predicts PPI response. We evaluated the protein signature of esophageal biopsies using a cohort of adult EoE (n = 25) patients and healthy controls (C) (n = 10). In EoE patients, esophageal biopsies were taken before (pre) and after (post) an 8-week PPI treatment, determining the histologic response. Eosinophil count PostPPI was used to classify the patients: ≥15 eosinophils/hpf as non-responders (non-responder) and < 15 eosinophils/hpf as responders (R). Protein signature was determined and differentially accumulated proteins were characterized to identify altered biological processes and signaling pathways. Comparative analysis of differentially accumulated proteins between groups revealed common signatures between three groups of patients with inflammation (responder-PrePPI, non-responder-PrePPI, and non-responder-PostPPI) and without inflammation (controls and responder-PostPPI). PPI therapy almost reversed the EoE specific esophageal protein signature, which is enriched in pathways associated with inflammation and epithelial barrier function, in responder-PostPPI. Furthermore, we identified a set of candidate proteins to differentiate responder-PrePPI and non-responder-PrePPI EoE patients before treatment. These findings provide evidence that PPI therapy reverses the alterations in esophageal inflammatory and epithelial proteins characterizing EoE, thereby providing new insights into the mechanism of PPI clinical response. Interestingly, our results also suggest that PPI response could be predicted at baseline in EoE.

Chondrocyte Response to Fresh Autologous Conditioned Serum Versus Freeze-Dried Allogenic Conditioned Serum.

To investigate the cytokine release profile and histological response of human cartilage after exposure to autologous conditioned serum (ACS) and freeze-dried allogenic conditioned serum (FD-CS). Cartilage explants were collected from 6 patients undergoing total knee arthroplasty. ACS and FD-CS were created from patient serum samples. Cartilage samples were divided into 6 groups: (1) untreated control, (2) ACS, (3) FD-CS, (4) untreated interleukin (IL)-1β (5 ng/ml), (5) IL-1β + ACS, and (6) IL-1β + FD-CS. After 12 days, cartilage samples were analyzed with glycosaminoglycan (GAG) concentration normalized to wet weight while comparing cytokine concentrations, and histological scoring. There was a significant decrease in pathology scoring for ACS (P = 0.0368) and FD-CS (P = 0.0368) in the IL-1β injury groups compared with the untreated IL-1β insult group. ACS and FD-CS significantly mitigate the IL-1β induced increase in basic fibroblast growth factor (bFGF) (P = 0.0009 and P = 0.0002, respectively). FD-CS showed a significant decrease in IL-1β concentration in the presence of IL-1β insult compared with the untreated IL-1β group (P < 0.0001). ACS-treated samples had significantly higher concentration of tumor necrosis factor (TNF)-α independent of IL-1β when compared with samples not treated with biologics (P = 0.0053). Explanted osteoarthritic cartilage responds favorably and equivalently to treatment with ACS and FD-CS from a histological perspective. Both ACS and FD-CS were able to mitigate the IL-1β-induced increases in bFGF and FD-CS lowered IL-1β concentration while increasing interleukin-1 receptor antagonist (IL-1Ra) concentration. Although the cytokine profile of cartilage tissue explants treated with FD-CS appears to be different than that of ACS, this difference does not seem to affect biologic activity of FD-CS.

Comparison of Biological Augmentation in Rotator Cuff Repair Using Inflamed Versus Noninflamed Bursal Tissue in Rats

PurposeTo examine how augmentation of a rotator cuff repair with inflamed versus non-inflamed bursal tissue affects tendon-to-bone healing in a rat model of rotator cuff repair. Methods136 Sprague-Dawley rats were randomly assigned to an inflamed or non-inflamed bursal tissue application group. After detachment the supraspinatus tendon was re-attached with bursal tissue sewn onto the tendon-to-bone interface. The specimens were analysed biomechanically 6 and at 7 weeks and immunohistologically at 1 and at 7 weeks after surgery. ResultsImmunohistological results showed no significant difference in the percentage of collagen type II in the tendon-to-bone interface at 1 (p = 0.97) and 7 weeks (p = 0.42) when utilising autologous non-inflamed bursal tissue in comparison to inflamed bursal tissue specimens. The inflamed bursa group also showed no significant difference in collagen I to III quotient (p= 0.14) after surgery in comparison to post-surgery non-inflamed bursa groups. Biomechanical assessment showed that tendon stiffness (p = 0.87 resp. p = 0.1) and the tendon viscoelasticity (p = 0.12 resp. p = 0.07) was the same after 6 and 7 weeks comparing inflamed bursa to the non-inflamed bursa group. There was no significant difference (p = 0.8 resp. p = 0.97) in load to failure between in both inflamed and non-inflamed bursa groups after 6 and 7 weeks. ConclusionAutologous inflamed bursal tissue derived from the Achilles bursa and implanted to the tendon-to-bone interface after rotator cuff repair facilitates the same histological and biomechanical healing response as using a non-inflamed bursa interposition in rats. Clinical relevanceDuring augmentation of a rotator cuff repair, it is irrelevant whether the bursa tissue is inflamed or not.