Impact of an Inter-Professional Clinic on Pancreatic Cancer Outcomes: A Retrospective Cohort Study.

Background: Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges in diagnosis, staging, and appropriate treatment. Furthermore, patients with PDAC often experience complex symptomatology and psychosocial implications that require multi-disciplinary and inter-professional supportive care management from health professionals. Despite these hurdles, the implementation of inter-professional clinic approaches showed promise in enhancing clinical outcomes. To assess the effectiveness of such an approach, we examined the impact of the Wallace McCain Centre for Pancreatic Cancer (WMCPC), an inter-professional clinic for patients with PDAC at the Princess Margaret Cancer Centre (PM). Methods: This retrospective cohort study included all patients diagnosed with PDAC who were seen at the PM before (July 2012-June 2014) and after (July 2014-June 2016) the establishment of the WMCPC. Standard therapies such as surgery, chemotherapy, and radiation therapy remained consistent across both time periods. The cohorts were compared in terms of survival rates, disease stage, referral patterns, time to treatment, symptoms, and the proportion of patients assessed and supported by nursing and allied health professionals. Results: A total of 993 patients were included in the review, comprising 482 patients pre-WMCPC and 511 patients post-WMCPC. In the multivariate analysis, adjusting for ECOG (Eastern Cooperative Oncology Group) and stage, it was found that post-WMCPC patients experienced longer median overall survival (mOS, HR 0.84, 95% CI 0.72-0.98, p = 0.023). Furthermore, the time from referral to initial consultation date decreased significantly from 13.4 to 8.8 days in the post-WMCPC cohort (p < 0.001), along with a reduction in the time from the first clinic appointment to biopsy (14 vs. 8 days, p = 0.022). Additionally, patient-reported well-being scores showed improvement in the post-WMCPC cohort (p = 0.02), and these patients were more frequently attended to by nursing and allied health professionals (p < 0.001). Conclusions: The implementation of an inter-professional clinic for patients diagnosed with PDAC led to improvements in overall survival, patient-reported well-being, time to initial assessment visit and pathological diagnosis, and symptom management. These findings advocate for the adoption of an inter-professional clinic model in the treatment of patients with PDAC.

The Development of Environmentally Sustainable Poly(vinyl chloride) Composite from Waste Non-Metallic Printed Circuit Board with Interfacial Agents.

The recycling of non-metallic printed circuit boards (NMPCB) as a filler in poly(vinyl chloride) (PVC) composite would help to encourage the use of waste NMPCB, thus, reducing some environmental concerns with regard to e-waste. The objective of this study was to comprehensively evaluate the effect of different interfacial agents, namely polypropylene grafted maleic anhydride (PP-g-MAH) and ϒ-aminopropyltriethoxy silane (ATPS) on the morphology and properties of PVC/NMPCB composites. A PVC/NMPCB composite was prepared by melt compounding with varying amounts of NMPCB ranging between 10, 20 and 30 wt.%. Fourier transform infrared spectroscopy-attenuated total reflectance (FTIR-ATR) analysis revealed the interactions between PVC and NMPCB when using both PP-g-MAH and ATPS interfacial agent. The properties and morphology of PVC/NMPCB composites were significantly dependent on the interfacial agent treated on the NMPCB surface. The phase morphology and mechanical properties of PVC/NMPCB composites (30 wt.% of NMPCB) were improved and the result also indicated that the higher compatibility of composites with ATPS as an interfacial agent led to our obtaining the maximum Young's modulus of 484 MPa. The dynamic mechanical analysis revealed the interaction at the interface, with the Tg shifting to a lower temperature in the presence of PP-g-MAH and strong interfacial adhesion noted with the improved Tg in the presence of the ATPS interfacial agent. Further evidence of the improved interaction was observed with the increment in density in the presence of ATPS when compared with PP-g-MAH in PVC/NMPCB composite. Hence, of the two interfacial agents, ATPS showed itself to be more effective when employed as an interfacial agent for NMPCB in PVC composite for industry.

Prevalence of Secondhand Smoke and Its Associated Factors Among Pregnant Women Attending Antenatal Care at a Hospital in Yangon Region, Myanmar.

Smokers are not the only ones who suffer the effects of tobacco; those around them are also harmed, particularly vulnerable groups such as pregnant women. This study aimed to describe the prevalence of secondhand smoke (SHS) among pregnant women and the factors associated with SHS exposure. This study was a cross-sectional descriptive study conducted at Central Women's Hospital in the Yangon Region in 2022. The prevalence of SHS exposure was described, and multivariate analyses were conducted to determine the associated factors. Out of 407 participants, the prevalence of SHS exposure was 65.4%. Education level, religion, smoking rules at home, visiting public places, and avoidance of SHS during pregnancy were significantly associated with SHS exposure. The findings highlighted the need for community guidance programs, policies, and interventions to establish smoke-free environments. It is also important to conduct behavioral interventions for smokers, especially to avoid SHS for pregnant women.

Interpretable attention-based deep learning ensemble for personalized ovarian cancer treatment without manual annotations.

Inhibition of pathological angiogenesis has become one of the first FDA approved targeted therapies widely tested in anti-cancer treatment, i.e. VEGF-targeting monoclonal antibody bevacizumab, in combination with chemotherapy for frontline and maintenance therapy for women with newly diagnosed ovarian cancer. Identification of the best predictive biomarkers of bevacizumab response is necessary in order to select patients most likely to benefit from this therapy. Hence, this study investigates the protein expression patterns on immunohistochemical whole slide images of three angiogenesis related proteins, including Vascular endothelial growth factor, Angiopoietin 2 and Pyruvate kinase isoform M2, and develops an interpretable and annotation-free attention based deep learning ensemble framework to predict the bevacizumab therapeutic effect on patients with epithelial ovarian cancer or peritoneal serous papillary carcinoma using tissue microarrays (TMAs). In evaluation with five-fold cross validation, the proposed ensemble model using the protein expressions of both Pyruvate kinase isoform M2 and Angiopoietin 2 achieves a notably high F-score (0.99±0.02), accuracy (0.99±0.03), precision (0.99±0.02), recall (0.99±0.02) and AUC (1.00±0). Kaplan-Meier progression free survival analysis confirms that the proposed ensemble is able to identify patients in the predictive therapeutic sensitive group with low cancer recurrence (p<0.001), and the Cox proportional hazards model analysis further confirms the above statement (p=0.012). In conclusion, the experimental results demonstrate that the proposed ensemble model using the protein expressions of both Pyruvate kinase isoform M2 and Angiopoietin 2 can assist treatment planning of bevacizumab targeted therapy for patients with ovarian cancer.

Landscape of MicroRNA Regulatory Network Architecture and Functional Rerouting in Cancer.

Somatic mutations are a major source of cancer development, and many driver mutations have been identified in protein coding regions. However, the function of mutations located in miRNA and their target binding sites throughout the human genome remains largely unknown. Here, we built detailed cancer-specific miRNA regulatory networks across 30 cancer types to systematically analyze the effect of mutations in miRNAs and their target sites in 3' untranslated region (3' UTR), coding sequence (CDS), and 5' UTR regions. A total of 3,518,261 mutations from 9,819 samples were mapped to miRNA-gene interactions (mGI). Mutations in miRNAs showed a mutually exclusive pattern with mutations in their target genes in almost all cancer types. A linear regression method identified 148 candidate driver mutations that can significantly perturb miRNA regulatory networks. Driver mutations in 3'UTRs played their roles by altering RNA binding energy and the expression of target genes. Finally, mutated driver gene targets in 3' UTRs were significantly downregulated in cancer and functioned as tumor suppressors during cancer progression, suggesting potential miRNA candidates with significant clinical implications. A user-friendly, open-access web portal (mGI-map) was developed to facilitate further use of this data resource. Together, these results will facilitate novel noncoding biomarker identification and therapeutic drug design targeting the miRNA regulatory networks. SIGNIFICANCE: A detailed miRNA-gene interaction map reveals extensive miRNA-mediated gene regulatory networks with mutation-induced perturbations across multiple cancers, serving as a resource for noncoding biomarker discovery and drug development.

Bacterial protein MakA causes suppression of tumour cell proliferation via inhibition of PIP5K1α/Akt signalling.

Recently, we demonstrated that a novel bacterial cytotoxin, the protein MakA which is released by Vibrio cholerae, is a virulence factor, causing killing of Caenorhabditis elegans when the worms are grazing on the bacteria. Studies with mammalian cell cultures in vitro indicated that MakA could affect eukaryotic cell signalling pathways involved in lipid biosynthesis. MakA treatment of colon cancer cells in vitro caused inhibition of growth and loss of cell viability. These findings prompted us to investigate possible signalling pathways that could be targets of the MakA-mediated inhibition of tumour cell proliferation. Initial in vivo studies with MakA producing V. cholerae and C. elegans suggested that the MakA protein might target the PIP5K1α phospholipid-signalling pathway in the worms. Intriguingly, MakA was then found to inhibit the PIP5K1α lipid-signalling pathway in cancer cells, resulting in a decrease in PIP5K1α and pAkt expression. Further analyses revealed that MakA inhibited cyclin-dependent kinase 1 (CDK1) and induced p27 expression, resulting in G2/M cell cycle arrest. Moreover, MakA induced downregulation of Ki67 and cyclin D1, which led to inhibition of cell proliferation. This is the first report about a bacterial protein that may target signalling involving the cancer cell lipid modulator PIP5K1α in colon cancer cells, implying an anti-cancer effect.

Pre-encoded responsiveness to type I interferon in the peripheral immune system defines outcome of PD1 blockade therapy.

Type I interferons (IFN-Is) are central regulators of anti-tumor immunity and responses to immunotherapy, but they also drive the feedback inhibition underlying therapeutic resistance. In the present study, we developed a mass cytometry approach to quantify IFN-I-stimulated protein expression across immune cells and used multi-omics to uncover pre-therapy cellular states encoding responsiveness to inflammation. Analyzing peripheral blood cells from multiple cancer types revealed that differential responsiveness to IFN-Is before anti-programmed cell death protein 1 (PD1) treatment was highly predictive of long-term survival after therapy. Unexpectedly, IFN-I hyporesponsiveness efficiently predicted long-term survival, whereas high responsiveness to IFN-I was strongly associated with treatment failure and diminished survival time. Peripheral IFN-I responsive states were not associated with tumor inflammation, identifying a disconnect between systemic immune potential and 'cold' or 'hot' tumor states. Mechanistically, IFN-I responsiveness was epigenetically imprinted before therapy, poising cells for differential inflammatory responses and dysfunctional T cell effector programs. Thus, we identify physiological cell states with clinical importance that can predict success and long-term survival of PD1-blocking immunotherapy.

Primary ambulatory thromboprophylaxis in patients with pancreatic cancer receiving chemotherapy: hope or hype?

Thrombosis is the second leading cause of death in cancer patients. Patients with pancreatic cancer (PC) have a very high risk of developing venous thromboembolism (VTE). Even though primary ambulatory thromboprophylaxis (PATP) could decrease this risk, there are uncertain issues with regard to the choice and dose of anticoagulants, duration of anticoagulant therapy, and patient selection criteria. In addition, the current practice guidelines on PATP in PC patients are equivocal. This review critically appraises the evidence on the use of PATP in PC patients receiving chemotherapy.

A Weakly Supervised Deep Learning Method for Guiding Ovarian Cancer Treatment and Identifying an Effective Biomarker.

Ovarian cancer is a common malignant gynecological disease. Molecular target therapy, i.e., antiangiogenesis with bevacizumab, was found to be effective in some patients of epithelial ovarian cancer (EOC). Although careful patient selection is essential, there are currently no biomarkers available for routine therapeutic usage. To the authors' best knowledge, this is the first automated precision oncology framework to effectively identify and select EOC and peritoneal serous papillary carcinoma (PSPC) patients with positive therapeutic effect. From March 2013 to January 2021, we have a database, containing four kinds of immunohistochemical tissue samples, including AIM2, c3, C5 and NLRP3, from patients diagnosed with EOC and PSPC and treated with bevacizumab in a hospital-based retrospective study. We developed a hybrid deep learning framework and weakly supervised deep learning models for each potential biomarker, and the experimental results show that the proposed model in combination with AIM2 achieves high accuracy 0.92, recall 0.97, F-measure 0.93 and AUC 0.97 for the first experiment (66% training and 34%testing) and high accuracy 0.86 ± 0.07, precision 0.9 ± 0.07, recall 0.85 ± 0.06, F-measure 0.87 ± 0.06 and AUC 0.91 ± 0.05 for the second experiment using five-fold cross validation, respectively. Both Kaplan-Meier PFS analysis and Cox proportional hazards model analysis further confirmed that the proposed AIM2-DL model is able to distinguish patients gaining positive therapeutic effects with low cancer recurrence from patients with disease progression after treatment (p < 0.005).

Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody-drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors.

PURPOSE: To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody-drug conjugate (ADC) ± nivolumab, in patients with selected tumors. PATIENTS AND METHODS: In an international phase I/IIa study [NCT02341625 (CA008-002)], patients received BMS-986148 monotherapy (0.1-1.6 mg/kg intravenously (i.v.) every 3 weeks or 0.4 or 0.6 mg/kg i.v. once weekly; n = 96) or BMS-986148 0.8 mg/kg + nivolumab 360 mg i.v. every 3 weeks (n = 30). The primary endpoint was safety and tolerability. RESULTS: In CA008-002, the most common (≥ 10%) treatment-related adverse events (TRAEs) included increased aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Grade 3/4 TRAEs occurred in 42 patients (49%) receiving BMS-986148 every 3 weeks monotherapy, three (25%) receiving BMS-986148 once-weekly monotherapy, and 10 (33%) receiving BMS-986148 + nivolumab every 3 weeks. Overall, 17 of 126 patients (13%) discontinued because of a TRAE. The MTD of BMS-986148 was 1.2 mg/kg i.v. every 3 weeks. The safety profile of BMS-986148 + nivolumab was similar to that of BMS-986148 monotherapy (0.8 mg/kg). Active ADC exposures increased in a dose-proportional manner with both dosing regimens (every 3 weeks and once weekly). Preliminary clinical activity was observed with BMS-986148 ± nivolumab. No association between mesothelin expression and response was detected. CONCLUSIONS: BMS-986148 ± nivolumab demonstrated a clinically manageable safety profile and preliminary evidence of clinical activity, supporting additional studies combining directed cytotoxic therapies with checkpoint inhibitors as potential multimodal therapeutic strategies in patients with advanced solid tumors.

A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma.

Background: Mitogen-activated protein kinase kinase (MEK) is activated by mutated KRAS in >90% of pancreatic ductal adenocarcinoma (PDAC). MEK and focal adhesion kinase (FAK) are frequently co-activated in PDAC providing a rationale for combining trametinib, an oral allosteric MEK1/2 inhibitor, with GSK2256098, an oral FAK inhibitor. Methods: Advanced PDAC patients whose disease progressed after first line palliative chemotherapy were treated with GSK2256098 250 mg twice daily and trametinib 0.5 mg once daily orally. The primary endpoint was clinical benefit (CB; complete response, partial response, or stable disease ≥24 weeks). Twenty-four patients were planned to enroll using a 2-stage minimax design (P0=0.15, P1=0.40; alpha =0.05, power 0.86). The combination would be considered inactive if 2/12 or fewer patients achieved CB at the end of stage 1, and would be considered active if >7/24 response-evaluable patients achieved CB by the end of stage 2. Serial blood samples were collected for circulating tumor DNA (ctDNA) mutation profiling. Results: Sixteen patients were enrolled and 11 were response evaluable. Of those 11, 10 had progressive disease as best tumor response and one had stable disease for 4 months. No treatment related grade ≥3 adverse events (AEs) were observed. The median progression free survival (PFS) was 1.6 (95% CI: 1.5-1.8) months and the median overall survival (OS) was 3.6 (95% CI: 2.7-not reached) months. One response-inevaluable patient achieved clinical stability for 5 months with reduction in CA19-9 and ctDNA levels with a MAP2K1 treatment resistance mutation detected in ctDNA at clinical progression. Conclusions: The combination of GSK2256098 and trametinib was well tolerated but was not active in unselected advanced PDAC.

Phase II Trial of Trametinib and Panitumumab in RAS/RAF Wild Type Metastatic Colorectal Cancer.

INTRODUCTION: MEK inhibition may overcome resistance to EGFR inhibition in patients with RAS wildtype (wt) metastatic colorectal cancer (mCRC). We evaluated antitumor activity of trametinib (MEK1/2 inhibitor) with panitumumab (EGFR monoclonal antibody) in a phase II trial. METHODS: Patients with KRAS, NRAS, and BRAF wt mCRC with prior 5-FU, irinotecan, oxaliplatin, +/- bevacizumab and no prior anti-EGFR therapy were treated with trametinib 1.5 mg oral daily and panitumumab 4.8 mg/kg IV every 2 weeks. Primary endpoint was clinical benefit rate (CB; CR, PR, or SD ≥24 weeks) by RECIST v1.1. A 2-stage minimax design was used. Serial plasma circulating free DNA (cfDNA) was collected and profiled using Oncomine Lung cfDNA assay. RESULTS: Fourteen patients were enrolled from November 2015 to April 2019. CB rate was 38% (5/13) and median progression free survival (PFS) was 4.4 months (95% CI, 2.9-7.1). Confirmed overall response rate was 38% (5/13). Treatment-related AE (trAE) included acneiform rash (85%), diarrhea (62%), maculopapular rash (54%), mucositis (46%), and others. Dose modifications and interruptions of trametinib occurred in 69% and panitumumab in 54% of patients. The trial did not progress to stage II accrual due to tolerability and short duration of response. RAS or BRAF mutations cfDNA were detected in 3/13 patients (23%) before radiographic disease progression. CONCLUSION: The addition of trametinib to panitumumab led to a high rate of tumor shrinkage in RAS/RAF wt metastatic colorectal cancer, with poor tolerability due to a high incidence of skin toxicity. Median PFS was similar to panitumumab alone in historical control data.

Plasmodesmata-Dependent Intercellular Movement of Bacterial Effectors.

Pathogenic microorganisms deliver protein effectors into host cells to suppress host immune responses. Recent findings reveal that phytopathogens manipulate the function of plant cell-to-cell communication channels known as plasmodesmata (PD) to promote diseases. Several bacterial and filamentous pathogen effectors have been shown to regulate PD in their host cells. A few effectors of filamentous pathogens have been reported to move from the infected cells to neighboring plant cells through PD; however, it is unclear whether bacterial effectors can traffic through PD in plants. In this study, we determined the intercellular movement of Pseudomonas syringae pv. tomato (Pst) DC3000 effectors between adjoining plant cells in Nicotiana benthamiana. We observed that at least 16 Pst DC3000 effectors have the capacity to move from transformed cells to the surrounding plant cells. The movement of the effectors is largely dependent on their molecular weights. The expression of PD regulators, Arabidopsis PD-located protein PDLP5 and PDLP7, leads to PD closure and inhibits the PD-dependent movement of a bacterial effector in N. benthamiana. Similarly, a 22-amino acid peptide of bacterial flagellin (flg22) treatment induces PD closure and suppresses the movement of a bacterial effector in N. benthamiana. Among the mobile effectors, HopAF1 and HopA1 are localized to the plasma membrane (PM) in plant cells. Interestingly, the PM association of HopAF1 does not negatively affect the PD-dependent movement. Together, our findings demonstrate that bacterial effectors are able to move intercellularly through PD in plants.

The Clinical Applicability of Primary Thromboprophylaxis in Ambulatory Patients With Pancreatic Cancer.

ABSTRACT: Thromboembolism is a leading cause of death in ambulatory patients with cancer. Patients with pancreatic adenocarcinoma have a very high risk of developing venous thromboembolism, especially within the first 6 months of diagnosis. Although primary thromboprophylaxis could reduce this risk, there are unresolved questions concerning choice of agents for anticoagulation, duration of anticoagulation treatment, and criteria for patient selection. Furthermore, the current clinical guidelines on primary thromboprophylaxis in ambulatory patients with pancreatic cancer are ambiguous. This review seeks out to understand and critically appraise the evidence supporting the use of primary thromboprophylaxis in patients with pancreatic cancer and its clinical applicability.

Suppression of ß-catenin signaling in colon carcinoma cells by a bacterial protein.

Colorectal cancer is one of the leading causes of cancer-related death worldwide. The adenomatous polyposis coli (APC) gene is mutated in hereditary colorectal tumors and in more than 80% of sporadic colorectal tumors. APC mutations impair ß-catenin degradation, leading to its permanent stabilization and increased transcription of cancer-driving target genes. In colon cancer, impairment of ß-catenin degradation leads to its cytoplasmic accumulation, nuclear translocation, and subsequent activation of tumor cell proliferation. Suppressing ß-catenin signaling in cancer cells therefore appears to be a promising strategy for new anticancer strategies. Recently, we discovered a novel Vibrio cholerae cytotoxin, motility-associated killing factor A (MakA), that affects both invertebrate and vertebrate hosts. It promotes bacterial survival and proliferation in invertebrate predators but has unknown biological role(s) in mammalian hosts. Here, we report that MakA can cause lethality of tumor cells via induction of apoptosis. Interestingly, MakA exhibited potent cytotoxic activity, in particular against several tested cancer cell lines, while appearing less toxic toward nontransformed cells. MakA bound to the tumor cell surface became internalized into the endolysosomal compartment and induced leakage of endolysosomal membranes, causing cytosolic release of cathepsins and activation of proapoptotic proteins. In addition, MakA altered ß-catenin integrity in colon cancer cells, partly through a caspase- and proteasome-dependent mechanism. Importantly, MakA inhibited ß-catenin-mediated tumor cell proliferation. Remarkably, intratumor injection of MakA significantly reduced tumor development in a colon cancer murine solid tumor model. These data identify MakA as a novel candidate to be considered in new strategies for development of therapeutic agents against colon cancer.

Current methods in translational cancer research.

Recent developments in pre-clinical screening tools, that more reliably predict the clinical effects and adverse events of candidate therapeutic agents, has ushered in a new era of drug development and screening. However, given the rapid pace with which these models have emerged, the individual merits of these translational research tools warrant careful evaluation in order to furnish clinical researchers with appropriate information to conduct pre-clinical screening in an accelerated and rational manner. This review assesses the predictive utility of both well-established and emerging pre-clinical methods in terms of their suitability as a screening platform for treatment response, ability to represent pharmacodynamic and pharmacokinetic drug properties, and lastly debates the translational limitations and benefits of these models. To this end, we will describe the current literature on cell culture, organoids, in vivo mouse models, and in silico computational approaches. Particular focus will be devoted to discussing gaps and unmet needs in the literature as well as current advancements and innovations achieved in the field, such as co-clinical trials and future avenues for refinement.

Systematic Review and STARD Scoring of Renal Cell Carcinoma Circulating Diagnostic Biomarker Manuscripts.

BACKGROUND: No validated molecular biomarkers exist to help guide diagnosis of renal cell carcinoma (RCC) patients. We seek to evaluate the quality of published RCC circulating diagnostic biomarker manuscripts using the Standards for Reporting of Diagnostic Accuracy Studies (STARD) guidelines. METHODS: The phrase "(renal cell carcinoma OR renal cancer OR kidney cancer OR kidney carcinoma) AND circulating AND (biomarkers OR cell free DNA OR tumor DNA OR methylated cell free DNA OR methylated tumor DNA)" was searched in Embase, MEDLINE, and PubMed in March 2018. Relevant manuscripts were scored using 41 STARD subcriteria for a maximal score of 26 points. All tests of statistical significance were 2 sided. RESULTS: The search identified 535 publications: 27 manuscripts of primary research were analyzed. The median STARD score was 11.5 (range = 7-16.75). All manuscripts had appropriate abstracts, introductions, and distribution of alternative diagnoses. None of the manuscripts stated how indeterminant data were handled or if adverse events occurred from performing the index test or reference standard. Statistically significantly higher STARD scores were present in manuscripts reporting receiver operator characteristic curves (P < .001), larger sample sizes (P = .007), and after release of the original STARD statement (P = .005). CONCLUSIONS: Most RCC circulating diagnostic biomarker manuscripts poorly adhere to the STARD guidelines. Future studies adhering to STARD guidelines may address this unmet need.

Aging-Affected MSC Functions and Severity of Periodontal Tissue Destruction in a Ligature-Induced Mouse Periodontitis Model.

Mesenchymal stem cells (MSCs) are known to play important roles in the repair of lost or damaged tissues and immunotolerance. On the other hand, aging is known to impair MSC function. However, little is currently known about how aged MSCs affect the host response to the local inflammatory condition and tissue deterioration in periodontitis, which is a progressive destructive disease of the periodontal tissue potentially leading to multiple tooth loss. In this study, we examined the relationship between aging-induced impairment of MSC function and the severity of periodontal tissue destruction associated with the decrease in host immunomodulatory response using a ligature-induced periodontitis model in young and aged mice. The results of micro computerized tomography (micro-CT) and histological analysis revealed a more severe bone loss associated with increased osteoclast activity in aged (50-week-old) mice compared to young (5-week-old) mice. Immunostaining analysis revealed that, in aged mice, the accumulation of inflammatory T and B cells was higher, whereas the percentage of platelet-derived growth factor receptor α (PDGFRα)+ MSCs, which are known to modulate the apoptosis of T cells, was significantly lower than in young mice. In vitro analysis of MSC function showed that the expression of surface antigen markers for MSCs (Sca-1, CD90, CD146), colony formation, migration, and osteogenic differentiation of aged MSCs were significantly declined compared to those of young MSCs. Moreover, a significantly higher proportion of aged MSCs were positive for the senescence-associated ß galactosidase activity. Importantly, aged MSCs presented a decreased expression of FAS-L, which was associated with a lower immunomodulatory property of aged MSCs to induce T cell apoptosis in co-cultures compared with young MSCs. In summary, this is the first study showing that aging-induced impairment of MSC function, including immunomodulatory response, is potentially correlated with progressive periodontal tissue deterioration.

Genitourinary extramammary Paget's disease: review and outcome in a multidisciplinary setting.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare malignant disease originating from the apocrine glands involving the perineum, vulva, axilla, scrotum, and penis. OBJECTIVE: To study the clinical presentation, extent of disease, efficacy of treatment, and survival outcomes of the cases in a single institution. METHODS: Retrospective observation data analysis of 19 EMPD cases was performed. Demographic information, clinical management records, and histopathologic data of individual cases were obtained from the inpatient hospital data registry. RESULTS: The mean age (years) at time of diagnosis was 62.4 with equal gender distribution. Synchronous tumors were detected in 6 cases (31.5%). 18 out of 19 patients underwent definitive surgical management in the form of wide local excision (WLE) and reconstructive surgery. Positive margins were found in 11 (68.8%) cases and 7 out of these 11 cases underwent second look surgical intervention to achieve oncological clearance or adjuvant oncology treatment. Follow-up period for living patients varied depending on time of diagnosis and definitive treatment. 10 out 19 cases (52.7%) were alive at the time of the study. Among the 7 cases of mortality from cancer, 5 cases died from progression of underlying associated malignancy and only 2 cases died with advanced stage of EMPD. CONCLUSION: EMPD can be quite aggressive, especially in the secondary form, and surgical management is challenging with a high rate of residual tumor at the surgical margin. EMPD can easily mislead the clinician and patient, leading to unnecessary delay prior to definitive effective management.