Lack Of Inflammation Research Articles

Lack of inflammation or immune response in cyst tissue of patients with symptomatic non-hydrocephalic pineal cysts

Pineal cysts are frequently encountered as incidental findings in magnetic resonance imaging, usually devoid of symptoms, yet some patients exhibit symptomatic manifestations possibly associated with the cyst, even in the absence of hydrocephalus. The etiology of these symptoms remains contentious. This study aims to investigate the presence of lymphatic endothelial cell (LEC) markers and indications of inflammation or immune response within the pineal cysts of patients experiencing symptomatic non-hydrocephalic presentations. Eight patients who underwent surgical excision of their cysts were included in the study. Immunohistochemistry was utilized to assess the expression of LYVE-1, PDPN, and VEGFR3 as LEC markers, alongside IL-6 and CD3 for indications of inflammation or immune activity. Our analysis revealed an absence of inflammatory markers or immune response. However, a distinct expression of VEGFR3 was observed, likely localized to neurons within the pineal cyst tissue. We propose that these VEGFR3+ neurons within the pineal cyst may contribute to the headache symptoms reported by these patients. Further investigations are warranted to substantiate this hypothesis.

Current Understanding of Giardia lamblia and Pathogenesis of Stunting and Cognitive Deficits in Children from Low- and Middle-Income Countries.

Giardia lamblia is a common intestinal parasite worldwide, mainly in children from low- and middle-income countries (LMIC). Also, it has been associated with increased intestinal permeability, stunting, and cognitive impairment. Nonetheless, the pathogenesis of long-term consequences is difficult to elucidate. Recent studies try to understand the long-term consequences of Giardia infections. First, well-characterized studies associate Giardia with intestinal damage and child growth. Second, infections appear not to be associated with inflammation, but "lack of inflammation" may not, however, entirely exclude a pro-inflammatory pathway. Finally, some important amino acids are lower and could contribute to prolongate stunting and cognitive deficit. Giardia infections in LMIC used to be associated with child growth shortfalls, gut permeability, and cognitive deficits. Multifactorial effects could be associated with Giardia, including nutritional, altered microbiota, and generation of potentially toxic microbial metabolic byproducts, all together increasing risk of long-term outcomes.

From Bacterial Toxin to Therapeutic Agent: The Unexpected Fate of Mycolactone

“Recognizing a surprising fact is the first step towards discovery.” This famous quote from Louis Pasteur is particularly appropriate to describe what led us to study mycolactone, a lipid toxin produced by the human pathogen Mycobacterium ulcerans. M. ulcerans is the causative agent of Buruli ulcer, a neglected tropical disease manifesting as chronic, necrotic skin lesions with a “surprising” lack of inflammation and pain. Decades after its first description, mycolactone has become much more than a mycobacterial toxin. This uniquely potent inhibitor of the mammalian translocon (Sec61) helped reveal the central importance of Sec61 activity for immune cell functions, the spread of viral particles and, unexpectedly, the viability of certain cancer cells. We report in this review the main discoveries that marked our research into mycolactone, and the medical perspectives they opened up. The story of mycolactone is not over and the applications of Sec61 inhibition may go well beyond immunomodulation, viral infections, and oncology.

Thoracic aortopathy in Marfan syndrome overlaps with mechanisms seen in bicuspid aortic valve disease.

Thoracic aortopathy is a serious complication which is more often seen in patients with Marfan syndrome (MFS) and patients with a bicuspid aortic valve (BAV) than in individuals with a tricuspid aortic valve (TAV). The identification of common pathological mechanisms leading to aortic complications in non-syndromic and syndromic diseases would significantly improve the field of personalized medicine. This study sought to compare thoracic aortopathy between MFS, BAV, and TAV individuals. Bicuspid aortic valve (BAV; n = 36), TAV (n = 23), and MFS (n = 8) patients were included. Ascending aortic wall specimen were studied for general histologic features, apoptosis, markers of cardiovascular ageing, expression of synthetic and contractile vascular smooth muscle cells (VSMC), and fibrillin-1 expression. The MFS group showed many similarities with the dilated BAV. Both patient groups showed a thinner intima (p < 0.0005), a lower expression of contractile VSMCs (p < 0.05), more elastic fiber thinning (p < 0.001), lack of inflammation (p < 0.001), and a decreased progerin expression (p < 0.05) as compared to the TAV. Other features of cardiovascular ageing differed between the BAV and MFS. Dilated BAV patients demonstrated less medial degeneration (p < 0.0001), VSMC nuclei loss (p < 0.0001), apoptosis of the vessel wall (p < 0.03), and elastic fiber fragmentation and disorganization (p < 0.001), as compared to the MFS and dilated TAV. This study showed important similarities in the pathogenesis of thoracic aortic aneurysms in BAV and MFS. These common mechanisms can be further investigated to personalize treatment strategies in non-syndromic and syndromic conditions.

Oligoclonal M bands unveil occult inflammation in multiple sclerosis

IntroductionRecent works demonstrate that patients with multiple sclerosis (pwMS) and oligoclonal M bands (OCMB) in cerebrospinal fluid (CSF) are at higher risk of conversion to secondary progressive course, suggesting a distinct pathophysiology pathway in these patients. ObjectivesTo analyze the relationship of serum neurofilament light chain (s-NFL) in absence of inflammatory activity in people with multiple sclerosis (pwMS) according to the presence of OCMB versus healthy controls (HC), and the effect of aging. MethodsTwo cohorts of HC were compared to a cohort of pwMS without clinical or radiological signs of acute inflammation. Lack of inflammation was defined as the absence of relapses or gadolinium-enhancing lesions (GEL) brain in an MRI performed within three months before and after s-NFL determination. S-NFL was measured with SIMOa technology. OCMB in the cerebrospinal fluid (CSF) were analyzed with isoelectric focusing and immunoblotting. Results254 people were studied: 124 healthy voluntary controls and 130 pwMS. Despite the absence of inflammatory activity, pwMS and OCMB showed higher levels of s-NFL compared to those without OCMB and HC (11.4 pg/mL, 8.9 pg/mL and 9.0 pg/mL, respectively). A positive and exponential correlation between age and s-NFL was observed, with highest increases among pwMS and OCMB in the CSF. DiscussionIn absence of overt inflammatory activity, pwMS and OCMB exhibit higher s-NFL levels, and a greater age-related increase. Thus, OCMB may portray an underlying inflammatory process not detected by conventional MRI studies and may explain the poorer prognosis of these patients.

Coronary artery bypass in infants with left main coronary artery atresia using an internal thoracic artery bypass graft

Coronary artery bypass in infants with left main coronary artery atresia using an internal thoracic artery bypass graft

Molecular Phenotypes of Frailty in Lung Transplant Candidates

<h3>Purpose</h3> The potential for heterogenous pathobiology underlying physical frailty might explain the inconsistent associations observed between frailty and poor outcomes in lung transplantation. We hypothesize that molecular phenotyping could refine frailty measurement and ultimately tailor interventions. <h3>Methods</h3> In a three-center cohort of lung transplant candidates, we measured frailty by the Short Physical Performance Battery (SPPB); demographic and clinical variables; body composition by bioelectrical impedance, and 17 serum biomarkers reflecting commonly cited causes of frailty including inflammation, sarcopenia, adiposity, mitochondrial and neurohormonal dysfunction. Among those pre-frail or frail (SPPB <12), we first applied latent class modelling to the baseline data and then followed participants forward in time. The best-fitting model was determined by the Bayesian Information Criteria and the Vuong-Lo-Mendell-Rubin test. We tested predictive validity of these classes with disability by the Lung Transplant Valued Life Activities scale and by candidate delisting for becoming too ill or death. <h3>Results</h3> In 442 participants, a 3 latent class model best fit (p = 0.046; Figure 1A). Type A was characterized by higher serum biomarkers of inflammation and sarcopenia (lower muscle mass [ASMI] and grip strength); Type B by sarcopenia, high adiposity (VFA), and lack of inflammation, and Type C was relatively fit (higher ASMI and grip strength) and without inflammation (Figure 1B). Amongst the Type A endotype, 13% of participants died or were delisted compared to 6% in both Type B and C (p = 0.15). Participants comprising Type A reported worse disability (LT-VLA 1.7) than Types B and C (1.4 and 1.3, respectively) (p < 0.001) and had shorter time to delisting or death (1.4 vs 8.0 and 4.0 months, respectively) (p < 0.001). <h3>Conclusion</h3> We identified distinct biological phenotypes of frailty. A frailty phenotype characterized by systemic inflammation and sarcopenia appears to be associated with worse clinical outcomes.

Identification of a Pain-Specific Gene Expression Profile for Pediatric Recurrent Abdominal Pain.

Objectives: Functional Abdominal Pain (FAP) and Irritable Bowel Syndrome (IBS) are common recurrent abdominal pain diagnoses with the hallmark, lack of inflammation. To identify a biological signature for IBS/FAP in the colon, this study used genetic profiling to uncover gene expression changes associated with IBS/FAP and abdominal pain.Methods: Patients (8 to 17 years) newly diagnosed with IBS or FAP were enrolled in the study. At diagnostic colonoscopy, three rectal biopsies were collected, and gene expression analysis was performed using a Qiagen PCR Array. Relative fold difference in gene expression for 84 pain-associated genes was calculated using the 2-ΔΔ Cq method compared with pain-free controls. Factors affecting pain burden (Pain Burden Interview; PBI) were analyzed, including age, sex, rectal inflammation, and gene expression. Data were analyzed using multiple stepwise linear regression and 2-tailed t tests (P ≤ 0.05).Results: Of the 22 total patients in the study, 19 were diagnosed with either IBS-Constipation (frequency of 5.26%), IBS-Diarrhea (47.37%), IBS-Mixed (10.53%), or FAP (36.84%). IBS/FAP patients reported significantly higher pain burden at the time of diagnosis compared to pain-free controls (p < 0.001), as well as significantly higher abdominal pain (p = 0.01). Of the 84 genes, expression of GRIN1 (p = 0.02), MAPK3 (p = 0.04), P2X4 (p = 0.04), and PTGES3 (p = 0.02) were all significantly associated with PBI score.Discussion: Abdominal pain associated with IBS/FAP in pediatric patients may be linked to the expression of GRIN1, MAPK3, P2X4, and PTGES3, pointing to potential novel therapeutic targets for management of recurring abdominal pain.

Role of S100A4 in atherosclerosis development

Abstract Background Smooth muscle cells (SMCs) accumulate into the intima during the process of atherosclerosis, where they switch from a contractile to a synthetic phenotype. We previously identified S100A4 as being a marker of the synthetic SMCs. Recently we have shown that extracellular S100A4 induces a pro-inflammatory-like SMC phenotype and is causally related to atherosclerotic plaque progression. Aim To study the role of intracellular S100A4 depletion in the SMC phenotypic transition during atherosclerosis. Methods We used a full S100A4 knockout (KO) mouse model, where we performed left common carotid ligation and collected carotid arteries after 4 weeks. Primary SMCs were cultured from wild type (WT) and KO animals. We investigated differentiation marker expression, NFκB activation with extracellular S100A4, proliferation and migratory capacities. Results are given as mean ± SD (Fig. 1A and B). Results In vivo, no difference in intimal thickening (IT) size and SMC differentiation marker expression was observed between WT and S100A4 KO mice. CD68 was absent and S100A4 was only detected in WT animals in the inner layer of the IT. In vitro, no difference in differentiation marker expression, proliferation (Fig. 1A) or NFκB activation (Fig. 1C) was observed. Interestingly, migration was decreased in the absence of S100A4 (Fig. 1B) Conclusion The in vivo abrogation of S100A4 does not interfere with IT progression, suggesting that the lack of inflammation in this model might render S100A4 expression neglectable and disguise a possible effect of S100A4 depletion in IT progression. In vitro, S100A4 plays a role in SMC migration. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation Figure 1

Inhibition of Epigenetic Modifiers LSD1 and HDAC1 Blocks Rod Photoreceptor Death in Mouse Models of Retinitis Pigmentosa

Epigenetic modifiers are increasingly being investigated as potential therapeutics to modify and overcome disease phenotypes. Diseases of the nervous system present a particular problem as neurons are postmitotic and demonstrate relatively stable gene expression patterns and chromatin organization. We have explored the ability of epigenetic modifiers to prevent degeneration of rod photoreceptors in a mouse model of retinitis pigmentosa (RP), using rd10 mice of both sexes. The histone modification eraser enzymes lysine demethylase 1 (LSD1) and histone deacetylase 1 (HDAC1) are known to have dramatic effects on the development of rod photoreceptors. In the RP mouse model, inhibitors of these enzymes blocked rod degeneration, preserved vision, and affected the expression of multiple genes including maintenance of rod-specific transcripts and downregulation of those involved in inflammation, gliosis, and cell death. The neuroprotective activity of LSD1 inhibitors includes two pathways. First, through targeting histone modifications, they increase accessibility of chromatin and upregulate neuroprotective genes, such as from the Wnt pathway. We propose that this process is going in rod photoreceptors. Second, through nonhistone targets, they inhibit transcription of inflammatory genes and inflammation. This process is going in microglia, and lack of inflammation keeps rod photoreceptors alive.SIGNIFICANCE STATEMENT Retinal degenerations are a leading cause of vision loss. RP is genetically very heterogeneous, and the multiple pathways leading to cell death are one reason for the slow progress in identifying suitable treatments for patients. Here we demonstrate that inhibition of LSD1and HDAC1 in a mouse model of RP leads to preservation of rod photoreceptors and visual function, retaining of expression of rod-specific genes, and with decreased inflammation, cell death, and Müller cell gliosis. We propose that these epigenetic inhibitors cause more open and accessible chromatin, allowing expression of neuroprotective genes. A second mechanism that allows rod photoreceptor survival is suppression of inflammation by epigenetic inhibitors in microglia. Manipulation of epigenetic modifiers is a new strategy to fight neurodegeneration in RP.

Differential gene expression in skin RNA of horses affected with degenerative suspensory ligament desmitis

BackgroundEquine degenerative suspensory ligament desmitis (DSLD) is a systemic connective tissue disorder first identified in Peruvian Paso horses but afflicting other horse breeds as well. Inappropriate accumulation of proteoglycans in connective tissues, most prominently in tendons and ligaments, leads to progressive and debilitating lameness and pain. It is largely unknown what drives the overproduction of proteoglycans, but our previous studies suggest involvement of bone morphogenetic protein 2 (BMP2), a member of the transforming growth factor-β (TGFβ) family, impacting synthesis of proteoglycans. To identify potential players in pathogenesis of DSLD a new approach utilizing next generation sequencing was undertaken.MethodsNext generation sequencing was performed using RNA extracted from skin biopsies of six control Peruvian Pasos and six horses with DSLD (4 Peruvian Pasos and 2 warmbloods). The CuffDiff result sets were validated with algorithms used to run them. This was based on the determined false discovery rates derived from the P values adjusted for multiple testing for any given result.ResultsBioinformatics analysis of transcriptomes revealed differential expression of over 1500 genes, including increased expression of genes for several growth factors (most prominently BMP2, FGF5, CTGF, many members of the EGF family), and mediators of signaling (Fos, Myc, MAPK system), and keratins. Two genes encoding for enzymes involved in synthesis of hyaluronan were also overexpressed. Gene expression was decreased for protein cores of many proteoglycans, several growth factors, most collagens, and many peptides with immune function.ConclusionsThe overexpression of BMP2 correlates well with our previous data. However, the decrease in expression of numerous proteoglycans was unexpected. A mutation in a gene of a less characterized proteoglycan and/or glycosyltransferase with subsequent increased production of hyaluronan and/or a proteoglycan(s) undetected in our study could account for the systemic proteoglycan deposition. Decreased collagen gene expression indicates abnormal connective tissue metabolism. The increased expression of keratin genes and FGF5 supports reports of skin abnormalities in DSLD. Underexpression of immune function genes corresponds with lack of inflammation in DSLD tissues. Finally, though the proteoglycan and/or glycosaminoglycan abundant in DSLD has not been identified, we validated our previous data, including overexpression of BMP2, and systemic nature of DSLD due to disturbed metabolism of the extracellular matrix.

Ocular Histopathological Findings in Semi-Domesticated Eurasian Tundra Reindeer (Rangifer tarandus tarandus) with Infectious Keratoconjunctivitis after Experimental Inoculation with Cervid Herpesvirus 2.

Infectious keratoconjunctivitis (IKC) is a common transmissible ocular disease in semi-domesticated Eurasian tundra reindeer (Rangifer tarandus tarandus). In large outbreaks, IKC may affect tens of animals in a herd, with the most severe cases often requiring euthanasia due to the destruction of the affected eyes and permanent blindness. An experimental inoculation with cervid herpesvirus 2 (CvHV2), alone or in combination with Moraxella bovoculi, demonstrated that CvHV2 has the ability to cause clinical signs of IKC in previously unexposed reindeer. Tissues collected from upper and lower eyelids, lacrimal gland and cornea, were processed for light and transmission electron microscopy. Histopathological analysis of the eyes inoculated with CvHV2 showed widespread and severe pathological findings. Mucosal tissues from these eyes showed fibrinous and purulent exudates, hyperemia, hemorrhages, necrosis, vascular thrombosis, vascular necrosis, infiltration of mononuclear cells and neutrophils, and lymphoid follicle reaction, which matches the described histopathology of IKC in reindeer. Characteristic alpha-herpesvirus particles matching the size and morphology of CvHV2 were identified by transmission electron microscopy in the conjunctival tissue. The quantification of viral particles by qPCR revealed high copy numbers of viral DNA in all CvHV2 inoculated eyes, but also in the non-inoculated eyes of the same animals. The histopathology of eye tissues obtained from the CvHV2 inoculated reindeer and the lack of inflammation from bacterial infection, together with the detection of CvHV2 DNA in swabs from the inoculated and non-inoculated eyes of the same animals, verified that CvHV2 was the primary cause of the observed histopathological changes.

Children With Metabolically Healthy Obesity: A Review.

Children with “metabolically healthy obesity” (MHO) are a distinct subgroup of youth with obesity, who are less prone to the clustering of cardiometabolic risk factors. Although this phenotype, frequently defined by the absence of metabolic syndrome components or insulin resistance, was first described during the early 1980s, a consensus-based definition of pediatric MHO was introduced only recently, in 2018. The purpose of this review was to concisely summarize current knowledge regarding the MHO phenomenon in youth. The prevalence of MHO in children varies from 3 to 87%, depending on the definition used and the parameters evaluated, as well as the ethnicity and the pubertal status of the sample. The most consistent predictors of MHO in youth include younger age, lower body mass index, lower waist circumference, and lower body fat measurements. Various hypotheses have been proposed to elucidate the underlying factors maintaining the favorable MHO phenotype. While preserved insulin sensitivity and lack of inflammation were previously considered to be the main etiological factors, the most recent findings have implicated adipokine levels, the number of inflammatory immune cells in the adipose tissue, and the reduction of visceral adiposity due to adipose tissue expandability. Physical activity and genetic factors also contribute to the MHO phenotype. Obesity constitutes a continuum-increased risk for cardiometabolic complications, which is less evident in children with MHO. However, some findings have highlighted the emergence of hepatic steatosis, increased carotid intima-media thickness and inflammatory biomarkers in the MHO group compared to peers without obesity. Screening should be directed at those more likely to develop clustering of cardiometabolic risk factors. Lifestyle modifications should include behavioral changes focusing on sleep duration, screen time, diet, physical activity, and tobacco smoke exposure. Weight loss has also been associated with the improvement of insulin sensitivity and inflammation. Further investigative efforts are needed in order to elucidate the mechanisms which protect against the clustering of cardiometabolic risk factors in pediatric obesity, to provide more efficient, targeted treatment approaches for children with obesity, and to identify the protective factors preserving the MHO profile, avoiding the crossover of MHO to the phenotype with metabolically unhealthy obesity.

Safety and Efficacy Evaluation of Aspiration Thrombectomy With Large Bore Catheters in a Porcine Model

Thrombectomy with aspiration catheters has shown to be effective for treatment of intracranial large vessel occlusion (LVO). We present preclinical evaluation of the safety and efficacy of React68 and React71 (Medtronic PLC, Irvine, CA) catheters in animal models of LVO. Invivo evaluation of catheter safety was performed in superficial cervical, internal maxillary, and renal arteries in a porcine model with or without clot (LVO). Animals were survived for 3 days and 30 days. Angiographic outcomes, usability, and histological parameters were compared for treatment with React68, React71, and ACE68 (Penumbra, Alameda, CA) catheters. The invivo angiographic analysis in a porcine thrombectomy LVO model demonstrated that there was no statistically significant difference in the rate of Thrombolysis in Cerebral Infarction scale 2b/3 recanalization between React68, React71, and ACE68 catheters. There were no physical or neurologic deficits in any of the treated animals throughout the survival period. Histologic analysis showed statistically non-inferior safety profile of React68 and React71 catheters relative to ACE68 catheters, with minimal but similar mild internal elastic lamina disruption and smooth muscle loss, but a lack of inflammation, fibrin deposits, and changes in the adventitia at both time points examined. React68 and React71 aspiration catheters have an excellent safety, efficacy, and usability profile in animal models of LVO.

Symptom-based patient-reported outcomes in adults with eosinophilic esophagitis: value for treatment monitoring and randomized controlled trial design.

In adults with eosinophilic esophagitis (EoE), a chronic, inflammatory immune-mediated condition of the esophagus, both inflammation and fibrosis are likely associated with symptom generation. Therefore, assessing symptom-based patient-reported outcomes (PROs), defined by US Food and Drug Administration as 'any report of the status of a patient's health condition that comes directly from the patients, without interpretation of the patient's response by a clinician or anyone else', is important in the context of trials and observational studies of emerging therapies. For purposes of treatment monitoring, lack of symptoms does not predict the absence of biologic inflammation; hence, endoscopy with esophageal biopsies should be performed to check for residual inflammation. Lack of inflammation does not predict lack of symptoms, and the presence of subepithelial fibrosis cannot be excluded. No published instrument currently measures the frequency of dysphagia described all possible ways, strategies of living with this symptom and various pain types. In randomized controlled trials, in which symptom response was detected using validated PRO measures, only modest decreases in symptom scores were observed. Accessing full EoE symptom spectrum and optimizing PRO measures remains a challenge that should be tackled to reliably assess response to existing and emerging therapies.

Itʼs Not Recurrence?

Case presentation A 53-year-old man was evaluated for nausea, fatigue and progressive weakness. He had a history of a 20cm (figure A) stage IIIb gastric high-grade, predominantly epithelioid, GIST (figure B, note the epithelioid appearing GIST within the black arrows, the oxyntic mucosa within the blue arrows and the muscularis separating the two areas) extirpated by partial gastrectomy and Billroth II ˜18 months prior. A 3cm LUQ mass was found on surveillance imaging 12 months later while being treated with adjuvant tyrosine-kinase inhibitors. Repeat imaging demonstrated an enlarging 6.7x7.0cm mass within the abdominal mesentery anterior to the left kidney. He was referred for laparoscopic partial small bowel resection and excision of a 10 cm mesenteric mass at the level of the efferent jejunal limb, a 3cm nodule at the level of the proximal ileum and 6 smaller nodules within the small bowel mesentery. Histopathology of the resected masses demonstrated a vimentin positive, uniform, spindled cell lesion with minimal inflammation and a rare mitotic figure. The lack of inflammation, storiform spindled pattern, mucin and obliterative vasculitis, helped exclude inflammatory myofibroblastic tumor and IgG4 disease. CD117 (c-kit) and CD34 were negative, excluding residual or recurrent GIST. However, the spindled cell did demonstrate nuclear and cytoplasmic positivity for beta-catenin, supporting the diagnosis of intra-abdominal mesenteric fibromatosis (figure C). Discussion Mesenteric fibromatosis or desmoid tumor is group of rare benign tumors that can be locally aggressive but do not metastasize. They develop in ˜20% of patients with FAP but can appear spontaneously, with tissue trauma and radiation exposure as reported risk factors. To date, there are about 30 reported cases of mesenteric fibromatosis following GIST resection. Co-existence of mesenteric fibromatosis with GIST has been reported as well. Distinguishing mesenteric fibromatosis from recurrent GIST may be difficult given common similarities in radiologic appearance and c-kit expression. Accurate diagnosis can only be made after surgical removal and histopathologic examination. Unfortunately, surgery for mesenteric fibromatosis is not always curative and high rates of recurrence are common. Watchful waiting should be considered after resection, especially in patients with minimal symptoms.2701_A Figure 1. CT of the abdomen2701_B Figure 2. Epithelioid GIST, 10X2701_C Figure 3. Jejunal mesenteric mass, desmin stain, 20x

Pathomorphological features of the inflammatory process of the tissues of the prostate cancer and benign prostatic hyperplasia in patients, depending on the infectious agents of sexually transmitted diseases

The objective: the detection of pathomorphological features of the inflammatory process in the intraoperatively removed prostate tissue of the prostate cancer patients (RPZ) and benign prostatic hyperplasia (BPH) depending on the infectious agents of sexually transmitted diseases.Materials and methods. 317 patients aged 42 to 83 years (mean 62 years) were examined, of which 122 patients with RPD had undergone radical prostatectomy and 195 patients with BPH - prostatectomy.Results. The obtained results suggest that the pronounced degree of inflammatory process occurs only in patients with prostate cancer infected with sexually transmitted diseases pathogens, whereas in noninfected, predominant light stomach or a lack of inflammation and pronounced degree is not determined at below. Patients with prostate cancer are more likely to have symptoms of severe inflammation, areas of the tumor beyond the tumor and poorly differentiated tumors.Conclusion. The established facts require further in-depth study of this problem in order to better understand the etiopathogenesis and improve treatment and prophylaxis of prostate tumors.

Periodontology for Geriatric Patients

Elderly population represents the fastest growing population segment and target group of many expert organizations developing strategies for successful aging. The substantial increase in man’s lifespan together with implementation of preventive dental programs resulted in decreased tooth loss and increased prevalence of periodontal disease. Hence, the present review focused on positioning periodontal health within aging process, characteristic of the senescent periodontium, periodontitis-aging interplay, clinical characteristics, and implications for periodontal care in geriatric patients. The senescent periodontium undergoes degenerative changes that are unrelated to progressive destruction in lack of inflammation. The pathological interplay periodontitis-systemic aging is evidenced. Geriatric patients demonstrate comparable treatment outcomes to those of patients ≤ 60 years regarding non-surgical and surgical periodontal treatment and implant therapy as well. Adequate oral hygiene and appropriate control of risk factors represent the key pre-conditions for successful periodontal and systemic aging.

Abstract PR06: Overcoming intratumor T-cell exclusion by modulation of lactate metabolism to improve immune checkpoint therapies in aggressive breast cancer

Abstract Background: Breast cancer (BC) has historically been considered immunologically silent; however, several observations indicate that potentiation of immune functions can benefit BC patients. Intratumor T-cell infiltration has prognostic significance in patients with BC across different molecular and histological categories. In addition, PD-L1 can be overexpressed in BC, in particular in the highly aggressive triple negative BC (TNBC) subtype. This is associated with poor prognosis specifically in patients with luminal B and basal-like phenotypes, thus making these subtypes rational targets of PD-1/PD-L1 axis blockade treatments. However, initial results from early-phase clinical trials show a modest activity of immune checkpoint blockade monotherapy against BC, with 19% TNBC and 3-12% hormone receptor-positive patients achieving a clinical response to anti-PD-1/PD-L1 therapies. Lack of inflammation and T-cell infiltration at the tumor site are characteristic features of tumors that do not respond to checkpoint blockade. Since BC is typically poorly infiltrated by T cells, having strategies that reverse this immune exclusion as well as non-invasive modalities to predict this effect are crucial to improve the clinical efficacy of immune checkpoint blockade. Experimental Design: Our working model is that tumor glycolysis (lactate) and T-cell infiltration are mechanistically interdependent, since we reasoned that a highly glycolytic tumor microenvironment (due to lactate production) could hamper survival, expansion and effector functions of T cells in BC lesions, thus explaining T-cell exclusion. Therefore, we tested whether genetic and/or pharmacologic inhibition of lactate production/consumption could restore intratumor T-cell infiltration and immune function in BC models, thus favoring tumor responsiveness to checkpoint blockade. Results: By interrogating a compendium of 4 BC patient gene expression datasets, we found that patients harboring tumors with high expression of lactate dehydrogenase A (LDH-A) or the lactate transporters MCT-1/4 have a significantly higher risk to develop metastases (p&amp;lt;10−16), whereas those having tumors with increased expression of CD3 and CD8 transcripts experience a better prognosis (p&amp;lt;10−16). Gene expression data from MSKCC's cBio Portal showed an inverse correlation between glycolysis- and immune-related gene expression signatures in BC patients, which was in agreement with our hypothesis. To mechanistically demonstrate the impact of lactate metabolism on intratumor T-cell infiltration in BC, we generated an LDH-A-knocked-down variant (LDH-A KD) of the metastatic TNBC murine model 4T1, and studied its growth and immune infiltrate in vivo in comparison with the control 4T1 tumor. Animals implanted with LDH-A KD 4T1 showed a 5-fold increase in tumor-infiltrating CD3+ T cells and a 4-fold reduction in tumor-associated macrophages, and experienced a significantly prolonged survival. LDH-A KD tumors could be completely eradicated in immunocompetent but not in immunodeficient mice, further supporting the immunologic basis of the antitumor effects of LDH-A inhibition. In vitro analyses showed that proliferation, activation and pro-inflammatory cytokine release of activated CD8 T cells were significantly hampered when they were co-cultured with 4T1 cells. Of note, blocking lactate transport with two new MCT-1/4 small-molecule inhibitors promoted immune functions of CD8 T cells cultured with 4T1, without showing significant toxicity in cultures of T cells alone. Citation Format: Roberta Zappasodi, Arnab Ghosh, Inna Serganova, Ivan Cohen, Yasin Senbabaoglu, Masahiro Shindo, Mayuresh M. Mane, Avigdor Leftin, Ellen Ackerstaff, Jason A. Koutcher, Jedd D. Wolchok, Ronald G. Blasberg, Taha Merghoub. Overcoming intratumor T-cell exclusion by modulation of lactate metabolism to improve immune checkpoint therapies in aggressive breast cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr PR06.

Mesenteric Arteriovenous Dysplasia/Vasculopathy Is Distinct From Fibromuscular Dysplasia.

Fibromuscular dysplasia (FMD) is a noninflammatory, nonatherosclerotic vasculopathy that usually affects the carotid and renal arteries. We have observed FMD-like vascular changes in specimens resected for ischemia or Crohn's disease (CD). On the basis of a systematic clinicopathologic review of these 11 cases identified between 1982 and 2014, we describe a distinct mesenteric vasculopathy that involves both arteries and veins [mesenteric arteriovenous dysplasia/vasculopathy (MAVD/V)] and is characterized by (1) concentric/eccentric smooth muscle collarette around the tunica media of both the artery and the vein in ≥2 foci, (2) varying degrees of intimal and medial hyperplasia and adventitial fibrosis, and (3) lack of inflammation or thrombi. MAVD/V cases were clinically diagnosed as CD (45%), mass/lesion (27%), ischemia (9%), obstruction (9%), or rectal prolapse (9%). Abdominal pain for >1 year was the most common symptom. Most patients were women (M:F=1:2.7; mean age, 63 y). Mucosal changes mimicking CD, such as architectural distortion (55%), multifocal ulcers (73%), and pyloric gland metaplasia (64%), were common; however, no granulomas or transmural lymphoid aggregates were identified. Ischemic pattern of injury was seen in 4 cases. Upon follow-up (mean, 31.2 mo), 8 patients were found to be asymptomatic, 2 had died of unrelated causes, and 1 was lost to follow-up. We propose the name MAVD/V for a distinct noninflammatory, nonatherosclerotic, localized form of mesenteric vasculopathy that involves both arteries and veins, distinct from FMD. Unlike FMD, surgical resection appears to be curative, with a favorable clinical outcome. Awareness of this vascular entity is important as patients may be potentially misdiagnosed as having CD and ischemic bowel disease.