Fatty acid metabolism promotes TRPV4 activity in lung microvascular endothelial cells in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a morbid disease characterized by significant lung endothelial cell (EC) dysfunction. Prior work has shown that microvascular endothelial cells (MVECs) isolated from animals with experimental PAH and patients with PAH exhibit significant abnormalities in metabolism and calcium signaling. With regards to metabolism, we and others have shown evidence of increased aerobic glycolysis and evidence of increased utilization of alternate fuel sources (such as fatty acids) in PAH EC. In the realm of calcium signaling, our prior work linked increased activity of the transient receptor potential vanilloid-4 (TRPV4) channel to increased proliferation of MVECs isolated from the Sugen/Hypoxia rat model of PAH (SuHx-MVECs). However, the relationship between metabolic shifts and calcium abnormalities was not clear. Specifically, whether shifts in metabolism were responsible for increasing TRPV4 channel activity in SuHx-MVECs was not known. In this study, using human data, serum samples from SuHx rats, and SuHx-MVECs, we describe the consequences of increased MVEC fatty acid oxidation in PAH. In human samples, we observed an increase in long-chain fatty acid levels that was associated with PAH severity. Next, using SuHx rats and SuHx-MVECs, we observed increased intracellular levels of lipids. We also show that increasing intracellular lipid content increases TRPV4 activity, whereas inhibiting fatty acid oxidation normalizes basal calcium levels in SuHx-MVECs. By exploring the fate of fatty acid-derived carbons, we observed that the metabolite linking increased intracellular lipids to TRPV4 activity was ß-hydroxybutyrate (BOHB), a product of fatty acid oxidation. Finally, we show that BOHB supplementation alone is sufficient to sensitize the TRPV4 channel in rat and mouse MVECs. Returning to humans, we observe a transpulmonary BOHB gradient in human patients with PAH. Thus, we establish a link between fatty acid oxidation, BOHB production, and TRPV4 activity in MVECs in PAH. These data provide new insight into metabolic regulation of calcium signaling in lung MVECs in PAH.NEW & NOTEWORTHY In this paper, we explore the link between metabolism and intracellular calcium levels in microvascular endothelial cells (MVECs) in pulmonary arterial hypertension (PAH). We show that fatty acid oxidation promotes sensitivity of the transient receptor potential vanilloid-4 (TRPV4) calcium channel in MVECs isolated from a rodent model of PAH.

Commonsense morality and the bearable automaticity of being.

Some research suggests that moral behavior can be strongly influenced by trivial features of the environment of which we are completely unaware. Philosophers, psychologists, and neuroscientists have argued that these findings undermine our commonsense notions of agency and responsibility, both of which emphasize the role of practical reasoning and conscious deliberation in action. We present the results of four vignette-based studies (N=1,437) designed to investigate how people think about the metaphysical and moral implications of scientific findings that reveal our susceptibility to automaticity and situational influences. When presented with lightly fictionalized narratives about these findings, participants exhibit no tendency toward changing judgments of freedom and responsibility compared to control groups. This suggests that people seem unwilling to adopt skeptical attitudes about agency on the basis of these scientific findings.

Purity is linked to cooperation but not necessarily through self-control.

Fitouchi et al. claim that seemingly victimless pleasures and nonproductive activities are moralized because they alter self-control. Their account predicts that: (1) victimless excesses are negatively moralized because they diminish self-control, and (2) restrained behaviors are positively moralized because they enhance self-control. Several examples run contrary to these predictions and call into question the general relationship between self-control and cooperation.

Rapport de cas Ossifying fibroma in the cervical vertebra of a dog.

The objective of this study was to describe the clinical signs, neurologic examination findings, diagnostic imaging results, and pathologic diagnosis of ossifying fibroma in the cervical vertebra of a dog. A 3-year-old spayed female Pembroke Welsh corgi dog exhibited severe cervical pain and left-sided postural reaction deficits. Magnetic resonance imaging (MRI) revealed a lobulated contrast enhancing mass associated with the C6 cervical vertebra. Due to the lack of response to pain medications, humane euthanasia was elected, and histopathologic evaluation of the mass revealed a fibro-osseous lesion most consistent with an ossifying fibroma. This neoplasm is most commonly associated with the mandible of young horses and has not been previously reported in vertebrae in veterinary medicine. Key clinical message: This case is the first report of a fibro-osseous lesion most consistent with an ossifying fibroma affecting a vertebra in veterinary medicine.

Fibrome ossifiant dans la vertèbre cervicale d'un chien. Décrire les signes cliniques, les résultats de l'examen neurologique, les résultats de l'imagerie diagnostique et le diagnostic pathologique du fibrome ossifiant dans la vertèbre cervicale d'un chien. Une chienne Pembroke Welsh corgi femelle stérilisée âgée de 3 ans présentait de fortes douleurs cervicales et des déficits de réaction posturale du côté gauche. L'imagerie par résonance magnétique (IRM) a révélé une masse lobulée augmentant le contraste associée à la vertèbre cervicale C6. En raison de l'absence de réponse aux analgésiques, l'euthanasie a été choisie et l'évaluation histopathologique de la masse a révélé une lésion fibro-osseuse plus compatible avec un fibrome ossifiant. Ce néoplasme est le plus souvent associé à la mandibule des jeunes chevaux et n'a jamais été signalé auparavant dans les vertèbres en médecine vétérinaire.Message clinique clé :Ce cas est le premier rapport d'une lésion fibro-osseuse plus compatible avec un fibrome ossifiant touchant une vertèbre en médecine vétérinaire.(Traduit par Dr Serge Messier).

Everolimus plus bevacizumab is an effective first-line treatment for patients with advanced papillary variant renal cell carcinoma: Final results from a phase II trial.

BACKGROUND: We previously reported on a phase 2 study of everolimus plus bevacizumab across various nonclear cell renal cell carcinoma (nccRCC) histologies and observed encouraging activity among patients with papillary RCC (pRCC) and unclassified RCC (uRCC) with a major papillary component. We subsequently expanded the study to enroll additional patients with pRCC variants. METHODS: Everolimus plus bevacizumab was administered at standard doses until disease progression or intolerance to therapy. The primary endpoint was the 6-month progression-free survival (PFS) rate; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Correlative analyses included next-generation sequencing (NGS) from tumor and germline across >341 genes of interest. RESULTS: In addition to 19 patients with pRCC variants in the original cohort, 20 patients with similar features were enrolled on the expansion cohort (uRCC with papillary features [n = 24], pRCC [n = 14], and translocation-associated RCC with papillary features [n = 1]). Among 37 evaluable patients, the 6-month PFS rate was 78%, the median PFS was 13.7 months (95% CI, 10.8-16.4 months), and the ORR was 35%. With a median follow-up of 17.6 months, the median OS was 33.9 months (95% CI, 23.3-71.9). Tolerance was consistent with prior reports for everolimus plus bevacizumab. NGS results (n = 33) identified responses in patients with a wide spectrum of genomic alterations, including ARID1A, FH, and MET mutations. CONCLUSION: The expansion cohort results confirm robust activity of everolimus plus bevacizumab in metastatic pRCC variants, supporting this regimen as a standard option for this patient population.

Long-term hypoxia uncouples Ca2+ and eNOS in bradykinin-mediated pulmonary arterial relaxation.

Bradykinin-induced activation of the pulmonary endothelium triggers a rise in intracellular Ca2+ that activates nitric oxide (NO)-dependent vasorelaxation. Chronic hypoxia is commonly associated with increased pulmonary vascular tone, which can cause pulmonary hypertension in responsive individuals. In the present study, we tested the hypothesis that long-term high-altitude hypoxia (LTH) diminishes bradykinin-induced Ca2+ signals and inhibits endothelial nitric oxide synthase (eNOS), prostacyclin (PGI2), and large-conductance K+ (BKCa) channels in sheep, which are moderately responsive to LTH, resulting in decreased pulmonary arterial vasorelaxation. Pulmonary arteries were isolated from ewes kept near sea level (720 m) or at high altitude (3,801 m) for >100 days. Vessel force was measured with wire myography and endothelial intracellular Ca2+ with confocal microscopy. eNOS was inhibited with 100 µM NG-nitro-l-arginine methyl ester (l-NAME), PGI2 production was inhibited with 10 µM indomethacin that inhibits cyclooxygenase, and BKCa channels were blocked with 1 mM tetraethylammonium. Bradykinin-induced endothelial Ca2+ signals increased following LTH, but bradykinin relaxation decreased. Furthermore, some vessels contracted in response to bradykinin after LTH. l-NAME sensitivity decreased, suggesting that eNOS dysfunction played a role in uncoupling Ca2+ signals and bradykinin relaxation. The Ca2+ ionophore A-23187 (10 µM) elicited an enhanced Ca2+ response following LTH while relaxation was unchanged although l-NAME sensitivity increased. Additionally, BKCa function decreased during bradykinin relaxation following LTH. Western analysis showed that BKCa α-subunit expression was increased by LTH while that for the ß1 subunit was unchanged. Overall, these results suggest that those even moderately responsive to LTH can have impaired endothelial function.

Vagus nerve stimulation in pregnant rats and effects on inflammatory markers in the brainstem of neonates.

BackgroundVagus nerve stimulation (VNS) is an Food and Drug Administration-approved method delivering electrical impulses for treatment of depression and epilepsy in adults. The vagus nerve innervates the majority of visceral organs and cervix, but potential impacts of VNS on the progress of pregnancy and the fetus are not well studied.MethodsWe tested the hypothesis that VNS in pregnant dams does not induce inflammatory changes in the cardio-respiratory control regions of the pups' brainstem, potentially impacting the morbidity and mortality of offspring. Pregnant dams were implanted with stimulators providing intermittent low or high frequency electrical stimulation of the sub-diaphragmatic esophageal segment of the vagus nerve for 6-7 days until delivery. After birth, we collected pup brainstems that included cardio-respiratory control regions and counted the cells labeled for pro-inflammatory cytokines (interleukin (IL)-1ß, IL-6, tumor necrosis factor-α) and high mobility group box 1.ResultsNeither pup viability nor number of cells labeled for pro-inflammatory cytokines in nucleus tractus solitarii or hypoglossal motor nucleus was impaired by VNS. We provide evidence suggesting that chronic VNS of pregnant mothers does not impede the progress or outcome of pregnancy.ConclusionVNS does not cause preterm birth, affect well-being of progeny, or impact central inflammatory processes that are critical for normal cardiovascular and respiratory function in newborns.

Why value values?

Doris argues that an agent is responsible for her behavior only if that behavior expresses (a relevant subset of) the agent's values. This view has problems explaining responsibility for mistakes or episodes of forgetfulness. These problems highlight a conceptual problem with Doris's theory of responsible agency and give us reasons to prefer an alternative (non-valuational) theory of responsible agency.

HK2 Proximal Tubule Epithelial Cells Synthesize and Secrete Plasma Proteins Predominantly Through the Apical Surface.

Renal proximal tubule epithelial cells (PTECs) are known to reabsorb salts and small plasma proteins filtered through Bowman's capsule. Following acute kidney injury, PTECs assume some characteristics of hepatocytes in producing various plasma proteins. We now demonstrate that even at a resting state, a PTEC cell line, HK2 expresses mRNAs for and synthesizes and secretes plasma proteins in a complex with complement C3, an α2 -macroglobulin family chaperone, including albumin, transferrin, α1 -antitrypsin, α1 -antichymotrypsin, α2 -HS-glycoprotein, ceruloplasmin, haptoglobin, C1-inhibitor, secreted phosphoprotein-24, and insulin-like growth factor-1. When grown on transwell inserts, HK2 cells predominantly secrete (∼90%) plasma proteins into the apical side and a smaller fraction into the basolateral side as determined by ELISA assays. When cultured in the presence of exogenous cytokines such as IL1ß, IL6, TNFα, BMP2, or TGFß1, HK2 cell mRNA expressions for plasma proteins were variably affected whereas basolateral secretions were elevated to or in excess of those of the apical level. In addition, HK2 cells produce proTGFß1 with its intact N-terminal latency associated peptide and latent-TGF-ß-binding proteins. The complex cannot be dissociated under conditions of SDS, heating, and electrophoresis. Moreover, HK2 cells maintain their ability to quickly uptake exogenously added serum proteins from the culture medium, as if they are recognized differently by the endocytic receptors. These results provide new insight into the hepatization of PTECs. In addition to their unique uptake of plasma proteins and salts from the filtrate, they are a source of urinary proteins under normal conditions as wells as in chronic and acute kidney diseases. J. Cell. Biochem. 118: 924-933, 2017. © 2016 Wiley Periodicals, Inc.

The role of IL-6 in neurodevelopment after prenatal stress.

Prenatal stress exposure is associated with adverse psychiatric outcomes, including autism and ADHD, as well as locomotor and social inhibition and anxiety-like behaviors in animal offspring. Similarly, maternal immune activation also contributes to psychiatric risk and aberrant offspring behavior. The mechanisms underlying these outcomes are not clear. Offspring microglia and the pro-inflammatory cytokine interleukin-6 (IL-6), known to influence microglia, may serve as common mechanisms between prenatal stress and prenatal immune activation. To evaluate the role of prenatal IL-6 in prenatal stress, microglia morphological analyses were conducted at embryonic days 14 (E14), E15, and in adult mice. Offspring microglia and behavior were evaluated after repetitive maternal restraint stress, repetitive maternal IL-6, or maternal IL-6 blockade during stress from E12 onwards. At E14, novel changes in cortical plate embryonic microglia were documented-a greater density of the mutivacuolated morphology. This resulted from either prenatal stress or IL-6 exposure and was prevented by IL-6 blockade during prenatal stress. Prenatal stress also resulted in increased microglia ramification in adult brain, as has been previously shown. As with embryonic microglia, prenatal IL-6 recapitulated prenatal stress-induced changes in adult microglia. Furthermore, prenatal IL-6 was able to recapitulate the delay in GABAergic progenitor migration caused by prenatal stress. However, IL-6 mechanisms were not necessary for this delay, which persisted after prenatal stress despite IL-6 blockade. As we have previously demonstrated, behavioral effects of prenatal stress in offspring, including increased anxiety-like behavior, decreased sociability, and locomotor inhibition, may be related to these GABAergic delays. While adult microglia changes were ameliorated by IL-6 blockade, these behavioral changes were independent of IL-6 mechanisms, similar to GABAergic delays. This and previous work from our laboratory suggests that multiple mechanisms, including GABAergic delays, may underlie prenatal stress-linked deficits.

Spp24 derivatives stimulate a Gi-protein coupled receptor-Erk1/2 signaling pathway and modulate gene expressions in W-20-17 cells.

Secreted phosphoprotein 24 kDa (Spp24) is an apatite- and BMP/TGF-ß cytokine-binding phosphoprotein found in serum and many tissues, including bone. N-terminally intact degradation products ranging in size from 14 kDa to 23 kDa have been found in bone. The cleavage sites in Spp24 that produce these short forms have not been definitively identified, and the biological activities and mechanisms of action of Spp24 and its degradation products have not been fully elucidated. We found that the C-terminus of Spp24 is labile to proteolysis by furin, kallikrein, lactoferrin, and trypsin, indicating that both extracellular and intracellular proteolytic events could account for the generation of biologically-active Spp18, Spp16, and Spp14. We determined the effects of these truncation products on kinase-mediated signal transduction, gene expression, and osteoblastic differentiation in W-20-17 bone marrow stromal cells cultured in basal or pro-osteogenic media. After culturing for five days, all forms inhibited BMP-2-stimulated osteoblastic differentiation, assessed as induction of alkaline phosphatase activity, in basal, but not pro-osteogenic media. After 10 days, they also inhibited BMP-2-stimulated mineral deposition in pro-osteogenic media. Spp24 had no effect on Erk1/2 phosphorylation, but Spp18 stimulated short-term Erk1/2, MEK 1/2, and p38 phosphorylation. Pertussis toxin and a MEK1/2 inhibitor ablated Spp18-stimulated Erk 1/2 phosphorylation, indicating a role for Gi proteins and MEK1/2 in the Spp18-stimulated Erk1/2 phosphorylation cascade. Truncation products, but not full-length Spp24, stimulated RUNX2, ATF4, and CSF1 transcription. This suggests that Spp24 truncation products have effects on osteoblastic differentiation mediated by kinase pathways that are independent of exogenous BMP/TGF-ß cytokines.

Fibroblastic synoviocytes secrete plasma proteins via α2 -macroglobulins serving as intracellular and extracellular chaperones.

Changes in plasma protein levels in synovial fluid (SF) have been implicated in osteoarthritis and rheumatoid arthritis. It was previously thought that the presence of plasma proteins in SF reflected ultrafiltration or extravasation from the vasculature, possibly due to retraction of inflamed endothelial cells. Recent proteomic analyses have confirmed the abundant presence of plasma proteins in SF from control and arthritic patients. Systematic depletion of high-abundance plasma proteins from SF and conditioned media from synoviocytes cultured in serum, and protein analysis under denaturing/reducing conditions have limited our understanding of sources and the native structures of "plasma protein" complexes in SF. Using Western blotting, qPCR, and mass spectrometry, we found that Hig-82 lapine fibroblastic synovicytes cultured under serum-free conditions expressed and secreted plasma proteins, including the cytokine-binding protein secreted phosphoprotein 24 kDa (Spp24) and many of the proteases and protease inhibitors found in SF. Treating synoviocytes with TGF-ß1 or BMP-2 for 24 h upregulated the expression of plasma proteins, including Spp24, α2 -HS-glycoprotein, α1 -antitrypsin, IGF-1, and C-reactive protein. Furthermore, many of the plasma proteins of mass <151 kDa were secreted as disulfide-bound complexes with members of the α2 -macroglobulin (A2M) family, which serve as intracellular and extracellular chaperones, not protease inhibitors. Using brefeldin A to block vesicular traffic and protease inhibitors to inhibit endogenous activation of naïve A2M, we demonstrated that the complexes were formed in the endoplasmic reticulum lumen and that Ca(2+) cysteine protease-dependent processes are involved.

A carboxy terminal BMP/TGF-ß binding site in secreted phosphoprotein 24 kD independently affects BMP-2 activity.

Secreted phosphoprotein 24 kD (spp24) is a bone matrix protein isolated during attempts to identify osteogenic proteins. It is not osteogenic but performs other important roles in the regulation of bone metabolism, at least in part, by binding to and affecting the activity of members of the BMP/TGF-ß family of cytokines. Spp24 exists in a number of forms that preserve the N-terminus and are truncated at the C-terminus. The hypothesized cytokine binding domain is present within the cystatin domain which is preserved in all of the N-terminal products. In this report, we describe a C-terminal fragment that is distinct from the cystatin domain and which independently binds to BMP-2 and TGF-ß. This fragment inhibited BMP-2 activity in an ectopic bone forming assay. A shorter C-terminal product did not inhibit BMP-2 activity but improved bone quality induced by BMP-2 and produced increased calcium deposition outside of bone. Spp24 has been used to develop several potential therapeutic proteins. These results provide more information on the function of spp24 and provide other materials that can be exploited for clinical interventions.

Secreted phosphoprotein 24 kD (Spp24) inhibits growth of human pancreatic cancer cells caused by BMP-2.

The emerging role of bone morphogenetic proteins (BMPs) in the initiation and progression of multiple cancers has drawn great attention in cancer research. In this study, we report that BMP-2 can promote the proliferation of the pancreatic tumor cell line, PANC-1. Secreted phosphoprotein 24 kD (Spp24), a BMP binding protein, did not affect the proliferation of the cells but promoted the apoptosis of the cells in vitro. In a xeneograft tumor model using PANC-1 cells, BMP-2 dramatically promoted tumor growth, while Spp24 not only abolished the effect of BMP-2, but also dramatically induced tumor shrinking when used alone. Activation of Smad1/5/8 participated in this process as demonstrated by immunohistochemical staining of phosphorylated Smad 1/5/8. We conclude that Spp24 can be developed into a therapeutic agent that could be employed in clinical situations where the inhibition of BMPs and related proteins is advantageous.

The strategic allocation theory of vigilance.

Despite its importance in different occupational and everyday contexts, vigilance, typically defined as the capacity to sustain attention over time, is remarkably limited. What explains these limits? Two theories have been proposed. The Overload Theory states that being vigilant consumes limited information-processing resources; when depleted, task performance degrades. The Underload Theory states that motivation to perform vigilance tasks declines over time, thereby prompting attentional shifts and hindering performance. We highlight some conceptual and empirical problems for both theories and propose an alternative: the Strategic Allocation Theory. For the Strategic Allocation Theory, performance on vigilance tasks optimizes as a function of intrinsic and extrinsic motivations, including metacognitive factors such as the expected value of effort and the expected value of planning. Limited capacities must be deployed across task sets to maximize expected reward. The observed limits of vigilance reflect changes in the perceived value of, among other things, sustaining attention to a task rather than attending to something else. Drawing from recent computational theories of cognitive control and meta-reasoning, we argue that the Strategic Allocation Theory explains more phenomena related to vigilance behavior than other theories, including self-report data. Finally, we outline some of the testable predictions the theory makes across several experimental paradigms. This article is categorized under: Philosophy > Foundations of Cognitive Science Psychology > Attention.

Believe in your self-control: Lay theories of self-control and their downstream effects.

Self-control is the ability to inhibit temptations and persist in one's decisions about what to do. In this article, we review recent evidence that suggests implicit beliefs about the process of self-control influence how the process operates. While earlier work focused on the moderating influence of willpower beliefs on depletion effects, we survey new directions in the field that emphasize how beliefs about the nature of self-control, self-control strategies, and their effectiveness have effects on downstream regulation and judgment. These new directions highlight the need to better understand the role of self-control beliefs in naturalistic decision-making.

Within your rights: Dissociating wrongness and permissibility in moral judgement.

Are we ever morally permitted to do what is morally wrong? It seems intuitive that we are, but evidence for dissociations among judgement of permissibility and wrongness is relatively scarce. Across four experiments (N = 1438), we show that people judge that some behaviours can be morally wrong and permissible. The dissociations arise because these judgements track different morally relevant aspects of everyday moral encounters. Judgements of individual rights predicted permissibility but not wrongness, while character assessment predicted wrongness but not permissibility. These findings suggest a picture in which moral evaluation is granular enough to express reasoning about different types of normative considerations, notably the possibility that people can exercise their rights in morally problematic ways.

A computational modeling approach to investigating mind wandering-related adjustments to gaze behavior during scene viewing.

Research on gaze control has long shown that increased visual-cognitive processing demands in scene viewing are associated with longer fixation durations. More recently, though, longer durations have also been linked to mind wandering, a perceptually decoupled state of attention marked by decreased visual-cognitive processing. Toward better understanding the relationship between fixation durations and visual-cognitive processing, we ran simulations using an established random-walk model for saccade timing and programming and assessed which model parameters best predicted modulations in fixation durations associated with mind wandering compared to attentive viewing. Mind wandering-related fixation durations were best described as an increase in the variability of the fixation-generating process, leading to more variable-sometimes very long-durations. In contrast, past research showed that increased processing demands increased the mean duration of the fixation-generating process. The findings thus illustrate that mind wandering and processing demands modulate fixation durations through different mechanisms in scene viewing. This suggests that processing demands cannot be inferred from changes in fixation durations without understanding the underlying mechanism by which these changes were generated.

Loyalty from a personal point of view: A cross-cultural prototype study of loyalty.

Loyalty is considered central to people's moral life, yet little is known about how people think about what it means to be loyal. We used a prototype approach to understand how loyalty is represented in Colombia and the United States and how these representations mediate attributions of loyalty and moral judgments of loyalty violations. Across seven studies (N = 1,984), we found cross-cultural similarities in the associative meaning of loyalty (Study 1) but found differences in the centrality of features associated with loyalty (Study 2) and the latent structure of loyalty representations (Study 3). Colombians represent loyalty in terms of more general moral characteristics, while U.S. participants represent loyalty in terms of interpersonal commitment, both in contrast with current approaches to loyalty. By comparing representations of loyalty and honesty, we establish that differences in loyalty conceptualizations reflect a different way of thinking about loyalty rather than morality more generally (Study 4). Further, Colombians attributed greater loyalty to individuals with general moral characteristics compared to participants from the U.S. sample (Study 5) and were more likely to classify nonloyal values as loyalty-related (Study 6). While the centrality of prototypical features predicts categorizing norm violations as loyalty-related, differences in prototypical structure account for differences in the severity of moral judgment for such violations (Study 7), which suggests that loyalty representations have similar functions, even though these representations differ in structural characteristics. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Nationwide Real-World Data of Microsatellite Instability and/or Mismatch Repair Deficiency in Cancer: Prevalence and Testing Patterns.

Determination of microsatellite instability (MSI)/mismatch repair (MMR) status in cancer has several clinical implications. Our aim was to integrate MSI/MMR status from patients tested in Greece to assess the prevalence of MSI-high (MSI-H)/deficient MMR (dMMR) per tumor type, testing patterns over time and concordance between MSI and MMR status. We retrospectively recorded MSI/MMR testing data of patients with diverse tumor types performed in pathology and molecular diagnostics laboratories across Greece. Overall, 18 of 22 pathology and/or molecular diagnostics laboratories accepted our invitation to participate. In the 18 laboratories located across the country, 7916 tumor samples were evaluated for MSI/MMR status. MSI/MMR testing significantly increased in patients with colorectal cancer (CRC) and other tumor types overtime (p < 0.05). The highest prevalence was reported in endometrial cancer (47 of 225 patients, 20.9%). MSI-H/dMMR was observed in most tumor types, even in low proportions. Among 904 tumors assessed both for MSI and MMR status, 21 had discordant results (overall discordance rate, 2.3%). We reported MSI-H/dMMR prevalence rates in patients with diverse cancers, while demonstrating increasing referral patterns from medical oncologists in the country overtime. The anticipated high rate of concordance between MSI and MMR status in paired analysis was confirmed.