As the outermost barrier of the body, the skin is exposed to multiple environmental factors, including temperature, humidity, mechanical stress, and chemical stimuli such as odorants that are often ...used in cosmetic articles. Keratinocytes, the major cell type of the epidermal layer, express a variety of different sensory receptors that enable them to react to various environmental stimuli and process information in the skin. Here we report the identification of a novel type of chemoreceptors in human keratinocytes, the olfactory receptors (ORs). We cloned and functionally expressed the cutaneous OR, OR2AT4, and identified Sandalore, a synthetic sandalwood odorant, as an agonist of this receptor. Sandalore induces strong Ca2+ signals in cultured human keratinocytes, which are mediated by OR2AT4, as demonstrated by receptor knockdown experiments using RNA interference. The activation of OR2AT4 induces a cAMP-dependent pathway and phosphorylation of extracellular signal-regulated kinases (Erk1/2) and p38 mitogen–activated protein kinases (p38 MAPK). Moreover, the long-term stimulation of keratinocytes with Sandalore positively affected cell proliferation and migration, and regeneration of keratinocyte monolayers in an in vitro wound scratch assay. These findings combined with our studies on human skin organ cultures strongly indicate that the OR 2AT4 is involved in human keratinocyte re-epithelialization during wound-healing processes.
Abstract Background Gleason grading is the strongest prognostic parameter in prostate cancer. Gleason grading is categorized as Gleason ≤6, 3 + 4, 4 + 3, 8, and 9–10, but there is variability within ...these subgroups. For example, Gleason 4 components may range from 5–45% in a Gleason 3 + 4 = 7 cancer. Objective To assess the clinical relevance of the fractions of Gleason patterns. Design, setting, and participants Prostatectomy specimens from 12 823 consecutive patients and of 2971 matched preoperative biopsies for which clinical data with an annual follow-up between 2005 and 2014 were available from the Martini-Klinik database. Outcome measurements and statistical analysis To evaluate the utility of quantitative grading, the fraction of Gleason 3, 4, and 5 patterns seen in biopsies and prostatectomies were recorded. Gleason grade fractions were compared with prostatectomy findings and prostate-specific antigen recurrence. Results and limitations Our data suggest a striking utility of quantitative Gleason grading. In prostatectomy specimens, there was a continuous increase of the risk of prostate-specific antigen recurrence with increasing percentage of Gleason 4 fractions with remarkably small differences in outcome at clinically important thresholds (0% vs 5%; 40% vs 60% Gleason 4), distinguishing traditionally established prognostic groups. Also, in biopsies, the quantitative Gleason scoring identified various intermediate risk groups with respect to Gleason findings in corresponding prostatectomies. Quantitative grading may also reduce the clinical impact of interobserver variability because borderline findings such as tumors with 5%, 40%, or 60% Gleason 4 fractions and very small Gleason 5 fractions (with pivotal impact on the Gleason score) are disclaimed. Conclusions Quantitative Gleason pattern data should routinely be provided in addition to Gleason score categories, both in biopsies and in prostatectomy specimens. Patient summary Gleason score is the most important prognostic parameter in prostate cancer, but prone to interobserver variation. The results of our study show that morphological aspects that define the Gleason grade in prostate cancer represent a continuum. Quantitation of Gleason patterns provides clinically relevant information beyond the traditional Gleason grading categories ≤3 + 3, 3 + 4, 4 + 3, 8, 9–10. Quantitative Gleason scoring can help to minimize variations between different pathologists and substantially aid in optimized therapy decision-making.
Objectives
To develop a routinely applicable severity index for the management of acute appendicitis in adults using combined clinical and radiological parameters and retroperitoneal space planes ...(RSP).
Methods
Two hundred consecutive patients with histologically proven acute appendicitis and available presurgical CT scans were analysed retrospectively. Two radiologists assessed all CT scans for morphologic sings of appendicitis and six RSP. Clinical parameters were age, body temperature, C-reactive protein (CRP), white blood cell count, and duration of symptoms. Radiological parameters were appendix diameter and wall thickness, periappendiceal fat stranding and fluid, intraluminal and extraluminal air, thinning of appendiceal wall, caecal wall thickening, appendicolith and abscess formation.
Results
One hundred and three patients (51%) had histologically proven complicated appendicitis. Based on three clinical (age ≥52 years, body temperature ≥37.5°C, duration of symptoms ≥48 h) and four computed tomography (CT) findings (appendix diameter ≥14 mm, presence of periappendiceal fluid, extraluminal air, perityphlitic abscess), the APSI was developed using regression coefficients of multivariate logistic regression analyses with a maximum of 10 points. A score of ≥4 points predicted complicated appendicitis with a positive predictive value of 92% and a negative predictive value of 83%. Substantial to excellent interobserver agreement was found for the four radiological parameters of the APSI intraclass correlation coefficient (ICC), 0.78-0.83. The RSP evaluation presented no added value for the diagnosis of complicated appendicitis.
Conclusions
Using APSI, an accurate and simple prediction of complicated appendicitis in adults was possible. The RSP count was not useful for the diagnosis of complicated appendicitis.
Key points
• Appendicitis severity score provides an accurate and simple prediction of complicated appendicitis
• Appendicitis severity score ≥4 accurately predicted complicated appendicitis (PPV 92%;NPV 83%)
• Evaluation of retroperitoneal space planes was not useful in diagnosing complicated appendicitis
Oncolytic activities of host defense peptides Al-Benna, Sammy; Shai, Yechiel; Jacobsen, Frank ...
International Journal of Molecular Sciences,
11/2011, Letnik:
12, Številka:
11
Journal Article, Book Review
Recenzirano
Odprti dostop
Cancer continues to be a leading source of morbidity and mortality worldwide in spite of progress in oncolytic therapies. In addition, the incidence of cancers affecting the breast, kidney, prostate ...and skin among others continue to rise. Chemotherapeutic drugs are widely used in cancer treatment but have the serious drawback of nonspecific toxicity because these agents target any rapidly dividing cell without discriminating between healthy and malignant cells. In addition, many neoplasms eventually become resistant to conventional chemotherapy due to selection for multidrug-resistant variants. The limitations associated with existing chemotherapeutic drugs have stimulated the search for new oncolytic therapies. Host defense peptides (HDPs) may represent a novel family of oncolytic agents that can avoid the shortcomings of conventional chemotherapy because they exhibit selective cytotoxicity against a broad spectrum of malignant human cells, including multi-drug-resistant neoplastic cells. Oncolytic activity by HDPs is usually via necrosis due to cell membrane lysis, but some HDPs can trigger apoptosis in cancer cells via mitochondrial membrane disruption. In addition, certain HDPs are anti-angiogenic which may inhibit cancer progression. This paper reviews oncolytic HDP studies in order to address the suitability of selected HDPs as oncolytic therapies.
In contrast to normal healing wounds, chronic wounds commonly show disturbances in proteins regulating wound healing processes, particularly those involved in cell proliferation and protein ...degradation. Multidimensional protein identification technology MS/MS was conducted to investigate and compare the protein composition of chronic diabetic foot exudates to exudates from split‐skin donor sites of burn victims otherwise healthy. Spectral counting revealed 188 proteins differentially expressed (more than twofold and p‐value <0.05) in chronic wounds. Most were involved in biological processes including inflammation, angiogenesis, and cell mortality. Increased expression of the inflammatory response stimulating S100 proteins, predominantly S100A8 and S100A9 (almost tenfold), was identified. Matrix metalloproteinases (MMPs) MMP1, MMP2, and MMP8 were identified to be elevated in chronic wounds with significant impact on collagen degradation and tissue destruction. Further, proteins with antiangiogenic properties were found at higher expression levels in chronic wounds. Reduced angiogenesis leads to drastic shortage in nutrition supply and causes increased cell death, demonstrated by Annexin A5 exclusively found in chronic wound exudates. However, excessive nucleic and cytosolic material infers cell death occurring not only by apoptosis but also by necrosis. In conclusion, mass spectrometric investigation of exudates from chronic wounds demonstrated dramatic impairment in wound repair with excessive inflammation, antiangiogenic environment, and accelerated cell death.
Chronic rejection remains the Achilles heel in vascularized composite allotransplantation. Animal models to specifically study chronic rejection in vascularized composite allotransplantation do not ...exist so far. However, there are established rat models to study chronic rejection in solid organ transplantation such as allogeneic transplantation between the rat strains Lewis and Fischer344. Thus, we initiated this study to investigate the applicability of hindlimb transplantation between these strains to imitate chronic rejection in vascularized composite allotransplantation and identify potential markers. Allogeneic hindlimb transplantation were performed between Lewis (recipient) and Fischer344 (donor) rats with either constant immunosuppression or a high dose immunosuppressive bolus only in case of acute skin rejections. Histology, immunohistochemistry, microarray and qPCR analysis were used to detect changes in skin and muscle at postoperative day 100. We were able to demonstrate significant intimal proliferation, infiltration of CD68 and CD4 positive cells, up-regulation of inflammatory cytokines and initiation of muscular fibrosis in the chronic rejection group. Microarray analysis and subsequent qPCR identified CXC ligands 9-11 as potential markers of chronic rejection. The Fischer344 to Lewis hindlimb transplantation model may represent a new option to study chronic rejection in vascularized composite allotransplantation in an experimental setting. CXC ligands 9-11 deserve further research to investigate their role as chronic rejection markers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nodal metastasis (N1) is a strong prognostic parameter in prostate cancer; however, lymph node evaluation is always incomplete.
To study the prognostic value of lymphatic invasion (L1) and whether it ...might complement or even replace lymph node analysis in clinical practice.
Retrospective analysis of pathological and clinical data from 14 528 consecutive patients.
Radical prostatectomy.
The impact of L1 and N1 on patient prognosis was measured with time to biochemical recurrence as the primary endpoint.
Nodal metastases were found in 1602 (12%) of 13 070 patients with lymph node dissection. L1 was seen in 2027 of 14 528 patients (14%) for whom lymphatic vessels had been visualized by immunohistochemistry. N1 and L1 continuously increased with unfavorable Gleason grade, advanced pT stage, and preoperative prostate-specific antigen (PSA) values (p<0.0001 each). N1 was found in 4.3% of 12 501 L0 and in 41% of 2027 L1 carcinomas (p<0.0001). L1 was seen in 11% of 9868 N0 and in 61% of 1360 N1 carcinomas (p<0.0001). Both N1 and L1 were linked to PSA recurrence (p<0.0001 each). This was also true for 17 patients with isolated tumor cells (ie, <200 unequivocal cancer cells without invasive growth) and 193 metastases ≤1mm. Combined analysis of N and L status showed that L1 had no prognostic effect in N1 patients but L1 was strikingly linked to PSA recurrence in N0 patients. N0L1 patients showed a similar outcome as N1 patients.
Analysis of lymphatic invasion provides comparable prognostic information than lymph node analysis. Even minimal involvement of the lymphatic system has pivotal prognostic impact in prostate cancer. Thus, a thorough search for lymphatic involvement helps to identify more patients with an increased risk for disease recurrence.
Already minimal amounts of tumor cells inside the lymph nodes or intraprostatic lymphatic vessels have a severe impact on patient prognosis.
To replace morbidity-prone lymph node analysis, we tested immunohistochemical analysis of lymphatic vessels to predict prognosis after radical prostatectomy. We found that minimal lymphatic invasion had a pivotal prognostic impact.
Innate defense regulators (IDRs) are synthetic immunomodulatory versions of natural host defense peptides (HDP). IDRs mediate protection against bacterial challenge in the absence of direct ...antimicrobial activity, representing a novel approach to anti-infective and anti-inflammatory therapy. Previously, we reported that IDR-1018 selectively induced chemokine responses and suppressed pro-inflammatory responses. As there has been an increasing appreciation for the ability of HDPs to modulate complex immune processes, including wound healing, we characterized the wound healing activities of IDR-1018 in vitro. Further, we investigated the efficacy of IDR-1018 in diabetic and non-diabetic wound healing models. In all experiments, IDR-1018 was compared to the human HDP LL-37 and HDP-derived wound healing peptide HB-107. IDR-1018 was significantly less cytotoxic in vitro as compared to either LL-37 or HB-107. Furthermore, administration of IDR-1018 resulted in a dose-dependent increase in fibroblast cellular respiration. In vivo, IDR-1018 demonstrated significantly accelerated wound healing in S. aureus infected porcine and non-diabetic but not in diabetic murine wounds. However, no significant differences in bacterial colonization were observed. Our investigation demonstrates that in addition to previously reported immunomodulatory activities IDR-1018 promotes wound healing independent of direct antibacterial activity. Interestingly, these effects were not observed in diabetic wounds. It is anticipated that the wound healing activities of IDR-1018 can be attributed to modulation of host immune pathways that are suppressed in diabetic wounds and provide further evidence of the multiple immunomodulatory activities of IDR-1018.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMP3 is an RNA binding protein required for ribosomal RNA processing, which has been suggested to be a prognostic marker in a large variety of human types of cancer. However, available data on the ...prevalence of IMP3 expression are largely discrepant. To systematically investigate the epidemiology and clinical relevance of IMP3 expression in human cancers we employed a two-step tissue microarrays (TMAs) approach. First, a normal tissue TMA and a multi-tumor TMA were analyzed for immunohistochemically detectable expression of IMP3 in 76 different normal tissue types and 3889 cancer samples from 95 different tumor categories. In a second step, we searched for associations between IMP3 expression and tumor phenotype and patient prognosis in TMAs containing 697 urinary bladder cancers, 1711 colon cancers, 343 esophageal adenocarcinomas, 251 esophageal squamous cell cancers, 673 lung cancers), 275 pancreatic cancers and 230 stomach cancers. In normal tissues, unequivocal IMP3 expression was found in placenta, lymphocytes and some types of glandular epithelial cells. In cancers, at least one case with weak expression could be found in 76 out of 95 (80%) different tumor types and 64 entities (67%) had at least one tumor with strong positivity. IMP3 expression was most frequently found in testicular cancer (including 71% seminomas and 96% non-seminomas), neuroblastoma (88%), and squamous cell cancer of various origins. Significant associations were found between IMP3 and adverse tumor features in esophageal adenocarcinomas and cancers of the urinary bladder, lung, stomach, and pancreas. In summary, IMP3 was frequently expressed in many different tumor types, and was typically associated with aggressive tumor features.
Carboxypeptidase A1 (CPA1) is a zinc metalloprotease that is produced in pancreatic acinar cells and plays a role in cleaving C-terminal branched-chain and aromatic amino acids from dietary proteins. ...This study assessed the utility of immunohistochemical CPA1 staining for diagnosing pancreatic acinar cell carcinoma (ACC). A total of 12,274 tumor samples from 132 different tumor types and subtypes as well as 8 samples each of 76 different normal tissue types were interpretable by immunohistochemistry in a tissue microarray format. CPA1 was strongly expressed in acinar cells of all normal pancreas samples but not in any other normal tissues. CPA1 immunostaining was detected in 100% of 11 pancreatic ACCs and 1 mixed acinar endocrine carcinoma, but absent in 449 pancreatic ductal adenocarcinomas, 75 adenocarcinomas of the ampulla Vateri, and 11,739 other evaluable cancers from 128 different tumor entities. A weak to moderate diffuse staining of epithelial and stromal cells of cancer tissues immediately adjacent to non-neoplastic pancreatic acinar cells often occurred and was considered to be caused by the diffusion of the highly abundant CPA1 from normal acinar cells that may have suffered some autolytic cell damage. In conclusion, our data show that CPA1 is a highly sensitive and largely specific marker for normal and neoplastic pancreatic acinar cells. CPA1 immunohistochemistry greatly facilitates the otherwise often difficult diagnosis of pancreatic ACC.
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