Colorectal carcinoma (CRC) results from the accumulation of genetic mutations and alterations in signaling pathways.
KRAS
is mutated in 40% of CRC cases and is involved in increased tumor cells ...proliferation and survival. Although
KRAS
mutations are a dominant event in CRC tumorigenesis, increased wild-type KRAS expression has a similar effect on accelerated tumor growth. In this study, we investigated the KRAS status in correlation with clinicopathological features in sporadic CRC and more importantly the role of
let-7a-5p
and
miR-544a-3p
in the regulation of wild-type KRAS protein expression in the tumor center (T1) and invasive tumor front (T2). Analysis showed that 39.1% of tumor samples had
KRAS
mutations. In wild-type
KRAS
tumors, 62.0% were positive for KRAS protein expression and there was a higher percentage of KRAS-positive tumor cells and a higher intensity of immunohistochemical reaction in T2 than in T1 samples. This could not be attributed to differences in
KRAS
mRNA levels, suggesting regulation via
miR-544a-3p
expression which was significantly decreased in T2 samples. Furthermore, we demonstrated that tumor samples carrying the
KRAS-LCS6
variant allele had significantly higher protein expression of the wild-type KRAS. Our results suggest the role of the
KRAS-LCS6
polymorphism and
miR-544a-3p
expression in the regulation of wild-type KRAS protein expression in sporadic CRC.
The synchronous or metachronous coexistence of gastrointestinal stromal tumors (GISTs) with solid and hematologic neoplasms has been addressed in a non-transplant population. However, the association ...with primary hepatic neoplasms and leukemias is uncommon. Scarce data exist considering association of GISTs and other neoplasms in a transplant population where long-term immunosuppression carries the additional burden of de novo malignancy. We present a case of posttransplant metachronous GIST and acute biphenotypic leukemia in a patient transplanted for intrahepatic cholangiocellular carcinoma, emphasizing the possible link between mechanisms of carcinogenesis and influence of other factors upon their development.
Teška sepsa i septički šok su ozbiljni globalni zdravstveni problem uz porast incidencije i visoku smrtnost. Najveći broj slučajeva septičnog šoka uzrokuju bolnički stečeni gram–negativni bacili ili ...gram–pozitivni koki. U dijagnostičkom algoritmu bolesnika u sepsi potrebno je učiniti mikrobiološku analizu tkiva i tjelesnih tekućina posebice u bolesnika s otprije poznatom infekcijom pojedinog organskog sustava. U slučaju kada su rezultati dijagnostičkih testova negativni ili se radi o teškoj kliničkoj slici bolesnika unatoč primijenjenim terapijskim postupcima moguće je učiniti i morfološku analizu uzoraka tkiva u dijagnostičke svrhe. Morfološke promjene koje se mogu vidjeti u bolesnika oboljelog od sepse uključuju reverzibilno i ireverzibilno stanično oštećenje, tj. nekrozu stanica, upalne i ostale patološke promjene koje dovode do funkcionalnog zatajenja organa. Analiza
uzročnika moguća je pomoću specijalnih metoda, histokemijskog, imunohistokemijskog i imunofl uorescentnog bojanja. Analizu
morfoloških promjena organa moguće je učiniti i u slučaju smrtnog ishoda bolesnika. Obdukcija je jedna od najpouzdanijih metoda u procjeni točnosti kliničkih dijagnoza. Morfološke promjene tkiva i organa koje se mogu analizirati u bolesnika oboljelih od sepse tijekom dijagnostičkog postupnika, te u slučaju smrtnog ishoda obdukcijom predstavljaju dijagnostičku i konačnu procjenu točnosti kliničkih dijagnoza. Kao takve izravno utječu na njegu i liječenje bolesnika te na poboljšanje kvalitete zdravstvene zaštite.
To evaluate the level of oxidative stress and antioxidative response in the transplanted liver and its role in acute cellular rejection (ACR). Particular attention was paid to ACR diagnosis in ...patients with hepatitis C (HCV), as histopathological features of ACR and viral disease recurrence overlap.
This retrospective study included 40 liver transplant patients who underwent liver transplantation with two consecutive liver biopsies performed during one hospitalization period: 1.) initial biopsy of the donor liver (before implantation) and 2.) indication biopsy (after suspected ACR). Based on the etiology, patients were divided into two groups: 22 patients with alcoholic liver cirrhosis (EtOH group) and 18 patients with hepatitis C cirrhosis (HCV group). We analyzed the presence of acrolein, HNE (4-hydroxynonenal), and the major antioxidant transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) in both biopsies.
The presence of acrolein and HNE in both biopsies indicates increased oxidative stress, while the decrease in these aldehydes in the indication biopsies indicates a decrease in oxidative stress over time, reflecting liver graft recovery. The absence of NRF2 in both biopsies reflects significantly reduced antioxidant protection in patients undergoing liver transplantation.
The results support the role of oxidative stress in the pathogenesis of ACR. The presence of acrolein and the absence of HNE in the indication biopsy in patients with ACR could contribute to the diagnosis of ACR in clinical practice when functional antibodies are tested in the clinical setting.
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Do We Have a New Psoriasis Drug? Šola, Marija; Skroza, Nevena; Mangino, Giorgio ...
The FASEB journal,
20/May , Letnik:
36, Številka:
S1
Journal Article
Recenzirano
Pentadekapeptide BPC 157 was used in numerous laboratory rat animal models with proven cytoprotective and organ protective properties. In different wound therapy (incisional/excisional wound, deep ...burns, diabetic ulcer, alkali burns) fast and complete tissue restitution was achieved. BPC 157 was found to rapidly stimulate the expression of various genes involved in the healing process of the skin and mucosal lesions in these models. Psoriasis is a chronic, relapsing, immune‐mediated skin disease pathogenically driven by proinflammatory cytokines of which: TNF‐alpha, IL‐12, IL‐17, IL‐23 play a key role. Since BPC 157 has shown a significant anti‐inflammatory effect in several studies, the aim of this study is to show that it has the same role in the regression of inflammatory skin lesions such as those in psoriasis. An experimental model of psoriasis in laboratory animals is easily feasible, using 5% imiquimod topically.
MATERIALS AND METHODS The experiment is done on male Wistar Albino rats. Animals are divided into groups of 6. „Psoriasis‐like” lesions are induced in all animals applying 5% imiquimod cream topically on shaved skin on their backs for 7 consecutive days. On the 7th day, 3 hours after applying imiquimod cream treatment starts usage BPC 157 in cream (conc. 1μg/g neutral cream) or only neutral cream (Belobaza) in control groups. Animals are treated and observed daily, video documentation was made. Animals are treated until the sacrifice day according to schedule. The severity of skin lesions is measured clinically using a modified version of Psoriasis Area Severity Index‐PASI score. Modified PASI includes scoring the following lesion features: erythema, infiltration, desquamation on scale 1‐4; maximum modified PASI value is 12. Two way ANOVA and Bonferroni post hoc test were used for statistical analysis. Data represented as mean SD for N=6/group.
RESULTS Animals treated using BPC 157 conc.1μg/g in a cream had significantly lower values of PASI score when compared to control group. Faster resolution of imiquimod induced „psoriasis‐like” lesions was achieved using BPC 157 when compared to control group.
CONCLUSION BPC 157 is well‐known peptide used in various experimental models without any side effects of it's use, with proven effects on the NO‐system, and excellent results in wound healing. Psoriasis is a rather common immune‐mediated skin disease driven by proinflammatory cytokines. TNF‐alpha, IL‐12, IL‐17, IL‐23 play a key role in the pathogenesis of psoriasis. It is undisputably that the use of BPC 157 topically successfully neutralizes the effects of imiquimod and induces regression of „psoriasis‐like“ lesions, the question that needs to be answered yet is whether BPC 157 has an impact on one of the above‐mentioned cytokines. It is yet to be explored which mechanism is the key to it´s beneficial effects in treating „psoriasis‐like“ lesions in experimental models.
Summary Notch signaling is implicated in the pathogenesis of multiple myeloma expressing high level of active Notch proteins NOTCH1 and JAGGED1 in tumor plasma cells. We investigated expression of ...NOTCH1 and JAGGED1 in bone marrow trephine biopsies of 80 newly diagnosed multiple myeloma and 20 monoclonal gammopathy of undetermined significance patients using immunohistochemical methods. The number of positive tumor cells was counted per 1000 tumor cells and the intensity of staining was assessed semi quantitatively. Multiple myelomas expressed NOTCH1 in 92.31% (72/78) and JAGGED1 in 92.21% (71/77) cases. NOTCH1 staining was strong in the majority of cases (59.7%), whereas JAGGED1 was predominately weak (67.6% of cases). In contrast, both markers were negative in all monoclonal gammopathy of undetermined significance cases. However, upon progression of disease from monoclonal gammopathy of undetermined significance to multiple myeloma (seen in 4 patients), analysis of the subsequent bone marrow biopsy showed weak expression of both markers in tumorous plasma cells. Immunohistochemistry results were compared with the pattern of bone marrow infiltration, plasma cell differentiation, and the presence of t(11;14)(q13,q32), t(14;16)(q32;q23),and t(4;14)(p16.3;q23) and overall survival in multiple myeloma patients. A significant correlation was found between strong NOTCH1 staining in multiple myeloma plasma cells and the diffuse type of bone marrow infiltration ( P = .002) and an immature morphologic type of plasma cells ( P = .043). After a median follow-up of 20.3 months, in multiple myeloma patients no difference in overall survival between NOTCH1 ( P = .484) and JAGGED1 ( P = .822) positive and negative cases were found. In conclusion, our results indicate importance of NOTCH1 and JAGGED1 expression in plasma cell neoplasia and a possible diagnostic value of their immunohistochemical evaluation of bone marrow infiltrates for multiple myeloma.
Epidermal growth factor receptor (EGFR) expression is commonly upregulated in sporadic colorectal cancer (CRC) and its high expression is associated with poor prognosis in patients with CRC. CA-SSR1 ...is a dinucleotide CA repeat of the
gene that can modulate
transcription and is a potential target of the mismatch repair machinery in tumours with microsatellite instability (MSI). In the present study, 160 sporadic colon cancer samples were analysed for
CA-SSR1 polymorphism and MSI status. Additionally,
mRNA and protein expression levels in the tumour centre and in the invasive tumour front, compared with those in adjacent normal tissue samples, were evaluated in 80 tumour samples. An inverse association was identified between
mRNA levels and the sum of repeats in both alleles of the CA-SSR1 polymorphism in normal tissues. Changes in CA-SSR1 were detected in the tumour centre as well as in the invasive tumour front and metastases in all MSI high (MSI-H) tumours. Analysis of EGFR expression at the mRNA and protein levels according to MSI status revealed lower
mRNA and protein expression in MSI-H tumours than microsatellite-stable (MSS) tumours. Furthermore, higher EGFR levels in the invasive tumour front compared with in the tumour centre in MSS tumours were identified, suggesting a role of EGFR in tumour progression and higher invasive potential of MSS than MSI-H tumours.
This review is focused on the healing of fistulas and stable gastric pentadecapeptide BPC 157. Assuming that the healing of the various wounds is essential also for the gastrointestinal fistulas ...healing, the healing effect on fistulas in rats, consistently noted with the stable gastric pentadecapeptide BPC 157, may raise several interesting possibilities. BPC 157 is originally an anti-ulcer agent, native to and stable in human gastric juice (for more than 24 h). Likely, it is a novel mediator of Robert's cytoprotection maintaining gastrointestinal mucosal integrity. Namely, it is effective in the whole gastrointestinal tract, and heals various wounds (i.e., skin, muscle, tendon, ligament, bone; ulcers in the entire gastrointestinal tract; corneal ulcer); LD1 is not achieved. It is used in ulcerative colitis clinical trials, and now in multiple sclerosis, and addressed in several reviews. Therefore, it is not surprising that BPC 157 has documented consistent healing of the various gastrointestinal fistulas, external (esophagocutaneous, gastrocutaneous, duodenocutaneous, colocutaneous) and internal (colovesical, rectovaginal). Taking fistulas as a pathological connection, this rescue is verified with the beneficial effects in rats with the various gastrointestinal anastomoses, esophagogastric, jejunoileal, colo-colonic, ileoileal, esophagojejunal, esophagoduodenal, and gastrojejunal. This beneficial effect occurs equally when the gastrointestinal anastomoses are impaired with the application of NSAIDs, cysteamine, large bowel resection, as well as concomitant esophageal, gastric, and duodenal lesions and/or ulcerative colitis presentation, short bowel syndrome progression, liver and brain disturbances presentation. Particular aspects of the BPC 157 healing of the fistulas are especially emphasized.
Significance:
The antiulcer peptide, stable gastric pentadecapeptide BPC 157 (previously employed in ulcerative colitis and multiple sclerosis trials, no reported toxicity (LD1 not achieved)), is ...reviewed, focusing on the particular skin wound therapy, incisional/excisional wound, deep burns, diabetic ulcers, and alkali burns, which may be generalized to the other tissues healing.
Recent Advances:
BPC 157 has practical applicability (given alone, with the same dose range, and same equipotent routes of application, regardless the injury tested).
Critical Issues:
By simultaneously curing cutaneous and other tissue wounds (colocutaneous, gastrocutaneous, esophagocutaneous, duodenocutaneous, vesicovaginal, and rectovaginal) in rats, the potency of BPC 157 is evident. Healing of the wounds is accomplished by resolution of vessel constriction, the primary platelet plug, the fibrin mesh which acts to stabilize the platelet plug, and resolution of the clot. Thereby, BPC 157 is effective in wound healing much like it is effective in counteracting bleeding disorders, produced by amputation, and/or anticoagulants application. Likewise, BPC 157 may prevent and/or attenuate or eliminate, thus, counteract both arterial and venous thrombosis. Then, confronted with obstructed vessels, there is circumvention of the occlusion, which may be the particular action of BPC 157 in ischemia/reperfusion.
Future Directions:
BPC 157 rapidly increases various genes expression in rat excision skin wound. This would define the healing in the other tissues, that is, gastrointestinal tract, tendon, ligament, muscle, bone, nerve, spinal cord, cornea (maintained transparency), and blood vessels, seen with BPC 157 therapy.
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