Abstract Introduction Infiltration of the maxillofacial region by multiple myeloma is common and typically appears as punched out osteolytic lesions of the jaws. Although swelling, bone pain, and ...tooth mobility are characteristic clinical symptoms, root resorption is rare in conjunction with myeloma nests. Methods A case of a 67-year-old man with multiple myeloma is presented. Root resorption of the second mandibular premolar and the first and second molars on the right side, with consecutive tooth mobility, was the initial manifestation of the disease and was primarily detected on a periapical radiograph. The treating dentist referred the patient to the department for further examination, which revealed multiple myeloma. The patient received tandem high-dose chemotherapy and autologous stem cell transplantation as standard myeloma treatment. Intravenous bisphosphonates were administered to curb the osteolytic lesions. Results No signs of bisphosphonate-related osteonecrosis of the jaw were observed until the end of the follow-up period. Conclusions Only 5 reports of myeloma-associated root resorption have been reported in the literature. In all cases, mandibular premolars or molars were involved, and the patients exhibited extensive involvement of the jaw by myeloma. This report highlights the importance of correct interpretation of clinical signs and radiographs by dental specialists in the diagnostic algorithm of systemic diseases. Furthermore, this is an example for the inevitable part of bisphosphonates in the treatment of osteolytic processes.
In recurrent epithelial ovarian cancer (EOC) most patients develop platinum-resistance. On molecular level the NRF2 pathway, a cellular defense mechanism against reactive oxygen species, is induced. ...In this study, we investigate AKR1C1/2, target of NRF2, in a well-established EOC collective by immunohistochemistry and in a panel of ovarian cancer cell lines including platinum-resistant clones. The therapeutic effect of carboplatin and MPA as monotherapy or in combination was assessed by functional assays, using OV90 and OV90cp cells. Molecular mechanisms of action of MPA were investigated by NRF2 silencing and AKR activity measurements. Immunohistochemical analysis revealed that AKR1C1/2 is a key player in the development of chemoresistance and an independent indicator for short PFS (23.5 vs. 49.6 months, p = 0.013). Inhibition of AKR1C1/2 by MPA led to a concentration- and time-dependent decline of OV90 viability and to an increased response to CP in vitro. By NRF2 silencing, however, the effects of MPA treatment were reduced. Concludingly, our data suggest that a combination therapy of carboplatin and MPA might be a promising therapeutic approach to increase response rates of EOC patients, which should be explored in clinical context.
The aim of this study was to investigate the expression of thyroid hormone receptor β1 (THRβ1) by immunohistochemistry in breast cancer (BC) tissues and to correlate the results with ...clinico-biological parameters. In a well-characterized cohort of 274 primary BC patients, THRβ1 was widely expressed with a predominant nuclear location, although cytoplasmic staining was also frequently observed. Both nuclear and cytoplasmic THRβ1 were correlated with high-risk BC markers such as human epidermal growth factor receptor 2 (HER2), Ki67 (also known as MKI67), prominin-1 (CD133), and N-cadherin. Overall survival analysis demonstrated that cytoplasmic THRβ1 was correlated with favourable survival (
= 0.015), whereas nuclear THRβ1 had a statistically significant correlation with poor outcome (
= 0.038). Interestingly, in our cohort, nuclear and cytoplasmic THRβ1 appeared to be independent markers either for poor (
= 0.0004) or for good (
= 0.048) prognosis, respectively. Altogether, these data indicate that the subcellular expression of THRβ1 may play an important role in oncogenesis. Moreover, the expression of nuclear THRβ1 is a negative outcome marker, which may help to identify high-risk BC subgroups.
Sirtuin 1 and Sirtuin 3 in Granulosa Cell Tumors Schmid, Nina; Dietrich, Kim-Gwendolyn; Forne, Ignasi ...
International journal of molecular sciences,
02/2021, Letnik:
22, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Sirtuins (SIRTs) are NAD
-dependent deacetylases that regulate proliferation and cell death. In the human ovary, granulosa cells express sirtuin 1 (SIRT1), which has also been detected in human ...tumors derived from granulosa cells, i.e., granulosa cell tumors (GCTs), and in KGN cells. KGN cells are an established cellular model for the majority of GCTs and were used to explore the role of SIRT1. The SIRT1 activator SRT2104 increased cell proliferation. By contrast, the inhibitor EX527 reduced cell numbers, without inducing apoptosis. These results were supported by the outcome of siRNA-mediated silencing studies. A tissue microarray containing 92 GCTs revealed nuclear and/or cytoplasmic SIRT1 staining in the majority of the samples, and also, SIRT2-7 were detected in most samples. The expression of SIRT1-7 was not correlated with the survival of the patients; however, SIRT3 and SIRT7 expression was significantly correlated with the proliferation marker Ki-67, implying roles in tumor cell proliferation. SIRT3 was identified by a proteomic analysis as the most abundant SIRT in KGN. The results of the siRNA-silencing experiments indicate involvement of SIRT3 in proliferation. Thus, several SIRTs are expressed by GCTs, and SIRT1 and SIRT3 are involved in the growth regulation of KGN. If transferable to GCTs, these SIRTs may represent novel drug targets.
Wnt pathway modulator Dickkopf 2 (Dkk2) and signaling of the G protein-coupled estrogen receptor (GPER) seem to have essential functions in numerous cancer types. For epithelial ovarian cancer (EOC), ...it has not been proven if either Dkk2 or the GPER on its own have an independent impact on overall survival (OS). So far, the correlation of both factors and their clinical significance has not systematically been investigated before.
Expression levels of Dkk2 were immunohistochemically analyzed in 156 patient samples from different histologic subtypes of EOC applying the immune-reactivity score (IRS). Expression analyses were correlated with clinical and pathological parameters to assess for prognostic relevance. Data analysis was performed using Spearman's correlations, Kruskal-Wallis-test and Kaplan-Meier estimates.
Highest Dkk2 expression of all subtypes was observed in clear cell carcinoma. In addition, Dkk2 expression differed significantly (p<0.001) between low and high grade serous ovarian cancer. A significant correlation of Dkk2 with the cytoplasmic GPER expression was noted (p=0.001) but not for the nuclear estrogen receptor alpha (ERα) or beta (ERβ). Patients exhibiting both, high expression Dkk2 (IRS>4) and GPER (IRS>8), had a significantly better overall survival compared to patients with low expression (61 months vs. 33 months; p=0.024).
Dkk2 and GPER expression correlates in EOC and combined expression of both is associated with improved OS. These findings underline the clinical significance of both pathways and indicate a possible prognostic impact as well as a potential for treatment strategies addressing interactions between estrogen and Wnt signaling in ovarian cancer.
There is partially conflicting evidence on the influence of the steroid hormones estrogen (E) and progesterone (P) on the development of ovarian cancer (OC). The aim of this study was to assess the ...expression of the receptor isoforms ER-α/-β and PR-A/-B in OC tissue and to analyze its impact on clinical and pathological features and patient outcome.
155 OC patients were included who had been diagnosed and treated between 1990 and 2002. Patient characteristics, histology and follow-up data were available. ER-α/-β and PR-A/-B expression were determined by immunohistochemistry.
OC tissue was positive for ER-α/-β in 31.4% and 60.1% and PR-A/-B in 36.2% and 33.8%, respectively. We identified significant differences in ER-β expression related to the histological subtype (p=0.041), stage (p=0.002) and grade (p=0.011) as well as PR-A and tumor stage (p=0.03). Interestingly, median receptor expression for ER-α and PR-A/-B was significantly higher in G1 vs. G2 OC. Kaplan Meier analysis revealed a good prognosis for ER-α positive (p=0.039) and PR-B positive (p<0.001) OC. In contrast, ER-β negative OC had a favorable outcome (p=0.049). Besides tumor grade and stage, Cox-regression analysis showed PR-B to be an independent prognostic marker for patient survival (p=0.009, 95% CI 0.251-0.823, HR 0.455).
ER-α/-β and PR-A/-B are frequently expressed in OC with a certain variability relating to histological subtype, grade and stage. Univariate analysis indicated a favorable outcome for ER-α positive and PR-B positive OC, while multivariate analysis showed PR-B to be the only independent prognostic marker for patient survival. In conclusion, ER and PR receptors may be useful targets for a more individualized OC therapy.
Inflammatory bowel disease increases the risk of developing colon cancer. Interleukin (IL-) 37 is a fundamental inhibitor of innate immunity by reducing systemic and local inflammation. IL-37 protein ...is expressed in healthy and diseased bowel and liver tissue. Here, we tested whether transgenic expression of human IL-37 protects IL-10 deficient (IL-10KO) mice from chronic colitis. IL-37tg mice were crossbred with IL-10KO mice. Homozygous IL-10KO/IL-37tg and IL10KO drank 2% dextran sulfate sodium (DSS) in water for 5 days to induce mild colitis. Colon carcinogenesis was triggered by intragastric administration of celecoxib. Endpoints were clinical parameters of colitis, cytokine responses in LPS-stimulated whole blood and explanted colon specimen and qPCR analysis of colon biopsies. Colon inflammation and number of adenoma-carcinoma were analyzed by histology. During the DSS-induction phase IL-10KO and IL-10KO/IL-37tg mice had a similar weight loss due to mild acute colitis. From day 115 there was a significantly improved weight gain in IL-10KO/IL37-tg mice, though colon length was similar. After
LPS stimulation whole blood of IL-10KO/IL-37tg compared to IL-10KO mice released less IL-6, IL-17, IFNγ, and TNFα and
colon cultures showed reduced IL-6 production both indicative of reduced inflammatory conditions under the influence of IL-37. Six out of 10 IL-10KO mice developed colon adenoma and carcinoma. Only one adenoma but no carcinoma was detected in colons of IL-10KO/IL-37tg mice. In conclusion, IL-37 transgene expression protects IL-10KO mice from colon carcinogenesis. It remains unclear whether IL-37 has direct tumor suppressing properties.
The enzymes Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) und 3 (RIPK3) as well as the protein Mixed lineage kinase domain like pseudokinase (pMLKL) play a role in the signaling ...cascade of necroptosis. This is a form of programmed cell death which is caspase-independent. High-risk human papilloma virus infection can inhibit necroptosis. Thereby, a persistent infection and consequently the development of cervical cancer can be triggered. Aim of this study was the analysis of the expression of RIPK1, RIPK3 and pMLKL in cervical cancer tissue and the evaluation of its prognostic value on overall survival, progression-free survival and additional clinical parameters.
The expression of RIPK1, RIPK3, and pMLKL in cervical cancer tissue microarrays of n = 250 patients was analyzed immunohistochemically. Further, the effect of C2 ceramide on several cervical cancer cell lines (CaSki, HeLa, SiHa) was examined. C2 ceramide is a biologically active short-chain ceramide that induces necroptosis in human luteal granulosa cells.
Significantly longer overall survival and progression-free survival rates could be detected in cervical cancer patients expressing nuclear RIPK1 or RIPK3 alone or simultaneously (RIPK1 and RIPK3). Cell viability and proliferation was reduced through C2 ceramide stimulation of cervical cancer cells. Simultaneous stimulation of C2 ceramide and the pan-caspase inhibitor Z-VAD-fmk, or the RIPK1-inhibitor necrostatin-1, partly reversed the negative effect of C2 ceramide on cell viability. This observation could imply that caspase-dependent and -independent forms of cell death, including necroptosis, can occur. AnnexinV-FITC apoptosis staining induced a significant increase in apoptotic cells in CaSki and SiHa cells. The stimulation of CaSki cells with C2 ceramide led to a significant percentual increase in necrotic/intermediate (dying) cells after stimulation with C2 ceramide. In addition, after stimulation with C2 ceramide, CaSki and HeLa cells live cell imaging showed morphological changes which are common for necroptosis.
In conclusion, RIPK1 and RIPK3 are independent positive predictors for overall survival and progression-free survival in cervical cancer patients. C2 ceramide can reduce cell viability and proliferation in cervical cancer cells by inducing most likely both apoptosis and necroptosis.
So far, studies about targeted therapies and predictive biomarkers for vulva carcinomas are rare. The leucine zipper downregulated in cancer 1 gene (LDOC1) has been identified in various carcinomas ...as a tumor-relevant protein influencing patients' survival and prognosis. Due to the lack of information about LDOC1 and its exact functionality, this study focuses on the expression of LDOC1 in vulvar carcinoma cells and its surrounding immune cells as well as its correlation to clinicopathological characteristics and prognosis. Additionally, a possible regulation of LDOC1 in vulvar cancer cell lines via the NF-κB signaling pathway was analyzed. Vulvar carcinoma sections of 157 patients were immunohistochemically stained and examined regarding LDOC1 expression by using the immunoreactive score (IRS). To characterize LDOC1-positively stained immune cell subpopulations, immunofluorescence double staining was performed. The effect of the NF-κB inhibitor C-DIM 12 (3,3'-(4-chlorophenyl)methylenebis1 H-indole) on vulvar cancer cell lines A431 and SW 954 was measured according to MTT and BrdU assays. Baseline expression levels of LDOC1 in the vulvar cancer cell lines A431 and SW 954 was analyzed by real-time PCR. LDOC1 was expressed by about 90% of the cancer cells in the cytoplasm and about half of the cells in the nucleus. Cytoplasmatic expression of LDOC1 was associated with decreased ten-year overall survival of the patient, whereas nuclear staining showed a negative association with disease-free survival. Infiltrating immune cells were mainly macrophages followed by regulatory T cells. Incubation with C-DIM 12 decreased the cell viability and proliferation of vulvar cancer cell line A431, but not of cell line SW 954. LDOC1 expression on mRNA level was twice as high in the cell line A431 compared to the cell line SW 954. Overexpression of LDOC1 was associated with unfavorable overall and disease-free survival. Tumor growth could be inhibited by C-DIM 12 in vitro if the expressed LDOC1 level was high enough.
Non-alcoholic fatty liver disease (NAFLD) is rising in prevalence, and a better pathophysiologic understanding of the transition to its inflammatory phenotype (NASH) is key to the development of ...effective therapies. To evaluate the contribution of the NLRP3 inflammasome and its downstream effectors IL-1 and IL-18 in this process, we applied the true-to-life "American lifestyle-induced obesity syndrome" (ALiOS) diet mouse model. Development of obesity, fatty liver and liver damage was investigated in mice fed for 24 weeks according to the ALiOS protocol. Lipidomic changes in mouse livers were compared to human NAFLD samples. Receptor knockout mice for IL-1 and IL-18 were used to dissect the impact of downstream signals of inflammasome activity on the development of NAFLD. The ALiOS diet induced obesity and liver steatosis. The lipidomic changes closely mimicked changes in human NAFLD. A pro-inflammatory gene expression pattern in liver tissue and increased serum liver transaminases indicated early liver damage in the absence of histological evidence of NASH. Mechanistically,
- but not
mice were protected from early liver damage, possibly due to silencing of the pro-inflammatory gene expression pattern. Our study identified NLRP3 activation and IL-18R-dependent signaling as potential modulators of early liver damage in NAFLD, preceding development of histologic NASH.
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