Work intensity and quality of life can be restored following double-level osteotomy in varus knee osteoarthritis.

PURPOSE: The purpose of this study was to assess changes in health-related quality of life (HRQL) and work intensity following double-level knee osteotomy (DLO). It was hypothesized that postoperative HRQL would be comparable to that of the general population and that work intensity can be restored in the short term. METHODS: Twenty-four patients (28 varus knees; mechanical tibiofemoral angle: -11.0 ± 3.0° (-6.0 to -17.0), age: 49.1 ± 9.5 (31-65) years) who underwent DLO were included. The duration the patients were unable to work was evaluated. HRQL was measured with the SF-36 questionnaire, which consists of a physical (PCS) and mental component summary score (MCS). The pre- to postoperative changes in the PCS and MCS were analysed. The PCS and MCS were also compared to those of the general population, who has a reference score value of 50 points. The work intensity measured with the REFA classification and the Tegner activity scale were assessed preoperatively and at the final postoperative follow-up examination (18.0 ± 10.0 (5-43) months). RESULTS: The duration that the patients were unable to work was 12.2 ± 4.4 (6-20) weeks. The PCS improved from 32.1 ± 11.3 (14.5-53.3) preoperatively to 54.6 ± 8.5 (25.2-63.7) (p < 0.001) at the final follow-up, and the MCS improved from 53.9 ± 11.1 (17.1-67.7) to 57.2 ± 3.1 (47.3-61.7) (n.s). The preoperative PCS was significantly lower than the reference score of the general population (p < 0.001), whereas the preoperative MCS was similar between the two groups (n.s.). At follow-up, no significant differences were observed between the PCS and the MCS of the patient group and those of the general population. Five patients who were unable to work prior to surgery due to knee symptoms returned to work with moderate (four patients) or even very heavy (one patient) workloads. The Tegner activity scale increased significantly from a median of 2.0 (0.0-5.0) to 4.0 (2.0-7.0) (p < 0.001). CONCLUSION: Our results demonstrate an improvement in quality of life and return to working activity following DLO in the short term. The HRQL can be improved by DLO in patients with varus knee osteoarthritis to the level of the general population. These results can assist surgeons in discussing realistic expectations when considering patients for DLO. LEVEL OF EVIDENCE: Study type: therapeutic, IV.

A Prospective, Multicenter Registry Study to Evaluate the Clinical Feasibility of Targeted Axillary Dissection (TAD) in Node-positive Breast Cancer Patients.

OBJECTIVE: This study aimed to investigate the feasibility and accuracy of non-radioactive TLN biopsy and TAD in routine clinical practice. BACKGROUND DATA: TAD involves TLN biopsy (TLNB) and sentinel lymph node biopsy and was recently introduced as a new standard for less invasive axillary staging in BC patients undergoing neoadjuvant systemic therapy (NST); however, clinical evidence is limited. METHODS: The SenTa study is a prospective registry study conducted at 50 centers. Patients with invasive BC who nderwent clip insertion into the most suspicious axillary lymph node were eligible. Axillary surgery was performed with or without sentinel lymph node biopsy, TLNB, and/or axillary lymph node dissection (ALND). Main endpoints were the detection rate and FNR of TLNB and TAD after NST. RESULTS: Between 2017 and 2018, 548 consecutive BC patients underwent clip placement into biopsy-confirmed positive lymph nodes. After NST (n = 473), the clipped TLN was intraoperatively resected in 329 of 423 patients [77.8%, 95% confidence interval (CI): 74.0-82.0]. TAD was successful in 199 of 229 patients (detection rate: 86.9%, 95% CI: 81.8-91.0), the SLN and TLN were identical in 129 patient (64.8%). FNRs were 7.2% (8 of 111, 95% CI: 3.1-13.6) for TLNB followed by ALND (n = 203) and 4.3% (2 of 46, 95% CI: 0.5-14.8) for TAD followed by ALND (n = 77). CONCLUSIONS: The SenTa study demonstrates the feasibility of TAD in a real-world cohort of BC patients. Our findings are of great importance for de-escalation of surgical strategies.

miR-203 is an independent molecular predictor of prognosis and treatment outcome in ovarian cancer: a multi-institutional study.

Ovarian cancer (OC) accounts for the most gynecological cancer-related deaths in developed countries. Unfortunately, the lack of both evident early symptoms and effective asymptomatic population screening results in late diagnosis and inevitably poor prognosis. Hence, it is urgent to identify novel molecular markers to support personalized prognosis. In the present study, we have analyzed the clinical significance of miR-203 in OC using two institutionally independent cohorts. miR-203 levels were quantified in a screening (n = 125) and a validation cohort (n = 100, OVCAD multicenter study). Survival analysis was performed using progression and death as clinical endpoint events. Internal validation was conducted by bootstrap analysis, and decision curve analysis was used to evaluate the clinical benefit. Increased miR-203 levels in OC patients were correlated with unfavorable prognosis and higher risk for disease progression, independently of FIGO stage, tumor grade, residual tumor after surgery, chemotherapy response and age. The analysis of the institutionally independent validation cohort (OVCAD study) clearly confirmed the shorter survival outcome of the patients overexpressing miR-203. Additionally, integration of miR-203 levels with the established disease prognostic markers led to a superior stratification of OC patients that can ameliorate prognosis and benefit patient clinical management. In this regard, miR-203 expression constitutes a novel independent molecular marker to improve patients' prognosis in OC.

miR-181a overexpression predicts the poor treatment response and early-progression of serous ovarian cancer patients.

Ovarian cancer (OC) remains a leading cause of gynecological cancer-related death worldwide, characterized by poor 5-year survival. Molecular markers could serve as crucial tools of personalized prognosis and therapy. Herein, we present miR-181a as novel predictor of OC prognosis, using five independent OC cohorts. In particular, a screening (n = 81) and an institutionally independent validation (n = 100, OVCAD multicenter study) serous OC (SOC) cohorts were analyzed. Bagnoli et al (2016) OC179 (n = 124) to OC133 (n = 100) and TCGA (n = 489) served as external validation cohorts. Patients' survival and disease progression were assessed as clinical endpoint events. Bootstrap analysis was performed for internal validation and decision curve analysis was utilized to evaluate clinical benefit. miR-181a overexpression was unveiled as powerful and independent molecular predictor of patients' poor survival and higher risk for disease progression after debulking surgery and platinum-based chemotherapy. Analysis of the OVCAD institutionally independent cohort, as well as of Bagnoli et al. and TCGA external cohorts further confirmed the unfavorable prognostic nature of miR-181a overexpression in SOC. Strikingly, multivariate prognostic models incorporating miR-181a with established disease markers clearly improved patients' risk-stratification and offered superior clinical benefit in OC prognostication. Conclusively, miR-181a evaluation could augment prognostic accuracy and support precision medicine decisions in OC.

Prognostic value of kallikrein-related peptidase 12 (KLK12) mRNA expression in triple-negative breast cancer patients.

BACKGROUND: The serine protease KLK12 belongs to the human fifteen-member family of kallikrein-related peptidases. Differential expression accompanied by either increased or decreased enzymatic activity has been linked to several diseases including cancer. Triple-negative breast cancer (TNBC) represents a very aggressive subgroup of breast cancer with high tumor recurrence rates and poor patient prognosis. Here, we quantified the KLK12 mRNA expression levels in tumor tissue of TNBC patients and analyzed their prognostic value. METHODS: In the present study, KLK12 mRNA expression in tumor tissue of TNBC patients (n = 116) was determined by quantitative real-time PCR assay. The association of KLK12 mRNA levels with clinical parameters, and patients' outcome was analyzed using Chi-square tests, Cox regression models and Kaplan-Meier survival analysis. RESULTS: Positive, but low KLK12 mRNA levels were detected in about half of the cases (54 out of 116; 47%), the other samples were negative for KLK12 mRNA expression. No significant association was observed between KLK12 mRNA levels and clinicopathological variables (age, lymph node status, tumor size, and histological grade). In univariate Cox analyses, positive KLK12 mRNA expression was significantly associated with shortened disease-free survival (DFS; hazard ratio [HR] = 2.12, 95% CI = 1.19-3.78, p = 0.010) as well as overall survival (OS; HR = 1.91, 95% CI = 1.04-3.50, p = 0.037). In multivariable Cox analysis, including all clinical parameters plus KLK12 mRNA, the latter - together with age - remained an independent unfavorable predictive marker for DFS (HR = 2.33, 95% CI = 1.28-4.24, p = 0.006) and showed a trend towards significance in case of OS (HR = 1.80, 95% CI = 0.96-3.38, p = 0.066). CONCLUSIONS: Positive KLK12 expression is remarkably associated with shortened DFS and OS, suggesting that KLK12 plays a tumor-supporting role in TNBC.

Quantitative assessment and clinical relevance of kallikrein-related peptidase 5 mRNA expression in advanced high-grade serous ovarian cancer.

BACKGROUND: In ovarian cancer, dysregulation of mRNA expression of several components of the family of the kallikrein-related peptidases (KLKs) is observed. In this study, we have analyzed the KLK5 mRNA expression pattern in tumor tissue of patients suffering from high-grade serous ovarian cancer stage FIGO III/IV. Moreover, we have correlated the KLK5 mRNA levels with clinical outcome. METHODS: We assessed the mRNA expression levels of KLK5 in tumor tissue of 138 patients using quantitative PCR (qPCR). The mRNA levels were correlated with KLK5 antigen tumor tissue levels measured by ELISA (available for 41 of the 138 patients), established clinical features as well as patients' outcome, using Chi-square-tests, Mann-Whitney U-tests and Spearman rank calculations as well as Cox regression models, Kaplan-Meier survival analysis and the log-rank test. RESULTS: A highly significant correlation between the mRNA expression levels and protein levels of KLK5 in tumor tissues was observed (rs = 0.683, p < 0.001). In univariate Cox regression analysis, elevated KLK5 mRNA expression was remarkably associated with reduced progression-free survival (PFS; p = 0.047), but not with overall survival (OS). Association of KLK5 mRNA expression with PFS was validated in silico using The Cancer Genome Atlas. For this, Affymetrix-based mRNA data (n = 377) were analyzed applying the Kaplan-Meier Plotter tool (p = 0.027). In multivariable Cox analysis, KLK5 mRNA values revealed a trend towards statistical significance for PFS (p = 0.095), whereas residual tumor mass (0 mm vs. > 0 mm), but not ascites fluid volume (≤500 ml vs. > 500 ml), remained an independent indicator for both OS and PFS (p < 0.001, p = 0.005, respectively). CONCLUSIONS: These results obtained with a homogenous patient group with all patients suffering from advanced high-grade serous ovarian cancer support previous results suggesting elevated KLK5 mRNA levels as an unfavorable marker in ovarian cancer.

Kallikrein-related peptidases 4, 5, 6 and 7 regulate tumour-associated factors in serous ovarian cancer.

BACKGROUND: Tissue kallikrein-related peptidases 4, 5, 6 and 7 (KLK4-7) strongly increase the malignancy of ovarian cancer cells. Deciphering their downstream effectors, we aimed at finding new potential prognostic biomarkers and treatment targets for ovarian cancer patients. KLK4-7-transfected (OV-KLK4-7) and vector-control OV-MZ-6 (OV-VC) ovarian cancer cells were established to select differentially regulated factors. METHODS: With three independent approaches, PCR arrays, genome-wide microarray and proteome analyses, we identified 10 candidates (MSN, KRT19, COL5A2, COL1A2, BMP5, F10, KRT7, JUNB, BMP4, MMP1). To determine differential protein expression, we performed western blot analyses, immunofluorescence and immunohistochemistry for four candidates (MSN, KRT19, KRT7, JUNB) in cells, tumour xenograft and patient-derived tissues. RESULTS: We demonstrated that KLK4-7 clearly regulates expression of MSN, KRT19, KRT7 and JUNB at the mRNA and protein levels in ovarian cancer cells and tissues. Protein expression of the top-upregulated effectors, MSN and KRT19, was investigated by immunohistochemistry in patients afflicted with serous ovarian cancer and related to KLK4-7 immunoexpression. Significant positive associations were found for KRT19/KLK4, KRT19/KLK5 and MSN/KLK7. CONCLUSION: These findings imply that KLK4-7 exert key modulatory effects on other cancer-related genes and proteins in ovarian cancer. These downstream effectors of KLK4-7, MSN and KRT19 may represent important therapeutic targets in serous ovarian cancer.

A randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study.

PURPOSE: The PELICAN trial evaluates for the first time efficacy and safety of pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line treatment of metastatic breast cancer (MBC). METHODS: This randomized, phase III, open-label, multicenter trial enrolled first-line MBC patients who were ineligible for endocrine or trastuzumab therapy. Cumulative adjuvant anthracyclines of 360 mg/m2 doxorubicin or equivalent were allowed. Left ventricular ejection fraction of >50 % was required. Patients received PLD 50 mg/m2 every 28 days or capecitabine 1250 mg/m2 twice daily for 14 days every 21 days. The primary endpoint was time-to-disease progression (TTP). RESULTS: 210 patients were randomized (n = 105, PLD and n = 105, capecitabine). Adjuvant anthracyclines were given to 37 % (PLD) and 36 % (capecitabine) of patients. No significant difference was observed in TTP [HR = 1.21 (95 % confidence interval, 0.838-1.750)]. Median TTP was 6.0 months for both PLD and capecitabine. Comparing patients with or without prior anthracyclines, no significant difference in TTP was observed in the PLD arm (log-rank P = 0.64). For PLD versus capecitabine, respectively, overall survival (median, 23.3 months vs. 26.8 months) and time-to-treatment failure (median, 4.6 months vs. 3.7 months) were not statistically significantly different. Compared to PLD, patients on capecitabine experienced more serious adverse events (P = 0.015) and more cardiac events among patients who had prior anthracycline exposure (18 vs. 8 %; P = 0.31). CONCLUSION: Both PLD and capecitabine are effective first-line agents for MBC.

Tissue kallikrein-related peptidase 4 (KLK4), a novel biomarker in triple-negative breast cancer.

Triple-negative breast cancer (TNBC), lacking the steroid hormone receptors ER and PR and the oncoprotein HER2, is characterized by its aggressive pattern and insensitivity to endocrine and HER2-directed therapy. Human kallikrein-related peptidases KLK1-15 provide a rich source of serine protease-type biomarkers associated with tumor growth and cancer progression for a variety of malignant diseases. In this study, recombinant KLK4 protein was generated and affinity-purified KLK4-directed polyclonal antibody pAb587 established to allow localization of KLK4 protein expression in tumor cell lines and archived formalin-fixed, paraffin-embedded TNBC tumor tissue specimens. For this, KLK4 protein expression was assessed by immunohistochemistry in primary tumor tissue sections (tissue microarrays) of 188 TNBC patients, mainly treated with anthracycline- or CMF-based polychemotherapy. KLK4 protein is localized in the cytoplasm of tumor and stroma cells. In this patient cohort, elevated stroma cell KLK4 expression, but not tumor cell KLK4 expression, is predictive for poor disease-free survival by univariate analysis (hazard ratio: 2.26, p=0.001) and multivariable analysis (hazard ratio: 2.12, p<0.01). Likewise, univariate analysis revealed a trend for statistical significance of elevated KLK4 stroma cell expression for overall survival of TNBC patients as well.

Plasmin(ogen) serves as a favorable biomarker for prediction of survival in advanced high-grade serous ovarian cancer.

In serous ovarian cancer, the clinical relevance of tumor cell-expressed plasmin(ogen) (PLG) has not yet been evaluated. Due to its proteolytic activity, plasmin supports tumorigenesis, however, angiostatin(-like) fragments, derived from PLG, can also function as potent anti-tumorigenic factors. In the present study, we assessed PLG protein expression in 103 cases of advanced high-grade serous ovarian cancer (FIGO III/IV) by immunohistochemistry (IHC). In 70/103 cases, positive staining of tumor cells was observed. In univariate Cox regression analysis, PLG staining was positively associated with prolonged overall survival (OS) [hazard ratio (HR)=0.59, p=0.026] of the patients. In multivariable analysis, PLG, together with residual tumor mass, remained a statistically significant independent prognostic marker (HR=0.49, p=0.009). In another small patient cohort (n=29), we assessed mRNA expression levels of PLG by quantitative PCR. Here, elevated PLG mRNA levels were also significantly associated with prolonged OS of patients (Kaplan-Meier analysis; p=0.001). This finding was validated by in silico analysis of a microarray data set (n=398) from The Cancer Genome Atlas (Kaplan-Meier analysis; p=0.031). In summary, these data indicate that elevated PLG expression represents a favorable prognostic biomarker in advanced (FIGO III/IV) high-grade serous ovarian cancer.

CXCL9 and CXCL10 predict survival and are regulated by cyclooxygenase inhibition in advanced serous ovarian cancer.

BACKGROUND: Tumour-infiltrating lymphocytes (TILs) are associated with improved survival in several epithelial cancers. The two chemokines CXCL9 and CXCL10 facilitate chemotactic recruitment of TILs, and their intratumoral accumulation is a conceivable way to improve TIL-dependent immune intervention in cancer. However, the prognostic impact of CXCL9 and CXCL10 in high-grade serous ovarian cancer (HGSC) is largely unknown. METHODS: One hundred and eighty four cases of HGSC were immunohistochemically analyzed for CXCL9, CXCL10. TILs were assessed using CD3, CD56 and FOXP3 staining. Chemokine regulation was investigated using the ovarian cancer cell lines OV-MZ-6 and SKOV-3. RESULTS: High expression of CXCL9 and CXCL10 was associated with an approximately doubled overall survival (n=70, CXCL9: HR 0.41; P=0.006; CXCL10: HR 0.46; P=0.010) which was confirmed in an independent validation set (n=114; CXCL9: HR 0.60; P=0.019; CXCL10: HR 0.52; P=0.005). Expression of CXCR3 ligands significantly correlated with TILs. In human ovarian cancer cell lines the cyclooxygenase (COX) metabolite Prostaglandin E2 was identified as negative regulator of chemokine secretion, whereas COX inhibition by indomethacin significantly upregulated CXCL9 and CXCL10. In contrast, celecoxib, the only COX inhibitor prospectively evaluated for therapy of ovarian cancer, suppressed NF-κB activation and inhibited chemokine release. CONCLUSION: Our results support the notion that CXCL9 and CXCL10 exert tumour-suppressive function by TIL recruitment in human ovarian cancer. COX inhibition by indomethacin, not by celecoxib, may be a promising approach to concomitantly improve immunotherapies.

Clinical relevance of kallikrein-related peptidase 6 (KLK6) and 8 (KLK8) mRNA expression in advanced serous ovarian cancer.

Most members of the kallikrein-related peptidase family have been demonstrated to be dysregulated in ovarian cancer and modulate tumor growth, migration, invasion, and resistance to chemotherapy. In the present study, we assessed the mRNA expression levels of KLK6 and KLK8 by quantitative PCR in 100 patients with advanced serous ovarian cancer FIGO stage III/IV. A pronounced correlation between KLK6 and KLK8 mRNA expression (rs = 0.636, p < 0.001) was observed, indicating coordinate expression of both peptidases. No significant associations of clinical parameters with KLK6, KLK8, and a combined score KLK6+KLK8 were found. In univariate Cox regression analysis, elevated mRNA levels of KLK6 were significantly linked with shortened overall survival (OS) (hazard ratio [HR] = 2.07, p = 0.007). While KLK8 values were not associated with patients' outcome, high KLK6+KLK8 values were significantly associated with shorter progression-free survival (HR = 1.82, p = 0.047) and showed a trend towards significance in the case of OS (HR = 1.82, p = 0.053). Strikingly, in multivariable analysis, elevated KLK6 mRNA values, apart from residual tumor mass, remained an independent predictive marker for poor OS (HR = 2.33, p = 0.005). As KLK6 mRNA and protein levels correlate, KLK6 may represent an attractive therapeutic target for potent and specific inhibitors of its enzymatic activity.

Regulation of human MutYH DNA glycosylase by the E3 ubiquitin ligase mule.

Oxidation of DNA is a frequent and constantly occurring event. One of the best characterized oxidative DNA lesions is 7,8-dihydro-8-oxoguanine (8-oxo-G). It instructs most DNA polymerases to preferentially insert an adenine (A) opposite 8-oxo-G instead of the appropriate cytosine (C) thus showing miscoding potential. The MutY DNA glycosylase homologue (MutYH) recognizes A:8-oxo-G mispairs and removes the mispaired A giving way to the canonical base excision repair that ultimately restores undamaged guanine (G). Here we characterize for the first time in detail a posttranslational modification of the human MutYH DNA glycosylase. We show that MutYH is ubiquitinated in vitro and in vivo by the E3 ligase Mule between amino acids 475 and 535. Mutation of five lysine residues in this region significantly stabilizes MutYH, suggesting that these are the target sites for ubiquitination. The endogenous MutYH protein levels depend on the amount of expressed Mule. Furthermore, MutYH and Mule physically interact. We found that a ubiquitination-deficient MutYH mutant shows enhanced binding to chromatin. The mutation frequency of the ovarian cancer cell line A2780, analyzed at the HPRT locus can be increased upon oxidative stress and depends on the MutYH levels that are regulated by Mule. This reflects the importance of tightly regulated MutYH levels in the cell. In summary our data show that ubiquitination is an important regulatory mechanism for the essential MutYH DNA glycosylase in human cells.

Function and clinical relevance of kallikrein-related peptidases and other serine proteases in gynecological cancers.

Gynecological cancers, including malignant tumors of the ovaries, the endometrium and the cervix, account for approximately 10% of tumor-associated deaths in women of the Western world. For screening, diagnosis, prognosis, and therapy response prediction, the group of enzymes known as serine (Ser-)proteases show great promise as biomarkers. In the present review, following a summary of the clinical facts regarding malignant tumors of the ovaries, the endometrium and the cervix, and characterization of the most important Ser-proteases, we thoroughly review the current state of knowledge relating to the use of proteases as biomarkers of the most frequent gynecological cancers. Within the Ser-protease group, the kallikrein-related peptidase (KLK) family, which encompasses a subgroup of 15 members, holds particular promise, with some acting via a tumor-promoting mechanism and others behaving as protective factors. Further, the urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 (plasminogen activator inhibitor-1) seem to play an unfavorable role in gynecological tumors, while down-regulation of high-temperature requirement proteins A 1, 2 and 3 (HtrA1,2,3) is associated with malignant disease and cancer progression. Expression/activity levels of other Ser-proteases, including the type II transmembrane Ser-proteases (TTSPs) matriptase, hepsin (TMPRSS1), and the hepsin-related protease (TMPRSS3), as well as the glycosyl-phosphatidylinositol (GPI)-anchored Ser-proteases prostasin and testisin, may be of clinical relevance in gynecological cancers. In conclusion, proteases are a rich source of biomarkers of gynecological cancer, though the enzymes' exact roles and functions merit further investigation.

Clinical value of protein expression of kallikrein-related peptidase 7 (KLK7) in ovarian cancer.

Expression of the kallikrein-related peptidase 7 (KLK7) is dysregulated in ovarian cancer. We assessed KLK7 expression by ELISA and quantitative immunohistochemistry and analyzed its association with clinicopathological parameters and patients' outcome. KLK7 antigen concentrations were determined in tumor tissue extracts of 98 ovarian cancer patients by ELISA. For analysis of KLK7 immunoexpression in ovarian cancer tissue microarrays, a manual quantitative scoring system as well as a software tool for quantitative high-throughput automated image analysis was used. In immunohistochemical analyses, expression levels of KLK7 were not associated with patients' outcome. However, in multivariate analyses, KLK7 antigen levels in tumor tissue extracts were significantly associated with both overall and progression-free survival: ovarian cancer patients with high KLK7 levels had a significantly, 2-fold lower risk of death [hazard ratio (HR)=0.51, 95% confidence interval (CI)=0.29-0.90, p=0.019] or relapse [HR=0.47, 95% CI=0.25-0.91, p=0.024), as compared with patients who displayed low KLK7 levels. Our results indicate that - in contrast to earlier findings - high KLK7 antigen levels in tumor tissue extracts may be associated with a better prognosis of ovarian cancer patients.

The immediate effect of discrimination on mental health: A meta-analytic review of the causal evidence.

This meta-analysis synthesizes experimental studies on the immediate effects of discrimination on mental health, exploring the effects of different paradigms and discrimination types on diverse facets of mental health. We analyzed data from a systematic literature search (73 studies; 12,097 participants; 245 effect sizes) for randomized controlled trials with manipulation of discrimination as a predictor and mental health as an outcome using a three-level random-effects model. Experimentally manipulated discrimination led to poorer mental health (g = -0.30), also after controlling for publication year, region, education level, and methodological quality. Moderator analyses revealed stronger effects for pervasive (g = -0.55) compared to single-event manipulations (g = -0.25) and a trend toward weaker effects for samples with nonmarginalized (g = -0.16) compared to marginalized identities (g = -0.34). Gender and age did not moderate the effect. Discrimination had the largest effects on externalizing (g = -0.66) and distress-related outcomes (g = -0.41); heterosexism (g = -0.66), racism (g = -0.32), and sexism (g = -0.30) had the largest effects on mental health. Convenience sampling compromised generalizability to subgroups and the general population, downgrading methodological quality for all included studies. When interpreting the findings, selective samples (mostly young female adults with higher education), often limited ecological validity, and ethical restrictions of lab-induced discrimination need to be considered. These constraints likely led to conservative estimates of the mental health effects of discrimination in this meta-analysis. Future research should investigate more diverse samples, further explain the heterogeneity of findings, and explore protective factors of the effects of discrimination on mental health. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Emerging clinical importance of the cancer biomarkers kallikrein-related peptidases (KLK) in female and male reproductive organ malignancies.

BACKGROUND: Tumor tissue-associated KLKs (kallikrein-related peptidases) are clinically important biomarkers that may allow prognosis of the cancer disease and/or prediction of response/failure of cancer patients to cancer-directed drugs. Regarding the female/male reproductive tract, remarkably, all of the fifteen KLKs are expressed in the normal prostate, breast, cervix uteri, and the testis, whereas the uterus/endometrium and the ovary are expressing a limited number of KLKs only. CONCLUSIONS: Most of the information regarding elevated expression of KLKs in tumor-affected organs is available for ovarian cancer; depicting them as valuable biomarkers in the cancerous phenotype. In contrast, for breast cancer, a series of KLKs was found to be downregulated. However, in breast cancer, KLK4 is elevated which is also true for ovarian and prostate cancer. In such cases, selective synthetic KLK inhibitors that aim at blocking the proteolytic activities of certain KLKs may serve as future candidate therapeutic drugs to interfere with tumor progression and metastasis.

Repression of miR-146a in predicting poor treatment outcome in triple-negative breast cancer.

OBJECTIVES: In the era of precision medicine, the highly aggressive and heterogenous triple-negative breast cancer (TNBC) is still characterized by limited options to support personalized prognosis and guide therapeutic interventions. Thereafter, the aim of the present study has been the thorough evaluation of miR-146a as a novel molecular indicator of TNBC prognosis and treatment outcome, utilizing four independent TNBC cohorts. DESIGN & METHODS: miR-146a levels were clinically evaluated in our screening (n = 122) and three external validation TNBC cohorts (de Rinaldis et al. 2013, n = 114; Jézéquel et al. 2015, n = 107; TCGA, n = 180). Analysis of miR-146a and validated gene targets was performed in Jézéquel et al. and TCGA validation cohorts. Patients' survival, recurrence and metastasis were determined as clinical endpoints for the survival analysis. Internal validation was performed by bootstrap analysis and clinical net benefit was evaluated by decision curve analysis. RESULTS: Reduction of miR-146a is strongly associated with patients' poor survival and can predict post-treatment disease early-recurrence, independently of tumor size, lymph node status, histological grade and patients' age. The analysis of the external validation cohorts corroborated the unfavorable nature of miR-146a repression regarding patients' survival and, strikingly, unveiled the ability of miR-146a to predict TNBC metastasis. Combined assessment of miR-146a levels and lymph node status resulted in superior risk-stratification of TNBC patients and higher clinical benefit regarding disease prognosis and post-treatment outcome. Ultimately, miR-146a was negatively associated with EGFR and SOX2 expression in TNBC. CONCLUSIONS: miR-146a evaluation could ameliorate personalized prognosis and support precision medicine decisions in TNBC.

Association of high miR-27a, miR-206, and miR-214 expression with poor patient prognosis and increased chemoresistance in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, associated with early metastasis and recurrence as well as poor patient outcome. TNBC does not or weakly respond to hormonal or HER2-targeted therapies. Therefore, there is a strong need to identify other potential molecular targets for TNBC therapy. Micro-RNAs play important roles in the post-transcriptional regulation of gene expression. Thus, micro-RNAs, displaying an association between elevated expression and poor patient prognosis, may represent candidates for such novel tumor targets. In the present study, we evaluated the prognostic impact of miR-27a, miR-206, and miR-214 in TNBC via qPCR in tumor tissue (n=146). In univariate Cox regression analysis, elevated expression of all three analyzed micro-RNAs was significantly associated with shortened disease-free survival (hazard ratio [HR] for miR-27a: 1.85, P=0.038; miR-206: 1.83, P=0.041; miR-214: 2.06, P=0.012). In multivariable analysis, the micro-RNAs remained independent biomarkers for disease-free survival (HR for miR-27a: 1.99, P=0.033; miR-206: 2.14, P=0.018; miR-214: 2.01, P=0.026). Furthermore, our results suggest that elevated levels of these micro-RNAs are linked to enhanced resistance to chemotherapy. Based on the association of high expression levels with shortened patient survival and increased chemoresistance, miR-27a, miR-206, and miR-214 may represent novel molecular targets for TNBC.

tRNA-derived small RNA 3'U-tRFValCAC promotes tumour migration and early progression in ovarian cancer.

INTRODUCTION: Despite recent advances in epithelial ovarian cancer (EOC) management, the highly heterogenous histological/molecular tumour background and patients' treatment response obstructs personalised prognosis and therapeutics. Herein, we have studied the role and clinical utility of the novel subclass of tRNA-derived small RNA fragments emerging via 3'-trailer processing of pre-tRNAs (3'U-tRFs) in EOC. METHODS: SK-OV-3 and OVCAR-3 cells were used for in vitro study. Following transfection, cell growth and migration were assessed by CCK8 and wound healing assays, respectively. 3'U-tRFs levels were assessed by reverse transcription quantitative PCR (RT-qPCR), following 3'-end RNA polyadenylation. A screening (OVCAD, n = 100) and institutionally independent validation (TU Munich, n = 103) cohorts were employed for survival analysis using disease progression and patients' death as clinical end-points. Bootstrap analysis was performed for internal validation, and decision curve analysis was used to evaluate clinical benefit on disease prognosis. RESULTS: Following primary clinical assessment, target prediction and gene ontology analyses, the 3'U-tRFValCAC (derived from pre-tRNAValCAC) was highlighted to regulate cell proliferation and adhesion, and to correlate with inferior patients' outcome. 3'U-tRFValCAC transfection of SK-OV-3 and OVCAR-3 cells resulted in significantly increased cell growth and migration, in a dose-dependent manner. Elevated tumour 3'U-tRFValCAC levels were associated with significantly higher risk for early progression and worse survival following first-line platinum-based chemotherapy, independently of patients' clinicopathological data, chemotherapy response, and residual tumour. Interestingly, 3'U-tRFValCAC-fitted multivariate models improved risk stratification and provided superior clinical net benefit in prediction of treatment outcome compared to disease established markers. CONCLUSIONS: 3'U-tRFValCAC promotes tumour cell growth and migration and supports modern risk stratification and prognosis in EOC.