Correction: Wu et al. Expression of MALAT1 Promotes Trastuzumab Resistance in HER2 Overexpressing Breast Cancers. Cancers 2020, 12, 1918.

In the original publication, there was a mistake in Figure 4B as published [...].

Correction: Hamilton et al. Receptors for Insulin-Like Growth Factor-2 and Androgens as Therapeutic Targets in Triple-Negative Breast Cancer. Int. J. Mol. Sci. 2017, 18, 2305.

In the original publication [...].

Inflammatory Cytokines Associated with Obesity, Type-2 Diabetes, and Hypertension Exacerbate Breast Cancer Risk in Underserved African American and Latin American Women.

Background: Comorbid chronic diseases, such as obesity, Type-2 Diabetes (T2D), and hypertension (HTN), are major public health issues and highly prevalent among underserved African Americans (AA) and Latin Americans (LA). Elevated inflammatory cytokines are underlying processes in comorbidities (obesity, T2D, and HTN) that could contribute to tumorigenesis and adverse cancer outcomes. Methods: A panel of 19 cytokines was measured by Luminex assay from 570 AA and LA women's serum samples. The comorbidities and breast cancer information were extracted from our existing clinical database. Comorbidity-associated cytokines were identified by linear regression analysis, and the odds ratios of increasing cytokines for breast cancer were evaluated by Logistic regression. Results: Women with obesity, T2D, and HTN elevated specific groups of cytokines. EGF, MCP1, MDC, MIP-1b, and Groα were independent of T2D and HTN significantly associated with obesity. TGFß1 and TGFß2 were T2D-associated cytokines, and MIB-1b, TNFα, and VEGFα were HTN-associated cytokines. Among those comorbidity-associated cytokines, CXCL1, CCL4, CXCL10, TNFα, TGFß1, and TGFß2 were also significantly associated with breast cancer diagnosed at age < 50. Two or more comorbidities further increased the levels of Groα, MIP-1b, TNFα, and TGFßs. Conclusions: Comorbidity-associate cytokines could augment the risk of breast cancer for AA and LA women.

Urinary ATP may be a biomarker of interstitial cystitis/bladder pain syndrome and its severity.

Urinary tract cells respond to bladder distension by releasing adenosine triphosphate (ATP). Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) exhibit elevated urinary ATP levels compared to asymptomatic controls. This study aimed to evaluate the potential of urinary ATP as a non-invasive biomarker for IC/BPS and its correlation with symptom severity. We included 56 patients diagnosed with IC/BPS and 50 asymptomatic controls. Urine samples were collected from both groups. Urinary ATP levels were quantified using the luciferin-luciferase bioluminescence method. The severity of IC/BPS symptoms was assessed using the visual analogue score (VAS), Interstitial Cystitis Symptom Index (ICSI), and Interstitial Cystitis Problem Index (ICPI) from the O'Leary-Sant score. We specifically examined the correlation between symptom scores and urinary ATP levels in IC/BPS patients. Urinary ATP levels were significantly higher in IC/BPS patients compared to the control group (P < 0.0001). There was a significant positive correlation between urinary ATP concentrations and VAS, ICPI, and ICSI scores among IC/BPS patients (P < 0.0001). The threshold value for ATP concentration was set at 56.6 nM, with an area under the receiver operating characteristic (ROC) curve of 0.811 (95% CI 0.730 - 0.892). Our findings indicate that IC/BPS patients excrete elevated amounts of ATP in their urine. This suggests that urinary ATP might serve as a non-invasive biomarker for IC/BPS, with a predictive potential in terms of symptom severity.

Local treatment Associated With Prognosis among Men With Metastatic Prostate Cancer: A SEER-Based Study.

INTRODUCTION: In order to identify the impact of local treatment on overall survival (OS) and cancer-specific survival(CSS) in men with mPCa. MATERIALS AND METHODS: Men with mPCa undergoing local treatment by radical prostatectomy (RP), radiotherapy (RT) including beam radiation and brachytherapy or no local treatment identified from Surveillance, Epidemiology, and End Results (SEER) database (2010-2015). To evaluate local therapy impact on OS and CSS in relation to baseline characteristics, univariate and multivariable Cox regression analysis was used to predict the prognostic value of local therapy in OS and CSS. RESULTS: A total of 902 (25.8%) patients received local treatment and 2598 (74.2%) patients did not receive local treatment in this study. The Kaplan-Meier curves showed that there was significant difference in OS between patients underwent local treatment and patients without local treatment (P = .013) but not in CSS (P = .068). While multivariate Cox regression analysis showed that local treatment may not significantly improve OS(P = .724). In subgroup analysis, Among patients with prostate-specific antigent (PSA)<10ng/ml, local treatment could significantly improve OS and CSS (all P < .05). Multivariate Cox regression analysis showed that local treatment could be used as an independent prognostic factor to improve OS in mPCa patients with PSA<10ng/ml (P = .031). Another multivariate Cox regression analysis demonstrated that patients with mPCa undergoing RP had better OS and CSS (all P < .05). CONCLUSIONS: Our results showed that local salvage therapy did not seem to be an independent prognostic factor in all mPCa patients, but we found that local therapy can show a better prognosis in patients with lower PSA levels. Compared with RT, patients who had experienced RP may have better prognosis. We still need prospective research to further study the application value of local treatment in mPCa patients.

Genetic variants in African-American and Hispanic patients with breast cancer.

Breast cancer is a disease with significant health disparity affecting mortality in minority women. The present study examined the genetic makeup of breast cancers in African-American and Hispanic/Latinx patients to determine specific genetic mutations associated with breast cancer in the minority population from South Los Angeles, United States. Whole-exome sequencing was performed on DNA extracted from breast cancer tumor biopsies collected from 13 African-American and 15 Hispanic women and 8 matched-normal samples for each ethnic category. The results were analyzed using Ensemble Variant Effect Predictor and Mutation Significance. Additionally, a comparative analysis with The Cancer Genome Atlas data was provided. Our data revealed somatic mutations in genes such as SET domain containing (lysine methyltransferase) 8, serine protease 1 and AT-rich interaction domain 1B (ARID1B) and known breast cancer genes, such as BRCA1/2, TP53 and the DNA damage response genes across all ethnicities. Additionally, Hispanic patients had BRCA1 associated RING domain 1B (BARD1) variants, while African-American patients had higher numbers of nonsynonymous variants in the RAD51 paralog B (RAD51B), ARID1B and X-ray repair cross complementing 3 (XRCC3) genes. In addition, our patients exhibited mutational signature enrichment that indicated DNA homologous recombination repair deficiencies. Therefore, African-American and Hispanic breast cancer samples showed considerable overlap in breast cancer genetic mutations. However, there are differences in specific genetic variants in TP53, BRCA1/2, BARD1 or ARID1B, which will require further study of their role in tumorigenesis.

CircRAD54L2 promotes triple-negative breast cancer progression by regulating the miR-888 family/PDK1 axis.

BACKGROUND: The long-term prognosis of breast cancer with metastasis remains extremely poor. Genetic alterations in tumor cells result in cellular heterogeneity, promoting cancer cells invasion and colonization in some organs during the metastatic process. CircRNAs are very promising as critical biological markers and precise diagnoses in identifying disease mechanisms and developing new methods for effective treatment. However, the role of aberrant expression of circRNAs in breast cancer progression remains largely unknown. METHODS: RNase R treatment and quantitative RT-PCR (qRT-PCR) were performed for circRNA detection. Transwell chamber assays were used to examine the chemotactic migration and invasion of breast cancer cells. RESULTS: This study identified and characterized the circRAD54L2 originating from exon 1, 2, 3, and 4 of the RAD54L2 gene. Importantly, we found that circRAD54L2, rather than RAD54L2 linear mRNA, was significantly upregulated in breast cancer cell lines. Furthermore, we found that inhibiting circRAD54L2 expression markedly reduced the invasion, metastasis, and proliferation of breast cancer cells via sponging of the miR-888 family, which downregulated the expression of pyruvate dehydrogenase kinase 1 (PDK1). CONCLUSION: Our results showed that circRAD54L2 could regulate PDK1 expression by sponging the miR-888 family competing for the ceRNA mechanism, indicating that circRAD54L2 may act as an essential upstream regulator and providing further mechanistic evidence to support the notion that circRAD54L2/miR-888s/PDK1 is a promising therapeutic target in the treatment of breast cancer.

Correction: Dutta et al. Transcriptional Regulation of CCL2 by PARP1 Is a Driver for Invasiveness in Breast Cancer. Cancers 2020, 12, 1317.

In the original publication, there was a mistake in Figure 5D as published [...].

Serum multi-cytokines screening identifies TRAIL and IL-10 as probable new biomarkers for prostate health index diagnostic utility adjustment in grey zone aggressive prostate cancer detection: A single-center data in China.

Objective: To identify less invasive and easily applicable serum cytokine-derived biomarkers which contribute to the diagnostic utility and risk assessment ability of the prostate health index (PHI) based multivariable model in grey zone aggressive prostate cancer (AG PCa) early detection. Methods: Serum 45 cytokines screening was performed in a small training cohort consisting of 10 sera by Luminex liquid array-based multiplexed immunoassays and identified TRAIL and IL-10 as new biomarkers for PHI diagnostic utility adjustment for further validation with a multivariable predictive model in a cohort including 79 aggressive prostate cancer patients and 209 benign prostatic hyperplasia or indolent PCa patients within the PSA grey zone. Results: TRAIL and IL-10 were identified as potential serum biomarkers for AG PCa detection by the result of multi-cytokines screening in the univariate analysis, while multivariable logistic regression confirmed the AUC of the full risk predictive model (0.915) including tPSA, fPSA, PHI, TRAIL, and IL-10 was higher than various diagnostic strategies. DCA suggested a superior net benefit and indicated a good discriminative ability of the full risk model consistently with the result of the nomogram. Conclusion: We suggest a significant advantage for the PHI-based multivariate combinations of serum TRAIL and IL-10 comparing to PHI or other serum-derived biomarkers alone in the detection and risk stratification of grey zone AG PCa.

Phytochemicals in Inhibition of Prostate Cancer: Evidence from Molecular Mechanisms Studies.

Prostate cancer is one of the leading causes of death for men worldwide. The development of resistance, toxicity, and side effects of conventional therapies have made prostate cancer treatment become more intensive and aggressive. Many phytochemicals isolated from plants have shown to be tumor cytotoxic. In vitro laboratory studies have revealed that natural compounds can affect cancer cell proliferation by modulating many crucial cellular signaling pathways frequently dysregulated in prostate cancer. A multitude of natural compounds have been found to induce cell cycle arrest, promote apoptosis, inhibit cancer cell growth, and suppress angiogenesis. In addition, combinatorial use of natural compounds with hormone and/or chemotherapeutic drugs seems to be a promising strategy to enhance the therapeutic effect in a less toxic manner, as suggested by pre-clinical studies. In this context, we systematically reviewed the currently available literature of naturally occurring compounds isolated from vegetables, fruits, teas, and herbs, with their relevant mechanisms of action in prostate cancer. As there is increasing data on how phytochemicals interfere with diverse molecular pathways in prostate cancer, this review discusses and emphasizes the implicated molecular pathways of cell proliferation, cell cycle control, apoptosis, and autophagy as important processes that control tumor angiogenesis, invasion, and metastasis. In conclusion, the elucidation of the natural compounds' chemical structure-based anti-cancer mechanisms will facilitate drug development and the optimization of drug combinations. Phytochemicals, as anti-cancer agents in the treatment of prostate cancer, can have significant health benefits for humans.

Modified Prostate Health Index Density Significantly Improves Clinically Significant Prostate Cancer (csPCa) Detection.

Background: Early screening of clinically significant prostate cancer (csPCa) may offer opportunities in revolutionizing the survival benefits of this lethal disease. We sought to introduce a modified prostate health index density (mPHI) model using imaging indicators and to compare its diagnostic performance for early detection of occult onset csPCa within the prostate-specific antigen (PSA) gray zone with that of PHI and PHID. Methods and Participation: Between August 2020 and January 2022, a training cohort of 278 patients (total PSA 4.0-10.0 ng/ml) who were scheduled for a prostate biopsy were prospectively recruited. PHI and PHID were compared with mPHI ( LD TRD × APD × TPV × PHI ) for the diagnosis performance in identifying csPCa. Pathology outcomes from systematic prostate biopsies were considered the gold standard. Results: This model was tested in a training cohort consisting of 73 csPCa, 14 non-clinically significant prostate cancer(non-csPCa), and 191 benign prostatic hyperplasia (BPH) samples. In the univariate analysis for the PSA gray zone cohort, for overall PCa, the AUC of mPHI (0.856) was higher than PHI (0.774) and PHID (0.835). For csPCa, the AUC of mPHI (0.859) also surpassed PHI (0.787) and PHID (0.825). For detection of csPCa, compared with lower specificities from PHI and PHID, mPHI performed the highest specificity (76.5%), by sparing 60.0% of unnecessary biopsies at the cost of missing 11 cases of csPCa. The mPHI outperformed PHI and PHID for overall PCa detection. In terms of csPCa, mPHI exceeds diagnostic performance with a better net benefit in decision curve analysis (DCA) compared with PHI or PHID. Conclusions: We have developed a modified PHI density (mPHI) model that can sensitively distinguish early-stage csPCa patients within the PSA gray zone. Clinical Trial Registration: ClinicalTrials.gov, NCT04251546.

Roles of Protein Disulfide Isomerase in Breast Cancer.

Protein disulfide isomerase (PDI) is the endoplasmic reticulum (ER)'s most abundant and essential enzyme and serves as the primary catalyst for protein folding. Due to its apparent role in supporting the rapid proliferation of cancer cells, the selective blockade of PDI results in apoptosis through sustained activation of UPR pathways. The functions of PDI, especially in cancers, have been extensively studied over a decade, and recent research has explored the use of PDI inhibitors in the treatment of cancers but with focus areas of other cancers, such as brain or ovarian cancer. In this review, we discuss the roles of PDI members in breast cancer and PDI inhibitors used in breast cancer research. Additionally, a few PDI members may be suggested as potential molecular targets for highly metastatic breast cancers, such as TNBC, that require more attention in future research.

The modified prostate health index (PHI) outperforms PHI density in the detection of clinical prostate cancer within the PSA grey zone.

OBJECTIVES: To compare the accuracy of several volume and diameters modified prostate health index (mPHI) models with PHI density (PHID), PHI, and other prostate-specific antigen (PSA) derivatives in detecting PSA grey zone prostate cancer (PCa). MATERIALS AND METHODS: Between August 2020 and September 2021, a consecutive cohort of 214 suspected PCa patients with elevated total PSA values ranged from 4.0 to 10.0 ng/mL were prospectively recruited and received PHI detections and transrectal ultrasonography (TRUS) measurements, followed by systematic prostate biopsies confirmation. RESULTS: Among the 214 patients enrolled in the project, a total of 80 were diagnosed with PCa. In univariate analysis for the training cohort, the area under curve (AUC) of mPHI-2 [Formula: see text] was 0.8310, which outperformed PHID in identifying PSA grey zone PCa (P ≤ 0.0001) and showed the best net benefit in decision curve analysis (DCA). By a threshold of 0.2835, the sensitivity and specificity in the prediction of PCa were 78.9% and 90.3%, while the positive predictive value (PPV) and negative predictive value (NPV) were 78.3% and 78.6%, respectively. CONCLUSIONS: According to our present single-center experience, the mPHI-2 risk predictor outperformed PHID or other classical parameters alone in the PCa detection with a grey zone PSA level in Asian males.

Comparison of the effects of extrinsic compression on the drainage performance of three ureteric stents.

OBJECTIVES: To share our centre's experience dealing with ureteric obstruction, in particular malignant obstructions, by investigating the deformation and flow velocity of three commonly used, readily accessible ureteric stents under at different compression levels and surface change at three time points (new, 1 month and 3 months after implantation). SUBJECTS AND METHODS: Scanning electron microscope (SEM) analysis was conducted on ureteric JJ stents, including the Cook Universa Soft, the Kang Yi Bo (KYB) antireflux and the Urovision Visiostar ESWL JJ stents. Deformation caused by compression was measured using a digital force gauge. Intraluminal flow velocity was tested with the stents subject to different compression levels. RESULTS: The Urovision Visiostar JJ stent demonstrated significantly better anti-compression capability. The Cook Universa Soft and KYB antireflux JJ stents showed favourable draining velocity without compression, but the velocity dropped substantially on compression. The velocity of the KYB antireflux JJ stent reduced substantially after 3 months of implantation, while the Urovision Visiostar achieved the best draining effect when under compression at all three time points. CONCLUSION: The Urovision Visiostar JJ stent demonstrated significantly greater resistance to compression than the other two JJ stents, as well as better drainage under compression. Patients with benign or malignant ureteric compression might benefit from use of the Urovision Visiostar stent. Large prospective clinical trials are needed to confirm these findings.

Tumor-Derived Exosomes in Tumor-Induced Immune Suppression.

Exosomes are a class of small membrane-bound extracellular vesicles released by almost all cell types and present in all body fluids. Based on the studies of exosome content and their interactions with recipient cells, exosomes are now thought to mediate "targeted" information transfer. Tumor-derived exosomes (TEX) carry a cargo of molecules different from that of normal cell-derived exosomes. TEX functions to mediate distinct biological effects such as receptor discharge and intercellular cross-talk. The immune system defenses, which may initially restrict tumor progression, are progressively blunted by the broad array of TEX molecules that activate suppressive pathways in different immune cells. Herein, we provide a review of the latest research progress on TEX in the context of tumor-mediated immune suppression and discuss the potential as well as challenges of TEX as a target of immunotherapy.

Elevated Baseline Serum PD-L1 Level May Predict Poor Outcomes from Breast Cancer in African-American and Hispanic Women.

BACKGROUND: The therapeutic targeting of PD-1/PD-L1 has shown clinical efficacy in treating metastatic breast cancer. We investigated the clinical significance of measuring serum PD-L1 levels in African-American and Hispanic women with breast cancer. METHODS: PD-L1 levels were measured with the ELISA method from the serum samples of 244 African-Americans and Hispanics with breast cancer and 155 women without cancers. The levels of INFα2 and TNFα were measured with a Luminex multiplex assay. The protein levels of pAkt and CD44/CD24 in tumor cells were tested with immunohistochemistry analysis. Cox regression was used to assess the predicting role of serum PD-L1 for disease-free survival (DFS). RESULTS: PD-L1 levels were significantly elevated in breast cancer cases compared to non-cancer cases. The high PD-L1 levels were associated with HER2-positive and triple-negative breast cancer. PD-L1 level independently predicted DFS in both African-American and Hispanic women. The evaluated PD-L1 level was found to be associated with high IFNα2 and TNFα in breast cancer patients. CONCLUSIONS: PD-L1 serum levels can predict DFS in African American and Hispanic women with breast cancer. Furthermore, a high level of PD-L1 is more likely to be associated with tumor loss PTEN and the activation of Akt or with breast cancer cells expressing CD44high/CD24low. Further validation studies are needed to determine if PD-L1 could serve as a biomarker for patient selection for anti-PD-L1 therapy and assess treatment outcomes.

Plasma IL-6 and TNF-α levels correlate significantly with grading changes in localized prostate cancer.

PURPOSE: To study the effect of inflammatory markers in blood such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) on the Gleason score (GS) changes in patients with prostate cancer (PCa) after radical prostatectomy (RP), we conducted this study. PATIENTS AND METHODS: From November 2012 to September 2021, a total of 237 patients underwent RP at our institution. Blood samples from all patients were collected within 1 week before surgery. Preoperative clinical characteristics include age, serum IL-6 and TNF-α, neutrophil-to-lymphocyte ratio, C-reactive protein, the platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, systemic immune-inflammation index, the prostate imaging reporting and data system (PI-RADS) score, prostate-specific antigen, and biopsy GS were assessed. Univariate and multivariate logistic regression analyzes were used to determine the risk factors of GS changes after RP. The efficiency of this prediction model was identified with the area under the curve of the receiver operating characteristic curve. RESULTS: Seventy-three patients (30.8%) had GS upgraded in the overall cohort, and 55 patients (23.2%) had GS downgraded. In comparing PCa patients with and without GS upgraded, multivariate logistic regression analysis showed that serum TNF-α (odds ratio [OR]: 2.518, p = 0.019) and IL-6 (OR: 0.478, p = 0.023) were independent factors predicting the occurrence of GS upgrade. We also compared the characteristics of patients with GS upgraded and GS downgraded; multivariate logistic regression analysis also demonstrated significant differences in serum IL-6 and TNF-α between these two groups (all p < 0.05). In addition, we found that low prostate volume and biopsy GS ≥ 7 were significantly associated with higher PI-RADS sores in multivariate analysis. CONCLUSION: The high expression of serum TNF-α level is positively correlated with GS upgraded in PCa patients. High expression of serum IL-6 level is negatively correlated with GS upgraded in PCa patients and positively related with GS downgraded.

[Circulating tumor cells in the diagnosis and treatment of early and advanced prostate cancer].

Circulating tumor cells (CTC) are tumor cells that escape from the primary or metastatic tumor into the circulatory system, and closely related to cancer metastasis. Since the samples can be obtained through simple and minimally invasive blood sampling operations, CTCs have a great clinical potential. PCa is one of the most common malignant tumors in men. In recent years, many scholars have conducted studies as to whether CTC technology can be used for the diagnosis and treatment of PCa, as well as for more accurate prediction of the risk of progression. This article summarizes the advances in researches relating CTC technology and the diagnosis and treatment of PCa. CTC detection has been developed from simple counting to phenotypic classification, and even to its combination with the determination of the expressions of specific genes (such as AR, AR-V7, etc.) and single-cell sequencing. Some reports showed that CTC technology has a certain significance in the early diagnosis of PCa, but its main value is demonstrated in drug sensitivity and prognosis evaluation in the late stage of the malignancy. The standardized detection methods and reference values of CTCs in PCa will be important research orientations in the near future.

A novel definition of microvessel density in renal cell carcinoma: Angiogenesis plus vasculogenic mimicry.

The present study proposed the novel concept of total microvessel density (TMVD), which is the combination of the MVD and the vasculogenic mimicry (VM) status, and evaluated its clinical significance in patients with renal cell carcinoma (RCC). For that purpose, tumor samples from 183 patients with primary RCC were examined by CD34 single or periodic acid Schiff (PAS)/CD34 dual histology staining. MVD and VM were determined according to previous literature. Clinical information (tumor stage and grade, and duration of survival) was retrieved and analyzed. Survival information and VM-associated gene expression data of patients with RCC were also retrieved from The Cancer Genome Atlas (TCGA) database and the clinical significance of each individual gene was analyzed. The results indicated that MVD exhibited obvious differences among patients with RCC; however, it was not correlated with the stage/grade or length of survival in patients with RCC. In total, 81 patients (44.3%) were CD34(-)/PAS(+) and defined as VM(+), and they had a significantly shorter survival compared with that of VM(-) patients (P=0.0002). VM was not associated with MVD. TMVD was able to distinguish between patients with high and low MVD in terms of survival, thus TMVD was better compared with MVD alone at distinguishing between patients with different survival prognoses. TCGA data analysis revealed that among the VM-associated genes, nodal growth differentiation factor, caspase-3, matrix metalloproteinase-9 and galectin-3 had a statistically significant impact on the overall/disease-free survival of patients with RCC. In conclusion, the TMVD concept may be more appropriate and sensitive compared with the MVD or VM alone in predicting tumor aggressiveness and patient survival, particularly in RCC, which is a highly vascularized, VM-rich neoplasm, and certain VM formation-associated genes are negatively associated with the survival of patients with RCC.