Proteome-wide Characterization and Pathophysiology Correlation in Non-ischemic Cardiomyopathies.

BACKGROUND AND OBJECTIVES: Although the clinical consequences of advanced heart failure (HF) may be similar across different etiologies of cardiomyopathies, their proteomic expression may show substantial differences in relation to underlying pathophysiology. We aimed to identify myocardial tissue-based proteomic characteristics and the underlying molecular pathophysiology in non-ischemic cardiomyopathy with different etiologies. METHODS: Comparative extensive proteomic analysis of the myocardium was performed in nine patients with biopsy-proven non-ischemic cardiomyopathies (3 dilated cardiomyopathy [DCM], 2 hypertrophic cardiomyopathy [HCM], and 4 myocarditis) as well as five controls using tandem mass tags combined with liquid chromatography-mass spectrometry. Differential protein expression analysis, Gene Ontology (GO) analysis, and Ingenuity Pathway Analysis (IPA) were performed to identify proteomic differences and molecular mechanisms in each cardiomyopathy type compared to the control. Proteomic characteristics were further evaluated in accordance with clinical and pathological findings. RESULTS: The principal component analysis score plot showed that the controls, DCM, and HCM clustered well. However, myocarditis samples exhibited scattered distribution. IPA revealed the downregulation of oxidative phosphorylation and upregulation of the sirtuin signaling pathway in both DCM and HCM. Various inflammatory pathways were upregulated in myocarditis with the downregulation of Rho GDP dissociation inhibitors. The molecular pathophysiology identified by extensive proteomic analysis represented the clinical and pathological properties of each cardiomyopathy with abundant proteomes. CONCLUSIONS: Different etiologies of non-ischemic cardiomyopathies in advanced HF exhibit distinct proteomic expression despite shared pathologic findings. The benefit of tailored management strategies considering the different proteomic expressions in non-ischemic advanced HF requires further investigation.

PPIB/Cyclophilin B expression associates with tumor progression and unfavorable survival in patients with pulmonary adenocarcinoma.

Cyclophilin B (CypB), encoded by peptidylprolyl isomerase B (PPIB), is involved in cellular transcriptional regulation, immune responses, chemotaxis, and proliferation. Recent studies have shown that PPIB/CypB is associated with tumor progression and chemoresistance in various cancers. However, the clinicopathologic significance and mechanism of action of PPIB/CypB in non-small cell lung cancer (NSCLC) remain unclear. In this study, we used RNA in situ hybridization to examine PPIB expression in 431 NSCLC tissue microarrays consisting of 295 adenocarcinomas (ADCs) and 136 squamous cell carcinomas (SCCs). Additionally, Ki-67 expression was evaluated using immunohistochemistry. The role of PPIB/CypB was assessed in five human NSCLC cell lines. There was a significant correlation between PPIB/CypB expression and Ki-67 expression in ADC (Spearman correlation r=0.374, P<0.001) and a weak correlation in SCC (r=0.229, P=0.007). In ADCs, high PPIB expression (PPIBhigh) was associated with lymph node metastasis (P=0.023), advanced disease stage (P=0.014), disease recurrence (P=0.013), and patient mortality (P=0.015). Meanwhile, high Ki-67 expression (Ki-67high) was correlated with male sex, smoking history, high pT stage, lymph node metastasis, advanced stage, disease recurrence, and patient mortality in ADC (all P<0.001). However, there was no association between either marker or clinicopathological factors, except for old age and PPIBhigh (P=0.038) in SCC. Survival analyses revealed that the combined expression of PPIBhigh/Ki-67high was an independent prognosis factor for poor disease-free survival (HR 1.424, 95% CI 1.177-1.723, P<0.001) and overall survival (HR 1.266, 95% CI 1.036-1.548, P=0.021) in ADC, but not in SCC. Furthermore, PPIB/CypB promoted the proliferation, colony formation, and migration of NSCLC cells. We also observed the oncogenic properties of PPIB/CypB expression in human bronchial epithelial cells. In conclusion, PPIB/CypB contributes to tumor growth in NSCLC, and elevated PPIB/Ki-67 levels are linked to unfavorable survival, especially in ADC.

Ablation of the deubiquitinase USP15 ameliorates nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) occurs due to the accumulation of fat in the liver, leading to fatal liver diseases such as nonalcoholic steatohepatitis (NASH) and cirrhosis. Elucidation of the molecular mechanisms underlying NAFLD is critical for its prevention and therapy. Here, we observed that deubiquitinase USP15 expression was upregulated in the livers of mice fed a high-fat diet (HFD) and liver biopsies of patients with NAFLD or NASH. USP15 interacts with lipid-accumulating proteins such as FABPs and perilipins to reduce ubiquitination and increase their protein stability. Furthermore, the severity of NAFLD induced by an HFD and NASH induced by a fructose/palmitate/cholesterol/trans-fat (FPC) diet was significantly ameliorated in hepatocyte-specific USP15 knockout mice. Thus, our findings reveal an unrecognized function of USP15 in the lipid accumulation of livers, which exacerbates NAFLD to NASH by overriding nutrients and inducing inflammation. Therefore, targeting USP15 can be used in the prevention and treatment of NAFLD and NASH.

Association of PTTG1 expression with invasiveness of non-functioning pituitary adenomas.

BACKGROUND: Pituitary tumor transforming gene 1 (PTTG1), paired-like homeodomain 2 (PITX2), and galectin-3 have been widely studied as predictive biomarkers for various tumors and are involved in tumorigenesis and tumor progression. We evaluated the usefulness of PTTG1, PITX2, and galectin-3 as predictive biomarkers for invasive non-functioning pituitary adenomas (NFPAs) by determining the relationship between the expressions of these three proteins and the invasiveness of the NFPAs. We also investigated whether PTTG1, E-cadherin, and Ki-67, which are known to be related to each other, show a correlation with NFPA features. METHODS: A retrospective study was conducted on 87 patients with NPFAs who underwent surgical removal. The NFPAs were classified into three groups based on magnetic resonance imaging findings of suprasellar extension and cavernous sinus invasion. Immunohistochemical staining for PTTG1, PITX2, galectin-3, E-cadherin, and Ki-67 was performed on tissue microarrays. RESULTS: PTTG1 expression showed a statistically significant correlation with the invasiveness of NFPAs, whereas PITX2 and galectin-3 did not have a relationship with the invasiveness of NFPAs. Moreover, there was no association among PTTG1, E-cadherin, and Ki-67 expression. CONCLUSIONS: PTTG1 has the potential to serve as a predictive biomarker for invasive NFPA. Furthermore, this study may serve as a reference for the development of PTTG1-targeted therapeutic agents.

Polo-like kinase 4 as a potential predictive biomarker of chemoradioresistance in locally advanced rectal cancer.

BACKGROUND: Polo-like kinase 4 (PLK4) is a serine/threonine protein kinase located in the centriole of the chromosome during the cell cycle. PLK4 overexpression has been described in a variety of many common human epithelial tumors. Conversely, PLK4 acts as a haploinsufficient tumor suppressor in some situations, highlighting the importance of strict regulation of PLK4 expression, activity, and function. Meanwhile, the importance of chemoradiation resistance in rectal cancer is being emphasized more than ever. We aimed to analyze PLK4 expression and the tumor regression grade (TRG) in patients with rectal cancer, treated with chemoradiotherapy (CRT). METHODS: A retrospective study was conducted on 102 patients with rectal cancer who received preoperative CRT. Immunohistochemistry for PLK4 in paraffin-embedded tissue was performed from the biopsy and surgical specimens. RESULTS: We found significant association between high expression of PLK4 and poor response to neoadjuvant CRT (according to both Mandard and The Korean Society of Pathologists TRG systems) in the pre-CRT specimens. Other clinicopathologic parameters did not reveal any correlation with PLK4 expression. CONCLUSIONS: This study revealed an association between high expression of PLK4 in the pre-CRT specimens and TRG. Our results indicated that PLK4 could potentially be a new predictor for CRT effect in patients with rectal cancer.

An Evaluation of Muscle Repair Techniques: Implications in Musculoskeletal Healing and Corollaries in Oral-Facial Clefting.

We performed an animal study to identify the techniques associated with the best muscle healing outcomes in cleft lip/palate surgery. The right triceps of thirty adult male Sprague-Dawley rats were cut and repaired by three different suture techniques: simple (n = 10), overlapping (n = 10), and splitting sutures (n = 10). Muscle tissues were isolated from 5 rats per group 1 and 8 weeks postoperation. The inflammatory response and muscle fiber healing were evaluated by hematoxylin and eosin (H&E) staining, Western blotting, immunohistochemistry for TNF-α and IL-1ß, and immunofluorescence for laminin and MyoD. Grip strength (N/100 g) and spatial gait symmetry were evaluated before surgery and 1, 2, 4 and 8 weeks postoperation. Eight weeks postoperation, grip force per weight was significantly higher in the simple suture (median, 3.49; IQR, 3.28-3.66) and overlapping groups (median, 3.3; IQR, 3.17-3.47) than the splitting group (median, 2.91; IQR, 2.76-3.05). There was no significant difference in range of motion between groups. The simple group exhibited significant remission of inflammation by H&E staining and lower expression of TNF-α and IL-1ß than the other groups by Western blotting and immunohistochemistry. Immunofluorescence revealed stronger expression of MyoD and weaker expression of laminin in the splitting group than in the other groups at week 8, indicating prolonged inflammation and healing followed by poor muscle fiber remodeling. Simple and overlapping sutures demonstrated similar functional healing, although greater inflammation and failure to maintain a thicker muscle belly were observed in the overlapping suture group compared with the simple suture group. Therefore, reconstruction of the philtral column with overlapping sutures alone may result in limited long-term fullness, and additional procedures may be needed.

Robust response of pulmonary pleomorphic carcinoma to pembrolizumab and sequential radiotherapy: A case report.

Pulmonary pleomorphic carcinoma (PPC) is a rare type of non-small cell lung cancer (NSCLC) with a more aggressive clinical course and a worse outcome than other types of NSCLC. Pembrolizumab, a monoclonal antibody targeting programmed cell death-1 (PD-1), has been approved as the first-line treatment for advanced NSCLC with robust PD-L1 expression in at least 50% of tumour cells, without epidermal growth factor receptor gene (EGFR) mutations or anaplastic lymphoma kinase gene (ALK) rearrangement. Here, we report the case of an 81-year-old man with multiple comorbidities who was diagnosed with PPC and showed a robust response to pembrolizumab followed by radiation therapy without adverse effects. In the absence of randomized clinical trials for PPCs, our case report demonstrates the potential application of pembrolizumab and radiation therapy for the treatment of PPCs.

Clinical Significance of Tumor Infiltrating Lymphocytes in Association with Hormone Receptor Expression Patterns in Epithelial Ovarian Cancer.

Hormone receptor expression patterns often correlate with infiltration of specific lymphocytes in tumors. Specifically, the presence of specific tumor-infiltrating lymphocytes (TILs) with particular hormone receptor expression is reportedly associated with breast cancer, however, this has not been revealed in epithelial ovarian cancer (EOC). Therefore, we investigated the association between hormone receptor expression and TILs in EOC. Here we found that ERα, AR, and GR expression increased in EOC, while PR was significantly reduced and ERß expression showed a reduced trend compared to normal epithelium. Cluster analysis indicated poor disease-free survival (DFS) in AR+/GR+/PR+ subgroup (triple dominant group); while the Cox proportional-hazards model highlighted the triple dominant group as an independent prognostic factor for DFS. In addition, significant upregulation of FoxP3+ TILs, PD-1, and PD-L1 was observed in the triple dominant group compared to other groups. NanoString analyses further suggested that tumor necrosis factor (TNF) and/or NF-κB signaling pathways were activated with significant upregulation of RELA, MAP3K5, TNFAIP3, BCL2L1, RIPK1, TRAF2, PARP1, and AKT1 in the triple dominant EOC group. The triple dominant subgroup correlates with poor prognosis in EOC. Moreover, the TNF and/or NF-κB signaling pathways may be responsible for hormone-mediated inhibition of the immune microenvironment.

Pregnancy Outcome, Antibodies, and Placental Pathology in SARS-CoV-2 Infection during Early Pregnancy.

There are reports that pregnant women infected with SARS-CoV-2 not only have increased morbidity but also increased complications and evidence of maternal and fetal vascular malperfusion on placental pathology. This was a retrospective study of pregnant women diagnosed with SARS-CoV-2 infection after March 2020. The results of reverse transcription polymerase chain reaction testing and IgM and IgG antibody testing of the amniotic fluid, cord blood, placenta, and maternal blood were confirmed at delivery. Placentas were evaluated histopathologically. The study included seven pregnant women diagnosed with SARS-CoV-2 infection during pregnancy at a mean gestational age of 14.5 weeks. Out of the seven women, five were infected during the first trimester. The mean gestational age at delivery was 38.4 weeks. The reverse transcription polymerase chain reaction results for maternal plasma, cord blood, placenta, and amniotic fluid were negative and IgG antibodies were detected in maternal plasma and cord blood. On placental pathology, maternal vascular malperfusion was found in only one case, fetal vascular malperfusion in four cases, and inflammatory changes were found in two cases. Pregnancy outcomes for women diagnosed with SARS-CoV-2 infection during early pregnancy are positive and it is likely that maternal antibodies are passed to the fetus, which results in a period of immunity.

IGF-1 Receptor Signaling Regulates Type II Pneumocyte Senescence and Resulting Macrophage Polarization in Lung Fibrosis.

PURPOSE: Type II pneumocyte (alveolar epithelial cells type II [AECII]) senescence has been implicated in the progression of lung fibrosis. The capacity of senescent cells to modulate pulmonary macrophages to drive fibrosis is unexplored. Insulin-like growth factor-1 receptor (IGF-1R) signaling has been implicated as a regulator of senescence and aging. METHODS AND MATERIALS: Mice with an AECII-specific deletion of IGF-1R received thoracic irradiation (n ≥ 5 per condition), and the effect of IGF-1R deficiency on radiation-induced AECII senescence and macrophage polarization to an alternatively activated phenotype (M2) was investigated. IGF-1R signaling, macrophage polarization, and senescence were evaluated in surgically resected human lung (n = 63). RESULTS: IGF-1R deficient mice demonstrated reduced AECII senescence (senescent AECII/field; intact: 7.25% ± 3.5% [mean ± SD], deficient: 2.75% ± 2.8%, P = .0001), reduced accumulation of M2 macrophages (intact: 24.7 ± 2.2 cells/field, deficient: 15.5 ± 1.2 cells/field, P = .0086), and fibrosis (hydroxyproline content; intact: 71.9 ± 21.7 µg/lung, deficient: 31.7 ± 7.9, P = .0485) after irradiation. Senescent AECII enhanced M2 polarization in a paracrine fashion (relative Arg1 mRNA, 0 Gy: 1.0 ± 0.4, 17.5 Gy: 7.34 ± 0.5, P < .0001). Evaluation of surgical samples from patients treated with chemoradiation demonstrated increased expression of IGF-1 (unirradiated: 10.2% ± 4.9% area, irradiated: 15.1% ± 11.5%, P = .0377), p21 (unirradiated: 0.013 ± 0.02 histoscore, irradiated: 0.084 ± 0.09 histoscore, P = .0002), IL-13 (unirradiated: 13.7% ± 2.8% area, irradiated: 21.7% ± 3.8%, P < .0001), and M2 macrophages in fibrotic regions relative to nonfibrotic regions (unirradiated: 11.4 ± 12.2 CD163 + cells/core, irradiated: 43.1 ± 40.9 cells/core, P = .0011), consistent with findings from animal models of lung fibrosis. CONCLUSIONS: This study demonstrates that senescent AECII are necessary for the progression of pulmonary fibrosis and serve as a targetable, chronic stimuli for macrophage activation in fibrotic lung.

Comparison between Cervical Ureaplasma spp. Colonization and the Intensity of Inflammatory Mediators in the Amniotic Fluid Retrieved during Cesarean Delivery in Preterm Birth.

We investigated whether cervical Ureaplasma spp. colonization affects the intensity of inflammatory mediators in amniotic fluid retrieved during cesarean delivery in singleton preterm birth. One hundred fifty-three cases in singleton preterm birth with 24-34 weeks' gestation were enrolled. The intensities of seven inflammatory mediators (interleukin (IL)-1ß, IL-6, IL-8, IL-10, tumor necrosis factor-α, and matrix metalloproteins (MMP)-8, MMP-9) of amniotic fluid were measured. We tested cervical swab specimens using real-time polymerase chain reaction assays to detect Ureaplasma spp. colonization. Histologic chorioamnionitis (HCA) was diagnosed when acute inflammation was observed in any of the placental tissues. Mean gestational age at delivery and birth weight were 30.9 ± 2.4 weeks and 1567 ± 524 g, respectively. Cervical Ureaplasma spp. colonization was detected 78 cases. The incidence of HCA was 32.3% (43/133). Although the intensities of all inflammatory mediators were significantly different according to presence or absence of HCA, there were no significant differences according to cervical Ureaplasma spp. colonization. In all 43 cases with HCA and 90 cases without HCA, there were no significant differences between cervical Ureaplasma spp. colonization and the intensity of inflammatory mediators. Cervical Ureaplasma spp. colonization did not affect the intensity of inflammatory mediators in the amniotic fluid retrieved during cesarean delivery.

Chronicity is associated with the glenohumeral synovitis in patients with a rotator cuff tear.

Synovitis of the glenohumeral joint (GHJ) and subacromial space (SAS) is one of the most common findings during arthroscopic rotator cuff repair (RCR). The purpose of this study is to determine clinical factors associated with the degree of synovitis in patients with a rotator cuff tear and whether macroscopic synovitis affects early clinical outcomes following arthroscopic RCR. Arthroscopic videos of 230 patients treated with arthroscopic RCR were randomly reviewed by two experienced shoulder surgeons. The synovitis scores of the GHJ using Davis's grading system and the SAS using Jo's grading system were rated with a consensus. Univariate and multivariate analyses were used to identify the associations between the synovitis scores and various parameters, including demographics, preoperative, and postoperative clinical outcomes. Univariate analyses revealed that age, side, body mass index, duration of symptoms, preoperative stiffness, diabetes, muscle atrophy, fatty infiltration, tear size, preoperative clinical scores, and preoperative range of motion were significantly associated with the GHJ synovitis score (all p < 0.05). Multivariate analyses revealed that the duration of symptoms, tear size, and diabetes was significantly associated with the GHJ synovitis score (p = 0.048, p = 0.025, p = 0.011, respectively). Longer duration of symptoms, larger tear size, and the presence of diabetes was independently associated with increased GHJ synovitis in patients with a rotator cuff tear. These results suggest that GHJ synovitis might be more involved in the pathogenesis for pain and tear progression of rotator cuff disease compared with SAS synovitis.

Tumor-associated macrophage, angiogenesis and lymphangiogenesis markers predict prognosis of non-small cell lung cancer patients.

BACKGROUND: The tumor microenvironment (TME) is a critical player in tumor progression, metastasis and therapy outcomes. Tumor-associated macrophages (TAMs) are a well-recognized core element of the TME and generally characterized as M2-like macrophages. TAMs are believed to contribute to tumor progression, but the mechanism behind this remains unclear. We aimed to investigate the clinical, angiogenic, and lymphangiogenic significance of TAMs in non-small cell lung cancer (NSCLC). METHODS: Utilizing combined immunohistochemistry and digital image analysis, we assessed CD68, CD163, VEGF-A, and VEGF-C expression in 349 patients with NSCLC. Subsequently, the potential association between M2 TAMs and angiogenic VEGF-A and/or lymphangiogenic VEGF-C was evaluated for its prognostic value. Furthermore, the effects of M2 TAMs on angiogenesis and lymphangiogenesis were explored via an in vitro co-culture system. RESULTS: CD68 and CD163 expression were found to directly correlate with VEGF-A and/or VEGF-C expression (all p < 0.001). Furthermore, elevated M2 ratio (CD163+/CD68+) was significantly associated with poor overall survival (p = 0.023). Dual expression of M2 ratiohigh and VEGF-Chigh (M2 ratiohighVEGF-Chigh) was correlated with worse overall survival (p = 0.033). Multivariate analysis revealed that M2 ratiohigh [HR (95% CI) = 1.53 (1.01-2.33), p = 0.046] and combined M2 ratiohighVEGF-Chigh expression [HR (95% CI) = 2.01 (1.28-3.16), p = 0.003] were independent predictors of poor overall survival. Notably, we confirmed that M2 macrophages significantly enhanced the protein and mRNA expression of both VEGF-A and VEGF-C, while M1 macrophages induced only mRNA expression of VEGF-A in A549 cells. CONCLUSIONS: This study suggests that TAMs are significantly associated with angiogenesis and lymphangiogenesis, contributing to the progression of NSCLC. Furthermore, elevated M2 ratio, similar to combined high M2 ratio and high VEGF-C expression, is a strong indicator of poor prognosis in patients with NSCLC, providing insight for future TAM-based immunotherapy strategies.

Different TERT Expression between Colorectal Adenoma and Serrated Polyp.

Background and Objectives: Telomere regulation have an association with colorectal cancer. Previous studies demonstrated its implication in colorectal carcinogenesis. This study aimed to identify the role of telomerase reverse transcriptase (TERT) in colorectal carcinogenesis and determine TERT expression and their associated genes in precancerous lesions. Materials and Methods: TERT expression in 93 colorectal precursor lesions was analyzed. This included 61 tubular adenomas (TAs) and 32 serrated polyps (SPs). Furthermore, KRAS and BRAF gene mutations and microsatellite instability were analyzed. Statistical tests were performed to analyze the relationship between variables. Results: TERT expression in TAs, when compared with those observed in paired adjacent nontumor tissues, was 0.92 ± 0.78. TERT expression levels were significantly lower in SPs (0.38 ± 0.14, p < 0.001). KRAS and BRAF mutations were mutually exclusive in TAs and SPs (p < 0.001). TERT expression tended to be associated with KRAS mutations (46.7% vs. 22.0%, p = 0.098) and low-grade tumors (35.0% vs. 16.0%, p = 0.096), but this difference was insignificant. Conclusions: TERT expression has a pivotal role in progression to TAs in colorectal tissue. Considering the association between TERT expression and KRAS mutation, therapeutic drugs targeting this pathway can be developed for cancer prevention.

Prognostic significance of USP10 and p14ARF expression in patients with colorectal cancer.

Ubiquitin-specific proteases (USPs) play an important role in fundamental cellular processes. Among these, USP10 is known for its association with tumor development and progression of multiple cancers. We aimed to investigate the clinical significance of USP10 expression in colorectal cancer and examined the potential link between USP10 and p14ARF in patients with colorectal cancer. USP10 and p14ARF protein expression was assessed via immunohistochemistry (IHC) on a tissue microarray from 280 colorectal cancer cases. IHC scores were evaluated by digital image analysis and compared with patients' outcomes. In addition, we examined DNA hypermethylation in colorectal cancer cell lines and tissues, which were matched with adjacent normal colon samples. USP10 expression was lost (USP10loss) in 18.6% of samples (52/280 cases), which was linked to lymphovascular invasion (p = 0.019) and distant metastases (p < 0.001). Similarly, loss of p14ARF expression (p14ARFloss) was associated with more advanced tumors. USP10 expression correlated positively with p14ARF expression (r = 0.617, p < 0.001). USP10loss, p14ARFloss, and dual loss of USP10 and p14ARF were significantly associated with shorter disease-free survival and overall survival in comparison to USP10intact, p14ARFintact, and dual loss of USP10 and p14ARF, respectively. Multivariate analysis revealed that USP10loss (p = 0.030) and dual loss of USP10 and p14ARF (p = 0.014) are independent prognostic factors for poor disease-free survival in colorectal cancer patients. Furthermore, aberrant hypermethylation of the USP10 promoter region was found in colorectal cancer cell lines and tissues. The present results suggest that USP10loss is a potential prognostic marker for colorectal cancer.

CDK7 is a reliable prognostic factor and novel therapeutic target in epithelial ovarian cancer.

OBJECTIVE: Cyclin-dependent kinase 7 (CDK7) engages tumor growth by acting as a direct link between the regulation of transcription and the cell cycle. Here, we investigated the clinical significance of CDK7 expression and its potential as a therapeutic target in epithelial ovarian cancer (EOC). METHODS: CDK7 expression was examined in 436 ovarian tissues including normal to metastatic ovarian tumors using immunohistochemistry, and its clinical implications were analyzed. Furthermore, we performed in vitro and in vivo experiments using CDK7 siRNA or a covalent CDK7 inhibitor (THZ1) to elucidate the effect of CDK7 inhibition on tumorigenesis in EOC cells. RESULTS: The patient incidence of high CDK7 expression (CDK7High) gradually increased from normal ovarian epithelium to EOC (P < 0.001). Moreover, CDK7High was associated with an advanced stage and high-grade histology (P = 0.035 and P = 0.011, respectively) in EOC patients and had an independent prognostic significance in EOC recurrence (P = 0.034). CDK7 inhibition with siRNA or THZ1 decreased cell proliferation and migration, and increased apoptosis in EOC cells, and this anti-cancer mechanism is caused by G0/G1 cell cycle arrest. In in vivo therapeutic experiments using cell-line xenograft and PDX models, CDK7 inhibition significantly decreased the tumor weight, which was mediated by cell proliferation and apoptosis. CONCLUSION: Mechanistic interrogation of CDK7 revealed that it is significantly associated with an aggressive phenotype of EOC, and it has independent prognostic power for EOC recurrence. Furthermore, CDK7 may be a potential therapeutic target for patients with EOC, whether platinum sensitive or resistant.

The Prognostic Value of Measuring PD-L1 mRNA Expression Levels in Surgically Resected Non-Small Cell Lung Cancer.

The expression of programmed cell death 1-ligand 1 (PD-L1) by tumor cells acts as an immune-checkpoint when it interacts with its receptor on immune cells, effectively preventing the immune system from attacking the tumor. Inhibitors against PD-L1 have shown remarkable therapeutic activity in non-small cell lung cancer (NSCLC); however, the prognostic value of this potential biomarker has yet to be conclusively shown. To investigate the clinicopathological and prognostic value of PD-L1 expression, we examined PD-L1 mRNA levels in surgically resected NSCLC. We compared PD-L1 mRNA expression in tumor and adjacent normal tissue from 71 NSCLC patient samples using real-time polymerase chain reaction. To validate PD-L1 mRNA expression by this method, PD-L1 protein expression by immunohistochemistry was analyzed and their strong correlation was confirmed (r=0.728, P=0.041). PD-L1 mRNA expression was significantly increased in tumor tissue as compared to adjacent normal tissue (P<0.001). Tumor tissue on average expressed 3.72 fold higher levels of PD L1 mRNA compared to normal tissue counterparts, and higher expression levels were found in 25.4% (18/71) of NSCLC samples. PD-L1 mRNA expression levels were not associated with clinicopathological characteristics of NSCLC. However, NSCLC patients with increased PD-L1 mRNA expression have a better prognosis than patients with low levels of PD-L1 mRNA (63.49 months vs. 98.53 months, χ2=3.73, p=0.053). Disease-free survival was 82.23 months and 45.68 months in patients with and without high levels of PD-L1 expression, respectively, although this difference was not significant (χ 2= 3.23, p=0.073). These results suggest that PD-L1 mRNA expression correlates to alterations in NSCLC disease progression; therefore, further comprehensive analyses should be performed.