Positive peritoneal lavage fluid cytology based on isolation by size of epithelial tumor cells indicates a high risk of peritoneal metastasis.

Background: Peritoneal metastasis (PM) is the most prevalent type of metastasis in patients with gastric cancer (GC) and has an extremely poor prognosis. The detection of free cancer cells (FCCs) in the peritoneal cavity has been demonstrated to be one of the worst prognostic factors for GC. However, there is a lack of sensitive detection methods for FCCs in the peritoneal cavity. This study aimed to use a new peritoneal lavage fluid cytology examination to detect FCCs in patients with GC, and to explore its clinical significance on diagnosing of occult peritoneal metastasis (OPM) and prognosis. Methods: Peritoneal lavage fluid from 50 patients with GC was obtained and processed via the isolation by size of epithelial tumor cells (ISET) method. Immunofluorescence and fluorescence in situ hybridization (FISH) were used to identify FCCs expressing chromosome 8 (CEP8), chromosome 17 (CEP17), and epithelial cell adhesion molecule (EpCAM). Results: Using a combination of the ISET platform and immunofluorescence-FISH, the detection of FCCs was higher than that by light microscopy (24.0% vs. 2.0%). Samples were categorized into positive and negative groups, based on the expressions of CEP8, CEP17, and EpCAM. Statistically significant relationships were demonstrated between age (P = 0.029), sex (P = 0.002), lymphatic invasion (P = 0.001), pTNM stage (P = 0.001), and positivity for FCCs. After adjusting for covariates, patients with positive FCCs had lower progression-free survival than patients with negative FCCs. Conclusion: The ISET platform highly enriched nucleated cells from peritoneal lavage fluid, and indicators comprising EpCAM, CEP8, and CEP17 confirmed the diagnosis of FCCs. As a potential detection method, it offers an opportunity for early intervention of OPM and an extension of patient survival.

Pan-cancer analysis of NFE2L2 mutations identifies a subset of lung cancers with distinct genomic and improved immunotherapy outcomes.

BACKGROUND: Mutations in the KEAP1-NFE2L2 signaling pathway were linked to increased tumorigenesis and aggressiveness. Interestingly, not all hotspot mutations on NFE2L2 were damaging; some even were activating. However, there was conflicting evidence about the association between NFE2L2 mutation and Nrf2-activating mutation and responsiveness to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) and other multiple cancers. METHODS: The study with the largest sample size (n = 49,533) explored the landscape of NFE2L2 mutations and their impact response/resistance to ICIs using public cohorts. In addition, the in-house WXPH cohort was used to validate the efficacy of immunotherapy in the NFE2L2 mutated patients with NSCLC. RESULTS: In two pan-cancer cohorts, Nrf2-activating mutation was associated with higher TMB value compared to wild-type. We identified a significant association between Nrf2-activating mutation and shorter overall survival in pan-cancer patients and NSCLC patients but not in those undergoing ICIs treatment. Similar findings were obtained in cancer patients carrying the NFE2L2 mutation. Furthermore, in NSCLC and other cancer cohorts, patients with NFE2L2 mutation demonstrated more objective responses to ICIs than patients with wild type. Our in-house WXPH cohort further confirmed the efficacy of immunotherapy in the NFE2L2 mutated patients with NSCLC. Lastly, decreased inflammatory signaling pathways and immune-depleted immunological microenvironments were enriched in Nrf2-activating mutation patients with NSCLC. CONCLUSIONS: Our study found that patients with Nrf2-activating mutation had improved immunotherapy outcomes than patients with wild type in NSCLC and other tumor cohorts, implying that Nrf2-activating mutation defined a distinct subset of pan-cancers and might have implications as a biomarker for guiding ICI treatment, especially NSCLC.

Cold atmospheric plasmas target breast cancer stemness via modulating AQP3-19Y mediated AQP3-5K and FOXO1 K48-ubiquitination.

Cold atmospheric plasma (CAP) is selective against many cancers with little side effect, yet its molecular mechanism remains unclear. Through whole transcriptome sequencing followed by assays in vitro, in vivo and using clinical samples, we propose CAP as a promising onco-therapy targeting cancer stemness via the AQP3/FOXO1 axis. CAP-generated reactive species penetrated cells via AQP3 and suppressed RPS6KA3, a shared kinase of AQP3 and FOXO1. Reduced AQP3-19Y phosphorylation suppressed SCAF11-mediated AQP3-5K K48-ubiquitination that led to sabotaged FOXO1 stability. Inhibited FOXO1 phosphorylation retarded its regulatory activities in maintaining cancer stemness including ALDH1 and IL6. Enhanced anti-cancer efficacy was observed through combining CAP with Atorvastatin in vitro and in vivo. We propose CAP as a 'selective' onco-therapeutic against cancer stemness, with the AQP3/FOXO1 axis being one molecular mechanism. We report SCAF11 as an E3 ubiquitin ligase of both AQP3 and FOXO1, identify AQP3-5K as an AQP3 K48-ubiquitination site, and emphasize the essential role of AQP3-19Y in this process. We reposition Atorvastatin into the onco-therapeutic portfolio by synergizing it with CAP towards enhanced efficacy. We anticipate the efficacy of CAP in targeting malignancies of high stemness alone or as an adjuvant therapy towards the hope of ultimate cancer cure.

Treatment with pyrotinib-based therapy in lapatinib-resistant HER2-positive metastatic breast cancer: a multicenter real-world study.

Background: Tyrosine kinase inhibitors (TKIs) are effective for treating human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. However, therapies subsequent to TKI progression remain controversial, and effective treatments for TKI resistance are urgently needed. We evaluate the practice of exchange of TKIs, which involves treatment with a different TKI following prior TKI failure. Specifically, this study investigated the efficacy of pyrotinib-based therapy in lapatinib-resistant HER2-positive metastatic breast cancer (NCT04899128). Methods: This real-world study included 76 patients diagnosed with HER2-positive metastatic breast cancer who received pyrotinib-based therapy after lapatinib progression at four Chinese institutions between August 2018 and March 2020. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and toxicity profiles were reported. Results: All patients received pyrotinib-based therapy in two or later line therapy. The median PFS was 8.0 months (95% CI 5.1-10.9). OS has not reached. The ORR and CBR were 17.1% and 60.5%, respectively. The median PFS was 7.1 months (95% CI 5.633-8.567) and intracranial ORR was 42.9% in patients who had brain metastasis (n = 14). Patients who benefited from lapatinib ⩾ 6.0 months prior exhibited a longer PFS (10.6 versus 6.0 months, p = 0.034, stratified hazard ratio (HR) 0.534, 95% CI 0.293-0.975). The most common adverse effects were diarrhea (n = 34, 44.7%) and hand-foot syndrome (n = 10, 13.2%). Conclusion: Pyrotinib-based therapy has the potential to improve survival in patients with lapatinib-resistant HER2-positive metastatic breast cancer, including those with brain metastases. Pyrotinib could provide a clinically significant increase in PFS for patients who benefited from prior lapatinib.

Efficacy of logistic regression model based on multiparametric ultrasound in assessment of cervical lymphadenopathy - a retrospective study.

OBJECTIVES: To investigate whether a multiparametric ultrasound (MPUS) diagnostic model improves differential diagnosis of benign and malignant cervical lymph nodes. METHODS: MPUS evaluation was performed on 87 lesions in 86 patients, and related characteristics and parameters of the patients and lesions were studied and logistic regression models based on the MPUS characteristics of cervical lymph nodes were built. A receiver operating characteristic curve and area under the curve (AUC) were built for the evaluation of diagnostic performances. RESULTS: Of the 87 lesions in 86 patients, there were 31 benign and 56 malignant lesions. Regression models for Duplex ultrasound and MPUS were established. The Duplex ultrasound regression model showed a sensitivity, specificity, positive predictive value and negative predictive value of 94.4, 61.3, 86.3 and 80.9%, respectively. The predictive accuracy was 82.4%, and the AUC was 0.861. The MPUS regression model showed a sensitivity, specificity, positive predictive value and negative predictive value of 98.1, 61.3, 81.5 and 95.0%, respectively. The predictive accuracy was 84.7%, and the AUC was 0.894. The differences in AUCs between the Duplex ultrasound model and MPUS model, ultrasound model and ultrasonic elastography (UE), and Duplex ultrasound and UE were not significant (all p > 0.05); the differences in AUCs between the MPUS model and Duplex ultrasound, Duplex ultrasound model and Duplex ultrasound, and MPUS model and UE were significant (all p < 0.05). CONCLUSIONS: The Duplex ultrasound and MPUS models achieve significantly higher diagnostic performance for differentiating between benign and malignant cervical lymph nodes.

Cold atmospheric plasma selectively induces G0/G1 cell cycle arrest and apoptosis in AR-independent prostate cancer cells.

Purpose: Androgen receptor-independent prostate cancers do not respond to androgen blockage therapies and suffer from high recurrence rate. We aim to contribute to the establishment of novel therapeutic approaches against such malignancies. Materials and Methods: We examined whether and how cold atmospheric plasma delivers selectivity against AR-independent prostate cancers via cell viability, transwell assay, wound healing, cell apoptosis assay, flow cytometry, intracellular hydrogen peroxide determination assay, RONS scavenger assay and western blot using human normal epithelial prostatic cells PNT1A and AR-negative DU145 prostate cancer cells. Results: We show that cold atmospheric plasma could selectively halt cell proliferation and migration in androgen receptor-independent cells as a result of induced cell apoptosis and G0/G1 stage cell cycle arrest, and such outcomes were achieved through modulations on the MAPK and NF-kB pathways in response to physical plasma induced intracellular redox level. Conclusion: Our study reports cold atmospheric plasma induced reduction on the proliferation and migration of androgen receptor-independent prostate cancer cells that offers novel therapeutic insights on the treatment of such cancers, and provides the first evidence on physical plasma induced cell cycle G0/G1 stage arrest that warrants the exploration on the synergistic use of cold atmospheric plasma and drugs such as chemotherapies in eradicating such cancer cells.

High CTC-TRPC5 Expression Significantly Associated With Poor Prognosis in Radical Resected Colorectal Cancer Patients.

Recurrence is the main reason of treatment failure of redical resected colorectal cancer (CRC). Although some factors including staging and differentiation have been proven to useful for recurrence evaluation, prognosis of certain patients does not conform to this evaluation approach. Circulating tumor cells (CTC) have been found to have prognostic value in CRC, and previous studies on CTC have primarily focused on their numbers. CTC are functionally heterogeneous cell populations, and different CTC subgroups may have different functions and clinical values. In our previous study, we discovered that elevated expression of the transient receptor potential channel TRPC5 was associated with a significantly poor prognosis in CRC. In this study, we collected peripheral blood from CTC-positive CRC patients, identified the TRPC5 protein expression on CTC (CTC-TRPC5), and analyzed the relationship between CTC-TRPC5 expression levels and the prognosis. The results showed that CTC-TRPC5 level is significantly related to the T stage and differentiation of tumors. High level of CTC-TRPC5 is more common in a high T stage as well as poorly differentiated tumors and is significantly associated with shorter disease free survival (DFS). The median DFS of CRC patients with high and low CTC-TRPC5 level was 17.1 and 22.0 months, respectively (p < 0.05). This study revealed a clinically significant CTC subgroup of CRC, providing a new indicator for clinical evaluation of CRC prognosis.

Weekly versus triweekly cisplatin-alone adjuvant chemoradiotherapy after radical hysterectomy for stages IB-IIA cervical cancer with risk of recurrence.

Weekly and triweekly cisplatin-alone concomitant chemoradiotherapy regimens after radical surgery were compared in stages IB-IIA cervical cancer with intermediate- or high-risk factors to identify the better therapeutic regimen. We retrospectively analyzed patients with stages IB-IIA cervical cancer who received radical hysterectomy followed by concurrent adjuvant chemoradiotherapy to compare the efficiency between weekly and triweekly regimen groups. We evaluated between-group differences in survival, recurrence, compliance, and adverse effects. A total of 217 patients were included in this study (triweekly group vs. weekly group; 97 vs. 120). The mean follow-up was 47.2 months. The 5-year disease-free survival (DFS) was 84.4% or 76.5% for patients treated with triweekly cisplatin chemotherapy or the weekly regimen, respectively (P = 0.110). The 5-year overall survival (OS) was 82.4 and 78.6% for the same treatment groups, respectively (P = 0.540). The DFS of the patients with pelvic lymph node metastasis were marginally better in triweekly regimen group compared with the weekly group (P = 0.031). Grades 3-4 leukopenia was significantly more common in the triweekly group (P = 0.028). The weekly cisplatin chemotherapy group experienced the same therapeutic effect as the triweekly cisplatin-alone chemotherapy group but with less toxicity. However, triweekly cisplatin regimen reduced the recurrence in patients with pelvic lymph node metastasis.

Validity of measurements of testicular volume obtained by a built-in software of ultrasound systems: with formula recommended by updated guidelines as reference.

Aim: To investigate the validity of measurement of testicular volume acquired by a built-in software in different ultrasound systems with reference to the updated guidelines. Materials and methods: Archives of 1,976 patients who had undergone scrotal ultrasound evaluation were reviewed. A total of 973 patients with 1,909 testes, who had undergone ultrasound measurement of the testicular volume, were included in the study, and 1,003 patients were excluded. The age of enrolled patients ranged from 17 to 66 years (median age of 39 years). The ultrasound systems included Siemens Sonoline S2000, Philips EPIQ5, GE Logiq E9, Hitachi Aloka prosoundα7, Mindray DC-8 and Mindray Resona7. The transducers have imaging frequencies of 5-14 MHz. Validity of the measurement of testicular volume acquired by a built-in software in different ultrasound systems was assessed with reference to the formula that Volume (V) = Length (L) × Width (W) × Height (H) × 0.71, recommended by the updated guidelines, by recalculating the original numbers using a calculator. Results: The values obtained by the built-in software of Mindray DC-8 and Mindray Resona7 ultrasound systems and measurements recalculated on a computer were all in concordance; and the values obtained by the built-in software of Siemens Sonoline S2000, Philips EPIQ5, GE Logiq E9, and Hitachi Aloka prosoundα7 ultrasound systems and measurements recalculated on computer were all discordant. The same testicular measurements calculated with different formulas (V = L×W×H×0.71 vs. V = L×W×H×0.52) produced 26.76% difference. Conclusion: Values of testicular volume obtained by some ultrasound systems are not accurate with reference to the formula recommended by the updated guidelines.

Curated findings and implications in duplex ultrasound interrogation of the scrotum or varicoceles.

The purpose of this study was to curate clustered findings of duplex ultrasound in the evaluation of spermatic venous varicoceles, and deliver more responses to the present concerns. Archives of 979 men who had undergone scrotum and spermatic venous plexus duplex ultrasound were reviewed. In the duplex ultrasound interrogation, the sizes of the larger vessels of the spermatic venous plexus, peritesticular vessels, and testicular volume and relevant parameters were measured. Findings of the vessels were analyzed. One hundred and eight-one out of 979 patients had varicoceles. Color Doppler flow signal was rendered in veins of pampiniform plexus but not in peritesticular vessels in 501 out of 979 patients; 101 out of 501 patients had veins of pampiniform plexus ≤ 3 mm, no color Doppler flow signal could be rendered in the veins in the 101 patients at supine and standing positions without Valsalva maneuver, color Doppler flow signal could be rendered in the veins in 82 out of 101 patients at supine and standing positions with Valsalva maneuver; no color Doppler flow signal could be rendered in the veins from 19 out of 101 patients with and without Valsalva maneuver at supine and standing positions. 37 out of 979 patients with 61 ipsilateral testicular volume ≤ 5 mL had no vessel diameter > 2 mm. The incidences of varicoceles corresponding to different ranges of testicular volume of 1-5 mL, 5.1-10 mL, 10.1-15 mL, 15.1-20 mL, 20.1-25 mL, and 25.1-30 mL were 0.0%, 6.9%, 8.3%, 6.63%, 20.94%, and 59.1%, respectively. The comparisons of incidences of varicocele between distribution percentages of different ranges of testicular volume of 1-5 mL and others (of 5.1 mL and more) were all significant (all P < 0.05). The correlation coefficient between the different ranges of testicular volume and the incidence of varicoceles was 0.829. Increased testicular volume may be also a factor for the development of varicoceles. Dilated peritesticular vessels may be collateral veins of spermatic veins, anterior and posterior scrotal veins, or proximal vas deferens.

Screening of folate-producing lactic acid bacteria and modulatory effects of folate-biofortified yogurt on gut dysbacteriosis of folate-deficient rats.

Folate deficiency is accompanied by gut dysbacteriosis. To understand dietary intervention in folate deficiency, a folate-deficient rat model was used to evaluate the modulatory effects of folate-producing lactic acid bacteria (LAB) and biofortified yogurt on gut dysbacteriosis. The high folate-producing strain was screened from 12 LABs, and its variant, namely Lactobacillus plantarum GSLP-7 V, with folate productivity in yogurt at 3.72 µg mL-1, was obtained by stressing with 5.0 mg L-1 methotrexate and 100.00 mg L-1 Ca2+. To our knowledge, this is the highest folate productivity in yogurt by LAB strains ever reported. To further examine the folate supplement effect in vivo, a folate-deficient rat model was established and fed a folate-free diet for 8 weeks. Also, the effects of L. plantrum GSLP-7 V, yogurt fermented with L. plantrum GSLP-7 V, plain yogurt, and chemical folic acid on folate deficiency and gut dysbacteriosis were examined. Analysis of the change in gut microbiota showed that the gut dysbacteriosis was significantly correlated with folate deficiency. Administration of L. plantrum GSLP-7 V and its fermented yogurt for 10 days restored the disrupted gut microbiota and recovered the serum folate and homocysteine to normal levels, while chemical folic acid worsened the gut dysbacteriosis. Chemical folic acid only enriched Akkermansia, while L. plantrum GSLP-7 V and its fermented yogurt modulated the gut microbiota comprehensively through 7 and 10 key genera, respectively. This study confirmed the effectiveness of dietary intervention with folate-biofortified yogurt through modulating gut microbiota, suggesting the potential of the folate-producing LAB as an agent for the treatment of folate-deficiency related diseases.

Development and validation of a nomogram to predict survival after curative resection of nonmetastatic colorectal cancer.

BACKGROUND: We aimed to develop a clinical applicable nomogram to predict overall survival (OS) for patients with curatively resected nonmetastatic colorectal cancer. METHODS: Records from a retrospective cohort of 846 patients with complete information were used to construct the nomogram. The nomogram was validated in a prospective cohort of 379 patients. The performance of the nomogram was evaluated with concordance index (c-index), time-dependent receiver operating characteristic (ROC) curves, calibration plots, and decision curve analyses for discrimination, accuracy, calibration ability, and clinical net benefits respectively, and further compared with AJCC 8th TNM staging and the MSKCC nomogram. Risk stratification based on nomogram scores was performed with recursive partitioning analysis. RESULTS: The nomogram incorporated age, Glasgow prognostic score, pretreatment carcinoembryonic antigen levels, T staging, N staging, number of harvested lymph nodes, and histological grade. Compared with the 8th AJCC staging and MSKCC model, the nomogram had a statistically higher c-index (0.77, 95% CI: 0.73-0.80), bigger areas under the time-dependent ROC curves (AUC at 3 years: 79; at 5 years: 79), and improved clinical net benefits. Calibration plots revealed no deviations from reference lines. All results were reproducible in the validation cohort. Nomogram-based risk stratification successfully discriminated patients within each AJCC stage (all log-rank P < .05). CONCLUSION: We established an accurate, reliable, and easy-to-use nomogram to predict OS after curative resection for nonmetastatic colorectal cancer (CRC). The nomogram outperformed the 8th AJCC staging and the MSKCC model and could aid in personalized treatment and follow-up strategy for CRC patients.

InvivoPen: A novel plasma source for in vivo cancer treatment.

Background: With the anti-cancer efficacies of cold atmospheric plasma being increasingly recognized in vitro, a demand on creating an effective tool feasible for in vivo animal treatment has emerged. Methods: Through the use of co-axial needles with different calibers in diameter, we designed a novel in situ ejection source of cold atmospheric plasma, namely invivoPen, for animal experiments. It punches just a single pinhole that could considerably ease the complexity of operating with small animals such as mouse. Results: We showed that invivoPen could deliver similar efficacies as plasma activated medium with reduced cost in suppressing cell proliferation and migration as well as potentially boosting the viabilities of mice receiving invivoPen treatment. Blood test, renal and liver functionalities tests all suggest that physical plasma could effectively return tumor-carrying mice to the healthy state without harm to body conditions, and invivoPen slightly outweighs PAM in boosting animal immunity and reducing inflammation. Conclusion: Our study contributes to the community in providing a minimal invasive in situ plasma source, having partly explained the efficacies of cold atmospheric plasma in treating triple negative breast cancers, and proposing the potential synergies between physical plasma and conventional drugs for cancer treatment.

Modulating cancer stemness provides luminal a breast cancer cells with HER2 positive-like features.

Breast cancers can be classified into luminal A, luminal B, HER2 positive and triple-negative subtypes, each with a distinct therapeutic response. Tumor stemness drives cancer malignancy that challenges cancer control. Understanding the revolutionary relationships driven by tumor stemness among breast cancer subtypes is fundamental to identifying feasible therapeutic modalities for each breast cancer subtype. Utilizing the endogenous tRNA-processing system, we established a multiplexing CRISPR/dCas9 system in breast cancer cells, and applied it to a four-gene panel controlling cell potency, i.e., OCT4, KLF, MYC, SOX2. The stable cell strain, OKMS#1 was obtained through concomitantly over-expressing these genes in luminal A breast cancer cells. OKMS#1 cells showed increased invasion, proliferation and cancer stemness, shared similar drug response pattern with HER2 positive cells, and exhibited altered MAPK and enhanced NFkB signaling. This study contributes in providing an efficient multiplexing CRISPR/dCas9 system that enriches our genetic modulation tool box, and suggests that HER2 positive cells are potential progenitors of luminal A cells and that these two breast cancer subtypes may share similar treatment strategies once rewired between the two states. Our results also implicate that triple negative breast cancer cells, though sharing similar cancer stemness with HER2 positive cells, represent a distinct type of disease and require unique treatment solutions.

Composition, coagulation characteristics, and cheese making capacity of yak milk.

Yak is one of the few species of which the rennet-coagulated cheese making characteristics of its milk are still not well understood. This study investigated composition and rennet-induced coagulation properties of milk from 17 individual yak cows in comparison with milk from 32 individual Holstein cows. Yak cows produced milk with generally higher concentrations of milk components. The concentrations of fat, protein, solids-not-fat (SNF), and calcium in yak milk were 1.89-, 1.68-, 1.46-, and 2-fold those in Holstein milk, respectively. The hydrodynamic radii of casein micelles (187.25 nm) and chymosin-induced paracasein (1,620 nm) were about twice the sizes of those found in Holstein milk. Higher concentrations of calcium in yak milk, together with larger sizes of casein micelles, explains the reason for its fast rate of curd formation and firmer curd texture. Optical microrheology analysis also showed that Ca2+ concentration had greater influence on the coagulation of yak milk than on Holstein milk. Cheese making trials with yak and Holstein milk proved the higher cheese yield of yak milk: 1.67-fold that of Holstein milk. Therefore, yak milk could be a suitable source of milk for enzyme-coagulated cheese making.

CD5+MYC+ predicts worse prognosis in diffuse large B-cell lymphoma.

The dual expression of CD5 and MYC protein (DECM) on B-lymphocytes may arise at a specific stage of de novo diffuse large B-cell lymphoma (DLBCL). This study retrospectively reviewed 210 patients with de novo DLBCL at the Affiliated Hospital of Jiangnan University between 2006 and 2017. DECM was significantly correlated with a worse prognosis than that in either the CD5+ or MYC+ or CD5-MYC- patients. Furthermore, patients with DECM showed a similar outcome to MYC+BCL2+ lymphoma patients who have extremely poor survival rates. Multivariate analysis demonstrated that DECM was a significant independent predictor for overall survival (P < .0001) and progression-free survival (P < .0001) in DLBCL. DLBCL patients with DECM showed significantly inferior clinical outcomes compared to the CD5+, MYC+ or CD5-MYC- patients. Combinational therapeutic modalities might be a candidate approach to improve the prognosis of these patients.

FA2H Exhibits Tumor Suppressive Roles on Breast Cancers via Cancer Stemness Control.

Background: Triple negative breast cancers are aggressive, enriched with cancer stem cells, and lack effective targeted therapies with little side effects. Methods: We isolated cancer stem cells from two triple negative breast cancer cell lines via cell sorting following transcriptome sequencing, bioinformatics analysis, experimental and clinical validations, as well as functional investigations to explore genes capturing triple negative breast cancer features for improved diagnosis and therapeutics in clinics. Results: We found that FA2H is under-expressed in triple negative breast cancers both in vitro and in clinics, and FA2H suppresses cancer stemness via inhibiting the STAT3/IL6 axis and NFkB signaling. Conclusions: This study reports the tumor suppressive roles of FA2H on breast cancer cells through cancer stemness control. FA2H and other candidates unveiled in this study that capture the features of cancer stem cells may contribute as diagnostic marker and/or effective therapeutic targets for improved triple negative breast cancer management.

ANLN and KDR Are Jointly Prognostic of Breast Cancer Survival and Can Be Modulated for Triple Negative Breast Cancer Control.

Purpose: Kinase insert domain receptor (KDR) is the primary vascular endothelial growth factor receptor mediating survival, growth, and migration of endothelial cells and is expressed also in various tumor cells through autocrine production. The PI3K/Pten pathway is one of the downstream signalings affected by KDR activation and most commonly altered in breast cancer. Here, we investigate whether KDR expression is associated with members in PI3K/Pten signaling on the prognosis of breast cancer patients. Methods: PI3K/Pten pathway components were defined by mapping The Cancer Genome Atlas (TCGA) protein data to the KEGG database complemented by literature searching, accounting for 36 proteins subject to the interaction analysis with KDR on breast cancer patient survival. The identified interaction gene pair was subjected to in vitro validation following functional analysis. Results: Anillin (ANLN) was found to interact with KDR at translational and transcriptional levels using the public TCGA protein expression data and five gene expression datasets. Favorable prognosis corresponds to high protein but low gene expression of ANLN when KDR is highly expressed. Externally modulating cells toward low ANLN and high KDR gene expression was shown to transit triple negative cells toward a luminal-like state with increased level of ER and elevated sensitivity to Tamoxifen. Conclusion: Our study proposes a two-gene panel prognostic of breast cancer survival and a novel therapeutic strategy for triple negative breast cancer control via transiting cancer cells towards a luminal-like state sensitive to established targeted therapy.

FOXA1 is Prognostic of Triple Negative Breast Cancers by Transcriptionally Suppressing SOD2 and IL6.

Having markers feasible for breast cancer subtyping, especially for triple negative breast cancer identification is crucial for improving the treatment outcome of such cancers. Here we explore the role of FOXA1 in characterizing triple negative breast cancers and the driving mechanisms. Through in vitro examination of the expression pattern at both transcriptional and translational levels, patient relapse-free survival analysis, immunohistochemistry staining and prediction power assessment using clinical samples, as well as functional studies, we systematically compared the role of FOXA1 in identifying triple negative and luminal type of breast cancers and explored the mechanisms driving such functionalities. We report that FOXA1 under-expression can lead to increased malignancy and cancer stemness, and is a subtyping marker identifying triple negative breast cancers rather than the luminal subtype by transcriptionally suppressing the expression of SOD2 and IL6. We are the first to systematically address the significance of FOXA1 in triple negative breast cancer identification as a biomarker and elucidate the mechanism at the molecular level, through a sequential bioinformatics analysis and experimental validations both in vitro and in clinics. Our discoveries compliment the current biomarker modalities once verified using larger clinical cohorts and improve the precision on characterizing breast cancer heterogeneity.

Prognostic significance of serum aspartic transaminase in diffuse large B-cell lymphoma.

BACKGROUND: Liver function is routinely assessed in clinical practice as liver function tests provide sensitive indicators of hepatocellular injury. However, the prognostic value of enzymes that indicate hepatic injury has never been systematically investigated in lymphoma, including diffuse large B-cell lymphoma (DLBCL). METHODS: This study examined the prognostic value of baseline aspartic transaminase (AST) in DLBCL patients. The association between AST and clinical features was analyzed in 179 DLBCL patients treated from 2006 to 2016. All enrolled patients were treated with R-CHOP or R-CHOP-like chemotherapy. Log-rank test, univariable analysis, and subgroup analysis were performed to evaluate the impact of AST on survival. RESULTS: AST 33.3 U/L was considered to be the optimal threshold value for predicting prognosis. A higher AST level was associated with advanced stage (P = 0.001), poorer performance status (P = 0.014), elevated lactate dehydrogenase level (P <  0.0001), presence of B symptoms (P = 0.001), high-risk International Prognostic Index (IPI, IPI 3-5) (P = 0.002), non-germinal center B-cell subtypes (P = 0.038), hepatitis B virus surface antigen positivity (P = 0.045) and more extra nodal involvement (ENI, ENI ≥ 2) (P = 0.027). Patients with a higher AST level had a shorter overall survival (OS) (2-year OS rate, 53.6% vs. 83.6%, P <  0.001). Subgroup analysis indicated that higher AST levels have poorer prognostic values in patients without B symptoms and LDH positive groups. CONCLUSION: A pretreatment AST level is associated with OS in DLBCL patients treated with R-CHOP or similar chemotherapy regimens. A high pretreatment AST level might be a reliable prognostic factor for predicting a dismal outcome in DLBCL patients. Serum AST levels may be investigated for use as an easily determinable, inexpensive biomarker for risk assessment in patients with DLBCL.